Official Journal of the Italian Society of Psychopathology
Organo Ufficiale della Società Italiana di Psicopatologia
Periodico trimestrale POSTE ITALIANE SPA - Spedizione in Abbonamento Postale - D.L. 353/2003 conv.in L.27/02/2004 n°46 art.1, comma 1, DCB PISA - Aut. Trib. di Pisa n. 9 del 03/06/95
journal of psychopathology, 20 (1), 1-106, 2014
ISSN 1592-1107
Editor-in-chief: Alessandro Rossi
Editorial
Original articles
Case report
Clinical psychopharmacotherapy
1
18° Congresso della Società Italiana di Psicopatologia: La Psicopatologia e le età della vita
6 Lithium and valproate in manic and mixed states: a naturalistic prospective study
11 Relazione tra disturbi psichiatrici e funzionamento adattivo in persone con disabilità
intellettiva
17 Current scientific research on paedophilia: a review
27 From psychopathology to neurocircuits: what we can learn from DBS? The case of obsessivecompulsive disorder
33 Internalization of sociocultural standards of beauty and disordered eating behaviours:
the role of body surveillance, shame and social anxiety
38 Towards a classification of alexithymia: primary, secondary and organic
50 The role of drug therapies in the treatment of anorexia and bulimia nervosa: a review of the
literature
66 Ekbom syndrome treated with olanzapine: a case report
69 Perfenazina, amitriptilina e perfenazina-amitriptilina: ruolo nella pratica clinica
80 Nalmefene: profilo clinico e real world evidence nel trattamento della dipendenza da alcol
92 Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca
www.gipsicopatol.it
Volume 20 • March 2014 • Number 1
Founders: Giovanni B. Cassano, Paolo Pancheri
Cited in: EMBASE - Excerpta Medica Database • Index Copernicus • PsycINFO • SCOPUS • Google Scholar
Official Journal of the Italian Society of Psychopathology
Organo Ufficiale della Società Italiana di Psicopatologia
Editor-in-chief: Alessandro Rossi
Editorial Coordinator
Roberto Brugnoli
Advisory Board
E. Aguglia
C. Altamura
A. Amati
L. Bellodi
M. Biondi
F. Bogetto
B. Carpiniello
M. Casacchia
G.B. Cassano
P. Castrogiovanni
F. Catapano
D. De Ronchi
L. Dell’Osso
M. Di Giannantonio
C. Faravelli
F. Ferro
F. Gabrielli
S. Galderisi
P. Girardi
D. La Barbera
C. Maggini
M. Maj
G. Muscettola
M. Nardini
G.C. Nivoli
L. Pavan
G.F. Placidi
R. Quartesan
R. Rossi
E. Sacchetti
P. Santonastaso
S. Scarone
A. Siracusano
E. Smeraldi
O. Todarello
E. Torre
Italian Society
of Psychopathology
Managing Editor
Patrizia Alma Pacini
Executive Council
Editorial Assistant
Patrick Moore
Editorial Board
B. Dell’Osso (Milano)
A. Fagiolini (Siena)
A. Fiorillo (Napoli)
B. Forresi (Modena)
G. Maina (Torino)
P. Monteleone (Napoli)
S. Pallanti (Firenze)
C. Pariante (Londra)
S. Paradiso (Iowa City)
S. Pini (Pisa)
P. Rucci (Pisa)
A. Serretti (Bologna)
G. Stanghellini (Chieti)
A. Vita (Brescia)
Treasurer
A. Siracusano
President
F. Bogetto
Vice-President
A.C. Altamura
Secretary
A. Rossi
Councillors
E. Aguglia
M. Biondi
M. Casacchia
B. Carpiniello
M. di Giannantonio
S. Galderisi
C. Maggini
G. Muscettola
E. Sacchetti
Honorary Councillors
G.B. Cassano
L. Ravizza
Editing
Lucia Castelli
Pacini Editore S.p.A.
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Tel. 050 3130224
Fax 050 3130300
lcastelli@pacinieditore.it
gipsicopatol@pacinieditore.it
Scientific Secretariat
Valentina Barberi
Pacini Editore S.p.A.
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Tel. 050 3130243
Fax 050 3130300
journal@jpsychopathol.net
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www.gipsicopatol.it
Volume 20 • March 2014 • Number 1
Founders: Giovanni B. Cassano, Paolo Pancheri
Cited in: EMBASE - Excerpta Medica Database • Index Copernicus • PsycINFO • SCOPUS • Google Scholar
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Schatzberg AF, Samson JA, Bloomingdale KL, et al. Toward a biochemical
classification of depressive disorders, X: urinary catecholamines, their metabolites, and D-type scores in subgroups of depressive disorders. Arch Gen
Psychiatry 1989;46:260-8.
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Kaplan HI, Sadock BJ. Comprehensive textbook of Psychiatry. Baltimore:
Williams & Wilkins 1985.
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and Guze’s method revisited. In: Robins LN, Barret JE, editors. The validity of
psychiatric diagnosis. New York: Raven Press 1989, p.74-85.
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Esempi di corretta citazione bibliografica per:
articoli e riviste:
Schatzberg AF, Samson JA, Bloomingdale KL, et al. Toward a biochemical
classification of depressive disorders, X: urinary catecholamines, their metabolites, and D-type scores in subgroups of depressive disorders. Arch Gen
Psychiatry 1989;46:260-8.
libri:
Kaplan HI, Sadock BJ. Comprehensive textbook of Psychiatry. Baltimore:
Williams & Wilkins 1985.
capitoli di libri o atti di Congressi:
Cloninger CR. Establishment of diagnostic validity in psychiatric illness: Robins
and Guze’s method revisited. In: Robins LN, Barret JE, editors. The validity of
psychiatric diagnosis. New York: Raven Press 1989, pp. 74-85.
Ringraziamenti, indicazioni di grant o borse di studio, vanno citati al termine
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Contents
Editorial
18° Congresso della Società Italiana di Psicopatologia: La Psicopatologia e le età della vita
18th Congress of the Italian Society of Psychopathology: Psychopathology and ages of life
F. Bogetto..............................................................................................................................................................................1
Original articles
Lithium and valproate in manic and mixed states: a naturalistic prospective study
Litio e valproato nel trattamento degli episodi maniacali e misti: studio prospettico osservazionale
C. Del Grande, M. Muti, L. Musetti, M. Corsi, I. Pergentini, M. Turri, G.U. Corsini, L. Dell’Osso.........................................6
Relazione tra disturbi psichiatrici e funzionamento adattivo in persone con disabilità intellettiva
Relationship between psychiatric disorders and adaptive functioning in individuals with intellectual disabilities
M. Bertelli, M. Rossi, D. Scuticchio, N. Varrucciu, F. Poli, C. Del Furia...............................................................................11
Current scientific research on paedophilia: a review
Recenti sviluppi nella ricerca scientifica sulla pedofilia: una review
G.A. Capra, B. Forresi, E. Caffo...........................................................................................................................................17
From psychopathology to neurocircuits: what we can learn from DBS? The case of obsessive-compulsive disorder
Dalla psicopatologia ai neurocircuiti: cosa possiamo apprendere dal DBS? Il caso del disturbo ossessivo-compulsivo
S. Pallanti, G. Grassi, V. Ramella Cravaro, W.K. Goodman..................................................................................................27
Internalization of sociocultural standards of beauty and disordered eating behaviours:
the role of body surveillance, shame and social anxiety
Interiorizzazione degli standard socioculturali di bellezza e comportamenti alimentari problematici:
il ruolo di sorveglianza del corpo, vergogna e ansia sociale
A. Dakanalis, M. Clerici, M. Caslini, L. Favagrossa, A. Prunas, C. Volpato, G. Riva, M.A. Zanetti.......................................33
Towards a classification of alexithymia: primary, secondary and organic
Verso una classificazione dell’alessitimia in primaria, secondaria e organica
A. Messina, J.N. Beadle, S. Paradiso....................................................................................................................................38
The role of drug therapies in the treatment of anorexia and bulimia nervosa: a review of the literature
Il ruolo delle terapie farmacologiche nel trattamento dell’anoressia e della bulimia nervosa: una revisione della letteratura
A. Tortorella, M. Fabrazzo, A.M. Monteleone, L. Steardo, P. Monteleone............................................................................50
Case report
Ekbom syndrome treated with olanzapine: a case report
Sindrome di Ekbom trattata con olanzapina: un caso clinico
Y. Barone, C. Niolu, M. Zanasi, A. Siracusano....................................................................................................................66
Clinical psychopharmacotherapy
Perfenazina, amitriptilina e perfenazina-amitriptilina: ruolo nella pratica clinica
Perphenazine, amitriptyline and perphenazine-amitriptyline: role in clinical practice
A. Fagiolini, A. Cuomo........................................................................................................................................................69
Nalmefene: profilo clinico e real world evidence nel trattamento della dipendenza da alcol
Nalmefene: clinical and real world evidence in the treatment of alcohol dependence
I. Maremmani, S. Presta, A. Petracca, M. Di Nicola, A.G.I. Maremmani, F. Ruggeri, L. Janiri..............................................80
Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca
Bipolar mixed states: evolution of the concept and implications for the treatment and research
C. Vampini, F. Nifosì............................................................................................................................................................92
Editorial
18° Congresso della Società Italiana di Psicopatologia:
La Psicopatologia e le età della vita
18th Congress of the Italian Society of Psychopathology:
Psychopathology and ages of life
L’eclatante aumento della durata della vita, in particolare
nei paesi ad alto livello socio-economico, accanto all’indubbio aspetto positivo ha portato con sé tutta una serie
di problemi non facili da affrontare.
Nell’ambito della medicina, un aumento degli anni trascorsi in malattia si pone come un’importante “altra faccia della medaglia” dell’efficacia delle cure e di molti
altri fattori favorevoli ambientali, igienici, sociali che
hanno prolungato così significativamente la durata della
vita. Accanto a ciò l’attenzione rivolta ai problemi psichici delle varie età della vita, infantile, adolescenziale,
adulta e senile, è cresciuta in conseguenza di cambiamenti culturali e del raffinamento dei mezzi di osservazione e cura.
Altro fattore cruciale è la vita non più segregata dei pazienti affetti da disturbi mentali, vita che porta a una
declinazione diversa, molto meno appiattita, delle manifestazioni del disturbo psichico. è così cresciuto l’interesse a osservare l’esordio e l’evoluzione dei disturbi
psicopatologici nelle diverse età della vita, studiando le
molteplici connessioni che i disturbi e le manifestazioni di uno stesso disturbo possono presentare nella storia
dell’individuo 1 2.
A questo modo di vedere le cose si è affiancata un’impostazione diversa delle terapie, in particolare psicofarmacologiche, sempre più valutate nella loro risposta longitudinale e nella loro capacità preventiva, oltre che nella
pur necessaria efficacia trasversale e nel controllo della
sintomatologia acuta 3.
Tutti i più importanti disturbi propongono significativi
esempi di quanto detto. A questo proposito, si sono delineati due importanti filoni di ricerca: da un lato lo studio delle caratteristiche psicopatologiche di un disturbo
psichiatrico in soggetti in età diverse, dall’altro lo studio
delle differenti modalità che conducono allo sviluppo di
disturbi psichiatrici.
Per quanto concerne il primo filone di ricerca, prendendo quale esempio il disturbo bipolare, esistono studi in
letteratura che si sono occupati di individuare se e quali
fossero le caratteristiche fenotipiche del disturbo, peculiari per fasce di età. In particolare, in età pre-puberale
Journal of Psychopathology 2014;20:1-5
esso sembra caratterizzarsi per la presenza di episodi
affettivi con umore irritabile, comorbidità con disturbo
da deficit di attenzione e iperattività (ADHD) e disturbi
della condotta, maggiore impairment funzionale, minore
risposta ai trattamenti farmacologici (in particolare ai sali
di litio). In età adolescenziale, invece, esso si caratterizza
per maggiore comorbidità con sintomatologia ansiosa e
maggiore probabilità di risposta ai sali di litio. Esistono,
poi, poche indicazioni rispetto alle manifestazioni cliniche tipiche dell’età senile (età > 65 anni), ma dagli esigui
dati di letteratura emerge come il disturbo, che in età senile sembra prevalere nel sesso femminile, si caratterizzi
per un decorso tendenzialmente irregolare, una minore
frequenza di comorbidità con disturbi da uso di alcool,
una maggiore incidenza di comorbidità neurologiche e
internistiche.
Il secondo filone di ricerca è rappresentato da quegli
studi che hanno fondato la propria ipotesi di lavoro sul
principio della continuità eterotipica (heterotypic development). Secondo questo principio, osservando mediante un’ottica longitudinale l’evoluzione dei disturbi
mentali nelle diverse epoche della vita dei pazienti, molti
disturbi psichici si manifesterebbero precocemente con
forme sindromiche inizialmente differenti rispetto alla
diagnosi poi conclamata. In un recente studio retrospettivo effettuato su un ampio campione di pazienti bipolari
(n = 1081), gli Autori hanno rilevato come in circa l’8%
dei pazienti, l’esordio del disturbo fosse rappresentato da
una sintomatologia ansiosa clinicamente significativa e
configurante un vero e proprio disturbo d’ansia (disturbo
d’ansia generalizzato [DAG], disturbo ossessivo-compulsivo [DOC], disturbo di panico, disturbo post-traumatico
da stress [DPTS]), piuttosto che da un episodio affettivo.
Esistono, poi, interessanti indicazioni derivanti dagli studi sugli antecedenti psicopatologici del disturbo bipolare
effettuati mediante ricerche prospettiche longitudinali,
condotte in soggetti ad alto rischio di sviluppare disturbo (ad esempio, figli di soggetti con diagnosi di disturbo
bipolare). Questi lavori hanno evidenziato come la presenza di disturbi d’ansia a esordio in età infantile (soprattutto se multipli) e di disturbi del sonno predicono
1
F. Bogetto
lo sviluppo successivo di franco disturbo bipolare. Mentre, per quanto sia un argomento ancora discusso e controverso, sembra che la presenza di ADHD nelle stesse
epoche infantili predica lo sviluppo in età giovane-adulta
di complicanze dell’ADHD o disturbi connessi come i
disturbi della condotta o i disturbi da uso di sostanze,
piuttosto che di un franco disturbo bipolare. Sulla base di
questi risultati, alcuni Autori hanno proposto di applicare
un modello di stadiazione clinica del disturbo bipolare
sovrapponibile a quelli già proposti per la schizofrenia:
in quest’ottica le manifestazioni psichiche diverse dal disturbo bipolare che precedono temporalmente l’esordio
dello stesso non sarebbero semplici comorbidità o elementi di generale vulnerabilità psicopatologica, ma dei
veri precursori aspecifici del disturbo stesso 4. Questi riscontri permetterebbero, sia pure in una categoria ristretta di individui considerati ad alto rischio, di identificare
strategie di prevenzione primaria per il disturbo bipolare.
Per quanto riguarda il DOC, più che di manifestazioni
differenti del disturbo a seconda delle età della vita, l’attenzione dei ricercatori si è concentrata sulla delineazione di sottotipi a seconda dell’età d’esordio 5: il DOC
a esordio precoce si differenzia da quello a esordio tardivo per essere più frequente nel genere maschile, più
frequentemente in comorbidità con disturbi da tic o altri
disturbi dello spettro ossessivo-compulsivo, e in presenza
di familiari di primo grado affetti da DOC. Nel decorso
longitudinale del disturbo, in genere si assiste a una riduzione in intensità della sintomatologia ticcosa mentre
emerge più franca quella ossessivo-compulsiva in adolescenza e prima età adulta. Il rilievo della comorbidità
con disturbi da tic in tali pazienti assume una particolare rilevanza in quanto la presenza di tic predice una
risposta preferenziale alla terapia di associazione tra SSRI
e antipsicotici atipici. Altri eventi che caratterizzano significativi periodi della vita particolarmente rilevanti per
l’esordio del DOC sono, per la donna, il menarca, la gravidanza e soprattutto il post-partum; il rilievo di un esordio spesso correlato a tali eventi riproduttivi rimanda alla
possibilità che le variazioni ormonali brusche possano
svolgere un’azione di destabilizzazione importante che
condurrebbe, in donne predisposte, all’esordio di una
sintomatologia ossessivo-compulsiva franca. L’esordio
nel postpartum si manifesta in genere con ossessioni di
aggressività rivolte contro il figlio, con estremo disagio e
allarme per la paziente e i familiari. Un secondo filone
di ricerca è rappresentato da studi di natura longitudinale
volti a identificare possibili caratteristiche psicopatologiche del DOC predittive dell’insorgenza di altri disturbi
psichiatrici, come il disturbo bipolare o la schizofrenia.
Questo filone di studi rilegge in chiave moderna quanto
già segnalato da Autori classici che segnalavano la possibilità che sintomi ossessivo-compulsivi proteggessero
2
i pazienti dalla disintegrazione psicotica, o ritardassero
l’evoluzione in franca psicosi. Studi recenti longitudinali
indicano che una quota di circa il 15-20% dei pazienti
con DOC evolve manifestando un disturbo bipolare in
età adulta; costituirebbero elementi predittivi di possibile
evoluzione in tale direzione l’esordio precoce, il genere maschile, la presenza di sintomatologia di tipo hoarding, la presenza in comorbidità di disturbi d’ansia e/o
disturbi da uso di sostanze, oltre che la familiarità per
disturbi dell’umore 6. Anche la presenza di un temperamento ciclotimico dominante predice il futuro evolvere
in disturbo bipolare. La letteratura è al momento attuale
scarna, invece, per quanto riguarda l’identificazione di
sottopopolazioni di pazienti con sintomatologia ossessivo-compulsiva ad alto rischio di evolvere verso psicosi
non affettive: tali soggetti si caratterizzano per la presenza di sintomi psicotici sottosoglia e attenuati, per la presenza di sintomi psicotici transitori lifetime, o ancora per
una compromissione del funzionamento complessivo, in
particolare quello socio-relazionale, in associazione a un
disturbo di personalità schizotipico, o infine per la presenza di almeno un familiare di primo grado affetto da un
disturbo psicotico. Tali caratteristiche cliniche sarebbero
presenti anni prima dell’esordio di franca sintomatologia
delirante e/o allucinatoria.
Anche per quanto riguarda la schizofrenia, va ricordato
come anch’essa sia caratterizzata da una traiettoria sequenziale che comporta una fase premorbosa con lievi
e non specifiche disfunzioni cognitive, motorie e sociali; una fase prodromica con sintomi positivi attenuati o
sintomi di base e compromissione del funzionamento;
un primo episodio psicotico che segna l’esordio formale della schizofrenia; una prima decade di malattia generalmente contrassegnata da ripetuti episodi di psicosi
con grado e durata parziali e variabili della remissione
inter-episodica con aggravamento della disabilità in concomitanza di ogni episodio di malattia (il declino del funzionamento è più marcato nei primi cinque anni seguenti
il primo episodio di psicosi, periodo in cui i pazienti possono raggiungere il peggio in termini di deterioramento)
e infine la fase stabile o plateau, quando i sintomi psicotici sono meno importanti e i sintomi negativi e i deficit
cognitivi predominanti 7. Per quanto riguarda il decorso
importanti osservazioni concernono aspetti di genere: il
picco di esordio tra i 20 e i 24 anni è prevalente nel genere maschile mentre nelle donne si osserva un moderato
aumento dell’incidenza dopo i 35 anni. Tuttavia, gli studi
osservazionali a lungo-termine sottolineano un’inversione del rapporto maschi-femmine con l’età, e coorti seguite sino all’età avanzata presentano nelle donne un più
alto rischio nel corso della vita 8.
Per quanto riguarda il tema del rapporto tra decorso e
trattamento, negli ultimi anni un numero crescente di
18° Congresso della Società Italiana di Psicopatologia: La Psicopatologia e le età della vita
studi ha dimostrato che l’identificazione e il trattamento
precoce delle psicosi è possibile ed efficace 9 10. Le strategie preventive per ridurre il tasso di transizione da uno
stadio prodromico e per migliorare l’outcome clinico a
lungo-termine includono il supporto psicoeducazionale,
la terapia cognitivo-comportamentale e interventi con
bassi dosaggi di antipsicotici atipici. Nonostante questi
promettenti risultati, gli strumenti psicometrici disponibili per valutare le fasi prepsicotiche non permettono di differenziare le fasi precoci della schizofrenia da quelle delle psicosi affettive, come la mania 11. La sovrapposizione
psicopatologica e fenotipica tra le due sindromi ostacola
lo sviluppo di strategie preventive disturbo-specifiche e
limita l’applicabilità in clinica della ricerca di base. Negli anni ’80 e primi anni ’90 la teoria predominante per
spiegare le alterazioni cerebrali osservate nella schizofrenia fu un’anomalia del neurosviluppo, basata sulla mancanza di gliosi nei cervelli postmortem, sulla presenza di
cambiamenti già al primo episodio e sulla mancanza di
correlazione tra durata di malattia e grado di anomalie.
Nell’ultima decade una nuova serie di studi MRI controllati hanno evidenziato progressivi cambiamenti del
cervello a favore di una componente neurodegenerativa.
Modificazioni strutturali del cervello sono riscontrabili
sia nella sostanza grigia sia nella sostanza bianca prima
dell’esordio della malattia e prima del trattamento con
antipsicotici; una progressione attiva può verificarsi prima dell’esordio dei sintomi; l’allargamento dei ventricoli
avviene più tardi ed è una conseguenza delle modificazioni della corteccia e la progressione è generalmente
molto estesa. Perché questo accada non è ancora noto. è
stato proposto che i cambiamenti nel tempo siano parte
del processo del disturbo controllato geneticamente, ma
altre spiegazioni sono possibili, quali varie esposizioni
ambientali. Sebbene ci siano diverse evidenze che i neurolettici possono modificare il tessuto cerebrale, il loro
utilizzo non può spiegare la progressione delle alterazioni del cervello riportate in molti studi. I dati attualmente
disponibili permettono di speculare solamente su quando queste alterazioni inizino. Dagli studi RM tali alterazioni sono già presenti nelle fasi prodromiche durante
l’adolescenza o nella giovane età adulta. è altamente
probabile che questo processo inizi molto prima, ancora
prima della nascita o durante lo sviluppo cerebrale dopo
la nascita, in quanto sono molte le evidenze di ritardato sviluppo e di altre sottili anomalie nelle persone che
presenteranno la schizofrenia. L’espressione del disturbo
dopo la pubertà suggerisce che i cambiamenti sinaptici
che avvengono nella corteccia con l’avanzare dell’adolescenza siano cruciali per questo processo. Sulla base
di una predisposizione genetica di origine indeterminata,
si può concludere che diversi fattori genetici agiscono
dalla nascita attraverso l’avanzare dell’età, influenzan-
do a tempi diversi differenti processi a seconda dell’età
dell’individuo, dalla migrazione dei neuroni nello sviluppo precoce corticale del cervello, alla plasticità cerebrale
e all’apoptosi durante l’avanzare dell’età 12.
Anche per il disturbo borderline di personalità (DBP),
che abitualmente esordisce alla fine dell’adolescenza o
nella prima età adulta, sono ritracciabili nell’infanzia e
nell’adolescenza fenomeni psicopatologici che possono
essere considerati un prodromo del disturbo. In particolare, studi prospettici hanno valutato che l’ADHD nei
bambini rappresenta un fattore di rischio per lo sviluppo
del disturbo borderline in età adulta con un odds ratio
di 13,16. I dati provenienti da numerosi studi sull’associazione tra i due disturbi hanno fornito evidenze consistenti a sostegno dell’ipotesi che l’ADHD sia uno stadio
precoce di sviluppo del DBP. Nelle fasi successive della
vita ci si attende che il DBP, come disturbo di personalità, mantenga caratteristiche stabili. In realtà, i dati clinici
disponibili confermano queste attese solo per i primi anni
di malattia, secondo alcuni Autori per i primi cinque anni di malattia, secondo altri fino a 40-50 anni di età. Se
invece si prendono in considerazione periodi di tempo
più prolungati, il decorso del DBP è tuttora oggetto di dibattito fra gli studiosi di questo settore. Gli studi presenti
in letteratura riguardanti l’evoluzione dei disturbi di personalità nella seconda metà della vita sono ancora molto
limitati e forniscono risultati controversi. Sebbene il DBP
presenti un corso di malattia più stabile rispetto a quello
di altri disturbi psichiatrici, le sue manifestazioni sindromiche tendono a cambiare nel tempo più di quanto ci
si aspetti per un disturbo di personalità. Alcuni studi di
follow-up a 15 anni riportano elevati tassi di remissione
del disturbo a partire dai 45 anni di età. In particolare, alcuni Autori sostengono che le dimensioni dell’instabilità
affettiva, che comprende gli accessi di rabbia e i sintomi
ansioso depressivi e dell’instabilità interpersonale tendono a essere stabilmente presenti nel corso del DBP,
mentre la dimensione sintomatologica dell’alterazione
del controllo degli impulsi tende ad attenuarsi nel tempo, o comunque a esprimersi in minor misura sul piano
comportamentale. Altri Autori hanno osservato, in uno
studio di follow-up a 27 anni, una riduzione significativa
della dimensione dell’instabilità relazionale e una certa
persistenza della dimensione instabilità affettiva nei pazienti con DBP e un’età media di 51 anni. è possibile
che alcuni criteri diagnostici del disturbo borderline non
vengano più soddisfatti in età più avanzata in quanto il
pattern relazioni interpersonali intense e instabili diventa
più difficile da valutare a causa della fisiologica riduzione della rete sociale in questa fase della vita; il disturbo
dell’identità, pur presente, diventa meno rilevante e le
manifestazioni comportamentali dell’impulsività meno
eclatanti anche in relazione a un processo di matura3
F. Bogetto
zione biologica. Inoltre, la dimensione dell’impulsività
è quella verso cui si orientano i principali trattamenti,
quindi è possibile che sia quella che si modifica più precocemente e in misura maggiore come effetto di terapie
relativamente specifiche. Tuttavia, la riduzione della sintomatologia caratteristica del DBP nel tempo rimane ancora oggi una questione aperta.
Ulteriore esempio di patologia che interessa la persona
nel suo sviluppo esistenziale è rappresentato dai disturbi del comportamento alimentare, malattie psichiatriche
tipiche delle società “sviluppate”, in forte crescita negli
ultimi decenni e ancora in evoluzione. I sintomi alimentari, come digiuno, emaciazione, sovrappeso e abbuffate, esprimono segnali di profonda sofferenza e patologia
del sé e al contempo sono tentativi di autocura, perversi
negli effetti, con complicate interazioni psicosomatiche,
somatopsichiche e relazionali. Un’alterata organizzazione della personalità è spesso evidente nelle persone con
disturbi del comportamento alimentare. Essa origina in
parte da fattori genetici, in parte da fattori biologici, in
parte dal contesto familiare e socio-culturale e soprattutto dalle relazioni di attaccamento. Un problematico
processo evolutivo dell’organizzazione della personalità
è oggi considerato il crogiuolo delle interazioni biologiche e psicologiche nell’infanzia e adolescenza: gli arresti
e le deformazioni dello sviluppo di tale processo sono
cruciali anche ai fini della relazione terapeutica – a suo
modo una relazione di attaccamento – in tutta la durata
della malattia. I disturbi del comportamento alimentare
esordiscono nella prima adolescenza ma a causa della
costante resistenza ai trattamenti questi disturbi spesso
si protraggono attraverso l’età adulta fino alla terza età.
Infatti, in molti casi, la sottile ma pervicace aggressività
che impregna le dimensioni della personalità di questi
pazienti, determina e mantiene nel tempo questi disturbi
e vanifica, non raramente, gli interventi riabilitativo-nutrizionali, farmacologici e psicoterapeutici del progetto
di cura 13.
Infine, la cura dei disturbi mentali è altamente influenzata dal ciclo vitale per almeno due ordini di motivi che
interessano tutte le forme di trattamento:
a. la possibilità di impiego delle terapie può presentare
delle limitazioni correlate alle diverse fasi della vita.
Numerosi esempi riguardano la prescrivibilità di alcuni farmaci: la paroxetina non può essere prescritta
sotto i 18 anni, l’aloperidolo non è prescrivibile in
gravidanza, l’atomoxetina (per l’ADHD) in Italia è
prescrivibile solo sotto i 18 anni ... Anche in psicoterapia la possibilità di impiego è talvolta condizionata
dall’età o dalla fase del ciclo vitale: ad esempio la
psicoanalisi è stata tradizionalmente considerata non
adatta per l’età avanzata e la terapia della famiglia
è indicata specificamente per la cura dei soggetti in
4
età infantile o adolescenziale (benché il trattamento
si applichi a tutti i componenti del nucleo familiare);
b. l’efficacia e la tollerabilità: l’età e la fase vitale influenzano la risposta e/o la tollerabilità al trattamento per numerosi farmaci in medicina. In psichiatria,
il dato è meno rilevante ma è comunque meritevole
di citazione. Ad esempio, l’età avanzata espone al rischio di effetti paradossi, di eccessi di sedazione, di
problemi di interazione con farmaci di varia tipologia
la cui assunzione, anche molteplice, è più frequente
in età avanzata 14.
Il Congresso si propone di fare il punto sullo stato attuale delle ricerche sulla psicopatologia nelle sue diverse
espressioni in rapporto alle età della vita, coinvolgendo
figure professionali diverse quali psichiatri, neuropsichiatri infantili, neurologi, psicologi, geriatri. I disturbi
psichiatrici oggetto delle relazioni plenarie e dei diversi
simposi previsti verranno trattati secondo un’ottica longitudinale evolutiva, cercando di identificare per ciascun
disturbo psichiatrico gli antecedenti psicopatologici (specifici e aspecifici), le manifestazioni differenziate in rapporto alle diverse età della vita e gli esiti in età avanzata.
Particolare attenzione verrà inoltre data al rapporto tra
eventi di vita riproduttivi della donna e manifestazioni
psicopatologiche. Infine, sezioni dedicate del Congresso
valuteranno la specificità degli interventi psicofarmacologici, psicoterapeutici e psicosociali in rapporto alle età
della vita dei pazienti.
Filippo Bogetto
Professore ordinario di Psichiatria, Università di Torino
Presidente, Società Italiana di Psicopatologia
Bibliografia
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Rocca P, Giugiario M, Montemagni C, et al. Quality of life
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5
Original article
Lithium and valproate in manic and mixed states:
a naturalistic prospective study
Litio e valproato nel trattamento degli episodi maniacali e misti: studio prospettico osservazionale
C. Del Grande1, M. Muti2, L. Musetti1, M. Corsi1, I. Pergentini1, M. Turri2, G.U. Corsini2, L. Dell’Osso1
Department of Clinical and Experimental Medicine, University of Pisa, Italy; 2 Department of Translational Research and New Technologies
in Medicine and Surgery, University of Pisa, Italy
1 Summary
Objectives
Lithium is still recommended as a first-choice treatment for
acute bipolar mania, especially in pure euphoric mania of mild
to moderate severity. Despite the large quantity of evidence
supporting the efficacy of lithium, in clinical practice its use has
often been limited because of management issues related to its
narrow therapeutic index. International guidelines suggest combining lithium with a second mood stabilizer (anticonvulsant
or atypical antipsychotic) for treatment of mixed states, rapid
cycling and severe forms of mania with atypical features, which
are classically considered to be poorly responsive to lithium
alone. To date, however, the specific modalities of these associations on the basis of different clinical presentations have been
poorly investigated in clinical trials. In this study, we aimed to
evaluate the modalities of use of lithium in a naturalistic setting
of manic and mixed bipolar patients, and to investigate the effects of its combination with valproate on the clinical course.
Materials and methods
Seventy-five bipolar I patients (DSM-IV-TR) in a manic (14.7%)
or mixed (85.3%) phase, treated with lithium alone or in association with valproate, were recruited at the day hospital of the
Psychiatric Unit of the Department of Clinical and Experimental
Medicine, University of Pisa, and followed-up in a naturalistic
trial for an average period of 6 months. Diagnosis was confirmed using SCID-I. All subjects recruited underwent at least
two standardized evaluations of clinical course, assessed by the
Introduction
Although in the last decades many pharmacological alternatives to lithium have become available, the drug is
still recommended as a first-choice treatment for acute
bipolar mania, as supported by the results of several clinical trials 1 2.
Lithium monotherapy is indicated especially for patients
with a classical (euphoric) presentation of mania of mild
to moderate severity 3 4. On the contrary, international
CGI-BP, at baseline and at each subsequent check of serum
lithium levels. Variables concerning clinical features of patients
and clinical course of episodes were analyzed by comparison
between the two treatment groups (lithium monotherapy vs.
lithium plus valproate).
Results
The group of subjects treated with the combination of lithium
and valproate (n = 41, 54.7%) was composed mainly of men,
had a higher percentage of rapid cyclers and a higher severity
of psychotic symptoms at baseline. The two treatment groups
did not differ in the other demographic and clinical features
analyzed. Patients treated with lithium plus valproate had a
higher remission rate at endpoint than subjects treated with
lithium monotherapy. The association of valproate significantly
reduced the severity of specific symptomatological dimensions,
such as mixed, anxiety and psychotic features.
Conclusions
Our data confirm the use of combination therapy in more severe forms of mania. Prospective data on the clinical course
have shown that the combination of lithium with valproate is
associated with a greater improvement of specific symptomatological dimensions, which are poorly responsive to lithium
monotherapy.
Key words
Lithium • Valproate • Mania • Mixed state • Treatment • Bipolar disorder
guidelines for the treatment of bipolar disorder (BD) 5-8
suggest combining lithium with a second mood stabilizer
(anticonvulsant or atypical antipsychotics) for the treatment of severe and atypical manifestations of mania, with
psychotic symptoms and high rates of psychiatric comorbidity 9-14. This is consistent with common clinical practice, where is often necessary to use a polypharmacotherapy to treat different psychopathological dimensions
of manic and mixed episodes 15-17. To date, however, few
Correspondence
Claudia Del Grande, Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, via Roma 67, 56100 Pisa, Italy • Tel. +39 050 2219760
• Fax +39 050 2219787 • E-mail: claudia_83@virgilio.it
6
Journal of Psychopathology 2014;20:6-10
Lithium and valproate in manic and mixed states
studies have systematically investigated the efficacy of
combination treatments in comparison with monotherapy consisting of single antimanic agent, and a proper
algorithm regarding the specific modalities of these associations according to different clinical presentations is
still lacking 18-21.
Many questions concerning the optimal conditions of use
of lithium remain open. Most of the studies with lithium
have been conducted with very strict diagnostic inclusion criteria for BD, with exclusion of patients presenting
atypical symptoms and psychiatric comorbidity. Thus,
the results of these studies may not be generalized to the
wide range of bipolar conditions 22. This modality of patient selection, which is very restrictive compared to the
current concept of bipolar spectrum 23 25, helps to explain
the discrepancy between “efficacy” and “effectiveness”
of this treatment. Furthermore, the risk of toxicity related
to the narrow therapeutic index of lithium has often limited its use in clinical practice, while increasing the prescription of other antimanic agents, such as valproate 26 27.
The optimal serum lithium concentration maintaining its
therapeutic efficacy while minimizing side effects, also
remain a debated question, as well as if specific combination treatments may have a selective efficacy on specific psychopathological dimensions.
The present study evaluated the prescribing patterns of
lithium in a naturalistic setting of manic and mixed bipolar patients, and investigated the effects of its combination with valproate on clinical course.
Materials and methods
In May 2010, the Psychiatric Unit of the Department of
Clinical and Experimental Medicine, in collaboration
with the Section of Pharmacology of the Department of
Translational Research and New Technologies in Medicine and Surgery, University of Pisa, started a naturalistic
prospective study, still on-going, to evaluate the use of
lithium in BD 28. As part of this study, 75 patients (30 men
and 45 women, mean age 37.45 ± 14.54 years) in a manic (n = 11, 14.7%) or mixed (n = 64, 85.3%) episode according to DSM-IV-TR criteria 29, and treated with lithium
alone or in combination with valproate, were recruited
and followed-up.
Patients were recruited among subjects consecutively
admitted at the day hospital of the Psychiatric Unit during a 2-year period (May 2010-March 2012). All patients
treated with antipsychotics or other mood stabilizers,
with substance/alcohol abuse until three months before
study entry and/or with severe somatic disorders were
excluded. All subjects participated voluntary in the study
after written informed consent for the assessment procedures was obtained.
The collection of data at baseline took place during an
interview lasting about two hours, often in the presence
of a family member, using the SCID-I (Structured Clinical
Interview for DSM-IV-TR Axis I Disorders) 30 to establish
the diagnosis of BD type I and the presence of a manic or
mixed episode. To complete the diagnostic picture, information obtained from every available source was used:
medical history, previous medical data and information
from first-degree relatives.
The 75 patients recruited underwent at least two standardized assessments of the symptomatology through the
administration of the Clinical Global Impression Bipolar
Version Scale (CGI-BP) 31. In addition to baseline evaluations, the CGI-BP was administered at each subsequent
check of serum lithium levels. All baseline and follow-up
assessments were performed by resident clinicians not directly involved in the clinical management of the patients
and trained to use the assessment scales. Clinicians from
the Section of Pharmacology analyzed blood samples of
patients to determine serum lithium levels.
Each patient was followed-up for an average period of 6
months. The frequency of clinical and biological assessments was established by independent psychiatrists who
were in charge of the therapeutic management of patients,
on the basis of variations in clinical symptoms. In the present study, data from clinical and biological evaluations
that had a minimum interval of 14 days and a maximum of
42 days (mean interval 25 days) were analyzed.
Considering pharmacological treatment, 34 patients
(45.3%) were treated with lithium monotherapy and
41 patients (54.7%) were treated with the combination of lithium and valproate. The daily dose was of
664 ± 165 mg/day for lithium carbonate (range: 4501200 mg/day) and 822 ± 294 mg/day for sodium valproate (range: 500-1250 mg/day). The mean serum lithium level (mean ± SD; mEq/l) was 0.50 ± 0.16, while
those of valproate (mean ± SD; mg/l) was 54.68 ± 23.41.
Variables concerning the clinical features of the sample and the clinical course of episode were analyzed by
comparison between the two treatment groups.
Episodes were considered to be in remission when the
CGI-BP score for global illness severity achieved and
maintained a value of 1 (normal, not ill) or 2 (minimally
ill) for at least two subsequent evaluations during the observational period. Symptomatic improvement was assessed by the reduction, between baseline and endpoint,
of at least 3 points in the CGI-BP scores indicating the
severity of different symptomatological dimensions of a
manic/mixed episode.
Statistical analysis
Comparison of categorical variables between the two
groups was carried out using chi-square analysis, whereas that of dimensional variables by the t-test. A p value
7
C. Del Grande et al.
Table I.
Demographic and clinical features. Caratteristiche cliniche e demografiche.
Lithium
(n = 34)
Lithium + Valproate (n = 41)
N (%)
N (%)
c2
p value
Gender (female)
26 (76.5%)
19 (46.3%)
7.030
.007
Marital status (married)
9 (26.5%)
16 (39%)
1.318
.184
Employment (employed)
23 (67.6%)
30 (73.2%)
.274
.393
Index episode (Mixed)
28 (82.4%)
36 (87.8%)
.441
.366
Polarity of onset (Manic/Mixed)
9 (40.9%)
18 (56.2%)
1.227
.203
Rapid cyclers
2 (5.9%)
12 (29.3%)
6.695
.009
Comorbidity PD
14 (41.2%)
20 (48.8%)
.434
.336
Comorbidity OCD
10 (52.6%)
5 (35.7%)
.930
.271
Previous alcohol/substances abuse
2 (12.5%)
8 (36.4%)
2.720
.099
M ± DS
M ± DS
F
p value
Mean age
38.00 ± 14.00
36.97 ± 15.16
.299
.766
Schooling (years)
13.88 ± 3.05
12.83 ± 3.63
.971
.388
Serum lithium level (mEq/l)
0.49 ± 0.15
0.50 l ± 0.17
.186
.853
Manic
3.86 ± 4.25
3.12 ± 3.09
.148
.707
Mixed
7.25 ± 3.41
5.00 ± 3.50
3.144
.086
Depressive
4.75 ± 2.95
4.21 ± 2.54
.246
.624
4.2 ± 1.1
4.4 ± 1.2
.616
.435
4.0 ± 1.0
4.1 ± 0.9
.476
.493
4.4 ± 1.0
4.7 ± 0.9
1.339
.252
Depressive symptoms
3.8 ± 0.9
3.7 ± 0.8
.574
.452
Anxiety symptoms
4.0 ± 1.0
4.4 ± 0.9
1.843
.179
3.7 ± 0.9
4.8 ± 1.1
8.566
.006
Numbers of previous episodes:
Severity of illness*
Severity of psychopathological dimensions of episode†:
Manic symptoms
Mixed symptoms
‡
‡
Psychotic symptoms
§
Scores at baseline assessed by the CGI-BP subscale for overall illness severity; † Scores at baseline assessed by the CGI-BP subscale for severity
of various psychopathological dimensions; ‡ Evaluated on 64 patients with mixed episode; § Evaluated on 36 patients with psychotic symptoms.
* less than 0.05 was considered statistically significant. All
statistical analyses were carried out using the Statistical
Package for Social Science, version 16.0.
Results
Comparing the demographic and clinical features of subjects between the two treatment groups, it emerged that
the group of patients taking lithium and valproate was
composed mainly of men (53.7% vs. 26.5%; c2 = 7.030;
p = .007); furthermore, these patients had a higher percentage of rapid cycling (29.3% vs. 5.9%; c2 = 6.695;
p = .009) and a higher CGI-BP score for the severity of
8
psychotic symptoms at baseline (4.8 ± 1.1 vs. 3.7 ± 0.9;
T = 8.566; p = .006), compared with those without valproate (Table I). The two treatment groups did not differ in
terms of polarity of onset, number of previous episodes,
rate of psychiatric comorbidity, polarity of index episode
or in severity of current episode assessed by the CGI-BP.
At endpoint, patients treated with the combination of lithium and valproate showed a higher remission rate than
those treated with lithium alone, although the difference
did not reach statistical significance (68.3% vs. 47.1%,
c2 = 3.456; p = .052). In particular, the association of
valproate produced a significantly higher improvement
of mixed (72.2% vs. 42.9%, c2 = 5.630; p = .017), psy-
Lithium and valproate in manic and mixed states
Table II.
Clinical course: remission of episode and improvement of psychopathological dimensions at endpoint. Decorso clinico: remissione
dell’episodio in atto e miglioramento delle singole dimensioni psicopatologiche al termine del periodo di osservazione.
% patients with remission of manic/mixed episode*
Lithium
(n = 34)
Lithium + Valproate
(n = 41)
χ2
16 (47.1%)
28 (68.3%)
3.456
p value
.052
% patients with symptomatic improvement
†
Manic symptoms
17 (50%)
29 (70.7%)
3.369
.055
Mixed symptoms‡
12 (42.9%)
26 (72.2%)
5.630
.017
Depressive symptoms‡
15 (53.6%)
18 (50%)
.080
.488
Anxiety symptoms
15 (44.1%)
33 (80.5%)
10.671
.001
Psychotic symptoms§
7 (46.7%)
17 (81%)
4.629
.037
Impulsivity
17 (54.8%)
23 (57.5%)
.050
.506
Remission: score of 1 (normal, not ill) or 2 (minimally ill) on CGI-BP subscale for overall illness severity maintained for at least two subsequent
evaluations; † Symptomatic improvement: reduction of at least 3 points in the CGI-BP scores for the severity of various psychopathological dimensions at endpoint; ‡ Evaluated on 64 patients with mixed episode; § Evaluated on 36 patients with psychotic symptoms.
* chotic (81% vs. 46.7%, c2 = 4.629; p = .037) and anxiety
symptoms (80.5% vs. 44.1%, c2 = 10.617; p = .001). In
contrast, there were no significant differences between
the two groups in terms of depressive symptoms and impulsivity (Table II).
Discussion and conclusions
Although the efficacy of lithium in the treatment of acute
mania has been widely documented, in clinical practice
it is often necessary to use complex drug combinations
for management of different clinical manifestations 1 2 14 16.
However, no specific indications are still available to
guide these association strategies.
Our data on the use of lithium in clinical practice, in
monotherapy or in combination with valproate, showed
that more than 50% of the sample was treated with the
combination of the two drugs. Most patients receiving
lithium plus valproate were male and rapid cyclers; furthermore, combination treatment was associated with a
higher severity of psychotic symptoms at baseline. This is
consistent with the common practice to administer polypharmacotherapy for the management of more severe
forms of BD 9 11 14.
Patients treated with the combination of lithium and valproate showed greater rates of clinical improvement at
endpoint compared with subjects with lithium alone. In
particular, co-administration of valproate significantly reduced the severity of specific psychopathological dimensions, such as mixed, anxiety and psychotic symptoms,
which are poorly responsive to lithium alone 10 14 17.
The present study suffers from some limitations: first, it
is naturalistic and second, it was carried out in a small
sample of patients followed-up for an average period of
6 months. Therefore, the results are not generalizable to
the wide spectrum of bipolar conditions.
Further investigations will be necessary to better define
possible advantages resulting from the association of lithium with valproate, and in particular, if serum lithium levels may be reduced when lithium is co-administered with
valproate, while enhancing its antimanic properties and
minimizing side effects related to high dosages of the drug.
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Original article
Relazione tra disturbi psichiatrici e funzionamento adattivo in persone
con disabilità intellettiva
Relationship between psychiatric disorders and adaptive functioning in individuals
with intellectual disabilities
M. Bertelli1,2, M. Rossi1, D. Scuticchio1, N. Varrucciu1, F. Poli3, C. Del Furia1
CREA (Centro di Ricerca ed Evoluzione AMG), Firenze; 2 WPA-SPID (World Psychiatric Association, Section Psychiatry of Intellectual Disability),
Ginevra (Svizzera); 3 PAMAPI, Firenze
1 Summary
Introduction
Though psychiatric disorders (PD) are three to four times
more prevalent in people with intellectual disability (PwID)
compared to the general population, research indicates that
the impact of PD on adaptive functioning in PwID has been
only minimally investigated with results that are not sufficiently clear. The few contributions present in the literature
focus on children, adolescents and individuals with autism
spectrum disorders (ASD). There are no studies evaluating
the unspecific impact of any type of PD on the abilities of
PwID, even if additional knowledge would be useful in explaining dysfunction and planning treatment. Moreover, for
many years, particular interest was reserved to “behavioral
phenotypes”, or the possibility that certain maladaptive patterns of behaviour are the result of specific genetic alterations. The most studied phenotypes were Down, X Fragile
and Prader-Willi syndromes. Literature reports have noted
significant correlations between ASD and difficulties in the
areas of socialisation, communication and motor-skills in
early adulthood or younger. Other correlations have been reported between ADHD and deficits in executive functions in
children and between mood disorders and some verbal skills
in adults. Significantly high scores were found in the areas
of communication and motor-skills in PwID and schizophrenia. Epilepsy appears to have the highest impairment in the
areas of socialisation and motor-skills. Comparisons between
PD and organic disorders, including neurological disorders
(ND), have not been performed.
Introduzione
Dagli studi presenti in letteratura si evidenzia come la
relazione tra disturbi psichiatrici (DP) e funzionamento
adattivo in persone con disabilità intellettiva (PcDI) sia
stata poco indagata e risulti tuttora non sufficientemente
chiara. Dal momento che nelle PcDI i DP sono presenti
Objective
The aim of this study was to assess the impact of the presence of a
PD on adaptive functioning of adults with ID.
Methods
Sixty-eight adults with ID, clients of residential facilities and day
centres in Tuscany, were randomly assessed with the Psychiatric
Instrument for the Intellectually Disabled Adult (SPAID-G), the
Diagnostic Manual - Intellectual Disability (DM-ID) criteria and
the Vineland Adaptive Behaviour Scales (VABS). Twenty-four individuals were previously diagnosed with a PD and 24 with a
ND. The scores were compared and the results were examined
for level of mental retardation and other background variables.
Results
The group with ID and PD scored significantly worse on the
VABS than the group with only ID, especially in the area of daily
skill for life. The level of interference with the adaptive functioning of PD was higher than that of ND.
Conclusions
The presence of a PD seems to have a relevant negative impact
on functioning of PwID that is higher than that of ND. Adequate
psychiatric assessment would facilitate the understanding of the
individual processes that modulate and differentiate adaptive
skills in adults with ID. It would also be very useful in the planning of rehabilitative interventions.
Key words
Adaptive behaviour • Adaptive functioning • VABS • Intellectual disability • Psychiatric disorders
in maniera significativamente superiore, da 3 a 4 volte,
rispetto alla popolazione generale 1, l’indagine di tale relazione potrebbe portare nuove acquisizioni utili al processo di cura di questi soggetti.
In questa popolazione le stime di prevalenza dei DP sono
estremamente variabili. Uno studio di Cooper et al. del
Correspondence
Marco Bertelli, CREA (Centro Ricerca ed Evoluzione AMG), via del Sansovino 176, 50142 Firenze, Italy • Tel. +39 0557392880 • Fax +39
0557392879 • E-mail: mbertelli@crea-amg.org; bertelli.fi@tiscali.it; segreteria: info@crea-amg.org
Journal of Psychopathology 2014;20:11-16
11
M. Bertelli et al.
2007 2 evidenzia come la comorbidità psichiatrica vari
considerevolmente in funzione dei criteri diagnostici utilizzati, passando dal 52,2% nel caso in cui la diagnosi si
basi esclusivamente su giudizi clinici, al 45,1% quando
venga fatta sui criteri diagnostici inglesi per gli adulti con
disabilità dell’apprendimento (DC-LD) 3, fino ad arrivare all’11,4% nelle indagini che utilizzino i criteri della
revisione della IV edizione del Manuale Americano per
la Statistica e la Diagnosi dei disturbi mentali (DSM-IVTR) 4 o addirittura al 10,9% se vengano impiegati i Criteri
Diagnostici per la Ricerca della Decima Classificazione
Internazionale dei Disturbi Mentali e Comportamentali
(ICD-10-DCR) 5. La prevalenza di doppia diagnosi sembrerebbe essere del 20-40% in riferimento all’età adulta 6
e del 40-60% per i bambini e gli adolescenti 7 8.
L’impatto dei DP sul funzionamento adattivo non è supportato da un numero adeguato di studi, anche se è individuabile una tendenza a riconoscerne l’esistenza 9.
Il funzionamento adattivo è definibile come l’insieme
delle competenze sociali, intellettive e pratiche che vengono apprese dalla persona nella vita quotidiana per rispondere alle richieste dell’ambiente 10 11.
Lo studio sul funzionamento adattivo nelle PcDI varia
considerevolmente all’interno di gruppi caratterizzati per
etiologia e fenomenologia 12. Da molti anni un interesse
particolare viene riservato ai “fenotipi comportamentali” 13, cioè alla possibilità che certi pattern comportamentali e disadattativi possano derivare da specifiche alterazioni genetiche.
I fenotipi più studiati sono risultati le sindromi di Down 14,
dell’X Fragile 15 e di Prader-Willy 16 17.
Nella sindrome di Down (SD), che interessa circa un
bambino su 700-1000 nati vivi 18 e rappresenta la sindrome genetica più comune tra quelle includenti ritardo
mentale, deficit adattivi importanti riguardano il processamento verbale 19 e le capacità motorie 20. Molti individui mostrano grave ritardo nel linguaggio, soprattutto in
termini di discrepanza fra capacità espressiva e ricettiva 21 22. I limiti nelle abilità motorie riguardano sia i movimenti grossolani che quelli fini 20. Nonostante tali deficit,
molti individui con SD mostrano buone abilità sociali 14,
comprese quelle di instaurare relazioni interpersonali 22
e di mantenere un’elevata performance nel gioco e nelle
attività ricreative. Tale fenotipo comportamentale sembrerebbe strutturarsi soprattutto in soggetti adulti con
gravi mancanze ambientali nello sviluppo personale 14.
Diverso è il caso di altri giovani adulti con SD che presentano uno scadimento delle funzioni esecutive e delle
abilità comportamentali a causa di un deterioramento
cognitivo precoce 23.
Anche le abilità delle persone con sindrome dell’X Fragile (SXF) sembrano variare significativamente in base al
profilo genetico. Nel fenotipo a mutazione completa le
difficoltà sociali, l’iper-reattività e l’iperattivazione sono
12
molto più marcate che nella pre-mutazione 24 25. È stato inoltre rilevato che bambini con bassa pervasività di
aspetti autistici e alta percentuale di espressione del gene FMRP mostrano buon adattamento in tutti gli ambiti
comportamentali. Quelli senza comportamenti autistici
ottengono punteggi più elevati e miglioramenti più rapidi
nelle abilità di vita quotidiana, mentre registrano i valori
più bassi nella socializzazione 15.
Per quanto riguarda la sindrome di Prader-Willy (SPW),
deficit nelle abilità sociali 26-28 e motorie 29 17 sono stati
spesso descritti. Anche qui è presente una variabilità su
base genetica: nei casi da disomia uniparentale prevalgono le difficoltà relazionali, mentre in quelli da delezione
l’aggressività è più bassa 30. Le persone con delezione
grande hanno una compromissione generale più marcata
di quelle con delezione piccola 16. In tutti i casi le abilità intellettive possono essere mascherate dall’immaturità
sociale 31.
La relazione tra DP e funzionamento adattivo in PcDI
è stata indagata soprattutto in riferimento all’infanzia,
all’adolescenza ed alla compresenza di disturbi dello
spettro autistico (DSA), mentre risultano gravi carenze in
riferimento all’età adulta 12.
Le ricerche sulle persone con DSA confermano difficoltà
prevalenti nei domini della socializzazione e della comunicazione 32, anche quando confrontate con persone
con altri disturbi pervasivi dello sviluppo o grave DI 33-35.
Tuttavia una correlazione positiva tra gravità della compromissione cognitiva e disfunzionamento sociale è stata
riscontrata anche nelle persone con sola DI 36.
Tra gli altri DP i disturbi dell’umore sembrano avere un
significativo impatto negativo sulle abilità delle PcDI.
Matson et al. 37 hanno evidenziato nel disturbo bipolare
abilità verbali relazionali peggiori di quelle di altre forme psicopatologiche o della sola DI. Anche nei casi di
più marcata compromissione cognitiva la tendenza alla
ruminazione depressiva sembra associarsi a punteggi più
bassi nelle abilità positive generali 38. Punteggi relativamente più alti sono stati reperiti nelle aree della socializzazione e delle abilità quotidiane 9.
Nella schizofrenia punteggi significativamente più alti
sono stati trovati nelle aree della comunicazione e della
motricità 9.
L’epilessia, unico fra i disturbi neurologici (DN) di cui
è stata reperita una valutazione strutturata dell’impatto
sulle abilità delle PcDI, sembra compromettere maggiormente le aree della socializzazione e della motricità 9.
Nessuno studio ha valutato l’impatto aspecifico sulle abilità della presenza di un DP in PcDI. Non sono neanche
stati eseguiti confronti fra DP e disturbi organici, inclusi
quelli neurologici.
L’obiettivo del presente studio è stato quello di valutare le
differenze di abilità in PcDI con e senza DP.
Relazione tra disturbi psichiatrici e funzionamento adattivo in persone con disabilità intellettiva
Materiali e metodi
Al fine di raggiungere l’obiettivo dello studio 68 soggetti
con DI sono stati reclutati consecutivamente in diverse
strutture residenziali della Regione Toscana per essere
sottoposti ad un protocollo di valutazione strumentale.
Il protocollo prevedeva la compilazione nell’arco di un
mese di un foglio di raccolta di dati socio-demografici,
dell’anamnesi medica, della Vineland Adaptive Behaviour Scale (VABS) 39 e della versione generale dello Strumento Psichiatrico per l’Adulto Intellettivamente Disabile
(SPAID-G) 40.
La compilazione del foglio dei dati socio-demografici e
della VABS è stata effettuata da 4 educatori professionali mentre quella dello SPAID-G da uno psichiatra e da
una psicologa clinica. Per entrambi i gruppi di valutatori
l’inter-rater reliability, calcolata attraverso la K di Cohen
prima dell’inizio dello studio in due sessioni di valutazione apposite, è risultata superiore a 0,7.
L’anamnesi medica, volta prevalentemente ad individuare disturbi non psichiatrici in atto o con esiti persistenti,
è stata raccolta dallo stesso psichiatra che ha eseguito la
compilazione di parte degli SPAID-G.
Le check-list, i questionari, le scale di valutazione e gli
altri documenti contenenti dati sensibili sono stati debitamente conservati in un archivio accessibile solo al personale autorizzato. Tutti i partecipanti e i loro rappresentanti legali hanno espresso consenso a partecipare allo
studio.
SPAID-G
Lo SPAID-G è la versione per l’orientamento diagnostico generale del sistema SPAID 41. Tutti gli strumenti che
costituiscono questa batteria sono stati costruiti pensando alla possibilità di identificare i sintomi psichiatrici a
partire dall’unica modalità d’indagine applicabile a tutti i
casi di DI, ovvero l’osservazione di atteggiamenti e comportamenti.
La forma G non riconosce alcun limite cronologico nella
rilevazione della sintomatologia.
I 52 item che compongono lo strumento rappresentano
gli indicatori comportamentali di tutti i sintomi che compaiono, con diversa aggregazione, nelle seguenti categorie diagnostiche del DSM-IV-TR 4: disturbo del comportamento alimentare, disturbi psicotici, disturbi depressivi,
disturbi maniacali, disturbi d’ansia, effetti collaterali da
farmaci, delirium, demenza, disturbi correlati a sostanze,
disturbi di personalità del gruppo strano, disturbi di personalità del gruppo drammatico, disturbi di personalità
del gruppo ansioso, disturbi del controllo degli impulsi,
disturbi dell’identità, simulazione, disturbi sessuali.
Per ogni item l’attribuzione del punteggio è dicotomica,
zero o uno, in base alla presenza o assenza del comportamento descritto. Il punteggio di un sintomo può contri-
buire al punteggio di diversi raggruppamenti, allo stesso
modo in cui alcuni sintomi sono trasversalmente presenti
in più condizioni psichiatriche. Il punteggio di un raggruppamento diviene meritevole di attenzione e viene
definito sopra-soglia quando più della metà degli item da
cui è composto ha ricevuto punteggio 1 41.
Per il calcolo rapido dei punteggi SPAID-G è stato utilizzato il software originale, nella versione per ambiente
Windows.
VABS
La scala Vineland rappresenta un facilitatore per la programmazione di interventi individuali educativi e riabilitativi ed è frequentemente utilizzata in numerosi settori
della ricerca. Si articola in 4 scale e 11 sottoscale:
• Comunicazione: Ricezione (ciò che il soggetto comprende), Espressione (ciò che il soggetto dice), Scrittura (ciò che il soggetto legge e scrive);
• Abilità quotidiane: Personale (come il soggetto mangia, si veste e cura l’igiene personale), Domestico
(quali lavori domestici il soggetto compie), Comunità
(come il soggetto usa tempo, denaro, telefono e proprie capacità lavorative);
• Socializzazione: Relazioni interpersonali (come il
soggetto interagisce con gli altri), Gioco e tempo libero (come il soggetto gioca e impiega il tempo libero),
Regole sociali (come il soggetto manifesta senso di responsabilità e sensibilità verso gli altri);
• Abilità motorie: Grossolane (come il soggetto usa
braccia e gambe per il movimento e la coordinazione), Fini (come il soggetto usa mani e dita per manipolare oggetti).
I dati raccolti nel modo sopra descritto sono stati inseriti
in un data base creato appositamente per questo studio
e sottoposti ad elaborazione statistica. Per le variabili socio-demografiche ed i punteggi VABS e SPAID-G è stato
eseguito il calcolo delle medie e delle deviazioni standard. Per determinare la significatività delle differenze tra
gruppi è stata utilizzato il test T di Student, controllato
con ANOVA post-hoc.
Per la creazione, per l’aggiornamento del database e per
l’elaborazione statistica è stato impiegato il pacchetto
statistico SPSS 12.0 per Windows.
Risultati
Il campione risultava composto da 68 soggetti di cui 45
maschi e 23 femmine (sex ratio 1,96). Questi risultavano avere un’età media di 45,22 anni (±12,69), riferita ad
un range compreso fra 20 e 75. Dodici (17,65%) presentavano DI di grado lieve, 31 (45,59%) moderato, 15
(22,6%) grave e 10 (14,71%) gravissimo. Cinquantadue
partecipanti (76,47%) provenivano da strutture residen13
M. Bertelli et al.
ziali (24h/24), 14 (20,59%) da centri diurni e 2 (2,94%)
dalle rispettive famiglie. Le caratteristiche di background
del campione sono sintetizzate in Tabella I.
Ventiquattro soggetti risultavano affetti da un DP, fra disturbi dell’umore, disturbi d’ansia, disturbi dello spettro
schizofrenico, disturbi pervasivi dello sviluppo e disturbi
di personalità, mentre gli altri 44 non presentavano alcun
DP associato. Ventiquattro avevano ricevuto una diagnosi
di DN, fra epilessia, para o tetraplegie, gravi distonie o
discinesie.
La presenza di un DP è risultata avere un impatto negativo significativo sulle abilità. Infatti i partecipanti con
DP hanno ottenuto punteggi VABS significativamente
più bassi di quelli con sola DI nella scala delle abilità
quotidiane in particolare nelle sottoscale delle abilità
personale e domestica (personale p < 0,014; domestica
p < 0,008).
Le indagini effettuate e le successive elaborazioni statistiche indicano che i disturbi neurologici sembrano impattare sul funzionamento in modo meno marcato, ad eccezione delle abilità grosso-motorie (p < 0,001) (Tab. II).
La valutazione statistica dell’interdipendenza della presenza di DP e DN sui punteggi VABS ha dato esito negativo. Le medie dei punteggi dei partecipanti con solo DP
(n = 16) e quelle dei partecipanti con DP + DN (n = 8)
non hanno mostrato differenze significative. Nel confronto fra partecipanti con solo DN (n = 16) e DN + DP
(n = 8) è stata individuata una sola differenza significativa
nella sotto-area delle abilità grosso-motorie (p = 0,07).
Tali reperti sono risultati validi per tutti i gradi di disabilità.
Discussione
Dall’analisi dei dati delle nostre indagini emerge come
nelle PcDI il livello di abilità possa variare in base alla
presenza di un DP.
Tale risultato conferma quelli di studi precedenti, anche
se riferiti all’impatto specifico di singoli disturbi. Di Nuovo e Buono 9 hanno individuato alcune possibili peculiarità dei disturbi pervasivi dello sviluppo, dell’umore,
dell’epilessia, dei disturbi di personalità e dell’ADHD,
rilevando comunque una generale tendenza a condizionare significativamente il funzionamento individuale.
Nel nostro campione l’impatto negativo di un DP sul livello di abilità appare più elevato nelle attività della vita
quotidiana, in particolare nelle sottoscale VABS “Personale” e “Domestico”.
Anche questo risultato è difficilmente comparabile con
quello di altri studi, nei quali si fa riferimento esclusivo
all’età evolutiva o, quando invece si consideri una popolazione adulta, alla compresenza specifica di disturbo pervasivo dello sviluppo. Comunque in tali studi si riscontra prevalentemente la presenza di un deficit di funzionamento
nelle aree della socializzazione e della comunicazione 32 42.
Contrariamente all’opinione comune, i nostri risultati indicano un impatto dei DP sul funzionamento generale significativamente superiore a quello dei DN. Se quest’ultimi possono considerarsi un esempio di gravi disturbi
fisici, il nostro reperto sembra suggerire il primato della
sofferenza psichica nella considerazione generale del
livello di funzionamento e verosimilmente anche della
qualità di vita degli individui con DI.
Tabella I.
Caratteristiche di background del campione. Background characteristics of the sample.
Campione generale
DI* e DP†
DI e DN‡
45,22
12,69
44,96
13,43
44,21
11,39
Sesso, n (%)
Maschi
Femmine
Sex Ratio
45 (66,18)
23 (33,82)
1,96
12 (50)
12 (50)
1
17 (70,83)
7 (29,17)
2,42
Grado di disabilità intellettiva, n (%)
Lieve
Moderata
Grave
Gravissima
12 (17,65)
31 (45,59)
15 (22,06)
10 (14,70)
7 (29,17)
10 (41,67)
5 (20,83)
2 (8,33)
2 (8,33)
8 (33,33)
10 (41,67)
4 (16,67)
Provenienza, n (%)
Residenza 24h/24
Centro diurno
Famiglia
52 (76,47)
14 (20,59)
2 (2,94)
18 (75)
6 (25)
0
17 (70,83)
7 (29,17)
0
Caratteristiche di background del campione
Età
Media
DS
DI: disabilità intellettiva; DP: disturbo psichiatrico; DN: disturbo neurologico.
14
Relazione tra disturbi psichiatrici e funzionamento adattivo in persone con disabilità intellettiva
Tabella II.
Analisi statistiche. Statistical analysis.
DP vs. SDP
Sottoscale VABS
DN vs. SDN
t
df
Sig.
(2-tailed)
Mean
difference
t
df
Sig.
(2-tailed)
Mean
difference
Comunicazione
Ricezione
Espressione
Scrittura
-1,238
-1,331
-0,833
66
66
66
0,220
0,188
0,408
-3,867
-17,008
- 3,875
-0,042
0,693
-0,931
66
66
66
0,967
0,491
0,355
-0,133
8,943
-4,326
Abilità quotidiane
Personale
Domestico
Comunità
-2,522
-2,729
-1,546
66
66
66
0,014
0,008
0,127
-35,769
-10,758
-11,670
1,946
1,675
0,032
66
66
66
0,056
0,099
0,975
28,110
6,822
0,242
Socializzazione
Relazioni interpersonali
Gioco e tempo libero
Regole sociali
-0,646
0,579
0,547
66
66
66
0,521
0,564
0,586
-3,318
3,280
2,330
-0,207
-0,091
0,139
66
66
66
0,837
0,297
0,890
-1,064
-0,519
0,591
Abilità motorie
Grossolane
Fini
-0,815
-1,893
65
65
0,418
0,063
-4,938
-9,754
3,508
1,817
65
65
0,001
0,074
19,781
9,474
VABS: Vineland Adaptive Behaviour Scale; DP: disturbo psichiatrico; SDP: senza disturbo psichiatrico; DN: disturbo neurologico; SDN: senza
disturbo neurologico.
Come suddetto, tali risultati sembrano essere validi per
tutti i gradi di disabilità, dal lieve al gravissimo.
I limiti del nostro lavoro sono numerosi e consistenti. Il
principale è rappresentato dalla scarsa numerosità del
campione. Inoltre la maggioranza dei reclutati è rappresentata da abitanti in residenze per disabili, solo un quarto è costituito da persone che vivono con la famiglia di
origine, di cui la maggior parte consiste in frequentatori
di centri diurni. Il nostro campione non è rappresentativo
della popolazione con DI anche rispetto alla gravità prevalente di ritardo mentale, che è infatti moderata-grave,
ed al sesso, che è per circa 2/3 maschile.
Conclusioni
I risultati del nostro studio suggeriscono quanto la presenza di un DP possa impattare negativamente sulle abilità delle PcDI, soprattutto rispetto all’autonomia quotidiana. Tale impatto sembra addirittura superiore a quello
dei DN. I dati emersi sembrano anche suggerire che nelle
PcDI la formulazione rapida di una diagnosi psichiatrica
o di un orientamento diagnostico può essere molto utile
ad organizzare l’intervento sul funzionamento adattivo.
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Original article
Current scientific research on paedophilia: a review
Recenti sviluppi nella ricerca scientifica sulla pedofilia: una review
G.A. Capra, B. Forresi, E. Caffo
Dipartimento di Medicina Diagnostica, Clinica e di Sanità Pubblica, Università di Modena e Reggio Emilia
Summary
Objective
Child sexual abuse is a very common problem in most parts of the
world. Sexually abused children and adolescents are at risk for a
wide range of mental health disorders and adjustment difficulties
that can persist until adult life. Paedophilia is therefore a major
public health issue and a worldwide concern, considering that sex
offenders show a preference for children as their primary sexual
interest and that this kind of offence has a high rate of recidivism.
Although neglected for a long time, research on this topic has increased substantially during the last two decades. In an effort to
more clearly understand paedophilia, the aim of this investigation
is to conduct a review of recently published articles to identify developments and trends that might be useful in clinical practice with
adult patients, and contribute in preventing child sexual abuse.
Methods
The Pubmed database (from January 2010 to February 2012)
was queried entering “paedophilia” as keyword. Reports of original data or reviews published in scientific journals addressing
assessment, diagnosis and treatment of paedophilia were reviewed. Relevant studies are described herein.
Introduction
Child sexual abuse is very common and represents a serious problem in most parts of the world. According to the
Child Maltreatment 2010 report (USDHHS, 2011) 1, 9.2%
of children in the USA suffered from sexual abuse.
Sexually abused children and adolescents are an “at
risk” population for a wide range of mental health disorders and adjustment difficulties. Apart from physical
consequences, the experience of being abused is associated with the development of a wide range of psychiatric
disorders, and these associations persist in adolescence
and adulthood 2-5. A recent survey 6 in 28 world countries
showed that early adversities (e.g. child sexual abuse) are
the strongest predictors of mental disorders in developmental age as well as in adulthood.
Childhood sexual abuse may negatively affect not only
Results
Our search strategy generated 72 records. From these 72 abstracts, 41 met the inclusion criteria. These studies raised many
fundamental questions such as the validity of current diagnostic
criteria for paedophilia in DSM IV-TR, the proposal of new diagnostic criteria for the DSM-5, influenced by the increasing use
of Internet by paedophiles, and the importance of an accurate
diagnosis. Findings from neurobiological studies showing neural
correlates of paedophilic interest are presented, suggesting new
clinical perspectives and rising new questions concerning assessment and treatment.
Conclusions
The theme of paedophilia is currently the subject of important
research and productive debate. Recent studies on functional
brain response are introducing new perspectives in the assessment of this disorder, and have relevant implications in terms of
targeted treatments and prevention. Further studies are needed, with larger samples and more rigorous research methods.
Key words
Paedophilia • Child sexual abuse • Pedophiles • Child molesters
the risk of developing a mental disorder, but also course
of illness and treatment outcomes: a recent meta-analysis
suggested that childhood maltreatment and sexual abuses
are associated with an elevated risk of developing recurrent and persistent depressive episodes, and with a lack of
(or less) response to treatments 7.
In addition to the long term consequences for child victims,
it is known that recidivism rates for child sex offenders are
very high, in the range of 10% to 50% for paedophiles depending on the type of offence 8: men who sexually abuse
“boy-victims” are usually considered to be at highest risk
of reoffending, compared with heterosexual paedophiles 9.
Identification and treatment of paedophiles should be
therefore of primary concern, as paedophiles display a preference for children as sexual interest that seems to play an
important role in sexual recidivism of paedophiles 10.
It is difficult, however, to accurately estimate the preva-
Correspondence
Giulia A. Capra, Dipartimento di Medicina Diagnostica, Clinica e di Sanità Pubblica, Università di Modena e Reggio Emilia, via Del Pozzo 71,
41124 Modena, Italy • Tel. +39 059 4224211 • E-mail: giulia.capra@unimore.it
Journal of Psychopathology 2014;20:17-26
17
G.A. Capra et al.
lence of paedophilia, because only a few paedophiles
voluntarily seek treatment, and most of the available data
come from samples of individuals involved with the legal
system 8. According to recent estimates, when considering
different child sex offender typologies 11, the proportion of
child sex offenders who meet DSM-IV-TR criteria for paedophilia seem to range from 25% to 45% 10. Among the
few surveys conducted in the general population, a recent
German study involving a community sample of about
2000 men aged 40-79 12 found that a paedophilic pattern
of sexual arousal was reported in sexual fantasies by 9.5%
of participants and in real-life sociosexual behaviour by
3.8%. Another study 13 found a greater sexual arousal to
children than to adults in child pornography offenders if
compared with sex offenders against children, sex offenders against adults and general sexology patients.
After a period of substantial neglect, in recent years the
international scientific community has been interested in
this phenomenon and several studies have been conducted, highlighting the need for an accurate definition of
paedophilia, which has several implications for science,
clinical practice and public policy. Interesting studies
have also been conducted on the effectiveness of treatment protocols for child sex offenders.
In an effort to more clearly understand paedophilia, mental health needs of paedophiles and treatment options, the
aim of this investigation is to identify research developments that might be useful in clinical practice with adult
patients and therefore contribute to child protection.
Methods
The aim of this study is to provide an up-to-date review
of scientific articles concerning paedophilia and paedophiles, published in the last two years. We systematically
reviewed the literature, using MEDLINE/Pubmed database, with the term “paedophilia” as keyword.
We included studies that (i) were published online between January 2010 and February 2012, (ii) included original data or reviews and (iii) were concerned with assessment and/or diagnosis and/or treatment of paedophilia.
As a consequence, we excluded publications that concerned child sexual offenders who were not recognized
as paedophiles. After the search was completed (72 articles), we selected relevant abstracts, according to the
inclusion criteria specified above. A total of 41 articles
were suitable for this review. The most relevant articles
were analyzed and described herein.
DSM-5 and current debate on the diagnosis
of paedophilia
Most of the recent literature about paedophilia addresses
diagnostic issues. Being able to identify, among child
18
molesters, those individuals who present specific characteristics (i.e. exclusive sexual interest for children, sexual
fantasies about children emerging in adolescence) and
who may therefore benefit from targeted treatment 14 15 is
of particular importance.
At the present time, according to the DSM-IV-TR 16, in
order to diagnose paedophilia it is necessary that, over
a period of at least 6 months, the person presents recurrent, intense sexually arousing fantasies, sexual urges, or
behaviours involving sexual activity with a prepubescent
child or children (criterion A); that the person has acted
on these urges, or the sexual urges or fantasies cause
marked distress or interpersonal difficulty (criterion B);
that the person is at least age 16 years and at least 5 years
older than the child or children involved (criterion C).
Several authors are now debating about the diagnosis of
paedophilia and are concerned about the appropriateness of it, both in terms of its fitting with the current idea
of mental disorder as presented in the DSM, and in terms
of its usefulness for clinical purposes.
The DSM-IV classification system for paedophilia has
been often criticized as unsatisfactory on logical or conceptual grounds 17, and the diagnosis of paedophilia
has been modified in every new edition of the DSM. In
particular, these changes have been related to the role
played by deviant behaviours, distress and impairment of
the subject 18 and are highly suggestive of the ambiguity
embedded in this phenomenon.
According to Malòn 18, diagnosis of paedophilia as it is formulated in DSM-IV-TR presents two important problems:
1) it is possible, for one person, to be a paedophile (because of the sexual interest in prepubescent children) and
at the same time not to be a paedophile (in a diagnostic
sense), if the person does not act and feel neither distress
nor impairment; 2) apparently it would be possible to act
as a paedophile, and be thus diagnosed, even if one does
not have paedophilic feelings requested by criterion A.
According to Blanchard’s report on paedophilia submitted to the Sexual and Gender Identity Disorders Work
Group 17, in the DSM-IV-TR a history of sexual acts involving children is a sufficient condition for diagnosing
paedophilia because it would satisfy both criterion A
(signs and symptoms) and criterion B (distress and impairment). Repeated sexual acts involving children appear indispensable as a diagnostic sign of paedophilia,
due to the general unavailability of phallometric testing
and self-reporting in paedophiles. However, this does not
take account of those individuals who engage children
sexually without an exclusive erotic preference for them,
or those who have fantasies or urges towards children
but do not act on them, or those not distressed over the
urges or fantasies. The existence of such individuals poses
a problem, respectively, for the signs/symptoms criterion
and for the distress/impairment criterion.
Current scientific research on paedophilia
To overcome this problem, Blanchard has proposed to
introduce the distinction between paraphilias (as a condition, when only criterion A is met) and paraphilic disorders (when both criteria A and B are fulfilled) in the
DSM-5, and this proposal is currently under debate. The
addition of the word “disorder” to the condition is meant
as a reminder that people who meet criterion A but not
criterion B can still be designated as paedophiles, for purposes such as research, even if they do not act on their
deviant sexual fantasies or are not impaired by them.
Another criticism towards the traditional definition of
paedophilia in the DSM-IV-TR is that of its exclusive reference to prepubescent children. The existence of people
showing an erotic interest towards pubescent (from 1112 to 14-15 years old) rather than prepubescent children
(0-11 years old) seems to be ignored. For this reason,
Blanchard has proposed to introduce the specification of
Hebephilic Type in the diagnostic criteria proposed for
the DSM-5, underlining the need to recognize not only patients attracted to prepubescent children, but also
those attracted to children who entered puberty but are
still physically immature.
Moreover, the DSM-IV-TR definition of “recurrent and intense” sexual features seems to lack clarity and to be open
to clinical interpretation. It also seems difficult for a clinician to diagnose a sexual fixation towards children for six
months, as required in criterion A, as many paedophiles
dissimulate the real object of their sexual impulse 19, especially to avoid legal and interpersonal consequences.
DSM-5 criteria for the Pedophilic Disorder (APA, 2012)
could be reformulated as follows*:
a. over a period of at least 6 months, an equal or greater
sexual arousal from prepubescent or early pubescent
children than from physically mature persons, as manifested by fantasies, urges or behaviours;
b. the individual has acted on these sexual urges, or the
sexual urges or fantasies cause marked distress or impairment in social, occupational, or other important
areas of functioning;
c. the individual must be at least 18 years of age and at
least 5 years older than the children in Criterion A.
Specify type:
Classic Type: Sexually Attracted to Prepubescent Children (Tanner Stage 1)
Hebephilic Type: Sexually Attracted to Early Pubescent
Children (Tanner Stages 2-3)
Paedohebephilic Type: Sexually Attracted to Both
Retrieved July, 9, 2012, from http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=186#
*
Specify type:
Sexually Attracted to Males
Sexually Attracted to Females
Sexually Attracted to Both
Specify if:
In a Controlled Environment
In Remission (No Distress, Impairment, or Recurring Behaviour for Five Years and in an Uncontrolled Environment)
According to the Rationale* for changing the proposed
diagnostic criteria, the new formulation would have several advantages. Firstly, the new criterion A “emphasizes
that the diagnosis does not apply to individuals who experience or manifest any detectable sexual response to
children but rather to individuals who respond as strongly
or more strongly to children than they do to physically
mature persons”. Secondly, the specifications “in a Controlled environment” and “in Remission”, introduced
here for the first time, underline changes in the individual’s status: the first seems to indicate that “the propensity
of an individual to act on paraphilic urges may be more
difficult to assess objectively when the individual has no
opportunity to act on such urges”; the second “was written so as to indicate remission from a paraphilic disorder.
It is silent with regard to changes in the presence of the
paraphilic interest “per se”, and this is because of the lack
of consensus about whether a paraphilic interest can be
removed by therapy or disappear spontaneously.
Several authors have expressed concerns about these
new criteria for paedophilic disorder, fueling prolific debate around this topic.
Among others, First 20 is particularly negative towards the
general tendency of DSM Workgroups to broaden the diagnostic umbrella of their assigned categories; this is intended to increase diagnostic coverage, by reducing the
possibility of false negatives, but inevitably increases the
risk of false positives (i.e. erroneously giving a diagnostic
label to an individual for whom it is not justified). According to this author, the presence of false positives in diagnosing paedophilia is problematic not only because of
the consequent stigma, but also for the inappropriate and
indefinite consequences in terms of forensic implications.
Both in the current DSM-IV-TR and in the proposal for the
DSM-5, “behaviours” are considered as one of the defining elements of paedophilia (criterion A). With regards to
this issue, First 20 underlines that making behaviours and
sexual urges/fantasies equivalent, in terms of definition,
may lead to false positive diagnoses of paedophilia, given
that inappropriate sexual behaviour may be driven by different motivations and different mental states, other than
a paedophilic urge.
On the other hand, O’Donohue 21 emphasizes that, rather
than the risk of false positives, the problem in diagnosing
19
G.A. Capra et al.
paedophilia is with false negatives, because of the tendency to denial and minimization of paedophiles and the
doubtful reliability of self-reports in assessing fantasies.
According to Berlin 22, the new edition of the DSM has
the advantage of considering individuals with low sexual
urges (not only intense, therefore) towards children as
qualified for a diagnosis of paedophilia: the expression
“intense” referred to sexual arousal has been removed
from the new criteria proposed.
Concerning the proposal to introduce the diagnosis of hebephilia, there are different opinions. O’Donohue 21 considers
the differentiation between paedophilia and hebephilia to
be a useful and informative distinction; on the other hand,
Green 23 criticizes it, considering it as founded on moral
standards and with little scientific credibility, arguing that
the age of legal consent to have sex is 14 in several European countries (Italy included) and that a sexual attraction
for 14-year-olds cannot be viewed as a mental disorder.
Regarding this topic, we observe that the specification of
Hebephilic Type has been introduced in the new formulation but, “in order to emphasize that pedophilic disorder is
defined by psychological reactions to maturational features
of the external anatomy, and not by violations of age of
consent laws in specific jurisdictions in specific historical
periods”, in the specification type of the current DSM-5
proposal it is indicated if sexually attracted to prepubescent
or early pubescent children, without specifying the age.
One of the most relevant matters of contention among
the other proposals for DSM-5 concerned the inclusion of
child pornography into diagnostic criteria for paedophilic
disorder, as it is considered an indicator of sexual orientation towards children 17 24. If the Sexual and Gender
Identity Disorders Work Group initially considered adding the use of child pornography to criterion B**, in the
current proposal the “use of pornography depicting children” is no longer present. According to First 25, this inclusion would have been in direct conflict with the newly
proposed distinction between Paraphilia and Paraphilic
Disorder. He suggested that the use of child pornography
would be better placed within criterion A, as an example
of behavioural manifestation of paedophilia.
Other interesting suggestions came from Seto 26. According to his point of view, paedophilia may be construed as
a male sexual orientation with regard to age, rather than
with regard to gender (as, for example, hetero- or homosexuality), and not as a choice of the individual or some-
The initially proposed Criterion B stated: “The person is distressed or impaired by such arousal, or the person has sought
sexual stimulation, on separate occasions, from three or more
pubescent or younger children (two if both are prepubescent),
or has used child pornography for a period of 6 months or longer” (as cited in O’Donohue 21, p. 587).
**
20
thing that can be learned. This hypothesis – admitting
the existence of a condition defined in terms of a sexual
orientation not necessarily accompanied by behavioural
manifestations – fits with the proposal of the DSM-5 to
distinguish paedophilia (only criterion A) from paedophilic disorder (both A and B); furthermore, it adds to the
discussion about people who may recognize that they are
attracted by children (self-identified paedophiles), but do
not commit any criminal action.
It is evident that this conceptualization of paedophilia
has several implications for scientific research about its
aetiology, as well as for clinical practice (bringing new
hypotheses about assessment, prognosis and treatment)
and for public policy, influencing social perception of
this phenomenon and law. However, although the author
clearly emphasizes that he is not equating gender and age
orientation, it is important to note that this proposal may
be seen as a justification by those groups who excuse
paedophilia (i.e. Boy Chat), or as a sort of recognition of
its legitimacy, with reference to the anti-discrimination
policy concerning sexual gender orientation.
In addition to the debate concerning the DSM-5 criteria,
there is a more general question related to difficulties in
the assessment of sexual interests towards children. An interesting study conducted by Wilson et al. 27 – in which
130 child sexual abusers were diagnosed using different
methods (phallometric testing, clinical interview with application of DSM-IV-TR criteria, Rapid Risk Assessment of
Sexual Reoffending [RRASOR] scores and an experienced
clinician’s judgment) – suggests that there is a very low level of agreement (concurrent validity) between these different diagnostic tools, with a consequent limited reliability
of the diagnosis made. Phallometric testing is widely considered the best psychophysiological procedure for assessing erotic preferences in men. Recently, a study by Lykins
et al. 28 on the phallometric test, found a good test-retest
correlation. However, this technique has been criticized
for its intrusiveness and limited reliability 29.
Other studies recently investigated alternative methods
to assess deviant sexual interests, with promising results.
Sexual arousal and gaze behaviour dynamics are used
to characterize deviant sexual interests in male subjects.
Renaud et al. 30 investigated eye movements in individuals exposed to virtual characters showing relevant sexual
features. They found significant differences between paedophiles and non-deviant subjects when critical information was processed. Therefore, it seems that this measure
can be used to characterize deviant sexual interests in
male subjects.
Mokros et al. 31 assessed paedophilic sexual interest by using an attentional Choice Reaction Time (CRT) task, which
is an experimental information-processing paradigm based
on an interference effect in visual attention. The task requires identification of the position of a dot superimposed
Current scientific research on paedophilia
on a picture of a person. They found that paedophiles took
longer to respond to pictures of children rather than to pictures of adults, showing a cognitive interference effect. This
result suggests the possibility to use the delay of response
time for diagnostic purposes.
Functional brain response patterns to sexual stimuli, as
analyzed in functional magnetic resonance imaging (fMRI) studies 29 32 presented in the next section, may be also
a viable option for future diagnostic procedures regarding
paedophilia, allowing detecting paedophilic orientation
before it is being acted out. Even brain disorders may release a predisposition to sexual attraction for children 33.
Understanding this connection could allow differentiating among different subtypes of paedophiles.
Recent findings from neurobiological studies
Although human eroticism is extremely complex, the
most frequently used test for detecting paedophiles is
represented by phallometric or plethismographic procedures. Erotic pictures involving children are presented to
adult males and volumetric changes in penile blood are
measured and associated with different levels of sexual
responses. In addition to these methods, sexual orientation is also assessed through self-report or reaction-time.
Recently, neuroanatomical and biological correlates of
sexual orientation have been identified 34, as it is evidenced by recent articles concerning the aetiology of
paedophilia.
Neuroscientific studies have found structural and functional differences in brain areas related to sex and suggest the existence of neurobiological correlates of paedophilia.
Some recent studies assessed neurocognition, and specifically executive functioning, in child molesters and
paedophiles, in order to identify possible neuropsychological abnormalities that may reflect specific structural
and/or functional brain alterations.
Two areas of investigation can be identified within the
reviewed articles: on one hand, several studies analyzed
executive functioning using neuropsychological tasks
to determine whether paedophilic and non-paedophilic
child molesters differ in some way; on the other hand,
other studies investigated neural correlates of paedophilia, i.e. specific structural and/or functional anomalies in
the brain of paedophiles compared to healthy controls,
by using neuroimaging techniques.
Regarding the cognitive profile, in a study conducted by
Cohen et al. 35 51 subjects with paedophilia, 53 subjects
with opiate addiction and 84 healthy controls were compared using neuropsychological tests assessing executive
functions. Subjects with paedophilia differed significantly
from those with opiate addiction on several tests, with
longer latency to response on the Matching Familiar
Figure Test, a measure of reflection-impulsivity (Kagan,
1966), and fewer completed mazes but also fewer errors
on Porteus Mazes, a nonverbal test of intelligence made
of a set of paper forms in which the subject is required to
trace a path through a drawn maze of varying complexity
(Porteus, 1955). Thus, while both subjects with paedophilia and those with opiate addiction show executive
dysfunctions compared with healthy controls, the nature
of those dysfunctions seems to be different between the
two groups, with paedophilic subjects being less prone to
cognitive impulsivity.
Kruger and Schiffer 36 examined neurocognitive performances and personality profiles in a group of paedophiles and found that, compared to healthy controls, they
showed lower intelligence, weaker performances in information processing, high scores for psychopathy and
paranoia, and signs of sexual obsessiveness and sexual
dysfunction. In contrast to previous reports, these authors
emphasize that some of these alterations could have
been, at least partly, explained by other factors than paedophilia, such as education level or age.
In another study by Eastvold 37, paedophiles were compared to non-paedophile child molesters and exhibited
a more deliberate and planned response style, characterized by greater self-monitoring and better performance
accuracy. The lack of cognitive impairments in paedophiles is also confirmed by Schiffer and Vonlaufen 38, who
found that paedophilic child molesters exhibit fewer deficits in cognitive functioning than non-paedophilic child
molesters.
Coming to the studies focused on the neural correlates of
sexual interest among paedophiles, they seem to present
an atypical cerebral development: structural and functional brain deficits are present which appear to be correlated to their sexual orientation and behaviour.
Current neuroimaging research, for example, suggests
that structural and functional changes in paedophilia appear for the most part in brain regions involved in sexual
functions. A few studies, usually referring single cases of
patients with paedophilia, reported the activation in the
left calcarine fissure, left insula, anterior cingulated cortex and left cerebellar vermis 39 or in the right amygdala
and the adjacent parahippocampal gyrus 40 in response to
erotic pictures of children. The activation in these areas
decreased as a consequence of treatment with leuprorelin or leuprolide acetate, suggesting that anti-androgens
may modify brain response to visual erotic stimulation 39.
A fMRI study by Poeppl et al. 32 revealed that the neural
response in paedophiles exposed to images of naked children is comparable to that observed in non-paedophilic
males stimulated with pictures of naked adults. Group
differences were found in the cingulated gyrus and the
insular region, areas which seem to have an important
role in paedophilic sexual interest: stimulated with erotic
21
G.A. Capra et al.
pictures of children (the response was significantly reduced in case of stimuli representing adults) paedophiles
showed an increased haemodynamic response in brain
areas involved in the processing of visual sexual stimuli. These results seem to be confirmed by another fMRI
study in which Ponseti et al. 29 analyzed changes in the
blood oxygen level-dependent signals to child and adult
sexual stimuli, and found that paedophiles had a typical
response pattern (i.e. preference-specific brain activity
in areas which are known to be involved in processing
sexually arousing stimuli, such as the caudate nucleus,
cingulate cortex, insula, fusiform gyrus, temporal cortex,
occipital cortex, thalamus, amygdala, and cerebellum) to
sexual stimuli depicting children.
Taken together, these results suggest that functional brain
response patterns to sexual stimuli could be helpful to
predict sexual orientation and to identify paedophiles
with higher accuracy and in a less intrusive way than
phallometry.
Other studies suggest the concept that paedophilic interest may be associated with specific neurological dysfunctions. A study by Mendez and Shapira 33 on eight patients
showing sexual behaviours towards prepubescent children in mid- or late-life, showed that paedophilic behaviour may be the result of frontal lobe executive deficits or
subcortical lesions. In particular, these authors observed
a lack of inhibition as a consequence of frontal-lobe area
deficits, sexual worries deriving from a right temporallobe deficits disease and hypersexuality provoked by subcortical disease in non-motor basal ganglia, hypothalamus or septal nuclei.
A recent study by Italian researchers raises a new hypothesis on the biological correlates of paedophilia, revealing a connection between late-onset heterosexual paedophilia and fronto-temporal dementia, in association
with a genetic mutation. Rainero et al. 41 report the case
of a 49-year-old patient who started to manifest sexual
arousal and urges towards his 9-year-old daughter, never
being sexually inappropriate before, and later developed
fronto-temporal dementia. In this study, these authors discovered an alteration of the progranulin (PGRN) gene, a
growth factor implicated, among the other processes, in
the development of sexual dimorphic behaviour.
The association of a mutated gene to deviant sexual behaviour is interesting in terms of new horizons and new
perspectives of research: for the first time, a genetic
anomaly could be correlated with a sexual dysfunction.
Although the reviewed literature focuses on neurobiological aspects to explain the aetiology of paedophilia,
it is important to note that there are also psychological
theories suggesting different ways leading to child molestation. For example, Marshall and Barbaree 42 proposed
an integrated theory of the aetiology of sexual offending, proposing that child sexual abuse occurs as a con22
sequence of different interacting factors, both distal and
proximal (e.g. poor parenting, inconsistent discipline,
physical abuse). More recently, Ward and Siegert’s 43
model of child abuse suggested the existence of four distinct psychological mechanisms whose interaction could
result in sexual offenses against children: intimacy and
social skills deficits, deviant sexual patterns, emotional
and cognitive distortions.
Online paedophiles: a new group of sex
offenders?
With the advent of the Internet, new means of communication have emerged. Internet provides ideal cover for online
sexual predators searching for potential victims. In fact, the
anonymity of cyberspace makes it difficult to understand if
an individual who enters in contact with a young person is
really what he/she says to be or not. As a consequence, the
Net can be the ideal space for paedophiles to get in contact with children as well as with other paedophiles. With
regard to this issue, Holt et al. 44 have explored how Internet can be used to promote attitudes and moral justifications for paedophiles, supporting and encouraging sexual
exchanges with children and adolescents in virtual as well
as in real settings.
At present, there is a significant debate as to whether online offenders are a distinct group of sex offenders or if
they are typical sex offenders just using new technologies 45. One point of view 46 is to consider online paedophilia (or, more in general, online sexual offending) as
simply what happens when traditional paedophiles have
access to the Internet: individuals who in the past would
have looked for child pornography in magazines, now
access it online. Similarly, chats and social networks allow contacting children in an easier way than before.
In contrast, some authors consider online paedophiles as
a new type of sex offenders with different deviant sexual
behaviours. An exploratory study by Briggs et al. on 51
participants convicted of an Internet-initiated sex offense
against adolescents 47, for example, suggests that Internet
chat room sex offenders may constitute a separate group,
characterized by less severe criminogenic factors than other sex offenders (i.e. rapists, offline child molesters): they
tend to avoid relationships in the real world, spend a lot of
time in online chat rooms looking for social/sexual contacts and engage in other sexually compulsive behaviours.
This new group, moreover, could be divided into two subgroups: a contact-driven group motivated to engage in offline sexual behaviours with adolescents, and a fantasydriven group motivated to engage adolescents in online
virtual sex, without an explicit request to meet offline.
Some recent research 48 49 has analyzed the profile of online sex offenders, individuating recurrent characteristics
that differentiate them from offline sex offenders: they are
Current scientific research on paedophilia
more likely to be Caucasian males, coming from different socio-economic contexts, and younger than offline
offenders. Compared to offline sex offenders, they seem
to have greater self-control (which is consistent with the
neuroscientific studies presented in the previous section)
and greater empathy for the victim, showing more psychological barriers to acting on their deviant interests.
However, as shown by Wolak et al. 48, online offenders
seem to have greater sexual deviancy, having images depicting children younger than 3 years, and having child
pornography videos – in particular, p2p users are more
likely to have larger and more extreme images (e.g.,
younger victims, sexual violence).
How many online paedophiles already have a history of
offline sexual offenses? What is the probability that an
online paedophile will commit a contact sexual offense
in the future? It is particularly important to understand
the likelihood that online paedophiles using and sharing
child pornography will commit sexual offenses involving
offline contacts with a victim. A first meta-analysis reported by Seto et al., which examined the contact sexual
offense histories of online offenders 50, shows that only
a small subgroup (approximately 1 in 8) of online sex
offenders had an official record for contact sexual offending. However, this result can be due to a limitation: in a
subset of six samples with self-report data, in fact, about
half of the online offenders admitted to have committed a
contact sexual offense in the past 50.
A second meta-analysis by the same authors, which examined the recidivism rates from follow-up studies of
online offenders 50, reveals that only 4.6% of online offenders committed a new sexual offense of some kind
during the follow-up period, with new child pornography
offenses being more likely than contact offenses. These
results would suggest the existence of a distinct subgroup
of “online-only” sex offenders who pose a relatively low
risk of committing contact sexual offenses in the future
and therefore with low rates of sexual recidivism.
Although this subgroup appears to be less dangerous,
given the absence of sexual contact with children, it must
however be kept in mind that the request for child pornography is the primary requirement of a large market
that provides images of sexually abused children and adolescents: therefore, even if online sex offenders do not
directly abuse children, they induce others to perpetrate
abuses. The risk deriving from this population must not be
underestimated.
At present, however, it is not clear whether the possession of child pornography leads to the identification of
individuals with paedophilic tendencies who otherwise
would not commit sexual acts with minors. More research is needed as at present it is still not clear whether
we should assess and treat online offenders the same as
other sexual offenders.
Evidence based treatment and new directions
Since the 1970’s, paedophiles have been usually treated
with psychodynamic therapy, cognitive-behavioural therapy and medical treatment, which are focused on the reduction of sexual interest and on relapse prevention (i.e.
further offenses against children), rather than modifying
their sexual orientation towards children. As suggested
by Seto 51, and supported by recent neurodevelopmental
studies, “there is no evidence that paedophilia can be
changed”.
While the effectiveness of psychodynamic therapies has
not been demonstrated 52 53, cognitive-behavioural therapy has been shown to significantly reduce sexual recidivism 54-56. These interventions are focused on the paedophile’s sexual preference and are aimed at changing both
sexual responses and cognitive distortions related to this
kind of sexual violence. Relapse prevention interventions
that target attitudes, beliefs and behaviours related to sexual offenses against children are widely used 57 and very
well known in their effectiveness 58.
With regard to promising research in the field of psychotherapy, Renaud et al. 59 proposed to use real-time
functional magnetic imaging (rt-fMRI) brain computer interface (BCI) as a new treatment for paedophilia. Neurofeedback mediated by interactive virtual stimuli is presented as the key process in this new kind of intervention.
Real-time fMRI can be used to feedback signal changes
from the brain to participants such that they can train to
modulate activation levels in specific brain areas when
facing virtual characters depicting sexual stimuli.
Many recently published articles are focused on medications that lower sexual impulse in paedophiles by interfering with or by suppressing the activity of testosterone 60 61.
A very recent pilot study by Moulier et al. 39 suggests that
leuprolelin (a GnRH agonist) may decrease activity in
regions known to mediate the perceptual, motivational
and affective responses to visual sexual stimuli, such as
the left calcarine fissure, left insula, anterior cingulated
cortex and left cerebellar vermis. These areas were active
in a paedophilic patient’s brain in response to pictures
representing children, but after 5-months of leuprolin
therapy this activation had disappeared. Neither such
activations nor decreases occurred in the age-matched
healthy control assessed 39.
In the so-called “chemical castration”, medroxyprogesterone acetate, leuprolide acetate, cyproterone acetate,
luteinizing hormone-releasing hormone and gonadotropin-releasing hormone agonists are used to suppress testosterone levels 10. The effects of anti-androgen-lowering
therapy in paraphilic patients, however, are uncertain
and the effects of testosterone-decreasing drugs on brain
mechanism and sexual recidivism are poorly known. As
far as we know, chemical castration is less effective in
23
G.A. Capra et al.
removing sexual impulses when offending is not driven
by libido, but rather is the expression of anger, aggression
and violence. Therefore, it is often used in conjunction
with cognitive behavioural therapies. Moreover, it must
be considered that paedophilic patients present alterations not only in testosterone levels but also in other endocrinological and neurochemical parameters, such as
hypothalamic-pituitary functions, prolactin, dopaminergic or serotoninergic levels 61.
More generally, all the reviewed articles have reinforced
that treatment of paedophilia is a relevant issue, because
of its implications not only for personal reasons but also
for social security and child protection. It is worth noting
that, although paedophilia is recognized as a mental disorder, paedophiles are usually punished without receiving any treatment.
In addition, as noted by Seto 26, treatment and support
services for paedophiles, where provided, are mostly
available to individuals who have already committed
sexual abuse against children and have been detected by
the legal system. This raises an important question: how
to treat those who have never acted on their paedophilic
fantasies, but report an attraction towards children? In order to effectively prevent child sexual abuse, treatment
should not only be administered to those who have already committed an abuse, but also to those who are at
risk for offending.
Other questions concern on one hand the need to develop different treatment options for different targets, and
on the other the prevention of paedophilia. Concerning
the former, different treatments should be developed for
child molesters (whose sexual preference is not exclusive
for children) and for subjects who show a paedophile
orientation. Similarly, it might be useful to have different
approaches to sexually motivated paedophiles and paedophiles with antisociality or impulsivity 62.
Regarding prevention, few resources are currently available to help-seeking, self-identified paedophiles to detect and treat them before they commit abuse. Potential
offenders (i.e. individuals who have not yet abused any
children but may be at risk of doing so, because they
recognize they feel attracted by them) and Dunkelfeld
offenders (i.e. undetected child molesters with a sexual
attraction for children, not officially known and therefore
not persecuted by the law) may indeed represent the ideal
target group for primary prevention of child sexual abuse,
even if at present it is difficult to individuate them 63. In
this regard, the Dunkelfeld Project in Germany is a very
interesting example of a nationwide media campaign
to inform potential child abusers of treatment solutions
specifically addressed to them. Schaefer et al. 63 used a
telephone screening procedure to conduct research with
these groups, finding that many participants reported recurrent sexual fantasies involving children, as well as re24
lated distress, and that more than half feared they would
sexually abuse a child.
Conclusions
In the last years, an increasing number of research related
to paedophiles and paedophilia has been published in
international journals. Currently, there is an interesting
debate concerning the diagnosis of paedophilia, as new
criteria have been proposed for the DSM-5. Several authors have expressed their view on proposals, but professional opinions are still divided. Progresses in neuroscience allow clinicians to identify neural correlates of paedophilia and, possibly, new forms of assessment that are
not exclusively based on behavioural indicators. These
neurobiological findings, supported by further studies,
could help in early identification of deviant sexual interests. Recent studies on single cases have documented an
association between anti-androgen therapies and brain
response, opening new possibilities for treatment. However, even in this case further studies with larger samples
are needed.
Furthermore, there has been increasing interest in exploring the link between the Internet and paedophilia.
There is an interesting debate about online paedophiles,
and whether they are a distinct group of sex offenders or
typical sex offenders. Recent studies have suggested that
online offenders seem to constitute a specific group that
is different from other offenders. It also seems that this
specific subculture of paedophiles is not at great risk of
committing offline child sexual abuse, but further studies
are needed to confirm this hypothesis.
While presenting these findings, we must consider that
research on paedophilia is also affected by many limits:
the majority of studies are based on biased samples of
persons who have committed criminal offenses and have
been detected. The majority of paedophiles are men, and
most studies are based on male participants 26.
Given the highest risk of reoffending in individuals who
sexually abuse male victims 9, this information is particularly important while considering that more than 80% of
clergy abuse victims are males 64: further studies and targeted efforts are warranted to understand and treat this
specific subgroup of paedophiles, which may be qualitatively different from the general sex offender population.
Research concerning relapse prevention should be enhanced, particularly focusing on specific factors that may
influence recidivism.
Little is known about those individuals who feel paedophilic interest, but who do not act on it and thus are
not involved in the criminal justice system. In fact, as for
other paraphilias, most people presenting paedophilia
probably do not seek treatment unless they are in legal
trouble. Paedophilia is not common in clinical contexts,
Current scientific research on paedophilia
because paedophiles tend to remain hidden, and more
information is needed about those with paedophilic interests per se. For these reasons, several findings reviewed
herein derive from single-case reports, and further studies
with wider samples are needed. Additional resources are
requested to facilitate the access to treatment for paedophiles independently of the juridical course, as well as
additional efforts for early detection of potential offenders
and develop targeted interventions to effectively prevent
child sexual abuse.
Seto MC, Cantor JM, Blanchard R. Child pornography offenses are a valid diagnostic indicator of paedophilia. J Abnorm Psychol 2006;115:610-5.
13
Dèttore D, Fuligni C. L’abuso sessuale sui minori. Valutazione e terapia delle vittime e dei responsabili. Seconda edizione. Milano: McGraw-Hill 2008.
14
Marshall WL. Paedophilia. Psychopathology and theory. In:
Laws DR, O’Donohue W, editors. Sexual deviance. Theory,
Assessment and Treatment. New York: The Guilford Press
1997, pp. 152-74.
15
American Psychiatric Association. Diagnostic and Statistical
Manual of Mental Disorders, Fourth Edition, Text Revision
(DSM-IV-TR). Washington, DC: American Psychiatric Association 2000.
16
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64
Original article
From psychopathology to neurocircuits: what we can learn from DBS?
The case of obsessive-compulsive disorder
Dalla psicopatologia ai neurocircuiti: cosa possiamo apprendere dal DBS?
Il caso del disturbo ossessivo-compulsivo
S. Pallanti1,2,3 , G. Grassi2, V. Ramella Cravaro2, W.K. Goodman1
1 3 Department of Psychiatry, Ichan School of Medicine, New York, USA; 2 Department of Psychiatry, University of Florence, Italy;
Institute of Neuroscience, Florence, Italy
Summary
Objectives
The aim of this review is to provide a brief summary of the existing data on the safety and effectiveness of deep brain stimulation
(DBS) for treatment-resistant and treatment-refractory obsessive-compulsive disorder (OCD). Another purpose is to discuss
the neurobiological mechanisms of DBS and their implications
for the understanding of OCD neurobiology and its link to OCD
psychopathology. In particular, we will focus on DBS of the nucleus accumbens because of the involvement of this area in the
reward system, which seems to be impaired in OCD patients.
Finally, we will provide a new psychopathological conceptualization of OCD.
Methods
Extensive review of the DBS literature for OCD patients was performed on PubMed.
Results
According to many neuroimaging studies, the neural circuit that
seems to be most involved in OCD is the cortico-striatum-thalamus-cortical circuit (CSTC). Therefore, to date, five different
components of this circuit have been tested as targets in DBS
of OCD and show different efficacy: anterior limb of the internal capsule (ALIC), nucleus accumbens (Nacc), ventral capsule/
ventral striatum (VC/VS), subthalamic nucleus (STN) and the inferior thalamic peduncle (ITP).
Conclusions
DBS is a promising tool in the treatment of refractory OCD patients. The existing data show that the nucleus accumbens and
the anterior limb of the internal capsule are the most promising
targets for this treatment. Furthermore, DBS has shown new and
interesting perspectives in the discovery of the neurobiological
underpinnings of OCD. These new insights can provide a new
psychopathological conceptualization of OCD, reconsidering
this disorder as a primary anxiety disorder, rapidly moving as a
behavioural addiction. However, further studies are needed to
better clarify the long-term efficacy and safety of the procedure,
and to better characterize the ideal patients that might have a
good response to DBS.
Key words
Deep brain stimulation • Obsessive-compulsive disorder • Nucleus accumbens
Introduction
DBS in psychiatry: safety and uses
Herein, the authors provide a brief summary of the existing data on the safety and effectiveness of deep brain
stimulation (DBS) for treatment-resistant and treatmentrefractory obsessive-compulsive disorder (OCD). Another aim is to discuss the neurobiological mechanisms
of DBS and their implications for the understanding of
OCD neurobiology and its link to OCD psychopathology. In particular, we will focus on DBS of the nucleus
accumbens because of the involvement of this area in
the reward system, which seems to be impaired in OCD
patients. Finally, we will provide a new psychopathological conceptualization of OCD.
DBS is a relatively new neurosurgical procedure, and its
first use dates to 1987 for the treatment of Parkinson disease 1. The use of DBS in the field of psychiatry was serendipitously borrowed from neurology, where DBS is an approved therapy for movement disorders (essential tremor
and Parkinson’s disease). The observation of non-motor effects in Parkinson’s disease when stimulating specific brain
targets led neurosurgeons and psychiatrists to hypothesize
that DBS could also be an interesting therapeutic option
for psychiatric disorders 2. To date, the psychiatric conditions for which DBS is considered a possible therapeutic,
though still experimental, option are: refractory obsessive-
Correspondence
Stefano Pallanti, Department of Psychiatry, University of Florence, via delle Gore 2H, 50100 Florence, Italy • Tel. +39 055587889 • Fax +39
055581051 • E-mail: stefanopallanti@yahoo.it
Journal of Psychopathology 2014;20:27-32
27
S. Pallanti et al.
compulsive, major depressive disorder, addiction and
Gilles de la Tourette syndrome.
DBS is a kind of brain pacemaker in which specific areas
are stimulated with the purpose of achieving a reduction
in symptoms. A DBS device consists of four main components: uni/bilateral electrodes, stereotactically placed
at specific target of stimulation; an anchoring device that
ensures the electrodes remain in the exact position in
which they were placed; a battery powered pulse generator placed subcutaneously in the chest; a subcutaneous
system of connection between the pulse generator and
the electrodes, consisting in thin cables 3. Although it is
an invasive technique, DBS has two main advantages:
reversibility and modifiability. Hence, if the stimulation
proves to be ineffective or even harmful, the device can
be removed to bring brain areas back to the status quo.
Furthermore, if the device settings (in terms of frequency,
pulse width, amplitude, and duration) are not able to ensure the desired goals, it can be modified to optimize the
therapy 4. Another important positive aspect is that the
clinic effect is obtained through functional impairment,
in contrast with ablative procedures where the anatomical damage is permanent. In addition, the patient can
immediately turn off the device if excessive adverse effects occur. In this regard, DBS is associated with several
types of adverse effects. These can be divided into three
main categories: 1) surgery-related adverse events. The
most dangerous complication is undoubtedly intra-operative haemorrhage, the incidence of which is around 2%
according to literature 5. Other frequent side effects are
post-operative, usually a transient state of confusion and
infections that rarely develop into meningitis/encephalitis 6; 2) device-related adverse events 7. The failure of the
device is a very rare event. The main problem is battery
depletion that requires periodic replacement with a new
battery through a small surgical intervention 3; 3) DBSrelated adverse effects (depending on site of implant and
on type of disorder).
Ethical issues
The use of DBS in OCD involves ethical issues because of
the high vulnerability of psychiatric patients. Neurosurgical psychiatric procedures are a very controversial topic.
“Psychosurgery” fell into disrepute due to the gruesome
use of earlier neurosurgical procedures, but DBS does
not stand in a continuous line with the old neurosurgery
techniques 2. The fear of modifications in mood and personality after neurosurgery, is an unexpected positive side
effect in DBS 8-10. At the moment, ethical guidelines for
application of DBS, as stated during an important consensus conference 11, include: multidisciplinary teams,
at minimum composed by neurosurgeons, psychiatrists,
neurologists and psychologists; the recruitment of adult
28
patients only; information from the patient’s clinicians to
establish possible comorbidities; documentation of the
failure of adequate therapeutic courses; evaluation of the
patient’s social condition and assessment of the patient’s
capacity to consent after providing all the information
about risks and benefits of DBS. Finally, another important ethical issue concerns publication of clinical results
to help patients and public opinion to separate solid data
from hype 12.
From psychopathology to research domain
criteria
In medicine, the transition from a diagnosis based on
signs and symptoms to one based on objective data
happened decades ago, whereas in psychiatry this is
a breakthrough yet to be achieved. By comparison, a
heart attack could be diagnosed simply on the basis of
chest pain. The problem is that the same symptom can
be caused by many different conditions, and clinically
different disorders could have the same aetiology 13. Currently, the diagnosis of mental illnesses depends uniquely
on clinical observation according to the DSM-IV 14 and
ICD10 15, which describe all mental disorders and the criteria for each. These, despite being two valid systems of
classification, present many limits. One is that they are
categorical diagnostic systems. This means that there is
a marked separation both between the status of illness
and non-illness, and between different illnesses. This approach creates neutral territories between a disorder and
another that are identified by hybrid diagnoses such as
atypical or mixed forms. Another limit is that drugs do
not respect the boundaries of categorical classification
(e.g. antidepressants are used to treat both mood and
anxiety disorders) 16. Research has made great strides in
the last decades, but there are still many doubts about
the pathophysiology of mental disorders. Difficulty in understanding the complex neural circuits and mechanisms
underlying the main brain functions, the complexity of
genetic alterations and the limitations of animal experiments, have not yet permitted neuroscientific findings
that are sufficient to alter the current criteria of classification of psychiatric diseases. However, the time has come
to lay the groundwork for the incorporation of objective,
neurobiological data.
It is in this context that United States NIMH (National institute of Mental Health) introduced the Research Domain
Criteria (RDoC) project to “develop, for research purposes, new ways of classifying mental disorders based on
dimensions of observable behavior and neurobiological
measures” 17. This project has been organized as a two-dimensional matrix, with rows represented by domains and
columns represented by units of analysis 18. Five subsets
of domains have been identified, reflecting different con-
From psychopathology to neurocircuits: what we can learn from DBS? The case of obsessive-compulsive disorder
ceptual typologies of function: negative valence systems,
positive valence systems, cognitive systems, systems for
social processes and arousal/regulatory systems. On the
other hand, the units of analysis represent the toolkit used
to investigate the domains. Eight different typologies of
analysis have been proposed: genes, molecules, cells,
circuits, physiology, behavior and self-report paradigms.
The matrix-organization is very useful, because at the intersections between units of analysis and domains, there
cells are populated by the findings of all the research in
that particular field. This kind of organization aims to integrate all the existing studies and to highlight possible
areas/cells of intersection lacking in findings, in order to
boost research. The basic concept of RDoC is that psychiatric disorders result from neural circuits alterations, and
that these dysfunctions can/will be identified by current
or future tools of neuroscience. In practice, the project includes a series of workshops with the participation of experienced researchers, each focusing on a single domain.
These workshops started in November 2011 and were
completed in June 2012, leading to an initial framework
of the project. Nonetheless, it will take years to have an
accurate view for each domain, even with the help of
neuroscientific tools that are not yet in use. If RDoC succeeds, it may be that future versions of the DSM will take
RDoC findings into account, bringing a revolution in the
classification of mental illnesses.
In this view, neuromodulation procedures, such as DBS,
could represent important tools for understanding the neurodysfunctional circuits underpinning psychopathology.
DBS in the treatment of obsessive-compulsive
disorder
OCD is a very heterogeneous, chronic and disabling
disorder. The two distinctive symptoms are obsessions
(unwanted recurrent intrusive thoughts causing anxiety)
and compulsions (repetitive, ritualized behaviours put in
place to reduce the anxiety that obsessions evoke) 19. If
not treated, OCD leads to a significant distress both at
work and in social relationships. Currently, the first-line
treatment consists of serotonin reuptake inhibitors (SRIs)
and cognitive behavioural therapy (CBT). However, despite the best therapeutic approach, about 40-60% of
patients continue to experience serious OCD symptoms,
and 10% of these patients who do not respond to the second and third line treatments are classified as treatmentrefractory 20 21. Within this 10% of refractory patients, according to strict criteria of selection, a small subgroup is
chosen to undergo neurosurgical procedures, which can
be divided in two main categories: ablative procedures,
such as cingulotomy, capsulotomy, bilateral anterior limbic leucotomy and subcaudatus tractotomy, and neuromodulation procedures, such as transcranial magnetic
stimulation, vagus nerve stimulation, magnetic seizure
therapy and DBS1 22.
According to data from many neuroimaging studies, the
neural circuit that seems to be most involved in OCD
is the cortico-striatum-thalamus-cortical circuit (CSTC) 23.
Therefore, to date, five different components of this circuit have been tested as targets in DBS of OCD: anterior
limb of the internal capsule (ALIC), nucleus accumbens
(Nacc), ventral capsule/ventral striatum (VC/VS), subthalamic nucleus (STN) and the inferior thalamic peduncle
(ITP) 24 25.
Although the precise mechanism of action of DBS is unknown, several studies have found that stimulation decreases the hyperactivity of the CSTC circuit, leading to a
parallel decrease of symptoms 26. The anterior limb of the
internal capsule (ALIC) was the first brain area stimulated
by DBS in OCD 27. The rationale of this target is based on
the efficacy of anterior capsulotomies in refractory OCD
patients and on brain imaging studies that confirm ALIC
involvement in the impaired CSTC circuit 28. Important
studies on ALIC-DBS have been published by Nuttin et
al. 27 and Abelson et al. 10 with similar outcomes of about
50% of responders (responder definition: > 35% YaleBrown Obsessive-Compulsive Scale [Y-BOCS] reduction).
Ventral caudate/ventral striatum (VC/VS) is another possible target 8 29 30. VC/VS denomination refers to the junction
area between the ventral caudate and ventral striatum.
VC/VS was chosen as a target on the basis of the positive
outcomes of lesioning procedures in the same regions 31.
With the passing of time, the stimulation became more
posterior according to the observation of greater benefits 29. The reason for this is probably the greater compactness of the bundles interconnecting the cortex and
thalamus via the inferior thalamic pedunculus. In 2010,
Greenberg et al. published a combined long-term study
on 26 patients from four different centres, obtaining a response rate up to 60% 29. In the same year, a similar result
was obtained by Goodman et al. in a blinded staggeredonset study 30 32-34. It is important to point out that VC/VS
stimulation unexpectedly led to a decrease in depressive
symptoms, often in comorbidity with OCD. In fact, VC/
VS is a current target for major resistant depression 35.
The subthalamic nucleus (STN) is another DBS target. It
is also called Luy’s body and is part of the basal ganglia.
The serendipitous observation of non-motor effects in
Parkinson’s disease DBS is the main and historical reason
of the choice of this target. These effects were confirmed
by a multicentre controlled clinical trial 34. Another study
revealed an interesting effect due to STN stimulation in
Parkinson’s patients, namely punding, a stereotyped motor behaviour with important compulsive traits 36. Mallet
et al. published an important study where 12 of 16 patients resulted responders (but with a responder definition
of > 25% Y-BOCS decrease) 34. Another interesting target
29
S. Pallanti et al.
is the inferior thalamic peduncle (ITP), which links the
OFC to the thalamus and vice versa. However, only one
study has been carried out on this area (Jimenez et al.
2005) and 5 of 5 patients were responders 37.
Finally, one of the most promising targets is the nucleus
accumbens (Nacc) 9 32 38 39. Nacc forms the main part of
ventral striatum and plays a central role in the reward
system, which may be impaired in OCD 40 41. This is
the main reason to consider Nacc as a target. The main
study regarding Nacc-DBS was published by Denys et al.
(2010). This study consisted of three phases: the first was
an open 8-month treatment phase where 9 of 16 OCD
patients responded to treatment with a mean decrease
in the Y-BOCS score of 72%; the second was a doubleblind, sham-controlled phase with randomly assigned
2-week periods of active or sham stimulation, obtaining a
Y-BOCS score difference between the two groups of 25%;
the third was an open 12-month maintenance phase
study 20. Furthermore, the authors also observed the same
antidepressant effect reported in the ALIC stimulation 8-10.
Denys et al. specified the sequential order of symptom
remission: depressive symptoms within seconds, anxiety
symptoms within minutes, obsessions within days and
compulsions within weeks or months 9.
Predictors of response
Clinical endophenotypic and neuroimaging features may
represent predictors of the efficacy of DBS. An interesting recent study observed that intra-operatory stimulation induced
laughter predicts an improvement of OCD symptoms. The
reason is probably that ALIC and Nacc are important areas
involved in emotional processing and in the pleasure and
reward system 42 43. Another important predictor of response
is the subtype of OCD. In particular, DBS seems to be less
effective in patients with characteristics of perfectionism and
symmetries 9. Moreover, further studies suggest that the preDBS metabolic status, evaluated with FDG-PET, is directly
correlated with the efficacy of DBS 44 45.
DBS of the Nacc and reward dysfunction
in OCD: the link to behavioural addictions
The effectiveness of deep brain stimulation of the Nacc
in treatment-refractory OCD patients highlights the role
of reward system in the pathophysiology of OCD. In fact,
the reward system involves widespread neurocircuitry in
the brain. In particular, the mesolimbic dopamine system and its projections to the nucleus accumbens have
a central role in reward system 46. Interestingly, a recent
study demonstrated that OCD patients showed a dysfunctional reward system 40. Figee et al. studied reward
function in OCD patients with predominantly contamination fear and high-risk assessment using a monetary
30
incentive delay task and fMRI. In their study, Figee et al.
compared brain activity during reward anticipation and
receipt in OCD patients and healthy controls. OCD patients showed attenuated reward anticipation activity in
the nucleus accumbens compared with healthy controls;
brain activity during reward receipt was similar between
OCD patients and healthy controls. A hint toward more
dysfunctional reward processing was found in treatmentresistant OCD patients who subsequently were successfully treated with deep brain stimulation of the nucleus
accumbens. Furthermore, after DBS of the Nacc these
patients showed normalization of Nacc activation during
reward anticipation.
A clinical example of reward system dysfunction in OCD
patients may be represented by a recent study of the same
group, focusing on the most powerful natural rewarding
stimulus: sex 47. In this study, the authors compared subjective appreciation of sexuality and sexual functioning
between female OCD patients and healthy subjects. They
also controlled for the influence of medications or OCD
subtypes on sexual functioning and satisfaction. The results showed that female patients with OCD reported low
sexual pleasure, high sexual disgust and diminished sexual functioning, which are often attributed to medications
or contamination obsessions.
Reward dysfunction represents a key feature of addiction progression. Several studies have demonstrated that
addicted patients showed a blunted Nacc activation to
natural rewarding stimuli versus drug-related stimuli in
comparison to healthy controls 46. The results of the study
by Figee et al. agree remarkably with the findings of functional imaging studies in addiction disorders, showing
blunted reactivity of the ventral striatum during anticipation of monetary gain 40. Moreover, drug-related stimuli in
addicted patients showed increased activity of the reward
system, and likewise OCD-provoking stimuli seem to increase reward circuitry activity in OCD patients 48.
In addition, data from a recent review of different targets
of DBS for patients with treatment-refractory addiction
showed that Nacc seems to be the most promising DBS
target in order to treat these patients 49. These data support the hypothesis that addiction and OCD share some
common neurobiological dysfunctions and corroborate
the idea that OCD may start as an anxiety disorder and
become a behavioural addiction through the same stages
of addiction. A common link between all the substance
abuse and addictive behaviours is their rewarding effect.
Compulsion is a suffering reducing activity that might step
on the border of rewarding experience due to its capacity
to reduce anxiety and distress generated by obsessions 40.
In this perspective, compulsion could be potentially addictive. In fact, many patients report to have a sort of “addiction to compulsions”. In this light, it is possible to conceptualize OCD progression as a slow progression to a “com-
From psychopathology to neurocircuits: what we can learn from DBS? The case of obsessive-compulsive disorder
pulsion addiction”. Accordingly, it is possible to hypothesize a sub-classification of the OCD course by the same
way of addiction course. The first stage will be represented
by the “binge stage”. At this point compulsion is functional
and effective in reducing anxiety (cleaning helps to reduce
anxiety). Thus, compulsion is rewarding. The second stage
would be represented by the “tolerance stage” in which
the compulsion increasingly expands because of tolerance
to the effect (one needs to clean at least 20 times to reduce
anxiety feelings instead of a few times). Gradually, the
compulsion loses its effectiveness (cleaning does not help
anymore to reduce the anxiety). The final stage would be
the “withdrawal/craving stage” in which the compulsion
may no longer be omitted to avoid intense distress, and it
manifests consequences in many if not all dimensions of
the patient’s life (cleaning is needed just to live).
This conceptualization of OCD as a behavioural addiction could have relevance in identifying psychopathological dimensions such as craving as new treatment targets.
In fact, several agents used in the treatment of addicted
patients, such as ondansetron and memantine, have been
shown to be effective in the treatment of OCD treatmentresistant patients 50 51. However, many questions remain
unsolved and further neuroimaging, psychopathological
and pharmacological studies are needed to support this
new conceptualization.
Conclusions and future perspectives
DBS has been shown to be a promising tool in the treatment of treatment-refractory OCD. The existing data show
that the nucleus accumbens and the anterior limb of the
internal capsule are the most promising targets for DBS
in OCD. Furthermore, DBS has highlighted new interesting perspectives in the discovery of the neurobiological
underpinnings of OCD. These insights can provide a new
psychopathological conceptualization of OCD, reconsidering this disorder as a primary anxiety disorder, rapidly moving as a behavioural addiction. However, further
studies are needed to better clarify the long-term efficacy
and safety of DBS, and to better characterize the ideal
patients that might have a good response.
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Original article
Internalization of sociocultural standards of beauty and disordered eating
behaviours: the role of body surveillance, shame and social anxiety
Interiorizzazione degli standard socioculturali di bellezza e comportamenti alimentari
problematici: il ruolo di sorveglianza del corpo, vergogna e ansia sociale
A. Dakanalis1,2, M. Clerici3,4, M. Caslini4, L. Favagrossa5, A. Prunas6, C. Volpato6, G. Riva7,8, M.A. Zanetti1
Department of Brain and Behavioral Sciences, University of Pavia, Italy; 2 Department of Philosophy and Social Studies, University of Crete,
Greece; 3 Department of Neurosciences and Biomedical Technologies, University of Milano-Bicocca, Italy; 4 “S. Gerardo” Hospital Mental Health
Care Trust, Monza, Italy; 5 Faculty of Psychology, University “Vita-Salute San Raffaele”, Milan, Italy; 6 Department of Psychology, University
of Milano-Bicocca, Italy; 7 Faculty of Psychology, Catholic University of Milan, Italy; 8 Istituto Auxologico Italiano, Milan, Italy
1 Summary
bootstrapping method was used to estimate the significance of
the indirect effects.
Objectives
Objectification theory is a suitable framework for understanding
how media pressure is translated into behavioural and emotional
risk factors, potentially promoting eating and body-related disturbances among women. A large body of research conducted
with American and Australian female samples support the tenets of this theory. The present study extending previous work
by investigating the internalization of sociocultural standards of
beauty promoted by media as an antecedent of the body objectification process and by examining the theory’s applicability in
a sample of Italian women.
Results
The pattern of correlations is consistent with the objectification
theory (Table I). Path analysis indicated that internalization of
media ideals leads to body surveillance, which in turn leads
to body shame and social anxiety, which both strongly predict
women’s disordered eating behaviours (Fig. 1). Body surveillance mediated the links of internalization to body shame and
social anxiety. Social anxiety was an additional mediator of the
link between body surveillance and disordered eating behaviours, whereas body shame mediated the links of internalization
and body surveillance to disordered eating behaviours (Table II).
Methods
A cross-sectional design was used. A sample of 408 young Italian
women completed questionnaire measures of internalization of
media ideals, disordered eating behaviours, as well as the proposed mediating variables of body surveillance, body shame
and social anxiety. Path analysis procedures within the Mplus
program were used to determine whether the hypothesized theoretical model provided a good fit to the data. Bias-corrected
Conclusions
The objectification theory provides a useful framework to identify predictors of disordered eating behaviours in women. Practical implications are discussed.
Shame, described as a negative evaluation of the self as a
whole, is a multifaceted self-conscious emotion, related
to a number of psychiatric disorders 1. However, in disordered eating investigations 2, as well as in clinical settings, “it is preferable to concentrate on those particular
aspects of the self that are actually the focus of shame”,
such as shame about body appearance 1. Indeed, a large
body of research conducted in clinical and non-clinical
samples has shown that body shame is a stronger predictor of women’s eating disturbances than general shame 2.
There is also strong evidence that women who endorse
the norms for body shape portrayed in the media and/or
invested in appearance for self-evaluation are more vulnerable to experience body shame 3-5, which is related to
eating disorders 1-3 5. Interestingly, investment on appearance 5 is a cornerstone of the objectification theory 6.
According to this theory, the exposure to media-idealized
female bodies influence women to adopt a view of themselves as objects whose value is based on physical appearance 6. This psychological process is known as “selfobjectification” 5 and is described as a form of self-consciousness characterized by body surveillance (i.e. monitoring of the body in terms of how it looks) 5 7, which leads
to increased body shame and social anxiety, which both
Key words
Shame • Body surveillance • Social anxiety • Internalization of sociocultural standards of beauty • Disordered eating behaviours
Correspondence
A. Dakanalis, Department of Brain and Behavioral Sciences, University of Pavia, piazza Botta 11, 27100 Pavia, Italy • Tel. +39 0382986275 • Fax
+39 0382986272 • E-mail: antonios.dakanalis@unipv.it
Journal of Psychopathology 2014;20:33-37
33
A. Dakanalis et al.
predict behavioural eating disorder symptomatology 6.
Regarding social anxiety, it has been demonstrated that
women with eating disorders tend to have higher scores
on measures of social anxiety compared to those without
eating disorders, and fear of negative evaluation by others in social situations is likely to precede the onset of an
eating disorder 3 8-10.
Considerable research conducted with American and
Australian female samples supports the tenets of the
objectification theory 5 11, yet virtually no study to our
knowledge has incorporated media effects (i.e. internalization of media ideals) into the objectification model despite the fact that the relationship is implied and particularly relevant for women 3 5 11-13. Hence, this study aims
at filling this gap and to examine the applicability of the
theoretical model in Italian women, who also report body
concerns and disordered eating behaviours in response to
sociocultural pressure 12-17. It is predicted that internalization of media ideals leads to body surveillance, which in
turn leads to body shame and social anxiety, which both
contribute to disordered eating behaviours. The significance of the indirect effects was also estimated.
Methods
Participants and procedures
Participants
were
408
undergraduate
women
(Mage = 20.82; SD = 1.90) from four Italian universities
(Milan, Naples, Rome, Pavia) who responded to campus
advertisements to participate in an online study. Mean
self-reported body mass index (BMI = kg/m2) was 20.97
(SD = 3.34); desired BMI (desired kg/m2) was 19.06
(SD = 1.53). A small number of the undergraduate women reported having been previously diagnosed with or
treated for anorexia nervosa (AN) (n = 2; 0.49%), bulimia
nervosa (BN) (n = 3; 0.74%), or eating disorder not otherwise specified (EDNOS) (n = 6; 1.47%).
It has been demonstrated that the presentation format of
self-report questionnaires (i.e. online vs. paper-and-pencil) does not change the quality of results 18. In order to
ensure there was no duplication, the IP address of every
participant was examined 18; no duplicate data were detected. Participants were informed about the purpose of
the study and, after providing their consent, completed
the survey instruments, which were counterbalanced to
reduce order effects 19.
Measures
Body surveillance and body shame were assessed by the
8-item Body Surveillance and the 8-item Body Shame
sub-scales, respectively, of the Italian version of The Objectified Body Consciousness Scale 17.
34
Internalization of media ideals was assessed by the 9-item
General Internalization subscale of the Italian Version of
The Sociocultural Attitudes Toward Appearance Scale-3 12.
Cognitive and affective aspects of social anxiety were assessed by the 15-item Italian version of the Interaction
Anxiousness Scale 20.
Disordered eating behaviours (DEB) were assessed by two
behavioural subscales (Drive for Thinness and Bulimia) of
the Italian version of Eating Disorder Inventory-2 (EDI-2) 21,
as the remaining 9 subscales of EDI-2 do not assess behavioural symptoms of eating disorders but measure variables
correlated with the onset and/or maintenance of eating
disturbances 13 22 23. The 14 items were used in combination
to create a composite measure of EDB, as they have been
found to reflect a disordered eating factor 22.
A brief demographic questionnaire 19 was used to assess
weight, desired weight, height, age and eating disorder
history (i.e., “Have you ever been diagnosed and/or treated for AN (Yes or No), BN (Yes or No), or EDNOS (Yes or
No)?”).
Results
An outlier analysis was performed and no case was excluded, as all cases were in the acceptable range (i.e.
Mahalanobis distance values). Skewness and kurtosis values for all variables were under the recommended range
(Table I), and thus no variable was transformed. There
were no missing data, given that the online self-report
questionnaires were formatted so that participants could
not skip individual items 7 13. Because preliminary analyses indicated that BMI was not significantly related to
variables examined in this article, it was not included as
covariate and reported in the analyses described.
Measure means, standard deviations, internal consistency reliability estimates (i.e. Cronbach’s alpha coefficients
and 95% confidence intervals) and correlations among
all variables of interest are shown in Table I. The pattern of
correlations is consistent with the objectification model
and is in excellent agreement with previous findings 11.
Path analysis procedures contained within the Mplus 5.1
program (maximum likelihood estimation) were used to
determine whether the hypothesized theoretical model
provided a good fit to the data24. Total scores on the measures served as the observed variables in the model. Several indices were used to determine the fit of the proposed
model. According to Byrne 24, comparative fit index (CFI)
and Tucker-Lewis Index (TLI) values ≥ 0.95, standardized
root-mean-square residual (SRMR) values ≤ 0.08 and
root-mean-square error of approximation (RMSEA) values ≤ 0.06 indicate a good fit for data. We also specified
Mplus to identify modification indices (MI) above 5.0,
as there may be significant paths between variables that
were not hypothesized and examined in the model 24.
Internalization and disordered eating
Table I.
Descriptive statistics and correlations among study variables (n = 408). Statistiche descrittive e correlazioni tra le variabili dello
studio (n = 408).
Variables
1
2
3
4
5
1. Internalization of Media Ideals
2. Body Surveillance
0.54*
3. Body Shame
0.33*
0.48*
4. Social Anxiety
0.31*
0.59*
0.22†
5. Disordered Eating Behaviours
0.41
*
0.51
0.58*
0.47*
M
28.13
38.85
33.17
32.02
31.33
SD
10.61
9.81
10.55
11.10
14.14
9-45
8-56
8-56
15-75
14-84
Scale Range
Alpha (95% CI)
*
0.90 (0.88-0.92) 0.93 (0.91-0.95) 0.94 (0.92-0.96) 0.89 (0.87-0.91) 0.92 (0.91-0.94)
Skewness
-0.422
0.360
-0.575
0.717
-0.677
Kurtosis
-0.499
-0.466
-0.542
-0.330
-0.389
*
p < 0.001; † p < 0.05
The results of model were mixed: the CFI (0.98) and
SRMR (0.05) supported its fit, whereas the TLI (0.94) and
RMSEA (0.08) did not. All model paths were significant
and this model accounted for 48% of the variance in
EDB. One MI exceeded 5.0 (i.e. the path from internalization to body shame was 9.55); thus, we included this
path and reanalyzed our model. All fit statistics indicated an excellent fit to the data (CFI = 1.00, TLI = 1.00,
SRMR = 0.01, RMSEA = 0.00), and all model paths were
significant (p < 0.05). The revised (final) model accounted
for 50.3% of the variance in women’s EDB, which is considered sizeable for path analysis 24. The path coefficients
are presented in Figure 1.
Consistent with tenets of the objectification model, we
planned to examine body shame and social anxiety as
mediators of the link between body surveillance and
EDB, and body shame as an additional mediator of the
link between internalization and EDS, as well as surveillance as a mediator of the links between social anxiety,
body shame and internalization. If at least one path of
Figure 1.
Path coefficients for the final model. Coefficienti di percorso del modello finale esaminato.
35
A. Dakanalis et al.
Table II.
Mediation: examination of indirect effects, bias-corrected 95% confidence intervals (95% CI). Stime degli effetti indiretti, intervalli
di confidenza al 95% (correzione della distorsione).
Indirect path
Indirect effect
95% CI
Direct path
significant?
Full or partial mediation
IMI > BSV > BSH
0.19*
0.097 to 0.450
Yes
Partial
IMI > BSH > DEB
0.07
*
0.023 to 0.142
No
Full
IMI > BSV > SA
0.24
*
0.143 to 0.445
No
Full
BSV > BSH > DEB
0.17*
0.048 to 0.300
No
Full
BSV > SA > DEB
0.23
0.157 to 0.355
No
Full
*
IMI: Internalization of Media Ideals; BSV: Body Surveillance; BSH: Body Shame; SA: Social Anxiety; DEB: Disordered Eating Behaviours.
*
p < 0.05
a hypothesized indirect effect was not significant, then
it precludes mediation 24. We used bias-corrected bootstrapping method with 1000 random samples to estimate
the significance of the indirect effects 24. This method involves generating confidence intervals (CI) around the
indirect effects through a process of random re-sampling
with replacement and offers a more powerful and rigorous approach to traditional mediation tests 24. All indirect effects examined were significant (i.e. the 95% CI
do not include zero 24). The standardized indirect effect,
bias-corrected 95% CI, as well as whether it represents
full or partial mediation (i.e. determined by whether there
was a significant direct path in the model 24) are shown
in Table II.
Discussion
Literature evidence highlights that sociocultural pressure
to be thin is central to the development of negative feelings about the body, which are recognised as the most
robust risk factor for clinical and subclinical eating disorders 1-4 17 25. The objectification theory 6 offers a more
complex account of the process involved in women’s
behavioural and emotional responses to their desire to
meet Western cultural ideals of physical appearance 5.
The purpose of this study was to extend previous work
by incorporating internalization of media ideals into the
objectification model and by examining the theory’s applicability in Italy, in which young women are not “immune” from eating and body-related disturbances in response to sociocultural pressure 12-17.
Consistent with objectification theory 6 and our hypothesis, the endorsement and acceptance of appearance media ideals lead women to become hyperaware of how
their body looks and to evaluate themselves in terms of
physical appearance 5, which in turn leads to body shame
(i.e. the emotion that can result from measuring oneself
against a cultural standard and perceiving oneself as fail36
ing to meet that standard 13 17 23) and social anxiety; both
strongly predict disordered eating behaviours in women 6.
The indirect influence of body surveillance on EDB is in
accord with previous findings 11. The results also suggest
that women who are more anxious in the interpersonal
arenas are also more likely to engage in disordered eating
behaviours and deserve further study given the role that
interpersonal factors are believed to play in maintaining
some forms of disordered eating behaviours 3 8-10 13.
Some limitations of the present study should be acknowledged. Although we employed only self-report
measures with established psychometric proprieties
and used several strategies to detect erroneous data, the
findings of this study are susceptible to possible reporting bias. Thus, replication with other methods of data
collection (such as semi-structured interviews) would be
beneficial. The cross-sectional data cannot determine
causality and longitudinal studies are needed to provide
empirical test of the relations specified in the model.
The sample consisted of college-aged Italian women
and limits the generalizability of the results. Future research should ascertain whether these findings can be
replicated among other groups of females (e.g. adolescent girls or older women). It needs also to address the
predictive ability of the objectification theory for diagnosable eating disorders.
In terms of practical implications, prevention programmes
(e.g. dissonance-based educational approach) as well as
the use of cognitive-behavioural and other integrated
treatments (e.g. virtual reality) which aim at decreasing
the central importance of appearance and the active pursuit of the thin-ideal, are essential to reduce eating and
body-related disturbances 3 5 15 25 26.
In conclusion, the objectification theory provides a useful
framework for understanding how sociocultural, behavioural and emotional variables work together to predict
disordered eating behaviours in women.
Internalization and disordered eating
Acknowledgements
Best Scientific Poster Award, New Directions in Psychiatry, A
Forum for European Young Psychiatrists, May 23-25, 2012, Sorrento Italy. The authors wishes to acknowledge Valentina E. Di
Mattei, Elena Pagani Bagliacca and Lucio Sarno for their assistance in preparation of this article.
Dakanalis A, Zanetti MA, Riva G, et al. Psychosocial moderators of the relationship between body dissatisfaction and
symptoms of eating disorders: A look at an Italian sample of
young women. Eur Rev Appl Psychol 2013;63:323-34.
13
14
Cotrufo P. Binge eating disorder: epidemiological data and
clinical characterisation. Ital J Psychopathol 1999;5:229-32.
15
Carta I, Zappa LE, Garghentini G, et al. Body image: a preliminary study of the administration of the Body Uneasiness
Test (BUT) to investigate specific features of eating disorders, anxiety, depression, and obesity. Ital J Psychopathol
2008;14:23-8.
16
Dakanalis A, Zanetti MA, Clerici M, et al. Italian version
of the Dutch Eating Behavior Questionnaire: Psychometric
Proprieties and Measurement Invariance across Sex, BMIstatus and Age. Appetite 2013;71:187-95.
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37
Original article
Towards a classification of alexithymia: primary, secondary and organic
Verso una classificazione dell’alessitimia in primaria, secondaria e organica
A. Messina1, J.N. Beadle2, S. Paradiso3,4
General Medicine Trainers, Health Department of Sicily, Catania, Italy; 2 University of Iowa, Iowa CIty, USA; 3 Universidad “Diego Portales”,
Santiago, Chile and 4 University of Hawaii at Manoa, Honolulu, USA
1
Summary
Background
Emotion processing is essential for well-being and psychosocial
adaptation. Alexithymia is widely viewed as an impairment in
emotion processing that includes difficulty identifying and describing emotions. While there is a significant understanding of
primary alexithymia, which is thought to be the result of developmental genetic and familial factors, secondary and organic
alexithymia are beginning to be focus of research.
Method and results
The present review of the literature suggests the importance of
differentiating between primary and secondary alexithymia, and
the organic subtype of secondary alexithymia. Secondary alexithymia is thought to be a consequence of psychological stress,
chronic disease, or organic processes (e.g. brain trauma or
stroke) that occur after childhood (whereas primary alexithymia
Introduction: origin of the concept
of alexithymia
Alexithymia is a psychological construct broadly describing individuals with deficits in emotion processing and
awareness 1. Individuals who score high on measures of
alexithymia show difficulty distinguishing emotions from
bodily sensations, discriminating between cognition and
emotions, and describing and communicating emotions
to others 2. Harvard psychiatrist Peter Sifneos first used the
term alexithymia (a = lack; lexis = word; thymos = emotion) to describe individuals who appeared, “different,
alien beings, having come from an entirely different
world, living in the midst of a society which is dominated
by feelings” (Goleman 3, p. 51).
Classically, alexithymia has been defined to include multiple facets including 4:
1. difficulty identifying and distinguishing emotions from
bodily sensations;
2. difficulty describing and verbalizing emotions;
is a developmental phenomenon). Organic insults to the brain
may bring about the organic form of alexithymia by altering cerebral structures involved in emotional processing (e.g. anterior
cingulate cortex, frontostriatal networks, callosum corpus, right
hemisphere cortex and amygdala). The usefulness of differentiating among alexithymia categories and their relationships with
brain structures known to subserve emotional processing is discussed.
Conclusion
We propose that differentiating between primary, secondary and
organic alexithymia may potentially serve to develop better treatments for alexithymia.
Key words
Alexithymia • Classification • Brain injury • Emotion
3. poverty of fantasy life;
4. externally oriented thinking style;
5. poor empathizing.
During dynamic psychotherapy, the capacity to symbolize
and translate emotions into language is often considered
to be critical for improving symptoms. These capacities
are greatly reduced or lacking in alexithymia. Sifneos’ interest in identifying individuals with alexithymia was motivated by the goal to select individuals who would show
improvement with short-term psychodynamic therapy 5.
The negative effect of alexithymia on psychotherapy has
been empirically demonstrated in group, psychoanalytic
and supportive psychotherapies 6. The reaction of the therapist to patients with alexithymia may also have a negative
effect on treatment 7.
Dating back to earlier research, the body or “soma” was
found to play a critical role in alexithymia 8. The present
review will describe the two-way relationship between
alexithymia and the body, beginning with a discussion of
historical views purporting that emotions are embodied
Correspondence
Sergio Paradiso, Neuroscience and MR Research, Department of Medicine, John A. Burns School of Medicine, University of Hawai’i, 1356 Lusitana
Street, University Tower, 7th Floor, Honolulu, HI 96813, USA • E-mail: sergiop@hawaii.edu or paradiso.sp@gmail.com
38
Journal of Psychopathology 2014;20:38-49
Towards a classification of alexithymia:
experiences. The potential utility of distinguishing between primary, secondary and organic alexithymia based
upon aetiology and proposed brain mechanisms will be
described.
Some historical views on emotion and the body
Ancient Greeks and Romans traditionally viewed emotions as “pertubationes animi” (literally, disturbances of
the soul), or modifications of the mental state of an individual not guided by reason (Cicero I sec. BC) 9. Today,
in light of progress in cognitive and affective neuroscience, the dichotomy between emotion and reason is less
tenable 10. The ability to perceive, modulate and express
emotions are core cognitive features of emotional intelligence 11. Knowing one’s own emotions is an essential
ability that promotes adaptive decision-making and goaldirected behaviour 12. Emotional awareness has been considered to be a prerequisite for managing bodily drives
and delaying gratification, while contributing to the selection of emotionally adaptive behavioural responses 12.
The philosopher and biologist Herbert Spencer (18201903) posited that an emotion is a subjective mental state
of pain or pleasure associated with bodily manifestations (“the inner and the outer face of the same change”
Spencer, 1855, p. 128) 13. Spencer believed that in the
animal kingdom emotions play a role in evolution and
adaptation, permitting a comprehensive classification of
impressions and inducing adaptive responses to specific
situations 13. Darwin’s theory of emotions 14 expanded
upon Spencer’s ideas and emphasized the concept that
an emotion is an automatic response with stereotyped
bodily changes. Darwin believed that an emotion was a
mental state causing somatic effects and observed similarities between somatic expressions of emotions among
humans and other animals (e.g. gnashing teeth in anger) 14. Darwin distinguished basic emotions including
joy, shame, anger, and disgust from social emotions such
as love or hate that generally are less stereotyped and
more complex 14.
William James and the Danish physician James Lange
viewed emotions as a link between the perception of an
event and the consequent behaviour: emotion (from Latin
e-moveo = to move towards) compels to act 15. According to James, an emotion is the consequence of an activation of the neurovegetative system 15. The perception of an
EVENT
>
aroused neurovegetative system generates emotion (Fig. 1).
To expand, it is James’ opinion that the behaviour that follows a perception is the emotion. He wrote: “the bodily
changes follow directly the perception of the exciting
fact, […] our feeling of the same changes as they occur is
the emotion” 15 16.
In contrast with James, Cannon viewed bodily expressions and cognitive appraisal of emotions as parallel processes 17. This signifies that Cannon believed that the neurovegetative changes were not the cause of the emotion.
Cannon highlighted that the perception of an emotional
event (e.g. danger) produces activation of subcortical
brain structures thus leading to a generalized sympathetic
response. Activation of cortical structures is necessary for
the conscious representation of the stimulus and its emotional tagging 17. The late Magda B. Arnold (1903-2002)
(American psychologist based at Loyola University, Chicago) thought that emotions are produced during a dialectical process occurring between the mind and external
objects. She thought that emotions are products of our
evaluation of events (the “appraisal theory of emotions”).
In addition she showed that (usually), positive emotions
generate approach behaviour while negative emotions
generate withdrawal. Hence, emotions are not exclusively inner processes, but are generated by interactions
between the subject (with her body) and the object 18.
Conscious representation of an event permits an evaluation of the basic perceptual data and may allow modification of the emotional response 18. In this model, Arnold
posits the pivotal role of emotional awareness in controlling emotion responses and emotion-activated behaviour.
In spite of the critical differences between various theories of emotion, this very brief account of the history of
emotion theory demonstrates the importance of the emotion-body connection.
Social role of emotion and alexithymia
Amidst the complexity of human societies and groups,
emotions play an important social role. Basic emotions
including fear, for instance, often promote affiliation
among individuals, as frightened individuals may seek
support from the group and utilize these group resources
against a real or imaginary enemy 19. Other emotions (for
instance empathy or envy) are eminently social in nature 19. Decreased levels of empathy have been linked to
NEUROVEGETATIVE AROUSAL
>
EMOTION
Figure 1.
James-Lange’s theory of emotion. La teoria delle emozioni di James-Lange.
39
A. Messina et al.
greater loneliness 20. Because of the importance of emotions both for the individual and social groups, the fact
that some individuals show a diminished capacity to recognize and describe emotions has been widely regarded
as a highly important psychological and clinical issue 21.
Individuals with moderate to high scores of alexithymia
show an array of difficulties in their relationships with
others, including interpersonal ambivalence, need for social approval and poor sociability 22 23. Interpersonal difficulties can cause emotional suffering and may prompt
individuals with alexithymia to seek psychotherapy.
However, individuals with alexithymia may not receive
the full benefit from dynamic, supportive, or group, psychotherapy because poorer access and reporting of personal emotions are negative prognostic factors in psychotherapeutic treatment 6.
Alexithymia: cognition, somatic symptoms
and disease
Alexithymia and cognition
Individuals with alexithymia typically have difficulties using language to describe their experiences of emotions
that are rooted in bodily sensations. This view is consistent with empirical studies showing the association
between alexithymia and language difficulties 24. For instance, Henry et al. 25 observed a significant inverse correlation between difficulty identifying emotions and verbal
fluency in patients with a history of traumatic brain injury. Furthermore, Onor et al. 26 showed that alexithymia
was associated with weaker functioning (albeit not in the
impaired range) in several cognitive domains including
language, attention, memory, visual spatial abilities, and
working memory. In a different sample of healthy adults,
the Paradiso lab showed that the severity of alexithymia
was associated with relatively poorer cognition, in particular in the domain of executive function 27. Thus, the
extant literature suggests that one mechanism for alexithymia is cognitive with relative language and abstract
reasoning and symbolization deficits 28.
Yet, the mechanisms of alexithymia may be more complex and may extend beyond traditional cognitive functions. As evidenced by research linking alexithymia to
awareness of personal emotional and brain regions supporting it (see below) 29, poor emotional self-awareness
and poor abstract thinking may underlie a diminished capacity to symbolically express emotions or alexithymia 30.
Alexithymia, disease, and somatic symptoms
The relationship between alexithymia and reported or
medically ascertained physical symptoms is complex.
Rather than having no emotional life, individuals with
alexithymia communicate their emotions using somatic
40
channels 31. In addition, individuals with alexithymia
show an excess of medically ascertained physical illness 32 and alexithymia among individuals with ascertained medical conditions may hinder recovery and delay
rehabilitation efforts 33. Understanding the complex relationship between poor emotion processing and physical
symptoms includes understanding that individuals with
alexithymia tend to complain of body ailments and disturbances independently from the actual presence of somatic illness 31. This issue is complicated by evidence of
individual differences among people with alexithymia.
Bermond 34 separates alexithymia into two types. Type
I alexithymia shows affective and cognitive alterations.
People with Type I alexithymia display poor awareness
and expression of emotions. On the other hand, Type II
alexithymia shows normal emotion awareness, but poor
emotion expression, and these individuals are more
prone to somatization than Type I 35.
Alexithymia is also associated with visceral hypersensitivity. There is evidence relating impaired processing of
emotions with functional gastrointestinal disorders 36. This
finding is consistent with the notion that physical symptoms in alexithymia may be related to somatosensory
amplification (SA). SA has been defined as: i) excessive
attention and hyper-vigilance to somatic symptoms; ii)
exaggerated sensitiveness to physical sensations; iii) misinterpretation of physical sensations interpreted as a sign
of disease 37. Somatosensory amplification 38 and somatization 31 39 are generally associated with difficulty identifying and describing feelings (but less so with externally
oriented thinking style).
However, not all research supports the association between alexithymia and somatic complaints. Some authors believe that alexithymia and somatization are two
different conditions that are only sometimes associated 40.
For example, children in particular show multiple somatic complaints without difficulty in describing or identifying feelings 41.
Alexithymia and psychopathology
Before addressing the differences between primary and
secondary alexithymia, a brief account on the association with psychopathology is needed. Alexithymia is a
risk factor for suicide in subjects with brain injury 42. This
finding is an important reminder of the vast literature
concerning the relationship between alexithymia and depression. This issue has been widely debated in the field.
Briefly, researchers now believe that a positive association between alexithymia and depression exists (i.e. the
greater the alexithymia scores, the greater the depression
scores). Longitudinal studies have also uncovered persistence of some degree of alexithymia following remission
of depression 43. Thus, alexithymia has both state-depen-
Towards a classification of alexithymia:
dent (e.g. mood but also general psychopathology 22) and
trait-dependent features 44. Trait dependent features, association with personality traits (including avoidant, schizotypal, dependent and passive-aggressive) 22 45 and lack of
association with histrionic features 45 reinforce the notion
that the construct of alexithymia captures psychological
dimensions related to individual differences. Alexithymia
is also found in other psychiatric conditions including
autism, eating disorders and schizophrenia, all of which
show degrees of deficits in social cognition 20 46 47. Based
on these data, it comes as no surprise that alexithymia together with personality disorders 48 is a predictor of poor
outcome in depression 49.
In the end, some have suggested that it may be useful
to distinguish between depression with strong and mild
alexithymia features 50, but further study in this area is
needed. If strong alexithymia prevents a consistent report
of emotion changes such that patients admit to sad mood
only erratically, depression may take the phenomenological form of depression without sadness (or non-dysphoric
depression) 51-53.
Primary versus secondary alexithymia
The need for distinguishing between primary and secondary alexithymia emerged rather early in the literature 54,
but it took some time before this distinction was widely
recognized in the field. Most studies that have contributed to the complex body of knowledge on alexithymia
have examined individuals with primary alexithymia.
Alexithymia is considered to be primary when emerging “as a life-long dispositional factor that can lead to
psychosomatic illness” (Lesser 55, p. 533). Primary alexithymia may derive from a psychic trauma occurring during childhood 56 or from negative primary caregivers interactions 57. It has been recently suggested that genetic
polymorphism of the 5-HT transporter-linked promoter
region (i.e. L/L alleles) may influence the occurrence of
alexithymia 58. Hence, primary alexithymia is currently
thought of as a more or less stable personality trait that
becomes molded during childhood and early adult years.
Therefore, primary alexithymia is developmental in nature. It also has no purported organic or psychological
risk factors (excluding those occurring in childhood, see
discussion below).
Secondary alexithymia is posited to arise not during development, but as a consequence of events occurring
later in life. These may be events with psychological significance and/or medical-surgical events (illnesses or disease) 59 that have a direct or indirect effect on brain functioning. Therefore, secondary alexithymia may have both
psychological and/or somatic (organic) mechanisms 60.
As evidenced briefly above, in addition to somatic symptoms, alexithymia can also be associated with mental
illness. Thus, whereas primary alexithymia may play a
role as a vulnerability factor for mental illness, secondary alexithymia is thought to be a consequence of the
illness 60.
If the stressful event is an illness (one that has no obvious
direct consequences on brain functioning such as a hip
fracture), alexithymia has been seen as a defense mechanism in an attempt to cope with the stress of the medical
illness 54. Based upon the study of alexithymia in 53 inpatients examined in a teaching hospital psychiatric consultation service, researchers suggested that “alexithymia in
the medically ill may play a defensive role as a state reaction” (Wise et al. 59, p. 287). In other words, alexithymia
secondary to a psychologically significant event may be
construed as a defense or protection against highly emotional events. This view is supported by the higher levels
of alexithymia found in holocaust survivors 61 and sexual
assault victims 62.
In summary, while primary alexithymia is widely thought
to be a personality trait, in which affective processing is
less developed than normal due to childhood trauma or
genetic predisposition (e.g. polymorphism of 5-HT transporter-linked promoter region), secondary alexithymia
is a condition occurring later in life either due to psychological trauma, or as a direct insult to brain regions
supporting emotion processing and awareness 63. Note
that this proposed sharp dichotomy is useful to frame the
field. Clinical experience illustrates that determination of
the primary or secondary nature of alexithymia may be in
some cases debated. Examples may be youth with severe
illness (alexithymia can be seen as secondary because of
the illness or primary due to its ensuing during development) or alexithymia resulting from prolonged emotional
stress during early development (e.g. hyperprotective
parental bonding and specifically excessive maternal
protection) mediating development of personality disorders 64. Therefore, primary and secondary alexithymia
may be better viewed as extremes of a continuum, while
individual decisions on aetiology are better left to the experienced clinician.
Organic alexithymia
As studies began to examine the hypothesis that alexithymia may be associated with localized brain damage 65,
the observation that alexithymia may occur “de novo,” as
a consequence of brain injury generated extensive interest in the field 63. The term organic alexithymia refers to
a condition in which alexithymia is purportedly caused
by organic damage to brain structures involved in emotional processing through indirect or direct insults to the
brain. We suggest that it is conceptually useful to categorize organic alexithymia under the rubric of secondary
alexithymia, with the understanding that further outcome
41
A. Messina et al.
Table I.
Neuroanatomical substrates of primary, secondary and organic alexithymia. Substrati neuroanatomici dell’alessitimia primaria,
secondaria e organica.
Brain region
Primary alexithymia
Secondary alexithymia
Organic alexithymia
(decreased Messina et al., 2011 (decreased Sturm et al., 2011 90; ParadiAnterior cingulate cortex Borsci et al., 2009
grey matter volume); Heinzel et al., oxygen tension) (purported as for so et al., 2008 89 (decreased
2012 127 (functional impairment)
the location)
grey matter volume)
78
72
Corpus callosum
Romei et al., 2008 108; Tabibnia
and Zaidel2005 116; Lumley, et al.,
2000 114; Parker et al., 1999 128 (interhemisperic transfer impairment)
TenHouten et al., 1986 126
(cerebral commissurotomy)
Basal ganglia
Lee et al., 2011 101 (functional impairment in caudate and frontostriatal circuitry)
Huang et al., 2012 66 (damage of basal ganglia after carbon monoxide poisoning)
Right temporal lobe
Borsci et al., 2009 78 (reduced grey
matter in right temporal lobe)
Right hemisphere
Lumley et al., 2000 114 (functional
impairment)
and treatment studies may indicate that this should be
considered altogether as a separate category. Organic
alexithymia is often more resistant to treatment 66, is not
associated with a specific pre-morbid personality and is
associated with cognitive impairment.
As briefly mentioned above, alexithymia observed
among patients with medical illness represents a clinical puzzle. The question refers to the extent to which
in a given patient alexithymia is a primary personality
feature or a phenomenon secondary to the stress of the
illness or a to direct or indirect brain alteration (induced by the medical condition). Determination of the
nature of alexithymia may be inferred from the clinical
history (e.g. asking a next of kin on personality features prior to illness or injury), and from characteristics
inherent to the alexithymia syndrome (e.g. cognitive
impairment).
Studies have examined the possibility that alexithymia
stems from direct brain damage. Spalletta et al. 65 observed that alexithymic characteristics were associated
with right hemisphere damage among patients with
stroke consistently with the role of right hemisphere in
emotion processing 67 68. Becerra et al. 63 reported on a 21
year old man who developed alexithymia after a motor
vehicle accident that caused damage to the orbitofrontal
cortex, a brain region playing a role in decoding emotional significance of an event and strongly connected
with many limbic regions including the amygdala 10 69.
Subsequently, a study examining 54 individuals (67%
men) with brain injury (which had occurred about 30
years prior) confirmed the strong association between
brain injury and alexithymia (odd ratio = 2.64) 70. The
42
Spalletta et al., 2001 65 (right
hemisphere stroke)
majority (61%) of subjects with history of traumatic
brain injury early in life developed alexithymia, which
in turn is a risk factor for suicide in subjects with history
of traumatic brain injury 42. The literature also shows that
hypoxic lesions of bilateral globus pallidus provoked by
carbon monoxide poisoning were related associated
with a severe and resistant form of alexithymia 66. As reported by the Paradiso lab, a 44-year-old man showed
impairment in emotional awareness after anoxic lesion
of globus pallidus 71. Another study that may be relevant
for this discussion showed, low levels of haemoglobin in
oncologic patients were directly associated with higher
level of alexithymia 72. The authors speculated that low
oxygen pressure level may modify the functioning of the
anterior cingulate cortex, a region critical for emotional awareness and particularly susceptible to perfusion
changes 72.
Whereas the existing literature on treatment of secondary and organic alexithymia remains wanting, it may offer guidance in some cases. For instance, improvement
in alexithymia was found when 64 psychiatric patients
underwent group therapy 73. Other studies show efficacy
of the serotonin-norepinephrine reuptake inhibitor (SNRI)
venlafaxine (75-150 mg daily) on alexithymia in patients
who suffered a stroke 74.
In summary, there may be at least two types of secondary
alexithymia. Specifically, one type develops as a consequence of psychosocial stressors and the psychological
(e.g. defence) mechanisms set forth to attempt to cope
with the stress 75, while the other (organic) occurs due to
a direct or indirect insult to the brain. As such, organic
alexithymia may follow alterations to brain regions sub-
Towards a classification of alexithymia:
Table II.
Alexithymia: classification based on clinical history. Alessitimia: classificazione in base alla storia clinica.
Primary alexithymia
Secondary alexithymia
Aetiology
Genetically mediated or familial Subsequent
distress
Onset mechanisms
Early onset
to
Early or late onset
Organic alexithymia
psychological Subsequent to trauma, vascular or
other brain damage
Early or late onset
Sociocultural education, socio- Linked to chronic disease (e.g, Linked to brain damage in regions
economic status
cancer, diabetes, Parkinson’s subserving emotion processing
disease)
Treatment response*
Psychotherapy treatment resis- Somewhat responsive to psy- Responsive
tance
chotherapy or pharmacological treatment
treatment
Outcome*
Poorer
*
Better
to
pharmacological
Better
Based on research studies and personal experience of one of the authors (SP)
serving emotional awareness or participating in linking
stimuli from the body to their abstract (language) conceptualization including neurodegenerative disorders (e.g.
frontal temporal dementia, semantic dementia, Alzheimer’s disease, cortical basal degeneration/progressive supranuclear palsy).
Neuroanatomy of alexithymia
Multiple brain structures have been posited to be involved in the pathogenesis of alexithymia (Table I). There
is a broad overlap of brain structures purportedly involved in alexithymia independently whether this may be
conceived as primary or secondary (including organic).
What appears to be the case is that the involvement of
one or another brain region does not allow distinction between primary and secondary or organic alexithymia. The
distinction continues to rely on clinical assessment (Table II). Regions purportedly associated with alexithymia
have included the anterior cingulate cortex, frontal striatal networks and basal ganglia, insula and amygdala, corpus callosum.
Anterior cingulate cortex
Since Papez’s initial postulation (1937), consensus has
broadened on the role of anterior cingulate cortex (ACC)
in emotion perception and regulation 76-78. Briefly, the
ACC shows at least two functional parts: a rostral region
playing a role in emotion processing and interconnected
with multiple limbic regions; and a dorsal region connected with the lateral prefrontal, parietal and supplementary motor cortex showing greater specialization for
attention and executive functions 79 80. Rostral and dorsal
ACC regions are closely connected allowing integration
between the experience and the mental representation
of an emotion 81. “Anatomical and functional continuum
rather than segregated operations” between cognition
and emotional components of the mind may take place
in the ACC (Messina et al. 82, p. 1). The importance of
ACC in alexithymia may be attributed to the presence
of spindle-shaped Von Economo’s neurons. These may
represent a trait d’union between perception and emotions 83. Von Economo neurons appeared in late phases
of evolution when they took a role in the regulation of
social and emotional functioning 84. The presence of these
neurons is related to absolute brain size 85. Homo sapiens
has a larger brain size (about 1500 cc on average) than
homo Neanderthal (1400 cc on average) 86.
Von Economo’s neurons (VENs) are bipolar neurons allocated in layer V of ACC and frontoinsular cortex in
humans 83. These neurons were also found in animals
with high social structure as apes, dolphins 87, elephants 85 macaques monkeys 88. The importance of Von
Economo’s neurons in social awareness, empathy and
self-referential processing stems from the observation of
selective destruction of VENs in early stages of frontotemporal dementia consistent with evidence from functional imaging 83.
The involvement of the ACC as a mechanism of alexithymia in later life was suggested by Paradiso et al. 89 who
reported a significant inverse correlation between the
grey matter volume of the right ACC and alexithymia, a
phenomenon that appeared to be a function of older age.
Consistent with this idea, a structural MR imaging study
showed that the right pregenual ACC grey matter volume in 7 healthy subjects was negatively correlated with
alexithymia 90, but the small sample size is a limitation.
Additional regions showing negative correlations with
alexithymia were the right middle and superior temporal
gyrus, the right postcentral gyrus, the right precuneus and
43
A. Messina et al.
the right inferior parietal lobe. Conversely, homologous
regions on the left hemisphere were not correlated with
alexithymia 90. Circuitry connecting temporal, parietal and
frontal areas has been posited to support processing of
information relating to the self and to emotional events 91.
Consistent with in vivo structural neuroanatomy studies,
functional neuroimaging studies have shown reduced
activity of ACC in individuals with high alexithymia
scores 92 and a reduction of grey matter in anterior cingulate cortex and in middle temporal gyrus in healthy
women 78. Paradiso et al. 93 recently reported that patients
with right middle cerebral artery (MCA) stroke show high
levels of alexithymia, perhaps as a consequence of distant functional effects of the stroke damage reducing the
functioning of the ACC. The ACC is vascularized by MCA
and some parts are highly sensible to hypoxia 94.
Functional networks involving the frontal lobe
Over the last decade, the concept of the default mode
network (DMN) has gained broad acceptance as a set
of functionally interconnected brain regions including
the dorsal medial and ventral medial prefrontal cortex,
the medial and lateral parietal cortex and the temporal
cortex and the posterior cingulate cortex 95-97. The DMN
is active during introspection, while this network is deactivated during “nonself-referential goal-directed tasks
in keeping with the folk-psychological notion of losing
one’s self in one’s work” (Sheline et al. 95, p. 1). A recent
study showed diminished connectivity within the DMN
among participants with alexithymia 98. The authors
studied 20 alexithymic subjects and 18 healthy participants using functional magnetic resonance imaging
(fMRI) and observed that brain areas of DMN (medial,
frontal, and temporal regions) showed weaker connections in alexithymic subjects than healthy individuals,
while connectivity between DMN and sensory-motor
areas was higher 98.
This body of work suggests that alexithymia may be related to malfunctioning of brain structures including the
cingulate and prefrontal cortex regulating and subserving emotional awareness 77 and self-oriented planning,
a mental state often associated with emotion. Hence, it
is plausible that when mental functions supported by regions in the DMN fail to work properly, the orderly linkage from body stimuli to emotions and to symbolic language is disrupted 99, leading to poor symbolization of
bodily stimuli and alexithymia.
Basal ganglia
Striato-thalamo-cortical circuits support emotional processing 100. Different basal ganglia structures (globus pallidus, ventral striatum, caudate, subthalamic nucleus)
have been associated with primary alexithymia 88 and
44
with organic alexithymia 66. Lee et al. 101 observed that
in 38 healthy subjects with higher levels of alexithymia
showed lower activation in right caudate nucleus in response to angry facial stimuli. Six subjects with focal
lesions of the left basal ganglia investigated by MRI and
PET neuroimaging techniques showed blunted emotions
and elevated scores on the assessment of alexithymia 102.
High frequency electrical stimulation of the subthalamic nucleus altered emotional perception of (positive or
negative) emotional visual stimuli in patients with Parkinson’s disease 103.
Corpus callosum
In homo sapiens, abstract reasoning, symbolization, language, and introspection are highly developed cognitive
functions. Emotional processing requires the capacity to
translate body language into symbolic (emotional) language. Some authors observed that patients with agenesis
of the corpus callosum showed an impairment in paralinguistic information and prosody and concluded that individuals with, “agenesis of [the] corpus callosum appear
to lack interhemispheric integration of critical aspects of
language” (Paul et al. 104, p. 1). In an observational study
performed on 28 healthy women, language and visuospatial abilities were found be linked to dimensions of
the corpus callosum measured by inversion recovery
magnetic resonance images. Verbal fluency was found
directly correlated with splenium of corpus callosum,
whereas an inverse correlation was observed between
splenium dimension and language lateralization 105. The
importance of the corpus callosum in the pathogenesis of
alexithymia has been posited for some time based on the
observed dysfunctional transfer of information between
right and left hemisphere 106-108.
Frontal lobe
Frontotemporal structures in particular in the right hemisphere play a fundamental role in processing emotions 109
and are involved in frontostriatal circuitry which plays a
role in emotional awareness 110. The orbitofrontal cortex
is widely connected with limbic structures and beyond
(i.e., parietal, temporal, occipital) 69. Moreover, the orbitofrontal cortex is crucial in recognizing emotional vocal
and facial expressions 111 112.
In a study on 314 alcohol dependent subjects, regression
analysis provided evidence that frontal lobe dysfunction,
as assessed using the Frontal Systems Behavior Scale, or
FrSBe,”mediated the relationship between alexithymia
(TAS-20 total score) and risky alcohol use” 113.
The role of the right hemisphere in alexithymia has
emerged from studies of patients with right hemisphere
stroke 65 114. Paradiso et al. 115 observed that depressed pa-
Towards a classification of alexithymia:
tients with right hemisphere stroke often presented with
an apathetic and nondysphoric depression believed to be
the result of reduced emotional processing abilities. In addition, frontal lobe dysfunction may mediate the relationship between alexithymia and risk for drug addiction 113.
The review by Tabibnia and Zaidel 116 suggests that the
extant data supports the role of deficit in interhemispheric information transmission and poorer right hemisphere
functioning in alexithymia. This view was confirmed in a
recent (albeit small) study showing that the grey matter of
the right hemisphere (not the left) negatively was associated with alexithymia 90.
Amygdala and insula of Weil
The amygdala is thought be critical for emotional processing 117. It is made up of several nuclei, including the
lateral nucleus that connects with sensory cortical areas,
the central nucleus that is the output and connects with
brain stem areas subserving the neurovegetative manifestations of emotions, and the basal nucleus that is the relay between lateral and central nucleus 118 119. The amygdala is a node between the sensory input (to be) labelled
with an emotion and the emotional manifestations of the
body 120. Reduced activity in the amygdala can be responsible for an alteration in emotional processing. Because
of the key role of amygdala in emotional processing, it
is reasonable to speculate that the amygdala can have
pathogenetic role in alexithymic subjects.
Difficulty identifying feelings from the faces of others was
observed in 21 healthy subjects with a reduced activation
of amygdala by fMRI 121. Difficulty identifying emotions
was significantly and negatively correlated with the neural response of the amygdala to sad faces 121. Alexithymic
patients with anorexia nervosa showed poor amygdala
activation (as well as cingulate cortex) 122.
Higher levels of activation were observed in right insula
and in inferior frontal lobe of alexithymic patients 123.
The insula is connected with the amygdala and ACC and
plays an important role as a “prelimbic area” during emotional processing 124. To the elevated levels of insula activity can be attributed the somatic tendency of individuals
with alexithymia.
In summary, several brain regions are purportedly associated with alexithymia. At first glance, alexithymia may
appear to be the result of several disparate mechanisms.
While this may remain a possibility, a more parsimonious
view is that focal dysfunction in differing nodes of emotional processing networks may disrupt the functioning of
the entire network. Thus, a pattern of mental and behavioural dispositions consistent with alexithymia may occur
in association with dysfunction in differing nodes of the
brain supporting emotion processing.
Conclusions
Emotional processing encompasses cortical and subcortical brain mechanisms. Subcortical structures (limbic regions, basal ganglia) may allow for emotional processing
to occur at a level below conscious awareness, while the
cortex plays a role in (self)-awareness of emotional processing. The interaction between sub-cortical and cortical structures is fundamental for adaptive emotion processing. In the philosophic meditations of ancient Greeks
and Romans, emotions were understood as unnecessary
passions and were often viewed as diseases of the mind.
Contemporary views purport that poor recognition and
identification of emotions, including personal emotions,
may be maladaptive. In this review, we discussed primary
alexithymia, understood as a condition arising from various sources including genetic and experiential and distinguished between primary and secondary alexithymia. In
addition, we further differentiated secondary alexithymia
as deriving either from a psychological stressor or due
to an event that indirectly or directly impacts the brain.
Thus, we conclude that:
1. recognition and treatment of primary alexithymia is
warranted because of its potential as a risk factor for
psychiatric disorders 60. While evidence for a definitive etiological role of alexithymia in physical illness
is sparse, alexithymia may exert influence on illness
behaviour based on, “physical symptoms, disability,
and excessive health care use” 125;
2. secondary alexithymia may be a response to the psychological distress of an organic disease or psychological trauma;
3. organic alexithymia may be considered to be a specific subtype of secondary alexithymia that is a consequence of brain damage (e.g. traumatic or vascular) to
specific regions including the anterior cingulate, basal
ganglia, amygdala, insula, right hemisphere, and corpus callosum. In vulnerable individuals with brain injury, alexithymia may increase the risk of suicide 42.
In future research, it may be important to distinguish between treatment responses in primary, secondary and organic alexithymia 33.
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49
Original article
The role of drug therapies in the treatment of anorexia and bulimia nervosa:
a review of the literature
Il ruolo delle terapie farmacologiche nel trattamento dell’anoressia e della bulimia nervosa:
una revisione della letteratura
A. Tortorella1, M. Fabrazzo1, A.M. Monteleone 1, L. Steardo 1, P. Monteleone1 2
Department of Psychiatry, University of Naples - SUN, Naples, Italy; 2 Chair of Psychiatry, Department of Medicine and Surgery,
University of Salerno, Italy
1 Summary
Background
The present review summarizes published papers reporting the
results of both open-label and double-blind studies, which explored the potential efficacy of antidepressants, antipsychotics
and mood stabilizers in the treatment of anorexia nervosa (AN)
and bulimia nervosa (BN).
Methods
The literature was sourced from recent searches on Pubmed updated to January 2013 using the terms “eating disorders”, “pharmacotherapy”, “anorexia nervosa”, “bulimia nervosa”, “therapy”
or “treatment”. Studies were selected for inclusion if they met a
level of evidence that minimized the risk of bias such as randomized controlled trials (RCTs) or systematic review of RCTs.
Results
This critical review seems to suggest that selective serotonin
reuptake inhibitors (SSRI) have a proven efficacy in BN. An-
Introduction
Eating disorders (EDs) are complex and multifactorial
psychiatric diseases frequently occurring in female adolescents and young women that are characterized by
severe disturbances in eating behaviour with acute, life
threatening consequences 1. According to the Diagnostic
and Statistical Manual of Mental Disorders - Text Revision (DSM-IV-TR), EDs are divided into: anorexia nervosa
(AN), bulimia nervosa (BN), and eating disorders not otherwise specified (ED-NOS), which include binge-eating
disorder (BED).
AN is a severe disabling illness with one of the highest
mortality rates among psychiatric disorders mainly due
to undernutrition and suicide 2 3. It is characterized by restricted eating, loss of weight, obsessive fears of weight
tipsychotics seem to be potentially promising options in the
treatment of severe adult and adolescent AN patients, revealing
positive psychopathological effects and good tolerability. Other
treatments, such as the anticonvulsant topiramate in BN, may
be promising.
Conclusion
Even if there have been useful researches on the efficacy of pharmacotherapy in the treatment of BN, there are still many unsolved issues regarding the optimal management of other EDs.
Future directions for pharmacological treatment researches in
EDs should include randomized controlled trials with different
medications, inpatient versus outpatient trials and the assessment of medication effects for relapse prevention in recovered
patients.
Key words
Pharmacologic treatment • Eating disorders • Anorexia nervosa • Bulimia nervosa • Binge eating disorder
gain, absence of menses and a disturbance in body image represented by the feeling of being fat even when
underweight and a denial of the seriousness of emaciation 4-7. The average prevalence of AN has been reported
to be approximately 0.5% to 1% and is higher among
adolescent girls and young women 8 9. BN is characterized by binge-eating episodes, in which the individual
consumes a large amount of food with a sense of loss
of control, followed by compensatory behaviours to prevent weight gain such as purging, laxative abuse, excess
physical exercise and fasting because of the pathological
fear of weight gain 10-12. The prevalence of BN is 1.5 % in
young females and 0.5% in men 13. BED is characterized
by recurrent binge-eating episodes without compensatory behaviours that cause obesity 14-18. The prevalence of
BED ranges from 1% and 5% 9 13.
Correspondence
Alfonso Tortorella, Department of Psichiatry, Univesity of Naples - SUN, L.go Madonna delle Grazie, 80138 Naples, Italy • Tel. +39 081 5666516
• Fax +39 081 5666523 • E-mail: alfonsotortorella@gmail.com
50
Journal of Psychopathology 2014;20:50-65
The role of drug therapies in treatment of anorexia and bulimia nervosa
The treatment of EDs is a complex process where nutritional counselling and psychotherapy are of primary
importance, whereas psychotropic drugs play a secondary role. Recent data from animal and human research
support the rationale for pharmacological treatment of
EDs with drugs acting on serotonergic, dopaminergic
and opioidergic systems 19 20. New pharmacological approaches to EDs may arise from other biological markers
involved in appetite modulation, such as ghrelin, leptin
and cholecystokinin 21 22. Nevertheless, at the moment,
the main reason behind the use of drug therapy in patients with EDs remains the presence of a clear comorbid
psychopathology and the similarity between some symptoms of EDs and the symptoms that usually respond to
pharmacotherapy, such as affective, anxious and obsessive symptoms. Drug treatment is more effective on these
“secondary” symptoms than on the basic features commonly considered typical of EDs such as fears of weight
gain, disturbance in body image, binge-eating episodes
with or without compensatory behaviours, etc. However,
the approach of treating EDs with psychotropic drugs that
are effective for phenomenologically similar conditions
has proven to be simplistic, moreover, no drug or class of
drugs has emerged as an effective agent to treat patients
with these disorders 23-25.
Although developing effective treatments for these disorders is critical, the challenge for drug treatments in EDs
patients should consider the restoration of body weight to
a normal range, in order to resolve most of the physical
and physiological complications, and the reduction of
the distorted perception of body image and related consequences (mood and anxiety symptoms, obsessive-compulsive behaviours, aggressiveness). On the other hand,
when using medications to treat comorbid conditions in
people with EDs, particular attention should be given to
dosage of drugs and physical monitoring. In particular,
side effects of psychotropic medications should be carefully investigated, since these drugs may sometimes lead
to development of adverse reactions or exacerbate the
physical complications already present in EDs patients 26.
The present review summarizes published papers reporting the results of both open-label and double-blind studies that explored the potential efficacy of antidepressants,
antipsychotics and mood stabilizers in the treatment
of AN and BN. The literature was sourced from recent
searches updated to January 2013 with a Pubmed search
using the terms eating disorders, pharmacotherapy, anorexia nervosa, bulimia nervosa, therapy or treatment.
Studies were selected for inclusion if they met a level of
evidence that minimized risk of bias such as randomized
controlled trials (RCTs) or systematic review of RCTs. We
also included studies of case series or case reports or
non-randomized trials where there were no RCTs of an
agent or where they were of relevance in presaging RCTs.
Antidepressant drugs
Anorexia nervosa
Tricyclic antidepressants
The use of tricyclic antidepressants (TCAs) in the treatment of AN has been explored since the 1980s with varying results. A double-blind placebo controlled study 27
evaluated the efficacy of clomipramine in a group of
16 AN inpatients. Compared to placebo, clomipramine
was significantly associated with increased hunger, appetite and energy intake, but there was a reduced rate
of weight gain.
Biederman et al. 28 evaluated amitriptyline as a short-term
treatment of AN patients. In a 5-week double-blind, placebo-controlled study, 11 patients received amitriptyline
and 14 received placebo. Eighteen patients who refused
to participate in the drug trial and received only psychosocial treatment were used as an additional comparison
group. No statistically significant differences between
placebo and amitriptyline were found in any outcome
variables, and there was no evidence of improvement in
either psychiatric symptomatology or body weight.
A placebo controlled double-blind study evaluated 72
AN patients randomly assigned to receive cyproheptadine (maximum daily dose 32 mg), amitriptyline (maximum daily dose 160 mg) or placebo. Cyproheptadine
significantly increased treatment efficiency for the nonbulimic patients, and significantly impaired treatment efficiency for the bulimic patients compared with the amitriptyline- and placebo-treated groups 29.
Selective serotonin reuptake inhibitors
A small open trial with fluoxetine was conducted by
Gwirtsman et al. 30 on 6 patients with chronic, refractory
AN. Fluoxetine treatment was associated with weight gain
and reduction of depressive symptoms. Kaye et al. 31 administered an open trial of fluoxetine to 31 AN patients. The
authors judged response as good in 10, partial in 17 and
poor in 4 anorexics as measured by improvements in eating
behaviour, mood and obsessional symptoms. Restrictingtype anorexics (AN-R) responded significantly better than
bulimic and/or purging-type anorexics (AN-BP).
Brambilla et al. 32 33 published two papers on AN patients.
In the first study, 22 female patients with AN-R, 14-35
years old, were treated with a 4-month course of combined cognitive-behavioural therapy, nutritional counselling and antidepressant drugs (nortriptyline, amineptine
and fluoxetine). Body mass index (BMI), depression, anxiety and Eating Disorder Inventory (EDI) scores improved
significantly and equally in both groups during the 4
months of therapy, while BITE scores did not change. In
the second study, 13 women with AN-BP, 17-43 years
51
A. Tortorella et al.
old, were treated and monitored in the same way with
similar results.
A randomized, placebo-controlled, double-blind study
was performed by Attia et al. 34. Thirty-one AN women
treated at an inpatient research unit with CBT were randomly assigned to fluoxetine (60 mg/day) or matching
placebo for 7 weeks. No significant differences emerged
in clinical outcome on any measure between the fluoxetine and placebo groups.
In a 24-month naturalistic, prospective longitudinal
follow up study conducted in 33 AN patients treated
with fluoxetine 35, there was no difference in probability at maintaining weight post discharge compared to
a matched historic case-control sample. In a second
study 36, the same research group investigated response
to fluoxetine in adolescents hospitalized for treatment of
AN. Patients received open label fluoxetine as add-on
to their multidisciplinary treatment regimen for 6 weeks.
Fluoxetine did not show any additive or synergistic therapeutic benefit compared with the effects of intensive,
multidisciplinary inpatient therapy.
More recently, Yu et al. 37 published a randomized clinical trial with 122 participants treated with CBT, drug
therapy (fluoxetine) or both (CBT + fluoxetine) for 12
months. The 52 participants who completed follow-up
increased mean body weight. Using most stringent criteria for recovery, only 21% of the completers recovered.
Fluoxetine has been studied also as a maintenance treatment in AN patients after recovery from BW. A double-blind placebo-controlled trial with fluoxetine in 35
weight-recovered AN outpatients was carried out by Kaye
et al. 38. After 1 year, 10 out 16 (63%) subjects remained
on fluoxetine, whereas only three out 19 (16%) remained
on placebo. The subjects remaining on fluoxetine for one
year had reduced relapse as shown by a significant increase in weight and reduction in symptoms.
Walsh et al. 39 performed a randomized, double-blind,
placebo-controlled trial in 93 weight-recovered AN patients; 49 were assigned to fluoxetine (mean dose 63.5
mg/day) and 44 to placebo. The study failed to demonstrate any efficacy of fluoxetine in the treatment of AN
patients following weight restoration.
The efficacy of the SSRI citalopram was evaluated in 32
AN-R patients, who were enrolled in a 6-month open trial with citalopram (20 mg/day) 40. At the end of the trial,
46.9% of patients showed a satisfactory response, while
34.4% had an unsatisfactory response considering both
clinically objective and subjective aspects.
Calandra et al. 41 investigated the efficacy and safety of 20
mg/day citalopram for 8 weeks in 18 ED patients (12 ANR - 6 BN). The results showed that citalopram is effective
and safe in the treatment of EDs, since patients showed
a significant improvement in body dissatisfaction, but no
effect on body weight.
52
An open trial was conducted by Fassino et al. 42 on 26
AN outpatients taking citalopram and 26 without medication. After 3 months of treatment, the citalopram group
showed an improvement in depression, obsessive-compulsive symptoms, impulsiveness and trait-anger without
any significant effect on BMI.
An open controlled trial with 22 AN-R patients compared
11 AN patients treated in an outpatient setting with sertraline to 11 AN patients evaluated as a control group.
After 14-weeks, the sertraline group reported a significant
effect on depressive symptoms, but not weight gain 43.
Other antidepressants
The efficacy of venlafaxine (75 mg/day) or fluoxetine (40
mg/day) plus CBT has been evaluated in 24 atypical AN
patients. After 6 months of treatment, venlafaxine and
fluoxetine were associated with an increase in BMI and a
significant improvement in eating psychopathology, suggesting that venlafaxine is as effective as fluoxetine when
combined with CBT in the treatment of atypical AN 44.
Case reports published in recent years also demonstrate
the efficacy of new generation antidepressants such as
duloxetine 45 and mirtazapine 46-50 in the treatment of
acute AN patients. Double-blind controlled studies are
needed to confirm the usefulness of these drugs in the
acute phase of AN.
Bulimia nervosa
Tricyclic antidepressants
In 1986, Hughes et al. 51 published a double-blind, placebo-controlled trial of desipramine in 29 BN outpatients.
Patients taking desipramine presented a significant benefit from treatment (91% decrease in binge frequency) in
contrast with the results from the placebo group (19%
increase in binge frequency). Subsequently, Barlow et
al. 52 conducted a double-blind crossover trial with desipramine 150 mg/day. Forty-seven normal weight BN
patients were randomly assigned to receive either desipramine for six weeks, no drug for three weeks, followed
by placebo for six weeks, or the reverse sequence. The
clinical effect was modest; desipramine was significantly
more effective in reducing the frequency of weekly vomiting and binging.
Blouin conducted two different trials with desipramine.
In the first study, desipramine and fenfluramine were administered to 22 normal weight BN patients in a 15-week,
double-blind, placebo-controlled, crossover design trial.
The results indicated that both drugs had beneficial effects on binge and vomit frequency, although a greater
proportion of patients responded better to fenfluramine
than to desipramine 53. In the second study, 24 normal
weight BN patients were assigned to a 15-week, rand-
The role of drug therapies in treatment of anorexia and bulimia nervosa
omized double-blind crossover design in which they
received either desipramine (150 mg/day) for six weeks,
and no drug for three weeks, followed by placebo for
six weeks or the reverse sequence. In terms of reduction
in binge frequency, seven responders were identified;
another seven were found to be borderline responders,
while 10 were labelled as non-responders 54.
A group of 80 BN patients (aged 18-45 years) entered
a 3-phase (8-week; 16-week; 4 month) treatment protocol to assess the efficacy of desipramine vs. placebo
in the treatment of BN. In the 8-week initiation phase,
desipramine was superior to placebo in reducing binge
frequency and in other measures of behavioural and psychological disturbances characteristic of BN. There were
not enough patients in the discontinuation phase to allow
clear conclusions about the need to continue antidepressant medication after 6 months of treatment 55.
Agras et al. 56 performed a 16-24 week controlled trial
in 71 BN outpatients randomly assigned to one of five
groups: desipramine (withdrawn at 16 or 24 weeks),
CBT (15 sessions), or combined treatment (18 sessions
of CBT plus desipramine, withdrawn at 16 or 24 weeks).
The results were analyzed as three groups (medication,
cognitive-behavioural therapy and combined treatment).
After 16 weeks and as five groups at subsequent assessment. At 16 weeks, both cognitive-behavioural therapy
and combined treatment were superior to medication
alone in reducing binge eating and purging. The combined treatment was superior to medication and more
effective in reducing dietary preoccupation and hunger.
Continuing CBT appeared to prevent relapse in patients
withdrawn from medication after 16 weeks. The results
demonstrated that CBT and combined therapy were superior to medication alone.
Recently, Walsh et al. 57 reviewed data from two previously published studies with desipramine in a total of
77 BN patients to evaluate whether an early response to
medication predicted the efficacy of treatment at the end
of a controlled trial. The authors concluded that BN patients who will not respond to antidepressant medication
can be identified in the first 2 weeks of treatment.
Pope et al. 58 conducted a double-blind study of imipramine versus placebo in 22 bulimic women. Imipramine
showed a significant reduction in the frequency of binge
eating and the improvement on several other measures
of eating behaviour. Agras et al. 59 performed a placebocontrolled double-blind trial with imipramine in 22 BN
patients over a period of 16 weeks. Patients receiving the
active drug demonstrated significantly greater reduction
in purging at both the 6th and 16th weeks as well as a reduction in depressive symptomatology at week 6.
Mitchell et al. 60 in a 12 week comparison study of imipramine and structured group psychotherapy in BN outpatients showed that the addition of imipramine to group
psychotherapy did not significantly improve outcome in
terms of eating behaviour, but reduced symptoms of depression and anxiety.
Alger et al. 61 in an 8 week placebo-controlled study with
imipramine (up to 150 mg/day), naltrexone (100-150 mg/
day) and placebo in 33 obese bingers and 22 normoweight bulimics showed a significant reduction of binge
duration with imipramine only in obese bingers.
Mitchell and Groat 62 conducted a placebo-controlled,
double-blind study of amitriptyline (150 mg at bedtime)
in a group of 32 BN outpatients showing a clear improvement in eating behaviour in both groups.
Selective serotonin reuptake inhibitors
Fichter et al. 63 randomly assigned 40 BN patients to either 60 mg fluoxetine or to a placebo control group in a
double-blind trial lasting 35 days. Even in the presence of
a significant reduction in body weight in the group treated with fluoxetine, especially during the first three weeks
of treatment, there was no significant difference between
the two groups in eating attitudes, eating behaviour and
general psychopathology. The authors noted that these
results were due to a “ceiling effect”.
The Fluoxetine Bulimia Nervosa Collaborative Study
Group in 1992 64 published an 8-week, double-blind trial
comparing fluoxetine (60 and 20 mg/day) with placebo in
387 BN outpatients. Fluoxetine 60 mg/day was superior
to placebo in decreasing the frequency of weekly binge
eating and vomiting episodes; depression, carbohydrate
craving, and pathologic eating attitudes and behaviours
also improved significantly. Fluoxetine at 20 mg/day produced an effect between that of the 60-mg/day dosage
and that of placebo.
Goldbloom et al. 65 evaluated 382 BN patients in an 8
weeks multicentre, double-blind, randomized clinical trial of placebo and fluoxetine 20 and 60 mg/day. Patients
receiving fluoxetine showed more clinically significant
changes in the majority of psychological measures than
those receiving placebo.
Beumont et al. 66 randomly assigned 67 BN patients treated with intensive nutritional counselling to either fluoxetine (60 mg/day) or placebo. Both groups of patients improved significantly during treatment, but the fluoxetine
group did slightly better than placebo in eating-related
psychopathology.
A large collaborative study published by Goldstein et
al. 67 confirmed that fluoxetine is effective and safe in
treating patients with BN. A total of 398 BN outpatients
were randomly assigned to either a 60 mg fluoxetine
group or to a placebo control group over 16 weeks, in
a multicentre double-blind placebo-controlled study.
Compared with placebo, fluoxetine treatment resulted
in significantly greater reductions in vomiting and binge
53
A. Tortorella et al.
Table I.
Summary of the main RCTs related to medications used in AN. Sintesi dei principali RCT riferiti ai farmaci usati nell’AN.
Medication
Daily doses
Effects
Authors
Antidepressant
Amitriptyline
115 mg
= placebo
Biederman et al. (1985)
Clomipramine
50 mg
+ hunger, appetite
Lacey & Crisp (1980)
Fluoxetine
56 mg
= placebo
Attia et al. (1998)
Fluoxetine
20 mg
reduced relapse vs. placebo
Kaye et al. (2001)
Fluoxetine
60 mg
reduced relapse after weight gain vs. placebo
Yu et al. (2011)
Pimozide
4-6 mg
= placebo
Vandereycken & Pierloot (1982)
Sulpiride
300-400 mg
= placebo
Vandereycken (1984)
Antipsychotic
Amisulpride
50 mg
+ weight gain vs. antidepressants
Ruggiero et al. (2001)
Olanzapine
5-20 mg
+ reduction in ruminations vs. 25-100 chlorpromazine
Mondraty et al. (2005)
Olanzapine
2.5-5 mg
+ weight gain and reduction psychological distress vs. placebo Brambilla et al. (2007)
Olanzapine
2.5-10 mg
+ weight gain and reduction obsessive symptoms vs. placebo
Bissada et al. (2008)
Olanzapine
2.5-10 mg
+ weight gain vs. placebo
Attia et al. (2011)
Olanzapine
2.5-10 mg
= placebo
Kafantaris et al. (2011)
Quetiapine
177.7 mg
= placebo
Powers et al. (2012)
Risperidone
2.5 mg
= placebo
Hagman et al. (2011)
AN: anorexia nervosa; RCT: randomized controlled trial.
eating episodes per week as well as an improvement in
other outcome measures. Goldstein et al. 68 made a retrospective analysis of two parallel, multicentre, doubleblind, randomized, placebo-controlled fluoxetine clinical trials in order to determine whether the antibulimic
effects of fluoxetine were related to its antidepressant effect. Treatment with fluoxetine (60 mg/day) significantly
reduced the mean number of binge eating and vomiting
episodes regardless of the presence or the absence of
depression, and thus fluoxetine’s efficacy in treating BN
was not considered to be simply a secondary effect of its
antidepressant properties.
The efficacy of fluoxetine in BN has also been evaluated
in comparison to psychotherapies or in combination with
psychotherapies. Walsh et al. 69 showed that patients receiving antidepressants (either fluoxetine or desipramine)
in combination with psychological treatment experienced greater, although modest, improvement in binge
eating and depression than patients receiving placebo
and psychological treatment.
In a double-blind trial, Goldbloom et al. 70 randomly
assigned 76 BN patients to either fluoxetine, CBT or
fluoxetine + CBT combination. At the end of the trial,
the combination of pharmacotherapy and psychotherapy
was superior to pharmacotherapy alone, but there was no
54
statistical evidence of an advantage of the combination
over CBT alone. Similarly, Ricca et al. 71 assigned 51 BN
outpatient either to CBT or combined Group Psychoeducation and fluoxetine treatment (GPF). The data obtained
suggested that GPF is as effective as CBT in reducing bulimic symptomatology.
A double-blind, placebo-controlled trial evaluated 22 BN
patients who had not responded to, or had relapsed following, a course of CBT or interpersonal psychotherapy.
The authors randomly assigned BN patients to a placebo
or fluoxetine group (60 mg/day) for 8 weeks. They found
a decreased frequency of binge eating and purging in the
group of patients treated with fluoxetine and concluded that
fluoxetine may be a useful intervention for patients with BN
who have not responded adequately to CBT treatment 72.
Two studies evaluated the efficacy of fluoxetine vs. selfhelp manual or guided self-help. Mitchell et al. in 2001 73
found that fluoxetine and a self-help manual were equally
effective in reducing the frequency of vomiting episodes
and in improving response rates for vomiting and binging episodes. Walsh et al. 74, on the other hand, found
that patients assigned to fluoxetine exhibited a greater reduction in binge eating and vomiting, and had a greater
improvement in psychological symptoms than those assigned to placebo or guided self-help.
The role of drug therapies in treatment of anorexia and bulimia nervosa
The long-term efficacy of fluoxetine in BN has been
evaluated vs. placebo or CBT. Jacobi et al. 75 found that
both CBT, fluoxetine and the combined treatments led to
equally significant improvements in ED symptoms and in
other psychological disturbances, which could be maintained at 1-year follow-up.
In the study of Romano et al. 76, 150 BN patients, responders to a single-blind 8-week treatment with fluoxetine or
placebo, were followed for 52 weeks in order to compare
the efficacy and safety of a treatment with fluoxetine (60
mg/day) versus placebo in preventing relapse. The fluoxetine group showed a time to relapse that was significantly
longer compared to placebo, but at 1-year follow-up there
were no significant differences between the two groups.
In the study of Fichter et al. 77, 72 BN patients treated
successfully with psychotherapy were randomized in a
double-blind, placebo-controlled study with fluvoxamine and placebo over a period of about 15 weeks. Fluvoxamine had a significant effect in delaying relapse of
bulimic behaviour.
Schmidt et al. 78 conducted a randomized, double-blind,
placebo-controlled trial with 267 BN patients divided into three groups: an 8 week short-term fluvoxamine therapy followed by 44 week placebo intake, a group receiving fluvoxamine over the entire 52 weeks and a placebo
control group. There was no significant difference among
the groups.
Milano et al. 79 performed a 12-week randomized placebo controlled trial with fluvoxamine (200 mg/day) in
12 female BN patients. Fluvoxamine determined a significant reduction in binge eating and purging episodes
compared to placebo.
The efficacy of citalopram in BN has been evaluated in
two studies. Sundblad et al. 80 randomized 46 BN patients
to receive either the androgen receptor antagonist flutamide, the serotonin reuptake inhibitor citalopram, flutamide + citalopram, or placebo alone. Only the groups
treated with flutamide showed a statistically significant
reduction in binge eating. Leombruni et al. 81 compared
fluoxetine with citalopram in the treatment of 37 BN patients. Patients treated with fluoxetine showed a greater
reduction in interjected anger, whereas those in the citalopram group displayed a greater reduction in depressive
feelings. The authors concluded that citalopram may be
useful in depressed patients with BN, whereas fluoxetine is
more specific for those with interjected anger and bulimia.
Two small trials 82 83 assessed the efficacy of sertraline in
BN patients and found a significant reduction in the number of binges and purges per week.
Monoamine oxidase inhibitors
Walsh et al. 84-86 conducted 3 different double-blind placebo-controlled studies comparing the efficacy of the in-
hibitor of monoamino-oxidase A (IMAO-A) phenelzine
and placebo. In all these studies, including a total of 100
BN patients, phenelzine was significantly superior to placebo in reducing binge frequency and several measures
of psychopathological status. Patients did not experience
severe side effects that could limit the use of phenelzine.
Rothschild et al. 87 examined the efficacy of phenelzine,
imipramine and placebo in 24 BN patients with comorbid atypical depression. The improvement observed for
both depressive and bulimic symptoms with phenelzine
was greater than that with either imipramine or placebo.
Two double-blind, placebo-controlled studies showed
that isocarboxazide 88 and brofaromine 89 significantly reduced binge eating and vomiting in BN patients.
A double-blind placebo-controlled trial was carried out to
assess efficacy and tolerability of 600 mg/day of moclobemide in the treatment of 52 BN patients. Six weeks of treatment were not significantly superior to placebo in reducing
the weekly number of binge eating episodes or in improving
several measures of eating attitudes and behaviour 90.
Other antidepressants
Two open studies 91 92 have suggested the efficacy of reboxetine in reducing both binge eating frequency and
eating-related psychopathology in BN.
The efficacy of bupropion was evaluated by Horne et al. 93
in 81 non-depressed BN patients randomly assigned to a
double-blind study with bupropion (n = 55) and placebo
(n = 26). Bupropion was significantly superior to placebo
in reducing episodes of binge eating and purging behaviour, but four subjects experienced grand mal seizures during treatment with bupropion, a frequency far higher than
that observed in previous studies with this drug.
Trazodone was shown to be significantly superior to placebo in reducing the frequency of episodes of binge eating
and vomiting in a double-blind placebo-controlled study 94.
Sabine et al. 95 published an 8-week randomized, placebo–controlled, double-blind study with mianserin in 50
BN patients. Patients treated showed improvement over
placebo for eating attitudes and behaviour as well as for
anxiety and depression scores.
Antipsychotic drugs
Anorexia nervosa
First generation antipsychotics
Chlorpromazine (up to 1,000 mg/day) was the first typical antipsychotic drug assessed for the treatment of AN
in a study by Dally and Sargant 96. Subsequently, three
controlled studies investigated the efficacy of pimozide
(4 or 6 mg/day) 97 98 and sulpiride (300-400 mg/day) 99.
In general, no effects on weight or eating behaviour
55
A. Tortorella et al.
were discernable. Ruggiero et al. 100 conducted a singleblind comparison to evaluate the efficacy of amisulpride,
fluoxetine and clomipramine at the beginning of the refeeding phase of the treatment of restricting AN patients.
After three months of treatment, the amisulpride (mean
dose 50 mg/day) and fluoxetine (mean dose 28 mg/day)
groups showed a significant increase in weight from
baseline to the end of trial, but no difference for weight
phobia, body image and eating behaviour. Finally, Cassano et al. 101 reported an open trial with 13 outpatients
affected by severe treatment-resistant ANR where haloperidol was effective when used as an adjunctive drug for
more than six months.
Second generation antipsychotics
Olanzapine
Four randomized double-blind, placebo-controlled, studies of olanzapine in adult subjects affected by AN have
been reported. Mondraty et al. 102, compared olanzapine
with chlorpromazine in the treatment of intrusive cognitions in female AN patients. Olanzapine was started at 5
mg/day and then increased by 2.5-5 mg/day to a maximum dose of 20 mg/day (n = 8), while the dose of chlorpromazine was 25 mg at the beginning of the trial and
increments of 25-50 mg/week up to a maximum dose of
2000 mg/day were allowed (n = 7). The Padua Inventory
(PI) Scale was employed in order to quantify the distress
and the level of rumination that subjects had about their
anorexic cognition, and the authors concluded that the
reduction in ruminative thinking, as shown by the PI subscale scores, was significantly greater in the olanzapine
group than in the control group and that these changes
were independent from weight gain or sedation, which
did not differ significantly between the two groups.
Brambilla et al. 103 reported the effects of olanzapine therapy in patients affected by AN after three months of CBT.
Thirty AN patients (18 restricted and 12 binge-purging)
were randomly assigned to a double-blind, placebo-controlled trial with oral olanzapine (2.5 mg for 1 month, 5
mg for 2 months). BMI increased significantly in both treatment groups without any significant difference between
the two treatments. When patients were divided according
to the type of AN (AN-R and AN-BP), the increase in BMI
was significantly greater in the CBT + olanzapine-treated
AN-BP patients than in all the other participants. The results of the Eating Disorder Inventory-2 (EDI-2) revealed
that there was no significant difference in the values of all
items between CBT + olanzapine and CBT + placebo patients at each point of the treatments except for the ineffectiveness and maturity of fear items, which improved only
in CBT + olanzapine-treated patients. No increase in bulimic symptomatology was observed in olanzapine + CBT
treated AN-BP patients. The Yale Brown Cornell for Eating
56
Disorders Rating Scale (YBC-EDS) for obsessiveness-compulsivity revealed significant improvement in total values
and in the obsessiveness score (preoccupations) in both
treatment groups, whereas only CBT + olanzapine-treated
patients showed a significant improvement in compulsivity score (rituals). Significant improvement was found in
total Buss-Durkee Hostility Inventory values in both treatment groups and in the subitem ‘direct aggressiveness’
only in CBT + olanzapine-treated patients. Depression improved significantly in both treatment groups, but the antidepressant effect was more significant in the CBT + olanzapine than in the CBT + placebo group. Taken together,
these data show that the pharmacological treatment was
significantly effective in improving specific aspects of AN
suggesting that, in the future, pharmacotherapies must be
targeted to well-known and carefully controlled brain biochemical impairments known to be responsible for specific psychopathological aspects.
A randomized, double-blind, placebo-controlled trial by
Bissada et al. 104 investigated the use of olanzapine in the
treatment of low-body weight and obsessive thinking of
women with AN. The study was a 10-week flexible dose
trial in which patients with AN (n = 34) were randomly
assigned to either olanzapine plus day hospital treatment
(n = 16) or placebo plus day hospital treatment (n = 18).
Olanzapine was prescribed according to a flexible dose
regimen, starting at the minimum dose of 2.5 mg/day and
titrated slowly by increments of 2.5 mg/week to a maximum dose of 10 mg/day. Growth curves were used for the
assessment of the differential rate or rapidity of increase in
BMI across treatment conditions, and the results showed
changes in the two trajectories indicating that all patients,
both those receiving placebo and those receiving olanzapine, presented significant increases in BMI across the
13 weeks of the trial. However, patients receiving olanzapine showed a greater rate of increase in BMI across
weeks compared to patients receiving placebo.
The efficacy of olanzapine was evaluated in AN outpatients by Attia et al. 105. A total of 23 anorexic individuals were randomly assigned, according to a double-blind
design, to receive olanzapine or placebo for 8 weeks
together with medication management sessions that emphasized compliance. The end-of-treatment BMI, with
initial BMI as a covariate, was significantly greater in the
group receiving olanzapine. Psychological symptoms
improved in both groups, but there were no statistically
significant differences. Of the 23 participants, 17 (74%)
completed the 8-week trial. Participants tolerated the
medication well with sedation being the only frequent
side effect, and adverse laboratory changes suggestive of
metabolic abnormalities were not observed. This small
study suggests that olanzapine is generally well tolerated
by AN patients and may provide more benefits than placebo for outpatients with this type of ED.
The role of drug therapies in treatment of anorexia and bulimia nervosa
The most recent studies conducted on adolescents include
3 different trials. Leggero et al. 106 performed a 6-month
trial with 13 adolescent AN-R patients (age range 9.616.3 years). Patients were enrolled in multimodal treatment and evaluated at baseline and 1 and 6 months after
starting low-dose olanzapine monotherapy (mean dose
4.13 mg/day). A significant improvement on weight, recovery and global functioning, hyperactivity, was evident
at the end of the first month of treatment, and further increased in the following 5 months, with minimal side effects. The authors concluded that low-dose of olanzapine
monotherapy may be useful as adjunctive treatment of
young patients with AN-R. It is suggested that its efficacy
may be mediated by a decrease of hyperactivity.
A placebo-controlled pilot study of adjunctive olanzapine
for adolescents with AN has also been recently published
by Kafantaris et al. 107. In a 10-week, double-blind, placebo-controlled study the authors explored whether the addition of olanzapine versus placebo increased weight gain
and improved psychological symptoms in 20 underweight
female adolescents with AN-R type, who were participating in a comprehensive EDs treatment program. Fifteen
out of 20 enrolled females (average age, 17.1 years; range,
12.3-21.8 years; mean BMI, 16.3) completed this 10-week
pilot study. Change in average body weight did not differ
between the treatment groups at midpoint or at the end
of the study. Both groups gained weight at a similar rate
and had similar improvements in eating attitudes and behaviours, psychological functioning and resting energy expenditure. A trend of increasing fasting glucose and insulin
levels was found only in the olanzapine group at week 10.
The conclusion of this study was that the findings do not
support a role for adjunctive olanzapine in underweight
adolescent females with AN-R types who were receiving
standard care in ED treatment program.
Moreover, Norris et al. 108 recently completed a retrospective, matched-group comparison study in which
they examined the assessment and treatment profiles of
adolescents with AN who received olanzapine compared
to untreated matched samples. Patients treated with olanzapine (the most common dose was 5 mg/day) displayed
greater evidence of psychopathology and medical compromise at the time of first assessment compared to untreated patients. Moreover, the rate of weight gain was
not statistically different between groups. Therefore, although this study provides some insight into the clinical
parameters that might drive olanzapine prescription as
an adjunctive treatment for adolescents with AN, the authors could not draw any firm conclusions about the potential efficacy of the antipsychotic because the patients
treated with olanzapine presented a greater acuity and a
more complex psychopathology than those not treated
with olanzapine, which rendered comparisons on the efficacy of the drug difficult.
The effectiveness of olanzapine has been analyzed in several case reports. La Via et al. 109 treated with olanzapine
in open trials 2 severe AN patients who had failed multiple other treatments. Olanzapine administration was associated with weight gain and maintenance as well as
reduced agitation and resistance to treatment. Mehler et
al. 110 published a case report of 5 children and adolescents with chronic AN treated with olanzapine, revealing
that a variable dose of the drug (from 2.5 up to 10 mg/
day) was efficacious in reducing weight phobia and body
image disturbances without a significant weight increase
induced by the drug. As a result, in the 5 cases reported,
treatment with olanzapine demonstrated consistent improvement in severe chronic AN. A case report published
by Boachie et al. 111 examined the therapeutic benefit
and tolerability of olanzapine (2.5 mg/day) as adjunctive
treatment in 4 children. Olanzapine use was associated
with considerable weight gain and a clinically notable
decrease in levels of agitation and premeal anxiety, and
almost immediate improvement in sleep, general functioning and overall compliance with treatment.
Two small open-label trials with olanzapine have been
published. The first by Powers et al. 112 is an open-label
10-week study of olanzapine 10 mg/day in 18 AN outpatients. All 14 patients who completed the study showed a
clinically-significant increase in body weight. In the second trial, published by Barbarich et al. 113, 17 AN patients
were enrolled in open-label treatment with olanzapine
for 6 weeks. Olanzapine administration was associated
with a significant reduction in depression, anxiety, eating symptoms and a significant increase in weight. An
open-label retrospective study in 18 AN patients by Malina et al. 114 reported a significant reduction in frequency
of obsessive thoughts about body image and fear of being fat, reduced anxiety before and during meals and an
increased ability or desire to eat meals. In addition, subjects reported being less upset if they gained weight.
Taken together, the data from studies on olanzapine in
adults, but not in adolescent anorexic patients, although
with a number of different limitations, show that this
pharmacological treatment can be significantly effective
in improving specific aspects of AN, but not all symptoms. Olanzapine, with its side effect profile of weight
gain and antiobsessive and antidepressant properties, is
a promising drug to study for the treatment of severely
emaciated and obsessional AN patients. Therefore, further studies are warranted to confirm these findings.
Quetiapine
An open, controlled 8-week trial with 8 AN patients
conducted by Bosanac et al. 115 revealed a significant effectiveness of quetiapine (doses ranged from 50 mg to
800 mg per day, according to efficacy and tolerability).
57
A. Tortorella et al.
Table II.
Summary of the main RCT related to medications used in BN. Sintesi dei principali RCT riferiti ai farmaci usati nella BN.
Medication
Daily doses
Effects
Authors
Imipramine
200 mg
Bulimic symptom reduction vs. Placebo
Pope et al. (1983)
Imipramine
300 mg
Outcome = placebo
Mitchell et al. (1990)
Desipramine
200 mg
Reduction on bingeing and vomiting vs. Placebo
Hughes et al. (1986)
Desipramine
desi 150 mg; fen 60 mg
Beneficial effects on bingeing and vomiting vs. Placebo
Blouin et al. (1988)
Desipramine
150 mg
Significant reduction on bingeing and vomiting vs. Placebo Blouin et al. (1989)
Desipramine
300 mg
Beneficial effect in binge frequency vs. Placebo
Walsh et al. (1991)
Desipramine
300 mg
Cbt and combined therapy superior to medication alone
Agras et al. (1992)
Phenelzine
60-90 mg
Bulimic symptom reduction vs. placebo
Walsh et al. (1984)
Phenelzine
90 mg
Bulimic symptom reduction vs. placebo
Walsh et al. (1985)
Phenelzine
90 mg
Bulimic symptom reduction vs. placebo
Walsh et al. (1988)
Isocarboxacid
60 mg
Bulimic symptom reduction vs. placebo
Kennedy et al. (1988)
Brofaromine
175-200 mg
Bulimic symptom reduction vs. placebo
Kennedy et al. (1993)
Moclobemide
600 mg
Bulimic symptom reduction vs. placebo
Carruba et al. (2001).
Fluoxetine
60 mg
= Placebo
Fichter et al. (1991)
Fluoxetine
20-60 mg
Bulimic symptom reduction vs. Placebo
(FBNCSG, 1992)
Fluoxetine
20-60 mg
Bulimic symptom reduction vs. Placebo
Goldbloom et al. (1993)
Fluoxetine
60 mg
Beneficial effects on bulimia symptom vs. Placebo
Beumont et al. (1997)
Fluoxetine
60 mg
Bulimic symptom reduction vs. Placebo
Goldstein et al. (1995)
Fluoxetine
flu 60 mg; desi 300 mg
Significant reduction on bingeing and depression vs. Pla- Walsh et al. (1997)
cebo
Fluoxetine
60 mg
Beneficial effects on bulimic symptom vs. Placebo
Fluoxetine
60 mg
Beneficial effects on bulimic symptom in pz non responded Walsh et al. (2000)
psychotherapy
Fluoxetine
60 mg
Beneficial effects on bulimic symptom vs. Placebo
Mitchell et al. (2001)
Fluoxetine
60 mg
Beneficial effects on bulimic symptom vs. Placebo
Walsh et al. (2004)
Fluoxetine
flu 20 mg; cit 20 mg
No diferences in outcome vs. Citalopram
Leombruni et al. (2006)
Fluvoxamine
300 mg
Significant effect in reducing the return of bulimic behavior Fichter et al. (1996)
vs. Placebo
Fluvoxamine
300 mg
No significant difference between the groups
Schmidt et al. (2004)
Fluvoxamine
200 mg
Significant reduction on bingeing vs. Placebo
Milano et al. (2005)
Citalopram
cit 40 mg; flut 500 mg
No significant difference vs. Placebo
Sundblad et al. (2005)
Sertraline
100 mg
Significant reduction on bingeing vs. Placebo
Milano et al. (2004)
Mianserin
30-60 mg
Bulimic symptom reduction vs. Placebo
Sabine et al. (1983)
Trazodone
355-400 mg
Bulimic symptom reduction vs. Placebo
Pope et al., (1989)
Bupropion
450 mg
Reduced bulimic symptoms with high seizure rates
Horne et al. (1988)
Topiramate
25-400 mg
Reduced bulimic symptoms + weight loss vs. Placebo
Hoopes et al. (2003)
TCAs
MAOIs
SSRI
Goldbloom et al. (1997)
Other
BN: bulimia nervosa; CBT: Cognitive Behavior Therapy; MAOIs: monoamine oxidase inhibitors; RCT: randomized controlled trial; SSRIs: selective serotonin re-uptake inhibitors; TCAs: tricyclic antidepressants.
58
The role of drug therapies in treatment of anorexia and bulimia nervosa
All participants treated with quetiapine adjunct to specialist multidisciplinary treatment over the course of 4
and 8 weeks had a clinically significant improvement of
anorexic symptoms, especially restrictive behaviour as
shown by the Eating Disorder Examination-12th Edition,
(EDE-12), whereas obsessive-compulsive and depressive
symptoms as assessed by Yale-Brown Obsessive-Compulsive Scale (YBOCS) and Montgomery-Åsberg Depression Rating Scale (MADRS) as well as anorexic delusional
beliefs about weight, eating and shape (as assessed by
the delusion subscale of the Scale for the Assessment of
Positive Symptoms (SAPS) after 4 weeks showed only a
trend towards improvement. After 4 weeks of treatment,
there was a significant difference in the restraint score of
the EDE-12, but no change in BMI, while at the end of
the 8-week study, significant differences both in BMI and
in EDE-12 restraint score were reported. Quetiapine was
safe and generally well tolerated in this group, except for
initial mild sedation, and no subjects experienced any
significant adverse events.
In an open, controlled 10 week trial quetiapine was administered to 19 AN subjects (5 patients dropped out and
two discontinued the drug mainly in relation to lack of
efficacy or fear of appetite increase) revealed that lower
dosages of quetiapine (150-300 mg/day) might be sufficient in the treatment of AN, although individual cases
needed higher doses up to 500 mg/day or even greater.
Quetiapine was well tolerated and patients had significant improvements in several subscales of the Positive
And Negative Syndrome Scale (PANSS) as well as decreases in measures of anxiety and depression 116.
Moreover, in three cases recently reviewed by MehlerWex et al. 117, quetiapine was used after insufficient response to conventional approaches and slowly titrated
to 200 mg/day within 2 weeks. Psychopathological improvement was observed after 2-3 weeks, thus making
the introduction of behavioural and cognitive therapeutic
approaches possible. The normalization of BMI in these
patients was not an indirect effect of quetiapine, and no
side effects were observed. The authors concluded that
quetiapine could be a potentially promising option in the
treatment of severe AN even in children and adolescents,
revealing positive psychopathological effects and good
tolerability, although the authors recommended careful
titration and intense drug monitoring.
In addition, Court et al. 118 conducted a randomized,
controlled, open-label 12 week trial in which a group
of 15 AN patients (14 females and 1 male, mean age of
23.8 ± 9.4) was treated with conventional therapy along
with quetiapine (100-400 mg/day) and compared to another group of 18 AN patients (all females, mean age
21.0 ± 3.3) treated only with usual therapy. Both groups
showed a modest weight gain over the 12-week trial period, with the mean weight gain in the quetiapine group
being 5.0 kg (SD 3.5) and 4.5 kg (SD 4.0) in the control
group. In addition, both groups showed an improvement
in their EDI-2 outcome scores at the 12-week assessment,
with the quetiapine group demonstrating a much greater improvement on most of the subscales. Importantly,
these improvements were maintained at weeks 26 and 52
in the quetiapine group, but despite the numerical size
of these improvements, they did not reach statistical significance, although this is not surprising in a small-scale
pilot study.
Powers et al. 119 recently completed a double-blind placebo-controlled trial of quetiapine in AN. After 6 weeks
there was no difference in outcome for any of the measures between the group of participants who received
quetiapine and the group who received placebo.
Risperidone
Two case reports published respectively by Fisman et
al. 120 and Newman-Toker et al. 121 raise the possibility
that low-dose risperidone (0.5-1.5 mg daily dose) can be
used in individual cases of AN. Higher doses were presumably avoided considering potential extrapyramidal
motor side effects and unknown disposition of cachexic
patients to long-term side effects such as tardive dyskinesia. Both case reports observed positive effects of risperidone on weight restoration and comorbid or eatingrelated psychopathology.
More recently, Hagman et al. 122, conducted a doubleblind, placebo-controlled, 9 week trial in a group of 40
adolescent AN patients (12 to 21 years) randomly assigned to risperidone (max 4 mg/day) or placebo. Patients
treated with risperidone showed a significant decrease
in the EDI-2 drive for thinness and interpersonal distrust
subscale; there were no significant differences between
groups at baseline or at the end of the study for the other
rating scales, change in weight, or laboratory measurements. The authors concluded that the study does not
demonstrate a benefit for treatment with risperidone in
adolescent AN patients.
Aripiprazole
A case report published by Aragona 123 reported the tolerability and efficacy of aripiprazole in a chronic psychotic
AN patient in comorbidity with epilepsy and chronic
renal failure, already treated with low-dose risperidone
without efficacy. The patient had also refused to take
olanzapine (fear of weight gain), but accepted a treatment with aripiprazole. This antipsychotic, at a dose of
30 mg/day, was associated with a considerable improvement of the scale for the assessment of negative and positive symptoms (SANS) and SAPS scores on hallucinations,
delusions, aggressivity, abulia and asociality. Weight remained stable and no side effects were reported.
59
A. Tortorella et al.
More recently, Trunko et al. 124 conducted an open trial
with 8 patients (five with AN and three with BN). Patients
were treated for periods ranging from 4 months to more
than 3 years and the drug, used at doses ranging from 5 to
30 mg/day, was well tolerated by all patients. A notable reduction in eating-specific anxiety and obsessive thoughts
about food, weight and body image was reported along
with a degree of change in the underlying traits of rigidity
and harm avoidance that may be significant, since such
traits often remain after recovery. Three of the AN patients gained weight to normal range BMIs, and two others
reached partially restored weight: all reported better tolerance to weight gain than they had experienced with other
medications, thus revealing a better compliance. Moreover, the authors noted that since all patients were taking
other medications, it was unclear whether the response
was due to aripiprazole alone or to combined treatment.
Similar results were observed in this study in 3 BN patients
treated with the atypical antipsychotic in combination
with different antidepressants (venlafaxine and trazodone
in one, escitalopram in the other two BN patients).
Further analyses investigating the effect of topiramate on
psychological symptoms associated with disordered eating were made by Hedges et al. 127 who analyzed the same
cohort of BN patients evaluated in the previous trial. The
authors reported that topiramate treatment improved multiple behavioural dimensions of BN characterized by the
reduction of binge and purge behaviours, improvements
in self-esteem, eating attitudes, anxiety and body image.
Nickel et al. 128 conducted a 10-week, double-blind placebo-controlled trial in BN patients randomly assigned
to receive topiramate or placebo. Compared to placebo,
the group treated with topiramate showed a significant
reduction in frequency of binge/purging, weight and improvement in the quality of life. In some cases sedation,
dizziness, headache and para-esthesia were reported, but
there were no serious side effects.
Carbamazepine
Mood stabilizers
The efficacy of carbamazepine was evaluated by Kaplan
et al. 129 in a double-blind crossover trial with carbamazepine in 6 BN patients. One of these patients, showing a
clear comorbidity with bipolar disorder, improved “dramatically” while the remaining five had no response.
Anorexia nervosa
Oxcarbamazepine
Lithium
The effect of lithium in AN was evaluated by Gross et
al. 125 in a 4-week, double-blind, parallel group study, in
16 AN patients. The small sample size and the short duration of the study does not allow for reliable assessment
except for weight gain. The results showed greater weight
gain in the lithium group at weeks 3 and 4 of treatment.
Bulimia nervosa
Topiramate
Topiramate is an innovative anticonvulsant recently tested in different neurological (migraine, neuropathic pain,
and essential tremor) and psychiatric conditions (bipolar
disorder, post-traumatic stress disorder, schizoaffective
disorder, BN and obesity).
Sixty-nine BN outpatients were randomly assigned to receive topiramate (median dose 100 mg/day) or placebo
for 10 weeks in a randomized, double-blind, placebocontrolled trial published by Hoopes et al. 126. Treatment
with topiramate significantly decreased the mean weekly
number of binge and/or purge days, the mean weekly
number of binge days and the mean binge frequency.
Three patients discontinued from the trial due to adverse
events. In this study, topiramate was associated with significant improvements in both binge and purge symptoms and represents a potential treatment for BN.
60
Two cases of BN patients with other psychiatric comorbidities and self-mutilating behaviour treated with oxcarbazepine were reported by Cordàs et al. 130. Self-mutilating behaviour disappeared with the treatment, but not
vomiting.
Lithium
Hsu et al. 131 conducted a double blind placebo controlled trial in 91 female BN outpatients randomly assigned to receive lithium carbonate or placebo. After 8
weeks, 68 patients completed the study. The treatment
with lithium decreased bulimic episodes, but it was not
more effective than placebo. However, depression and
other psychopathologies decreased with improvement in
bulimic behaviour.
Conclusions
The scientific literature is particularly lacking in the area
of drug treatment of EDs because pharmacological trials
for the treatment of these disorders are highly variable
with large differences between results in AN and BN patients. The presence of a common neurobiological basis (serotonin dysfunction), psychopathological features
(depressive and obsessional psychopathology) and high
rates of lifetime comorbidity with depression and obsessive-compulsive symptomatology have suggested a role
for antidepressant treatment in both AN and BN.
The role of drug therapies in treatment of anorexia and bulimia nervosa
Antidepressant treatment does not seem to be helpful in
increasing weight in AN patients, but may be useful in
improving depressive and obsessive-compulsive symptomatology in long-term treatment. This topic is still debated in the literature as several authors have reported
that antidepressants do not seem to significantly impact
depressive symptomatology in this population.
For this reason, it is desirable that in AN patients antidepressants are used only with anxious, depressive or with
obsessive compulsive comorbidity, and, in general, managing patients with AN using medications alone is not
appropriate.
Typical antipsychotics have not proven helpful despite
the weight gain side effects and the presence of ideas and
beliefs that are often of almost delusional intensity and
severity. A few randomized placebo-controlled studies
appear to suggest that atypical agents such as quetiapine
and olanzapine may be helpful in the treatment of psychopathological features of AN, such as depression, anxiety, obsessiveness and aggressiveness.
Despite the large number of publications in recent years,
there are several points that still need to be clarified. For
example: a) a clear pharmacological strategy is not defined yet; b) there is a lack of a substantial documentation
in long-term efficacy of different drugs; c) almost all randomized controlled trials have a small number of patients
because of the high drop-out rate.
10
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Case report
Ekbom syndrome treated with olanzapine: a case report
Sindrome di Ekbom trattata con olanzapina: un caso clinico
Y. Barone, C. Niolu, M. Zanasi, A. Siracusano
Department of Systems Medicine, Università di Roma “Tor Vergata”; Psychiatric Clinic, Fondazione Policlinico “Tor Vergata,” Roma, Italy
Summary
had a history of recurrent depressive episodes with many admissions to psychiatric wards.
Objectives
Ekbom syndrome is a rare psychiatric disorder also known as
delusional parasitosis or delusional infestation or dermatozoic
delusion. There is no consensus on the most appropriate treatment. Traditionally, typical antipsychotic pimozide has been
considered as first choice. Due to the side effects of typical
antipsychotics, atypical antipsychotics (AA) can be taken into
consideration as a valid alternative.
Results
The patient agreed to be hospitalized and to be treated with
antipsychotics. Olanzapine was administered. The initial dose
was 5 mg/day, then increased stepwise to 20 mg/day. After
about 4 weeks, the patient showed improvement regarding her
delusion: she improved her critical ability about the infestation;
appetite and sleep also improved.
Method
We report a case of Ekbom syndrome treated with olanzapine.
We examined the case of a 69-year-old woman. About three
years ago, the patient began feeling as if infested by worms and
eggs after a butterfly landed on her hair. She referred that the
worms were spread throughout her body and amassed under
her skin, and in her eyes, mouth, nose and genitals. The patient
perceived materials such as lint or skin debris as worms and
eggs, and collected them in pieces of paper as “proof” of infestation. The patient believed to have infected her husband and
was worried about infecting other family members. The patient
Introduction
Ekbom syndrome is a rare psychiatric disorder also known
as delusional parasitosis (DP) 1 or delusional infestation
or dermatozoic delusion. Initially described by Thiberge
in 1894, the syndrome was defined in 1938 by Ekbom 1.
The syndrome is characterized by the conviction of being infested by invisible mites or insects, despite clear
evidence of the contrary. These pathogens, often but not
always, cause itching, and the patient obtains skin lesions
by scratching. Additional symptoms such as illusions or
hallucinations may be present 2.
According to the aetiological classification of Lepping and
Freudenmann 3, primary and secondary DP can be distinguished (Table I). In primary DP, the delusion occurs independently of any medical condition; in secondary DP,
the delusions arise in the setting of another major medi-
Conclusions
This case report shows the efficacy of olanzapine in this type
of disturbance, and that can be used as a first-line agent in delusional parasitosis. In addition to drug therapy, establishing a
therapeutic alliance was crucial. In fact, while at the beginning
the patient was reluctant to accept psychiatric help, at the end
a good therapeutic alliance was established and she was fully
adherent to pharmacotherapy.
Key words
Delusional parasitosis • Classification • Pimozide • Atypical antipsychotics • Olanzapine
cal (infection, somatic illnesses associated with itching or
para-aesthesia, e.g. diabetes mellitus, uraemia, jaundice,
cancer), neurological disorder (e.g. dementia, brain tumour,
stroke) or psychiatric disorder such as schizophrenia, major
depressive disorder or mania; finally, DP can be induced
by psychotropic and non-psychotropic substances. Establishing the prevalence of this psychiatric disorder is difficult
because patients usually consult only dermatologists or general practitioners instead of psychiatrists; those who do end
up consulting a psychiatrist usually have low insight regarding their condition, thus leading to poor adherence. Women
are more often affected than men. Trabert et al. show that
the mean age onset is 57.02 ± 14.6 years 2.
There is no consensus on the most appropriate treatment.
Traditionally, typical antipsychotic pimozide has been
considered as first choice 4. Due to the side effects of typ-
Correspondence
Ylenia Barone, via Nomentana 1362, 00137 Rome, Italy • Tel. +39 06 41400129 • E-mail: ylenia.barone@hotmail.it
66
Journal of Psychopathology 2014;20:66-68
Ekbom syndrome treated with olanzapine
Table I.
Ekbom syndrome: aetiopathogenetic classification. Sindrome
di Ekbom: classificazione eziopatogenetica.
Aetiopathogenetic classification*
I. Primary
A. No organic or psychiatric cause
II. Secondary
A. Organic cause
1. B12 deficiency, folic acid deficiency
2. Hearth failure, arrhythmias
3. Meningitis, syphilis, encephalitis, leprosy, tuberculosis, HIV
4. LES, rheumatoid arthritis
5. Vascular dementia, multiple sclerosis, cerebrovascular accidents, tumours, trauma
B. Substance
1. Cocaine, amphetamine
2. Corticosteroid, ciprofloxacin, IMAO, captopril,
bleomycin, clonidine
C. Psychiatric
1. Schizophrenia
2. Mood disorders
3. Anxiety
debris like worms and eggs, and collected them in pieces
of paper as “proof” of infestation. The patient believed
to have infected her husband and she was worried about
infecting other family members. The patient had a history
of recurrent depressive episodes with many admissions to
psychiatric wards. Eleven years ago the patient underwent
surgery for carotid stenosis, and she suffers from advanced
osteoporosis that developed in the years after a hysterectomy when she was 39 years old. She was on treatment
with aspirin, citalopram and benzodiazepines. The patient agreed to be hospitalized and to be treated with antipsychotics. Laboratory tests were within normal range.
The mental state examination showed no cognitive deficit
(MMSE = 30); the clock drawing test was normal. Cerebral
CT showed initial brain atrophy compatible with age. At
the moment, the patient’s mood was euthymic. A diagnosis of primary delusional parasitosis was made, according
to diagnostic criteria for delusional disorder, somatic type
in DSM-IV-TR and ICD-10 criteria for persistent delusional disorder. According to the upcoming DSM-5 criteria,
the patient would also be diagnosed a delusional disorder. Following the current NICE guidelines 5, we treated
the patient with olanzapine. The initial dose was 5 mg/
day, then increased stepwise to 20 mg/day. After about
4 weeks the patient showed improvement regarding her
delusion: she improved her critical ability about the infestation; appetite and sleep also improved as.
4. Folie à deux
Adapted from Lepping et al. 3.
* ical antipsychotics, atypical antipsychotics (AA) can be
taken into consideration as a valid alternative. We report
a case of primary DP treated with olanzapine.
Case report
We present the case of a 69-year-old woman hospitalized
at the Psychiatry Department of Policlinico “Tor Vergata”
Hospital in Rome. About three years ago, the patient began feeling as if infested by worms and eggs after a butterfly landed on her hair. She reported that these worms
were spread throughout her body and amassed under
her skin, and in her eyes, mouth, nose and genitals. The
patient consulted general practitioners, dermatologists,
gynaecologists and ophthalmologists; she accused physicians of not understanding, while at the same time she
refused to consult psychiatrists due to lack of insight. She
then spent most of her time trying to remove the parasites
from her skin, showering multiple times a day and using
disinfectants and lotions. Insomnia and hyporexia were
soon added to the symptomatology. Illusions were present: the patient perceived materials such as lint or skin
Discussion
This case is a typical example of primary DP. The patient
is a woman, age of onset of 66 years, with a duration of
disease of about 3 years. Our data are consistent with
literature data which shows a major prevalence in the
female population, mean age of onset at 55 years and
mean duration of illness to be 3.31 years 2. Collecting bits
of skin and other small particles as evidence of infestation
is characteristic, and is referred to as “matchbox sign” 6.
Our patient was married and had a know and old history
of psychiatric didease. This is in contrast with literature is
findings for Ekbom syndrome’s patient.
DP is usually treated with the antipsychotic pimozide 7 8.
Pimozide, like other typical antipsychotics, is associated
with extrapyramidal side effects. Moreover, pimozide
therapy can cause prolongation of the QT interval, requiring baseline and periodic electrocardiographic monitoring. Due to these serious adverse effects, the use of
atypical antipsychotics (AA) has been suggested. Comprehensive reviews of the clinical efficacy of AA in the
treatment of both primary and secondary DP have been
reported 3 8-13. Other studies have shown full or partial remission with olanzapine 14-16. We performed a review of
the recent literature to select cases of DP (primary or secondary) treated with olanzapine. Studies were selected
67
Y. Barone et al.
Table II.
DP cases treated with olanzapine. Casi DP trattati con olanzapina.
References
Dose
Outcome
Kumbier et al., 2002
10 mg
++
Nicolato et al., 2006
5 mg + citalopram 20 mg
++
Meehan et al., 2006
2.5- 20 mg
++
Freudenmann et al., 2007
2.5 mg - 7.5 mg
++
Bosman et al., 2007
10 mg
++
Mercan et al., 2007
10 mg
++
++ Remission
through PubMed. We used the following keywords: delusional parasitosis and olanzapine; delusion of parasitosis
and olanzapine; dermatozoic delusion and olanzapine.
We selected studies published since 2002 (Table II). This
case report shows the efficacy of olanzapine at a 20 mg/
day dosing, although there has been evidence of effectiveness at lower doses.
In conclusion, this case report shows the efficacy of olanzapine in this type of disturbance and that it can be used
as a first-line agent in delusional parasitosis. In addition
to drug therapy, establishing a therapeutic alliance was
crucial. In fact, while at the beginning the patient was
reluctant to accept psychiatric help, at the end a good
therapeutic alliance was established and she was fully
adherent to pharmacotherapy.
References
1
Ekbom KA, Yorston G, Miesch M, et al. The pre-senile delusion of infestation. Hist Psychiatry 2003;14(54Pt2):229-56.
2
Trabert W. 100 years of delusional parasitosis. Meta-analysis
of 1,223 case reports. Psychopathology 1995;28:238-46.
3
4
Lepping P, Russell I, Freudenmann RW. Antipsychotic treatment of primary delusional parasitosis: systematic review. Br
J Psychiatry 2007;191:198-205.
Driscoll MS, Rothe MJ, Grant-Kels JM, et al., Delusional
parasitosis: a dermatologic, psychiatric, and pharmacologic
approach. J Am Acad Dermatol 1993;29:1023-33.
5
National Institute for Health and Clinical Excellence. Schizophrenia: NICE guidelines. Accessed 30 October 2007.
6
Lee WR. Matchbox sign. Lancet 1983;2:457-8.
68
7
Johnson GC, Anton RF. Pimozide in delusions of parasitosis.
J Clin Psychiatry 1983;44:233.
8
Riding J, Munro A. Pimozide in the treatment of monosymptomatic hypochondriacal psychosis. Acta Psychiatr Scand
1975;52:23-30.
9
Freudenmann RW, Lepping P, Second-generation antipsychotics in primary and secondary delusional parasitosis: outcome and efficacy. J Clin Psychopharmacol 2008;28:500-8.
10
Mercan S, Altunay IK, Taskintuna N, et al., Atypical antipsychotic drugs in the treatment of delusional parasitosis. Int J
Psychiatry Med 2007;37:29-37.
11
Nicolato R, Corrêa H, Romano-Silva MA, et al., Delusional
parasitosis or Ekbom syndrome: a case series. Gen Hosp
Psychiatry 2006;28:85-7.
12
Kenchaiah BK, Kumar S, Tharyan P. Atypical anti-psychotics
in delusional parasitosis: a retrospective case series of 20
patients. Int J Dermatol 2010;49:95-100.
13
Huber M, Lepping P, Pycha R, et al., Delusional infestation:
treatment outcome with antipsychotics in 17 consecutive
patients (using standardized reporting criteria). Gen Hosp
Psychiatry 2011;33:604-11.
14
Freudenmann RW, Schonfeldt-Lecuona C, Lepping P. Primary delusional parasitosis treated with olanzapine. Int Psychogeriatr 2007;19:1161-8.
15
Meehan WJ, Badreshia S, Mackley CL. Successful treatment
of delusions of parasitosis with olanzapine. Arch Dermatol
2006;142;352-5.
16
Bosmans A, Verbanck P. Successful treatment of delusional
disorder of the somatic type or “delusional parasitosis” with
olanzapine. Pharmacopsychiatry 2008;41:121-2.
Clinical psychopharmacotherapy
Perfenazina, amitriptilina e perfenazina-amitriptilina:
ruolo nella pratica clinica
Perphenazine, amitriptyline and perphenazine-amitriptyline: role in clinical practice
A. Fagiolini, A. Cuomo
Università di Siena, Dipartimento di Medicina Molecolare e dello Sviluppo, Sezione Psichiatria
Summary
Typical antipsychotics, also called conventional antipsychotics,
first-generation antipsychotics or major tranquilizers, and tricyclic antidepressants, are drugs developed since 1950 and still
used in the treatment of many psychiatric disorders, despite several compounds that were developed later, with the intention of
improving their therapeutic response and tolerability. Although
the efficacy, tolerability, value and usefulness of the new com-
pounds are undeniable, none of these is so effective and tolerated to make us consider the older generation drugs as always
and completely overtaken. This paper evaluates and reviews the
pharmacological and clinical properties of perphenazine, amitriptyline and the association of these two medications.
Introduzione
napina, clozapina, olanzapina, quetiapina, paliperidone, risperidone e ziprasidone). Come accennato sopra,
gli antipsicotici tipici di prima generazione, sono stati
introdotti in terapia negli anni ‘50; gli antipsicotici atipici di seconda generazione sono invece stati introdotti
a partire dagli anni ‘90 (con l’eccezione della clozapina, prima introdotta, poi ritirata dal commercio e poi di
nuovo introdotta), nel tentativo non solo di aumentarne
l’efficacia, ma anche di ridurre gli effetti collaterali, in
particolare le manifestazioni extrapiramidali, propri delle molecole di prima generazione 1 2. Tuttavia, effetti collaterali come l’aumento di peso e altri disturbi metabolici associati con l’uso dei nuovi antipsicotici hanno finito
con il porre in dubbio il fatto che questi farmaci siano
più sicuri sempre e comunque rispetto ai loro predecessori. Queste preoccupazioni sono state accresciute dai
dati epidemiologici relativi ai pazienti affetti da schizofrenia, che indipendentemente dal trattamento tendono
ad avere un’aspettativa di vita ridotta rispetto alla popolazione generale e a presentare una maggiore incidenza
di malattie cardiovascolari, infettive e respiratorie 3. Al
fine di valutare l’efficacia relativa e la sicurezza degli
antipsicotici di seconda generazione, negli anni scorsi
è stato effettuato negli Stati Uniti un trial multicentrico
(Clinical Antipsychotic Trials for Intervention Effectiveness, CATIE), che li ha confrontati con un antipsicotico
tipico, la perfenazina 2. In questo studio, la perfenazina
ha dimostrato un livello di efficacia simile a quello degli
antipsicotici di seconda generazione, con un’incidenza
Il trattamento farmacologico della psicosi e della depressione è iniziato negli anni ’50, con la scoperta delle fenotiazine (come la perfenazina), degli inibitori delle
monoaminossidasi e degli antidepressivi triciclici (come
l’amitriptilina). Diversi farmaci sono stati sviluppati successivamente, con l’intento di migliorare la risposta terapeutica e la tollerabilità, ma, nonostante l’indubbio valore
di tali nuovi composti, nessuno di questi è risultato tanto
efficace e tollerato da far considerare completamente sorpassati i farmaci di più vecchia generazione, che a buon
diritto sono ancora compresi nel nostro armamentario terapeutico. In questo articolo, verranno valutate e descritte
le proprietà farmacodinamiche, l’efficacia clinica e la tollerabilità della perfenazina, dell’amitriptilina e dell’associazione dei due farmaci.
Perfenazina
Negli ultimi decenni la principale categoria di composti
utilizzati nel trattamento delle psicosi è stata quella dei
farmaci antipsicotici: attualmente esistono oltre 70 molecole che hanno come meccanismo comune la capacità di bloccare i recettori D2 della dopamina e sono state
classificate in due gruppi: i farmaci antipsicotici di prima
generazione (come perfenazina, clorpromazina, aloperidolo, ecc.), chiamati anche tipici, e gli antipsicotici di
seconda generazione o atipici (come aripiprazolo, ase-
Key words
Perphenazine • Amitriptyline • Perphenazine-amitriptyline
Correspondence
A. Fagiolini, Department of Mental Health, University of Siena, AOUS, USL7, viale Bracci 1, 53100 Siena, Italy • E-mail: andreafagiolini@gmail.com
Journal of Psychopathology 2014;20:69-79
69
A. Fagiolini, A. Cuomo
di effetti extrapiramidali non superiore a essi. è opportuno tuttavia ricordare che lo studio CATIE ha escluso
i pazienti con discinesia tardiva dall’assegnazione al
gruppo trattato con perfenazina, con potenziale esclusione indiretta dei pazienti a maggior rischio per altri
effetti extrapiramidali. è comunque anche opportuno
notare che altri studi hanno dimostrato che l’incidenza
di effetti collaterali extrapiramidali nei pazienti trattati
con perfenazina è simile a quella osservata nei pazienti
trattati con risperidone 4-6.
In un’analisi sui pazienti che hanno interrotto perfenazina nello studio CATIE, e sono stati assegnati a un altro farmaco a causa di effetti collaterali extrapiramidali,
Stroup et al. hanno osservato che questi soggetti tolleravano olanzapina e quetiapina meglio del risperidone,
suggerendo dunque l’esistenza di un sottogruppo di pazienti particolarmente sensibili agli effetti collaterali extrapiramidali, che tollerano meglio farmaci come olanzapina e quetiapina e peggio farmaci come perfenazina e
risperidone 7.
Infine, è utile notare che gli Autori dello studio Catie
riconoscono che la perfenazina è uno degli antipsicotici
tipici con minori rischi di effetti extrapiramidali ma, allo
stesso tempo, specificano che i risultati relativi alla perfenazina non possono essere applicati ad altri antipsicotici
tipici, come ad esempio l’aloperidolo 7.
Meccanismo d’azione
Il meccanismo d’azione della perfenazina è simile a quello degli altri antipsicotici e consiste nel blocco del recettore D2 della dopamina a livello cerebrale, in particolare
nella corteccia temporale e striatale e nell’ipotalamo,
come è stato dimostrato anche con studi PET (Positron
Emission Tomography) e SPECT (Single Photon Emission
Computed Tomography) 8 9. Tali studi hanno evidenziato
come una soglia di occupazione dei recettori D2 compresa tra il 65 e l’80% sembri rappresentare la finestra
terapeutica atta a minimizzare il rischio di insorgenza di
effetti extrapiramidali per gli antipsicotici di prima generazione. L’importanza dei meccanismi dopaminergici
nella psicosi e dell’effetto antidopaminergico degli antipsicotici è stata ampiamente dimostrata (Fig. 1) 10. Tuttavia, va ricordato che ogni farmaco ha un suo specifico
profilo recettoriale, che lo caratterizza e ha importanti
conseguenze non solo per la sua efficacia antipsicotica
(Tab. I) 11, ma anche per gli effetti collaterali 11: la perfenazina, oltre a un’elevata affinità per i recettori D2, ha
un profilo peculiare nell’ambito degli antipsicotici tipici,
in quanto ha affinità per quelli serotoninergici 5-HT2A,
alfa1-adrenergici e H1-istaminergici, mentre ha bassissima affinità per quelli serotoninergici 5-HT1A e 5-HT2C,
alfa2-adrenergici e anticolinergici sia centrali (M1) che
periferici (M2-4) 7. L’affinità per i recettori 5-HT2A, che
70
è propria soltanto della perfenazina nell’ambito degli
antipsicotici di prima generazione, è particolarmente
importante: essa determina infatti una ridotta incidenza
di effetti collaterali extra-piramidali e un rilevante effetto antipsicotico/antimaniacale, oltre a non indurre un
peggioramento delle funzioni cognitive e dell’umore
(Tab. II). Queste caratteristiche la rendono più simile a
un antipsicotico di seconda generazione che a uno di prima generazione. Inoltre la notevole affinità per i recettori
istaminergici H1 ne spiega l’azione sedativa (e, almeno
in parte, ansiolitica), che può risultare ideale nei quadri
clinici che presentano agitazione psicomotoria, aggressività, insonnia. Infine, la scarsa attività adrenolitica e
anticolinergica è alla base degli scarsi effetti collaterali
cardiovascolari e anticolinergici. In effetti, studi clinici
dimostrano che la perfenazina, rispetto ad altri antipsicotici di prima generazione come l’aloperidolo 12, tende
ad avere una minore incidenza di effetti extrapiramidali
(per il bilanciamento del rapporto anti-D2/anti-5-HT2A)
e di effetti anticolinergici, avendo uno spettro recettoriale
simile a quello del risperidone 13. In un recente studio 14,
l’incidenza di effetti extrapiramidali dovuti a perfenazina
era infatti simile a quella di alcuni antipsicotici di seconda generazione (olanzapina, quetiapina, risperidone e
ziprasidone).
Efficacia clinica
L’efficacia clinica della perfenazina nel trattamento della schizofrenia è stata dimostrata in numerosi studi: in
una Cochrane review 15 sono stati presi in considerazione 25 studi clinici, che comprendevano circa 2500 pazienti; in 6 perfenazina è stata confrontata con placebo
e in 20 con altri antipsicotici. I risultati di questa metaanalisi hanno dimostrato che la perfenazina ha un effetto terapeutico maggiore rispetto al placebo e simile a
quello di altri farmaci antipsicotici nel trattamento della
schizofrenia. Risultati simili, come è detto, sono stati
evidenziati nello studio CATIE 2. Questo effetto vale per
tutto lo spettro delle manifestazioni della schizofrenia,
compresi i comportamenti violenti, in cui anzi la perfenazina ha dimostrato di avere una maggiore efficacia
rispetto alla quetiapina 16. In effetti, avendo proprietà
sedative e ansiolitiche, la perfenazina può essere particolarmente utile nei pazienti psicotici agitati e disforici.
Anche dal punto di vista dei sintomi depressivi che si
manifestano nella schizofrenia cronica, la perfenazina,
a differenza dell’aloperidolo 17, ha dimostrato un’efficacia comparabile con quella degli antipsicotici di seconda generazione (olanzapina, quetiapina, risperidone
e ziprasidone), come evidenziato dalle variazioni del
punteggio della scala CDSS (Calgary Depression Scale
for Schizophrenia) 18.
Perfenazina, amitriptilina e perfenazina-amitriptilina: ruolo nella pratica clinica
Predisposizione
genetica/ambientale
La diminuzione della rilevanza
permette la risoluzione
del sintomo attraverso
processi di “estinzione
e disimparamento”
Disregolazione della
trasmissione dopaminergica
e del rilascio di dopamina
Aberrante interpretazione delle nuove
informazioni e anomala attribuzione
di importanza a stimoli esterni
e a rappresentazioni interne
Il paziente cessa la terapia
Si verifica una ricaduta
I deliri rappresentano uno schema
cognitivo che il paziente sviluppa
per concettualizzare
le esperienze anomale
Gli antipsicotici bloccano
la dopamina e modulano l’attribuzione
di rilevanza ai sintomi
Quando queste irregolari percezioni
alterano il comportamento
o causano stress,
catalizzano l’attenzione
Gli antipsicotici possono anche
ridurre l’intensità motivazionale
degli eventi normali
Figura 1.
Rappresentazione diagrammatica dell’ipotesi che lega la dopamina alla psicosi e agli antipsicotici (da Kapur et al., 2005) 10.
Diagrammatic representation of the hypothesis that dopamine binds to psychosis and antipsychotics (from Kapur et al., 2005) 10.
Tollerabilità
Per quanto riguarda gli effetti collaterali, oltre a quelli di
tipo extrapiramidale cui si è già accennato, per i quali
non è stata dimostrata una maggiore incidenza rispetto al
trattamento con antipsicotici di seconda generazione 2,
perfenazina possiede bassa attività anticolinergica 19 e
un profilo metabolico migliore di quello di molti antipsicotici di seconda generazione: in uno studio 20 che ha
preso in considerazione le manifestazioni della sindrome
metabolica, che come è noto, è legata a un’aumentata
incidenza di diabete mellito, dislipidemia, ipertensione,
con aumentato rischio di cardiopatia ischemica, perfenazina ha ridotto la circonferenza della vita, un importante
indice di obesità addominale e rischio cardiovascolare,
al contrario degli antipsicotici di seconda generazione,
tra i quali soprattutto olanzapina e quetiapina, ma anche
risperidone, con variazioni significativamente differenti e
più sfavorevoli rispetto a perfenazina. L’uso di perfenazina era associato anche a una riduzione dei valori di pressione arteriosa, sia sistolica che diastolica, probabilmente come effetto del blocco dei recettori alfa1-adrenergici.
In un altro studio prospettico randomizzato 21, che ha
stimato il rischio di sviluppare cardiopatia ischemica a
10 anni, perfenazina, risperidone e ziprasidone sono risultati associati a una riduzione del rischio, a differenza
di olanzapina e quetiapina; tale differenza era statistica-
mente significativa per olanzapina rispetto a perfenazina
e risperidone nel sesso maschile. In effetti, l’Associazione
Americana di Psichiatria e quella di Diabetologia raccomandano ai clinici di essere attenti nell’uso di farmaci
con potenziali implicazioni metaboliche, specialmente
con olanzapina e clozapina, e di monitorare tutti i criteri
della sindrome metabolica: circonferenza addominale,
livelli sierici di colesterolo HDL e trigliceridi in tutti i pazienti in trattamento con antipsicotici atipici. Per quanto
riguarda il rischio cardiovascolare, è noto che vi sono
antipsicotici che sono stati riconosciuti dalle Autorità regolatorie come capaci di aumentare il rischio di Torsione
di punta, in particolare aloperidolo e clorpromazina 22. A
questo proposito il Pharmacovigilance Working Party (un
organo tecnico dell’EMEA) ha emanato un atto regolatorio che è stato recepito a livello italiano attraverso una
determinazione che prescrive l’esecuzione di indagini
cardiologiche nei pazienti che devono essere sottoposti a
trattamento con aloperidolo.
Rapporto costo-efficacia
A causa del costo notevolmente inferiore della perfenazina rispetto agli antipsicotici di seconda generazione, gli
studi che hanno preso in considerazione il rapporto costo/
efficacia hanno dimostrato la superiorità della perfenazina: ad esempio, in uno studio 23 condotto su quasi 1500
71
72
660c
N/A
> 1.600c > 10.000c
N/A
N/A
> 10.000c > 10.000c
350c
8.318c
27c
5,09c
1.520c
N/A
M4
AMI: amisulpride; ARI: aripiprazolo; ASE: asenapina; CLO: clozapina; ILO: iloperidone; OLA: olanzapina; PALI: paliperidone; QUE: quetiapina; SER: sertindolo; ZIP: ziprasidone; HAL:
aloperidolo; MOL: molindone; PER: perfenazina
a
I dati sono rappresentati come costante di equilibrio (Ki) (nM), cioè quantità nanomolare di antipsicotico necessaria a bloccare il 50% dei recettori in vitro. Perciò un numero inferiore
denota una maggiore affinità di legame recettoriale; b Agonismo parziale; c Dati ottenuti da recettori cerebrali umani clonati; d Dati provenienti dal ratto; e Dati provenienti dalla cavia.
500
8
1.500
N/A
1.848c
80
8
80
190
154
600
3,4
5.2
19
440
4,6
260
>10.000c
c
c
c
c
> 10.000 > 10.000 120
5.000
300 c
> 10.000
>10.000
> 10.000c > 10.000c 630c
N/A > 3.000c > 10.000c
N/A
> 10.000c > 10.000c 1.320c 2.692c > 1.300c > 10.000c > 10.000c
280
0,08
2,5c
622c
126c
1.600d
> 10.000e
N/A
N/A
N/A
a2
H1
M1
M2
M3
74b
30c
6.780c
3.510c
4.680c
9,5c
9,0c
5,09c
4,5c
4,67c
158
3,1
1,4c
204c
109c
3
12,3
4.898c
3.311c
> 10.000c
1,4c
421
5c
132c
10
120
3,797c
5.000
>10.000c
2.500
625
2,6
1,800
61
4,700
17
2,6
1,9b,c
0,12
0,9
2,6
770
300
31
3.500
8,1
3,77
190
0,15
32
2,7
2,7
2.200
0,14
6,0
3,9
QUE
RIS
SER
ZIP
Antipsicotici di prima
generazione
HAL
MOL
PER
Classe di
Antipsicotici di seconda generazione
farmaci
Recettore
AMI
ARI
ASE
CLO
ILO
OLA
PALI
Profili farmacodinamici: affinità di legame recettoriale (Ki)
D2
1,3c
0,66b,c
8,9c
210
3,3
20
2,8
d
b,c
5-HT1A
> 10.000
5,5
8,6c
160
33
610
480
2.000d
8,7c
10,15c
2,59
0.2
1,5
1,2
5-HT2A
d
c
5-HT2c
> 10.000
22
10,46c
4,8
14
4,1
48
a1
7.100d
26c
8,9c
6,8
0.31
44
10
Tabella I.
Profilo di legame recettoriale, espresso come affinità recettoriale (Ki), dei farmaci antipsicotici (da Correll, 2010, mod.) 11. Profile of receptor binding, expressed as
receptor affinity (Ki) of antipsychotic drugs (from Correll, 2010, modified) 11.
A. Fagiolini, A. Cuomo
pazienti affetti da schizofrenia, la perfenazina è
risultata almeno altrettanto efficace, in termini
sia di qualità di vita (esaminata tramite punteggio
QUALY, quality-adjusted life year) che di risposta
clinica (Positive and Negative Syndrome Scale,
PANSS), ma con un costo medio inferiore del 2030% rispetto a quello di olanzapina, quetiapina,
risperidone e ziprasidone.
Amitriptilina
Gli antidepressivi triciclici sono da tempo considerati come farmaci di seconda scelta nel trattamento della depressione, soprattutto a causa
dei loro effetti collaterali dovuti alla capacità di
bloccare i recettori H1 istaminergici, colinergici
muscarinici e alfa 1 adrenergici, nonché all’azione chinidino-simile di stabilizzazione delle
membrane. Sebbene ben pochi Autori e Clinici
suggeriscano l’opportunità di preferire un triciclico (TCA) a un farmaco di nuova generazione,
è possibile che gli svantaggi dei TCA in comparazione ai nuovi farmaci disponibili siano stati
nel tempo esagerati 24 ed è osservazione comune che ancora oggi esista un buon numero di
pazienti per i quali il rapporto rischi/benefici dei
TCA rimane favorevole, purché la cura venga
adeguatamente personalizzata, anche tenendo
conto delle differenze tra un TCA e l’altro di cui
ai paragrafi seguenti.
Meccanismo d’azione
L’amitriptilina è un farmaco antidepressivo triciclico che agisce principalmente come inibitore
della ricaptazione della serotonina-norepinefrina, con forti effetti sul trasportatore della norepinefrina ed effetti moderati sul trasportatore della
serotonina. Ha un effetto trascurabile sul trasportatore della dopamina, circa 1.000 volte più
debole rispetto a quello della serotonina 25 26.
Inoltre l’amitriptilina funziona come un antagonista ai recettori 5-HT2A, 5-HT2C, 5-HT6,
5-HT7, recettore adrenergico-α1, H1, mAch e
come recettore σ1 agonista 26-32. Il farmaco funziona inoltre come modulatore allosterico negativo per il recettore NMDA, nello stesso sito di
legame della fenciclidina 33.
Recentemente, è stato dimostrato che l’amitriptilina agisce come un agonista dei recettori TrkA
e TrkB e che promuove la eterodimerizzazione
di queste proteine in assenza del NGF, con una
potente attività neurotrofica sia in vivo che in
vitro nei modelli murini 34.
L’amitriptilina è assorbita bene per via orale, si
Perfenazina, amitriptilina e perfenazina-amitriptilina: ruolo nella pratica clinica
Tabella II.
Profilo di legame recettoriale della perfenazina e correlazione con gli effetti clinici. Receptor binding profile of perphenazine and
correlation with the clinical effects.
Recettori dopaminergici D2 (+++)
Blocco significativo, con attività antidelirante e antiallucinatoria. Effetto antipsicotico e antimaniacale
Recettori serotoninergici 5HT2A (++)
Blocco significativo, con ridotta incidenza di effetti collaterali extra-piramidali.
Mancato peggioramento funzioni cognitive e tono dell’umore
Recettori antiistaminergici H1 (++)
Blocco significativo, con azione sedativa (ideale nei quadri clinici che presentano agitazione psicomotoria, aggressività, insonnia)
Recettori alfa2-adrenergici (-) e colinergici cen- Scarsa attività di blocco per questi recettori: ridotti effetti collaterali cardiovatrali (M1) e periferici (M2-M4) (-)
scolari e anticolinergici
lega in alta percentuale alle proteine del plasma e subisce l’azione degli enzimi microsomiali P450 del fegato.
Sono stati identificati otto metaboliti, tra i quali la nortriptilina è terapeuticamente attiva. L’emivita media di una
dose singola è di 16 ore 35.
Efficacia clinica
L’efficacia di amitriptilina è stata dimostrata in svariati
trial clinici, nei quali il farmaco è risultato superiore al
placebo e almeno equivalente ad altri antidepressivi 36-39.
Le indicazioni di amitriptilina includono: depressione
endogena, fase depressiva della psicosi maniaco-depressiva, depressione reattiva, depressione mascherata,
depressione neurotica, depressione in corso di psicosi
schizofreniche, depressioni involutive, depressioni gravi in corso di malattie neurologiche o di altre affezioni
organiche, trattamento profilattico dell’emicrania e delle
cefalee croniche o ricorrenti.
Tollerabilità
Esistono differenze di tollerabilità ed efficacia su sintomi
specifici tra un TCA e l’altro. Ad esempio, la nortriptilina
(amina secondaria) è un farmaco con un ampio margine
tra gli effetti desiderati, gli effetti collaterali e la tossicità, che agisce soprattutto sulla ricaptazione della noradrenalina. La clomipramina (amina terziaria) inibisce
invece sia la ricaptazione di serotonina che di noradrenalina ed è ad esempio particolarmente efficace nel disturbo ossessivo compulsivo, sebbene comporti di solito
un maggior numero di effetti collaterali della nortriptilina. L’amitriptilina è tra i TCA con maggiori evidenze
di efficacia antidepressiva, per quanto queste non siano
necessariamente superiori a quelle del suo metabolita
nortriptilina. In effetti, la nortriptilina ha un decimo degli
effetti antimuscarinici dell’amitriptilina e un quindicesimo degli effetti sedativi 39. In pazienti per i quali tali effetti siano particolarmente dannosi (ad esempio, soggetti
con ipertrofia prostatica o glaucoma ad angolo chiuso,
per quanto riguarda gli effetti anticolinergici, o soggetti
con ritardo psicomotorio, per quanto riguarda gli effetti
antistaminici), è dunque opportuno privilegiare i tricilici
a più basse proprietà anti colinergiche o sedative, come
la nortriptilina o la desipramina, o meglio ancora un farmaco di nuova generazione. Tuttavia, esistono pazienti
per i quali gli effetti antimuscarinici sono ben tollerati ed
esistono inoltre pazienti (ad esempio quelli che assumono un antipsicotico a rischio di sintomi extrapiramidali)
per i quali l’attività anticolinergica centrale può portare
dei benefici, mitigando gli effetti extrapiramidali. Analogamente, gli effetti sedativi possono essere utili in alcuni
pazienti con insonnia, agitazione o ansia. L’amitriptilina
è comunque controindicata nei pazienti con glaucoma,
ipertrofia prostatica, stenosi pilorica e altre affezioni stenosanti dell’apparato gastro-enterico e genito-urinario,
soprattutto a causa della sua attività anticolinergica. è
inoltre controindicata nelle malattie epatiche, insufficienza cardiaca, disturbi del ritmo e della conduzione
miocardica e nel periodo di recupero post-infartuale.
Poiché amitriptilina può causare ipotensione ortostatica,
variazioni della glicemia, turbe dell’emopoiesi, del fegato e del rene, è raccomandabile eseguire periodici controlli della pressione arteriosa, della glicemia, della crasi
ematica e della funzionalità epatica e renale con speciale riguardo agli ipertesi, ai diabetici, ai nefropatici e nei
soggetti con affezioni, in atto o pregresse, dell’apparato
emopoietico. In caso di comparsa di febbre, angina e altri
sintomi influenzali è necessario un controllo della crasi
ematica onde escludere la presenza di agranulocitosi che
occasionalmente è stata segnalata durante la terapia con
antidepressivi triciclici 34.
Associazione perfenazina-amitriptilina
L’associazione perfenazina-amitriptilina consente di
combinare gli effetti antipsicotici, sedativi e ansiolitici
della perfenazina con l’attività antidepressiva di amitriptilina ed è utilizzata sia nel trattamento dei pazienti affetti da psicosi con depressione sia, modificando il
73
A. Fagiolini, A. Cuomo
dosaggio dei due farmaci, in varie malattie caratterizzate dalla coesistenza di ansia, agitazione e depressione.
L’amitriptilina è il più utilizzato tra gli antidepressivi triciclici e, dopo più di 50 anni dalla sua introduzione in
commercio, è ancora utilizzata come uno dei farmaci
di riferimento nei trial sui nuovi antidepressivi 39. Una
terapia combinata con antidepressivi e neurolettici può
essere ad esempio utilizzata nel paziente schizofrenico
che vada incontro a depressione. La classificazione e il
trattamento dei pazienti con schizofrenia e concomitante depressione costituiscono un argomento abbastanza
complesso, a causa della parziale sovrapposizione di
alcuni sintomi delle due malattie. Gli studi dimostrano comunque che i soggetti con schizofrenia tendono
a presentare sintomi depressivi con maggior frequenza
rispetto alla popolazione generale: ad esempio, il National Comorbidity Study 40 ha rilevato che il 59% dei pazienti affetti da schizofrenia rientravano nei criteri DSM
per la depressione maggiore o minore. L’associazione
tra perfenazina e amitriptilina, in questo senso, è pienamente logica ed è stata analizzata in un trial in doppio
cieco rispetto a placebo: l’aggiunta dell’amitriptilina alla perfenazina, rispetto alla sola perfenazina, era più efficace nel ridurre i sintomi della depressione in pazienti
affetti da schizofrenia cronica 41.
L’associazione perfenazina-amitriptilina è stata utilizzata anche in altre forme di psicosi con depressione 42 43,
in cui la maggiore efficacia dell’associazione rispetto
al singolo farmaco è stata correlata a 3 fattori: un aumento delle concentrazioni plasmatiche di amitriptilina
dovuta a inibizione competitiva del processo di idrossilazione epatica indotta dalla perfenazina, il blocco
dopaminergico e la maggiore attività serotoninergica e
noradrenergica.
La variazione dei dosaggi di perfenazina (2 e 4 mg) e
di amitriptilina (10 e 25 mg) contenuti nei preparati di
associazione consente, tra l’altro, di modulare al meglio
l’attività antipsicotica e ansiolitica di perfenazina e l’attività antidepressiva di amitriptilina.
La combinazione di perfenazina 4 mg + amitriptilina 10
mg (Mutabon ansiolitico), è indicata in Italia per: disturbi
mentali, sia reattivi sia endogeni, caratterizzati dalla coesistenza di ansia, tensione e agitazione con depressione;
stati di ansia associata a sintomi relativamente scarsi o
lievi di depressione; grave insonnia associata ad ansia
e depressione). Di solito è sufficiente una compressa di
Mutabon ansiolitico 3-4 volte al giorno. è opportuno tenere presente che l’azione tranquillante si manifesta più
rapidamente (2 o 3 giorni) di quella antidepressiva (1 settimana o più); pertanto i sintomi di tensione e di ansietà
di solito scompaiono prima di quelli depressivi. Questa
formulazione può essere particolarmente utile nei pazienti per i quali l’ansia, tensione o agitazione prevalgano sugli aspetti depressivi.
74
La combinazione di perfenazina 2 mg + amitriptilina
10 mg (Mutabon mite) è indicata per: disturbi mentali,
sia reattivi sia endogeni, in cui la semplice ansia è associata con sintomi relativamente scarsi o lievi di depressione; grave insonnia associata ad ansia e depressione.
Di solito è sufficiente una compressa di Mutabon mite
1-3 volte al giorno. Questa combinazione può essere
utile nei pazienti con sindromi ansiose e depressive più
moderate, che richiedano dosaggi inferiori di perfenazina e amitriptilina. La combinazione di perfenazina
2 mg + amitriptilina 25 mg (Mutabon antidepressivo)
è indicata per: disturbi mentali, sia reattivi sia endogeni, caratterizzati dalla coesistenza di ansia, tensione e
agitazione con depressione; disturbi emotivi caratterizzati da depressione e ansia dovuti o associati a malattie organiche o funzionali, forme psicosomatiche, ecc.;
sintomi depressivi; grave insonnia associata ad ansia e
depressione. Di solito è sufficiente una compressa 3-4
volte al giorno. Occorre tenere presente che l’azione
tranquillante si manifesta più rapidamente (2 o 3 giorni)
di quella antidepressiva (1 settimana o più); pertanto i
sintomi di tensione e di ansietà scompaiono assai prima
della sintomatologia depressiva. Questa combinazione
può essere utile nei pazienti con predominanti sintomi
depressivi, pure in presenza di ansia.
La combinazione di perfenazina 4 mg+amitriptilina
25 mg (Mutabon forte), è indicata per disturbi mentali,
sia reattivi sia endogeni, caratterizzati dalla coesistenza
di ansia, tensione e agitazione con depressione, disturbi
psiconeurotici e psicosomatici, sindrome da menopausa,
depressione e ansia associate con malattie organiche, alcoolismo acuto e cronico, sindrome depressiva e maniaco-depressiva, reazioni schizofreniche, psicosi involutive, deviazioni sessuali, problemi del comportamento associati a deficienza mentale, grave insonnia associata ad
ansia e depressione. Di solito è sufficiente una compressa
di Mutabon forte 3-4 volte al giorno. Alcuni pazienti, dopo un trattamento iniziale con questo farmaco possono
migliorare sufficientemente da richiedere un quantitativo
di perfenazina inferiore ai 4 mg presenti in ogni compressa di Mutabon forte; in tali casi si potrà continuare la
terapia con Mutabon antidepressivo che contiene solo 2
mg di perfenazina. A volte può invece essere necessario
aggiungere a Mutabon forte un ulteriore quantitativo di
perfenazina. Si tratta dei casi in cui l’ansia, la psicosi e
l’agitazione sono particolarmente severi e rappresentano
il disturbo primario, per cui è desiderabile un maggior effetto antipsicotico e sedativo. Questa combinazione può
dunque essere utile nei pazienti psicotici con coesistenza
di severa ansia e depressione.
Conflitto di interessi
Il prof. Fagiolini è stato un consulente e/o un relatore e/o ha partecipato a simposi sponsorizzati da, e/o ha ricevuto finanziamen-
Perfenazina, amitriptilina e perfenazina-amitriptilina: ruolo nella pratica clinica
ti di ricerca da: Angelini, Astra Zeneca, Bristol-Myers Squibb,
Boehringer Ingelheim, Pfizer, Eli Lilly, Janssen, Lundbeck, Novartis, Otsuka, Sigma Tau, Takeda e Neopharmed Gentili che ha
contribuito alla realizzazione di questo articolo.
A. Cuomo non ha alcun conflitto di interesse.
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Perfenazina
Struttura chimica
• è una piperazinil fenotiazina (4-[3-(2-clorofenotiazin-10-il)propil]-1-piperazineetanolo), con peso molecolare 403,97 kD (Fig. 2).
Figura 2.
Struttura chimica della perfenazina. Chemistry of perphenazine.
Farmacocinetica
• le concentrazioni plasmatiche di picco vengono raggiunte dopo 1-3 ore
• emivita (indipendente dalla dose): 9-12 ore
• lo steady-state viene raggiunto entro 72 ore
• è estesamente metabolizzata nel fegato a una serie di metaboliti, principalmente da parte del citocromo P450 2D6; questo
tipo di metabolismo è soggetto a polimorfismo genetico, per cui il 7-10% della popolazione caucasica ha una scarsa attività
enzimatica ed è denominata “scarsi metabolizzatori”
Farmacodinamica
• elevata affinità per i recettori dopaminergici D2
• buona affinità per i recettori serotoninergici 5-HT2A
• buona affinità per i recettori alfa1-adrenergici e H1-istaminergici
• bassissima affinità per i recettori serotoninergici 5-HT1A e 5-HT2C, alfa2-adrenergici e anticolinergici sia centrali (M1) che
periferici (M2-4)
76
Perfenazina, amitriptilina e perfenazina-amitriptilina: ruolo nella pratica clinica
Amitriptilina
Struttura chimica
• è un antidepressivo triciclico (3-(10,11-diidro-5H-dibenzo[a,d]cicloeptene-5-ylidene)-N,N-dimetilpropan-1-amina), con peso
molecolare 277,40 kD (Fig. 3)
Figura 3.
Struttura chimica della amitriptilina. Chemistry of amitriptyline.
Farmacocinetica
• le concentrazioni plasmatiche di picco vengono raggiunte in 4-8 ore
• emivita: 13-36 ore (media 16 ore)
• lo steady-state viene raggiunto in 3-8 ore
• va incontro a una notevole eliminazione presistemica da parte del fegato, per cui la sua biodisponibilità sistemica varia dal 33
al 62%. è un composto altamente lipofilo, ha un’emivita di 10-28 ore come amitriptilina e di 16-80 ore come nortriptilina, il
suo metabolita attivo, ottenuto per demetilazione a livello epatico
Farmacodinamica
• potente inibitore del reuptake della noradrenalina e della serotonina a livello delle terminazioni nervose
• notevole effetto anticolinergico
Mutabon ansiolitico
Composizione
• perfenazina 4 mg, amitriptilina 10 mg
Indicazioni
• disturbi mentali, sia reattivi sia endogeni, caratterizzati dalla coesistenza di ansia, tensione e agitazione con depressione
• stati di ansia associata a sintomi relativamente scarsi o lievi di depressione
• grave insonnia associata ad ansia e depressione
Posologia
• una compressa 3-4 volte al giorno (dosaggio da individualizzare a seconda del tipo di disturbo da trattare). Va tenuto presente
che l’azione tranquillante si manifesta più rapidamente (2 o 3 giorni) di quella antidepressiva (1 settimana o più); pertanto i
sintomi di tensione e di ansietà scompaiono assai prima della sintomatologia depressiva
Mutabon antidepressivo
Composizione
• perfenazina 2 mg, amitriptilina 25 mg
Indicazioni
• disturbi mentali, sia reattivi sia endogeni, caratterizzati dalla coesistenza di ansia, tensione e agitazione con depressione
• disturbi emotivi caratterizzati da depressione e ansia dovuti o associati a malattie organiche o funzionali, forme psicosomatiche, ecc.
• sintomi depressivi, poiché nella maggior parte di essi coesiste uno stato di tensione, anche se questo non è evidente o può
essere mascherato
• grave insonnia associata ad ansia e depressione
Posologia
• una compressa 3-4 volte al giorno (dosaggio da individualizzare a seconda del tipo di disturbo da trattare). Va tenuto presente
che l’azione tranquillante si manifesta più rapidamente (2 o 3 giorni) di quella antidepressiva (1 settimana o più); pertanto i
sintomi di tensione e di ansietà scompaiono assai prima della sintomatologia depressiva
77
A. Fagiolini, A. Cuomo
Mutabon forte
Composizione
• perfenazina 4 mg, amitriptilina 25 mg
Indicazioni
• disturbi mentali, sia reattivi sia endogeni, caratterizzati dalla coesistenza di ansia, tensione e agitazione con depressione
• disturbi psiconeurotici e psicosomatici
• sindrome da menopausa
• depressione e ansia associate con malattie organiche
• alcoolismo acuto e cronico
• sindrome depressiva e maniaco-depressiva
• reazioni schizofreniche
• psicosi involutive
• deviazioni sessuali
• problemi del comportamento associati a deficienza mentale
• grave insonnia associata ad ansia e depressione
Posologia
una compressa 3-4 volte al giorno (dosaggio da individualizzare a seconda del tipo di disturbo da trattare). Va tenuto presente che
l’azione tranquillante si manifesta più rapidamente (2 o 3 giorni) di quella antidepressiva (1 settimana o più); pertanto i sintomi di
tensione e di ansietà scompaiono assai prima della sintomatologia depressiva
Mutabon mite
Composizione
• perfenazina 2 mg, amitriptilina 10 mg
Indicazioni
• disturbi mentali, sia reattivi sia endogeni, in cui la semplice ansia è associata con sintomi relativamente scarsi o lievi di depressione
• grave insonnia associata ad ansia e depressione
Posologia
• una compressa 1-3 volte al giorno (dosaggio da individualizzare a seconda del tipo di disturbo da trattare)
Per tutte le formulazioni
Speciali avvertenze e precauzioni per l’uso
• pazienti anziani (eventuale aggiustamento della posologia)
• induzione di variazioni del tempo di reazione (attenzione nei soggetti addetti ai macchinari o alla guida di veicoli)
• effettuare periodicamente controlli dell’esame emocromo e della funzionalità renale ed epatica
• in caso di malattie cardiovascolari, fare un ECG
• attenzione all’eventuale sviluppo di discinesia tardiva, specie nei soggetti anziani
• come in qualsiasi trattamento con farmaci antipsicotici, pericolo di sviluppare una sindrome neurolettica maligna
• la perfenazina può abbassare la soglia delle convulsioni in soggetti predisposti
Interazioni
Perfenazina
• possibile potenziamento degli effetti depressivi sul sistema nervoso centrale di oppiacei, barbiturici o altri sedativi, antistaminici, anestetici, tranquillanti, alcool e meperidina (e di altri analgesici oppiacei)
• usare con cautela in pazienti trattati con atropina o farmaci simili, a causa di effetti additivi anticolinergici
• l’uso di alcool deve essere evitato, poiché si possono avere effetti additivi e ipotensione
• somministrare con cautela in concomitanza a terapia antiipertensiva con reserpina, guanetidina, metildopa, betabloccanti o
composti simili, per la possibile comparsa di ipotensione
• se il paziente è in trattamento con anticonvulsivanti, può essere richiesta una dose maggiore di questi farmaci
• gli antiacidi a base di sali di alluminio possono inibire l’assorbimento delle fenotiazine
• in caso di somministrazione in concomitanza con farmaci che prolungano il QT, il rischio di insorgenza di aritmie cardiache
aumenta
• non somministrare in concomitanza con farmaci che determinano alterazioni degli elettroliti
78
Perfenazina, amitriptilina e perfenazina-amitriptilina: ruolo nella pratica clinica
Amitriptilina
• la somministrazione concomitante di farmaci triciclici e inibitori delle monoaminoossidasi (IMAO) può provocare reazioni
simili a un avvelenamento da atropina, con conseguenti crisi iperpiretiche, convulsioni e morte
• l’uso concomitante di anticolinergici o amine simpaticomimetiche, tra cui epinefrina associata ad anestetici locali, può incrementare l’attività dell’amitriptilina o dell’amina simpaticomimetica
• l’impiego concomitante di anticolinergici o antistaminici può potenziarne gli effetti anticolinergici
• l’uso concomitante di agenti con azione depressiva sul Sistema Nervoso Centrale (SNC), quali alcool, barbiturici, sedativi o
analgesici oppiacei, può potenziare gli effetti depressori sul SNC, tra cui la depressione respiratoria
• l’assunzione concomitante di diazepam determina un aumento dell’emivita e dei livelli plasmatici costanti dell’amitriptilina
• l’uso concomitante di anticonvulsivanti può ridurre il controllo effettivo delle convulsioni nei pazienti epilettici
79
Clinical psychopharmacotherapy
Nalmefene: profilo clinico e real world evidence nel trattamento
della dipendenza da alcol
Nalmefene: clinical and real world evidence in the treatment of alcohol dependence
I. Maremmani1, S. Presta2, A. Petracca3, M. Di Nicola4, A.G.I. Maremmani5, F. Ruggeri4, L. Janiri4
Docente di Medicina delle Farmacotossicodipendenze, Università di Pisa e Responsabile dell’Unità di Doppia Diagnosi “Vincent P. Dole”,
Dipartimento di Neuroscienze, Ospedale “S. Chiara” dell’Università di Pisa; 2 Specialista in Psichiatria; Dottore di Ricerca in Neuropsicofarmacologia
Clinica, Università di Pisa; Perfezionato in Psicopatologia dello Sviluppo, Università di Pisa; Perfezionato in Farmacologia e Farmacoterapia
dei Disturbi d’Ansia, Università di Siena; 3 Scuola di Psichiatria, Università di Pisa; 4 Istituto di Psichiatria e Psicologia, Università Cattolica
del Sacro Cuore, Roma; DH di Psichiatria Clinica e Farmacodipendenze, Policlinico Universitario “A. Gemelli”, Roma; 5 Unità di Doppia
Diagnosi “Vincent P. Dole” del Dipartimento di Neuroscienze, Ospedale “Santa Chiara”, Università di Pisa e Associazione per l’Utilizzo
delle Conoscenze Neuroscientifiche a fini Sociali (AU-CNS), Pietrasanta, Lucca
1
Summary
Alcohol dependence is a major public health problem with a
huge social and economic burden. However, alcohol dependence is both underdiagnosed and undertreated, as it is estimated
that less than 10% of people diagnosed with alcohol dependence or abuse in Europe receive any form of treatment. Among
the factors that have contributed to this undertreatment is the
fact that the therapeutic strategy has always been based on
achieving and maintaining abstinence from alcohol, a goal often
difficult to achieve. Recently it has been made available a new
therapeutic approach to alcohol dependence, nalmefene, based
on the reduction of alcohol consumption. In fact, nalmefene is
the first drug to be approved in Europe for as-needed use to
reduce alcohol consumption in alcohol-dependent adults with a
high drinking risk level and who continue to have a high drinking risk level 2 weeks after initial assessment. Nalmefene reduces
the reinforcing the effects of alcohol, helping to reduce alcohol
consumption, through the modulation of the opioid system.
Efficacy and tolerability of as-needed nalmefene for the reduction of alcohol consumption was evaluated in 3 double-blind,
randomized, placebo-controlled clinical trials conducted in Europe: two (ESENSE 1 and ESENSE 2) evaluated the efficacy of
6 months as-needed treatment and a third (SENSE) examined
the efficacy of one year as-needed treatment with nalmefene
in patients with alcohol dependence. All patients took part in
a motivational and adherence-enhancing psychosocial support
(BRENDA). Post hoc subgroup analysis of ESENSE 1, ESENSE 2
and SENSE trials were conducted in patients who had at least a
high drinking risk level according to WHO (> 60 g/day for men
Introduzione
La dipendenza da alcol è stata definita dal DSM-IV-TR
come “una modalità patologica d’uso dell’alcol con disagio e compromissione clinicamente significativa, come
manifestato da almeno tre delle seguenti condizioni che
ricorrono in un qualunque momento dello stesso periodo
and > 40 g/day for women) at both screening and randomization (i.e. the target population). In the pooled target population of ESENSE 1 and ESENSE 2, there was a superior effect of
nalmefene compared to placebo in reducing both the number
of heavy drinking days (p < 0.0001) and total alcohol consumption (p < 0.0001) at the end of treatment, as well as in improving
(p < 0.05) the adjusted mean change in the CGI-S score and the
adjusted mean CGI-I score. Significantly improved (p ≤ 0.01)
levels of ALT were demonstrated in patients treated with nalmefene compared to those treated with placebo in the analysis of
the target population of ESENSE 1 and ESENSE 2. The reduction
of GGT levels was significantly greater (p < 0.001) with nalmefene compared to placebo in the subgroup of the target population of ESENSE 1 study, but not in the ESENSE 2 study. SENSE
trial gave results similar to ESENSE 1 and 2 studies. As-needed
nalmefene was generally well tolerated in patients with alcohol
dependence.
These studies demonstrate the clinical efficacy and tolerability
of nalmefene in patients with alcohol dependence: the effect is
larger in patients with at least a high drinking risk level at the start
of treatment. Nalmefene has the potential to engage in treatment
patients who otherwise would not have sought help, thus representing a new pharmacological treatment paradigm, in terms of
treatment goal (reduction of alcohol consumption) and dosing
regimen (as-needed) in alcohol dependent patients.
Key words
Nalmefene • Alcohol dependence • Reduction in alcohol consumption•
Opioid receptors
di 12 mesi: tolleranza, astinenza, assunzione in quantità
maggiore o per periodi più prolungati del previsto; desiderio persistente o tentativi infruttuosi di ridurre o controllarne l’uso; grande quantità di tempo speso per procurarsi o assumere l’alcol o a riprendersi dai suoi effetti;
attività sociali, lavorative o ricreative abbandonate o ridotte; uso continuativo nonostante la consapevolezza di
Correspondence
Luigi Janiri – E-mail: luigi_janiri@fastwebnet.it • Icro Maremmani – E-mail: maremman@med.unipi.it • Alberto Petracca – E-mail: apetracca@
alice.it • Silvio Presta – E-mail: silvio.presta@virgilio.it
80
Journal of Psychopathology 2014;20:80-91
Nalmefene: profilo clinico e real world evidence nel trattamento della dipendenza da alcol
conseguenze fisiche o psicologiche causate dall’alcol”. Il
DSM-5, pubblicato recentemente, ha abbandonato la distinzione tra abuso e dipendenza da alcol per seguire un
approccio dimensionale: abuso e dipendenza sono confluiti nel disturbo da uso di alcol distinto in lieve, moderato e grave in funzione dei criteri diagnostici soddisfatti
tra gli 11 proposti.
Al di là delle definizioni, la dipendenza da alcol rappresenta un importante problema di salute pubblica 1. In
Europa si registrano i più elevati livelli mondiali di consumo – con un’assunzione media annua di alcol di 12,5 l
pro capite – e si stima che vi siano quasi 15 milioni di
persone alcoldipendenti 2 3. Circa 137.000 cittadini europei di età compresa tra 15 e 64 anni muoiono prematuramente ogni anno per le conseguenze del consumo di
alcol 2, tra cui 39.000 casi di cirrosi epatica, 13.000 casi
di disturbi neurologici e psichiatrici, 11.000 casi di malattie cardiovascolari, 26.000 casi di neoplasie e 18.000
suicidi 4. L’impatto netto del consumo di alcol nei paesi
dell’Unione Europea è di 1 morte su 7 nel sesso maschile
e di 1 morte su 13 in quello femminile 2 e le conseguenze
economiche dell’alcolismo sono enormi 5.
Si stima infatti che in Europa i costi totali diretti della
dipendenza da alcol all’anno, per lo più dovuti a ospedalizzazione (si parla di una spesa variabile da 1.591
a 7.702 euro per ogni ricovero) siano dell’ordine dello
0,04-0,31% del PIL per ciascuna nazione, mentre i costi
indiretti annuali raggiungano cifre pari allo 0,64% del PIL
per ciascuna nazione 5.
Tuttavia, la dipendenza da alcol è sia sottodiagnosticata
sia sottotrattata e meno del 10% delle persone cui viene diagnosticato abuso o dipendenza da alcol in Europa
riceve una qualsiasi forma di trattamento 6. In Italia, secondo i dati del Ministero della Salute, solo poco più di
58.000 persone sono in carico presso i servizi dedicati
per la cura delle dipendenze 7.
Tra i fattori che hanno contribuito a questo sottotrattamento della dipendenza da alcol vi è il fatto che la strategia terapeutica è sempre stata basata sul raggiungimento
e il mantenimento della condizione di astensione dall’alcol, un obiettivo non realistico e spesso difficile da raggiungere da parte dei pazienti alcoldipendenti 8. Questo
dipende anche dal fatto che i farmaci disponibili finora
in Italia erano indicati nel mantenimento dell’astensione
(disulfiram, naltrexone, acamprosato, sodio oxibato) e
nel controllo della sindrome da astinenza da alcol (sodio
oxibato).
Recentemente è stato reso possibile un nuovo approccio
terapeutico alla dipendenza da alcol, che si basa sulla riduzione del consumo di alcol. In effetti, il nalmefene, un
modulatore del sistema degli oppiodi, è il primo farmaco
a essere approvato in Europa per ridurre il consumo di
alcol nei soggetti alcoldipendenti 9. La riduzione del consumo di alcol va considerata come una tappa intermedia
nel percorso verso l’astensione totale 10. Inoltre, si ritiene
che una riduzione del consumo di alcol sia associata a
una riduzione del rischio di morbilità e mortalità 11.
In particolare, nalmefene è indicato per la riduzione del
consumo di alcol in pazienti adulti con dipendenza da
alcol che hanno livelli di consumo a elevato rischio secondo l’Organizzazione Mondiale della Sanità (OMS)
(ovvero con un consumo di alcol > 60 g/die negli uomini e > 40 g/die nelle donne), senza sintomi fisici da
sospensione e che non richiedono immediata disintossicazione 12. Inoltre, nalmefene deve essere prescritto solo
congiuntamente a un supporto psico-sociale continuativo, mirato all’aderenza al trattamento e alla riduzione del
consumo di alcol, e deve essere iniziato solo in pazienti
che continuano ad avere un livello di consumo a rischio
elevato due settimane dopo la valutazione iniziale 12.
Caratteristiche farmacodinamiche
di nalmefene
L’alcol altera numerosi sistemi di neurotrasmettitori a
livello cerebrale, compresi quello del glutammato, del
GABA, della serotonina e soprattutto della dopamina 13.
Numerosi studi suggeriscono che il sistema degli oppioidi
endogeni sia implicato nello sviluppo della dipendenza
da alcol 13. L’assunzione acuta di alcol stimola il rilascio
di peptidi oppioidi endogeni (β-endorfine, encefaline e
dinorfine): il legame delle β-endorfine ed encefaline ai
recettori oppioidi µ e δ determina il rilascio di dopamina
a livello del nucleo accumbens, dando effetti di rinforzo
e gratificazione. Al contrario, il legame delle dinorfine
ai recettori k riduce i livelli di dopamina nel nucleus accumbens e può indurre effetti di tipo avversivo 9 14.
Studi di neuroimaging funzionale suggeriscono che l’uso
cronico di alcol sia associato a profonde modificazioni
e adattamenti del sistema oppioide 14. In particolare, il
rilascio di β-endorfine non è mantenuto 15 e si verifica
un’iperattività del sistema dinorfine/recettori k, che può
portare alla comparsa di uno stato affettivo negativo e
contribuire all’aumento dell’assunzione di alcol per rinforzo negativo 16 17.
Nalmefene è un ligando selettivo dei recettori oppiodi,
con un distinto profilo recettoriale µ, δ e k 11. Si ritiene
che nalmefene riduca gli effetti di rinforzo dell’alcol, aiutando a ridurne il suo consumo, attraverso una modulazione del sistema oppioide 4 9: esso è infatti un antagonista dei recettori oppioidi µ e δ e un agonista parziale dei
recettori k 9 12. Dati preclinici indicano che nalmefene è
in grado di ridurre l’autosomministrazione di alcol sia nei
ratti non dipendenti sia in quelli dipendenti dall’alcol:
si ritiene che tale effetto dipenda dall’antagonismo dei
recettori µ e δ nei ratti non dipendenti e anche dall’agonismo parziale dei recettori k nei ratti dipendenti dall’alcol, in cui nalmefene agisce come antagonista funzionale
81
I. Maremmani et al.
nel contesto di un sistema dinorfine/recettori k upregolato 18. Inoltre, negli animali alcoldipendenti, nalmefene
è risultato significativamente più efficace nel sopprimere
l’assunzione di etanolo rispetto a naltrexone 16, differenza che viene attribuita al diverso profilo di affinità per i
recettori oppioidi delle due molecole. Nalmefene infatti
ha un’affinità simile a naltrexone per i recettori µ, mentre presenta una maggiore affinità per i recettori k e δ;
naltrexone inoltre è un antagonista dei recettori µ, δ e
k 4 19-21. In aggiunta a questo, nalmefene presenta rispetto
a naltrexone un legame più efficace ai recettori centrali
degli oppioidi 4 19, un’emivita più lunga 22, una maggiore biodisponibilità e l’assenza di tossicità epatica dosedipendente 4 23.
Nell’uomo è stata dimostrata una lenta dissociazione di
nalmefene dal recettore µ. Le immagini PET (Positron
Emission Tomography) hanno rivelato un’occupazione
dei recettori µ pari all’87-100% 3 ore dopo la somministrazione orale di dosi singole o ripetute di nalmefene
18 mg in volontari sani. A 74 ore l’occupazione dei recettori µ era pari al 12-32% dopo una dose singola di
nalmefene 24.
Nalmefene non è associato con un potenziale d’abuso o
dipendenza 12.
Nalmefene è controindicato nei pazienti che stanno assumendo analgesici oppioidi, con attuale o recente dipendenza da oppioidi, con sintomi da sospensione di oppioidi
in fase acuta e pazienti per i quali si sospetti un recente
utilizzo di oppioidi. Deve essere usata cautela quando
vengono utilizzati medicinali contenenti oppioidi 12.
Caratteristiche farmacocinetiche di nalmefene
Dal punto di vista farmacocinetico, nalmefene è altamente idrosolubile ed è rapidamente assorbito dopo somministrazione orale, con una biodisponibilità del 41%; è
legato alle proteine plasmatiche per circa il 30%; supera
velocemente la barriera ematoencefalica; viene metabolizzato ampiamente e rapidamente a livello epatico
a opera principalmente dell’enzima UGT2B7 (in misura
minore UGT1A3, UGT1A8 e CYP3A4/5); la principale
via di eliminazione di nalmefene e dei suoi metaboliti è
l’escrezione renale, con una emivita di circa 12,5 ore 12.
Nalmefene è controindicato nei pazienti con grave compromissione epatica o con grave compromissione renale,
mentre nei pazienti con una compromissione epatica o
renale lieve o moderata è richiesta cautela, anche se non
si richiede un aggiustamento posologico 12.
Sulla base degli studi in vitro, non sono prevedibili interazioni clinicamente rilevanti tra nalmefene, o i suoi
metaboliti, e i medicinali somministrati in concomitanza,
metabolizzati dai più comuni enzimi CYP450 e UGT o
da trasportatori di membrana. La cosomministrazione di
nalmefene e di un potente inibitore dell’UGT2B7 può far
82
aumentare l’esposizione a nalmefene stesso, in particolare in caso di cotrattamento di lungo termine; è richiesta
quindi cautela quando nalmefene viene cosomministrato
con potenti inibitori dell’UGT2B7. Inoltre, la cosomministrazione con un induttore dell’UGT può ridurre le concentrazioni plasmatiche di nalmefene 12.
Efficacia, sicurezza e tollerabilità
di nalmefene nel trattamento
della dipendenza da alcol
La registrazione europea di nalmefene nella riduzione
del consumo di alcol si basa sui risultati ottenuti in 3 trial
clinici in doppio cieco, randomizzati, controllati con placebo effettuati in Europa, due 25 26 che hanno esaminato l’efficacia di 6 mesi di trattamento secondo necessità
(ESENSE 1 e ESENSE 2) e un terzo 27 che ha esaminato
l’efficacia di un anno di trattamento secondo necessità
(SENSE) in pazienti con dipendenza da alcol. Nel complesso, gli studi di fase III hanno incluso 1.997 pazienti,
tutti trattati anche con un supporto psicosociale (BRENDA) volto ad aumentare l’aderenza al trattamento e alla
riduzione del consumo di alcol 28. La somministrazione
secondo necessità prevedeva che il paziente assumesse il
farmaco sperimentale (nalmefene 18 mg o placebo) ogni
giorno in cui percepiva il rischio di assumere alcol, preferibilmente 1-2 ore prima dell’ora prevista per il consumo;
se il paziente aveva già iniziato a consumare alcol senza
aver preso nalmefene, doveva assumere una compressa
il più presto possibile, con al massimo una compressa al
giorno.
Gli studi ESENSE 1 25 e ESENSE 2 26 avevano un disegno
identico e hanno incluso pazienti con una diagnosi di dipendenza da alcol secondo i criteri del DSM-IV-TR (604
in ESENSE 1 e 718 in ESENSE 2), con almeno 6 Heavy
Drinking Days al mese (HDD = giorno con consumo di
alcol ≥ 60 g nell’uomo e ≥ 40 g nella donna) e con un
consumo medio di alcol superiore al livello di rischio
medio secondo l’OMS nelle 4 settimane precedenti lo
screening. Gli studi comprendevano 1-2 settimane di
screening, dopo le quali i pazienti sono stati randomizzati a ricevere nalmefene 18 mg o placebo secondo necessità per 24 settimane. Il periodo di trattamento di 24
settimane era seguito da una fase di run-out di 4 settimane in doppio cieco, durante la quale i pazienti precedentemente trattati con nalmefene erano randomizzati ad assumere nalmefene o placebo e i pazienti trattati
con placebo continuavano ad assumere placebo. Gli
endpoint co-primari erano la variazione al mese 6 nel
numero di HDDs e nel consumo totale di alcol rispetto
al basale 25 26.
Nello studio ESENSE 1, dopo 6 mesi di trattamento vi
era un significativo effetto di nalmefene rispetto al placebo nella riduzione del numero di HDDs (p = 0,0021)
Nalmefene: profilo clinico e real world evidence nel trattamento della dipendenza da alcol
e del consumo totale di alcol (p = 0,0003) 25. Nello studio ESENSE 2 26, dopo 6 mesi, la differenza è risultata
significativamente maggiore nel gruppo nalmefene rispetto al gruppo placebo per quanto riguarda gli HDDs
(p = 0,012), ma non ha raggiunto la significatività per il
consumo totale di alcol (p = 0,088).
Va evidenziato che nel periodo di 1-2 settimane che era
compreso tra la valutazione iniziale (screening) e l’inizio
del trattamento si è assistito a una considerevole riduzione del consumo alcolico in un buon numero di soggetti
sia nello studio ESENSE 1 (18%) sia nello studio ESENSE 2
(33%) 29. Questo fenomeno è stato riportato in precedenza in altri trial e indica che una percentuale di pazienti è
stata trattata senza la prospettiva di un ulteriore miglioramento. L’inclusione di questi pazienti nell’analisi di
efficacia può aver portato a una sostanziale sottostima
dell’effetto del trattamento. Per effetto di questo fenomeno, l’efficacia di nalmefene è stata valutata nel sottogruppo di pazienti che presentavano un livello di consumo a
rischio elevato allo screening e che lo avevano mantenuto anche all’atto della randomizzazione (indicati come
popolazione target), cioè nei pazienti che si prevedeva
potessero trarre il beneficio maggiore dal trattamento con
nalmefene 29.
L’analisi post-hoc della popolazione target aggregata dei
due studi ESENSE 1 ed ESENSE2, ha incluso 667 pazienti
(335 nel gruppo nalmefene e 332 nel gruppo placebo) 29.
La Tabella I riporta le caratteristiche demografiche e cliniche al basale della popolazione target aggregata 29 30.
In media, i pazienti in trattamento con placebo hanno assunto il farmaco in studio nel 72% dei giorni nel periodo
principale di trattamento, mentre i pazienti trattati con
nalmefene hanno assunto il farmaco in studio nel 58%
dei giorni 29.
In questa popolazione target aggregata era evidente
l’effetto superiore di nalmefene rispetto al placebo nel
ridurre sia il numero di HDDs (p < 0,0001) che il consumo totale di alcol (p < 0,0001) al termine del trattamento (Fig. 1) 29. Nella popolazione target aggregata,
la variazione media stimata dal basale degli HDDs al
mese 6 era pari a -9,4 ± 0,7 giorni/mese per il gruppo
placebo e -12,6 ± 0,7 giorni/mese per il gruppo nal-
Tabella I. Caratteristiche demografiche e cliniche basali. Demographic and baseline clinical characteristics.
Placebo [332]
Nalmefene [335]
Razza
Caucasica
329 (99,1%)
333 (99,4%)
Sesso
Uomo
216 (65,1%)
223 (66,6%)
48,7 (10,5)
48,4 (10,5)
Indice di massa corporea (BMI) (kg/m )
26,1 (4,4)
26,0 (4,8)
Età di insorgenza del problema del consumo di alcol
35,1 (11,6)
35,6 (12,3)
Numero totale di HDDs mensili (giorni)
22,4 (6,0)
22,9 (5,9)
103,3 (44,5)
108 (45,0)
4,3 (1,4)
4,3 (1,4)
57,6
55,8
29,1
29,5
97,4
97,7
2,6 (1,5)
2,8 (1,7)
Punteggio totale del Drinker Inventory of Consequences
42,2 (22,2)
41,1 (22,3)
Punteggio totale della Alcohol Dependence Scale
13,3 (5,7)
14,0 (6,0)
Età (anni)
2
Consumo totale di alcol (g/giorno)
Clinical Global Impression – Severity of Illness
γ -Glutamiltransferasi (UI/l)
a
Alanina aminotransferasi (UI/l)a
Volume corpuscolare medio (fl)
a
Transferrina carboidrato-deficiente (%)
Vive con qualcuno
Sì
233 (70,2%)
247 (73,7%)
Occupato
Sì
183 (55,1%)
197 (58,8%)
Istruzione superiore
Sì
96 (28,9%)
98 (29,3%)
Trattato in precedenza per la dipendenza da alcol
Sì
112 (33,7%)
105 (31,3%)
Trattato in precedenza per i sintomi di astinenza da alcol
Sì
59 (17,8%)
49 (14,6%)
Anamnesi familiare di problemi di alcolismo
Sì
209 (63,0%)
211 (63,0%)
a
Media geometrica; i dati indicano media (DS) o numero di pazienti (%). DS: deviazione standard; HDDs: heavy drinking days.
83
I. Maremmani et al.
Variazione media aggiustata rispetto
al basale degli heavy drinking days
A
0
Placebo
-2
Nalmefene
-4
-6
-8
-10
*
-12
*
*
-14
*
*
*
5
6
-16
B
1
2
3
4
Periodo mensile
Variazione media aggiustata rispetto al
basale del consumo totale di alcol (g/die)
B
0
Placebo
-10
Nalmefene
-20
-30
-40
-50
*
-60
*
-70
*
*
-80
*
*
5
6
-90
B
1
2
3
4
Periodo mensile
Placebo
322
322
289
268
255
236
225
Nalmefene
319
319
280
246
219
198
188
* p < 0,05 rispetto al placebo.
I valori rappresentano le medie ± ES. B = basale
Figura 1.
Variazione media aggiustata mensile rispetto al basale di (A)
HDDs e (B) consumo totale di alcol per i pazienti con livello
di consumo a elevato rischio allo screening (basale) e alla
randomizzazione sulla base dei dati aggregati degli studi
ESENSE 1 ed ESENSE 2. Monthly adjusted mean change from
baseline in (A) HDDs and (B) total alcohol consumption for
patients with high drinking risk level at screening (i.e. baseline)
and randomization from ESENSE 1 and ESENSE 2 pooled.
mefene, corrispondenti a un effetto del trattamento di
-3,2 HDDs/mese (IC 95%: da -4,8 a -1,6, p < 0,0001) a
favore di nalmefene 29. Nella popolazione target aggregata, la variazione media stimata dal basale del consumo totale di alcol al mese 6 era pari a -51,4 ± 2,8 g/die
per il gruppo placebo e -65,7 ± 2,8 g/die per il gruppo
84
nalmefene, corrispondenti a un effetto del trattamento
di -14,3 g/die (IC 95%: da -20,8 a -7,8, p < 0,0001) a
favore di nalmefene 29.
Al mese 6, la variazione media aggiustata del punteggio CGI-S e il punteggio medio aggiustato CGI-I erano
significativamente (p < 0,05) a favore dei pazienti trattati
con nalmefene rispetto al placebo nell’analisi della popolazione target di entrambi gli studi ESENSE 1 e ESENSE 2 29. Un miglioramento significativamente (p ≤ 0,01)
maggiore dei livelli di ALT è stato dimostrato nei pazienti
trattati con nalmefene rispetto a quelli trattati con placebo nell’analisi di ambedue i sottogruppi 29.
I livelli di GGT si sono ridotti in misura significativamente (p < 0,001) maggiore con nalmefene rispetto al placebo nell’analisi del sottogruppo della popolazione target
dello studio ESENSE 1, ma non in quella dello studio
ESENSE 2 29.
Il profilo di sicurezza e tollerabilità di nalmefene nei pazienti con un livello di consumo a elevato rischio sia al
momento dello screening sia a quello della randomizzazione è risultato simile a quello osservato nella popolazione generale. Durante il periodo di trattamento, circa
il 77% dei pazienti nel gruppo trattato con nalmefene ha
presentato uno o più eventi avversi, tra i quali i più frequenti sono risultati il capogiro, la nausea e l’insonnia 29.
La maggior parte di questi eventi avversi erano transitori
(3-7 giorni), si verificavano entro un giorno dalla prima
dose ed erano di intensità lieve o moderata 29.
Lo studio SENSE 9 27 ha valutato l’efficacia e la tollerabilità del trattamento con nalmefene secondo necessità
per un anno nei pazienti con dipendenza da alcol. Sono
stati inclusi 675 pazienti con diagnosi di alcoldipendenza secondo i criteri del DSM-IV-TR, con almeno 6
HDDs al mese e con un consumo medio di alcol anche
a rischio basso (OMS) nelle 4 settimane precedenti lo
screening. I pazienti sono stati randomizzati a ricevere
nalmefene o placebo secondo necessità. Tutti i pazienti
hanno preso parte a un intervento mirato a migliorare la
motivazione e l’aderenza al trattamento (BRENDA). Gli
endpoint primari di efficacia erano analoghi agli studi
ESENSE. Nel trial SENSE, il 39% dei pazienti ha ridotto
in maniera sostanziale il consumo di alcol nel periodo
tra lo screening e la randomizzazione; pertanto, anche
nello studio SENSE è stata effettuata un’analisi post-hoc
nel sottogruppo di pazienti con un consumo a elevato
rischio sia allo screening sia alla randomizzazione 9 31.
Nei pazienti della popolazione target, il trattamento secondo necessità con nalmefene ha ridotto il numero di
HDDs e il consumo totale di alcol in misura significativamente maggiore rispetto a quelli trattati con placebo 9. Una differenza significativa (p < 0,05) tra i gruppi,
che favoriva nalmefene, è stata osservata ai mesi 2, 3 e
7-13 per la riduzione del numero di HDDs e dal mese 2
in poi per la riduzione del consumo totale di alcol. Per
Nalmefene: profilo clinico e real world evidence nel trattamento della dipendenza da alcol
quanto riguarda i punteggi delle scale CGI, vi era una
differenza significativa (p < 0,05) tra i pazienti trattati
con nalmefene e quelli trattati con placebo nella media
aggiustata del punteggio CGI-I alle settimane 8, 20, 32,
36 e 48. La riduzione dei livelli di GGT alla settimana
52 rispetto al basale, ma non dei livelli di ALT, era significativamente (p = 0,0062) maggiore nel gruppo trattato con nalmefene 9. Anche in questo studio, nalmefene
ha presentato un profilo di tollerabilità favorevole. Gli
eventi avversi che si sono verificati più frequentemente
nei pazienti trattati con nalmefene sono stati la nausea,
l’insonnia e il capogiro; la maggior parte di questi eventi
erano transitori e si verificavano subito dopo la prima
dose del farmaco 31.
Questi studi dimostrano l’efficacia clinica e la tollerabilità
di nalmefene nei pazienti con dipendenza da alcol, con
un effetto particolarmente evidente nei pazienti che risultano ancora a elevato rischio al momento dell’inizio del
trattamento. Nalmefene ha le potenzialità per coinvolgere
nel trattamento pazienti che altrimenti non avrebbero cercato aiuto e rappresenta un nuovo paradigma di trattamento farmacologico, sia in termini di obiettivo terapeutico
(riduzione del consumo di alcol) sia in termini di regime
posologico (secondo necessità), nei pazienti che non riescono a ridurre da soli il consumo di alcol.
Oltre a presentare le evidenze degli studi clinici di nalmefene in termini di efficacia e tollerabilità, l’obiettivo di
questo articolo è anche quello di fornire informazioni riguardo all’uso di nalmefene nella pratica clinica, tramite
la descrizione di case report di pazienti con dipendenza
da alcol. L’esperienza clinica può infatti costituire un ulteriore strumento di supporto alle evidenze scientifiche e
ai dati dei trial clinici associati all’uso di Nalmefene nei
pazienti con dipendenza da alcol. Di seguito verranno
descritti quattro case report di pazienti con dipendenza
da alcol, trattati con nalmefene.
Case Report 1: Signora S.
M. Di Nicola, F. Ruggeri, L. Janiri
Caratteristiche generali
S. è una donna caucasica di 44 anni. Parametri vitali e
antropometrici: PA: 130/85 mmHg; FC: 74 bpm; SO2:
99%; peso: 80 kg; altezza: 170 cm; BMI: 27,7 kg/m2.
Sintesi anamnestico-clinica
Genitori deceduti per carcinoma del pancreas e disturbi
cerebrovascolari. Familiarità nella linea materna per disturbo da uso di alcol e gioco d’azzardo patologico.
Parto eutocico a termine e primo sviluppo psicofisico
nella norma. Scolarità: diploma di scuola secondaria superiore. Stato civile: coniugata con due figli. Casalinga.
Non riporta rilevanti patologie organiche attuali e/o pregresse. Riferisce un episodio depressivo all’età di 25 anni,
di natura reattiva a una delusione sentimentale, trattato
ambulatorialmente con terapia farmacologica (sertralina
e alprazolam) e colloqui di supporto psicologico sino a
remissione completa.
Riconduce l’esordio del potus a circa cinque anni fa, inizialmente in maniera occasionale, in contesti sociali e
ricreativi, ma da circa un anno in modo continuativo e
ingravescente, con un consumo nell’ultimo mese di 75100 ml di vino al dì (6-9 UA/die) prevalentemente ai pasti. Afferma di avere incrementato l’uso di alcol a seguito
di difficoltà coniugali e di ricercare un effetto sedativo e
ipnoinducente. Nega l’assunzione attuale e/o pregressa
di altre sostanze psicoattive. Dopo alcuni tentativi infruttuosi di ridurre autonomamente il consumo alcolico, richiede per la prima volta un consulto specialistico per la
problematica alcol-correlata.
Al colloquio clinico, la paziente è vigile, lucida e orientata nei tre assi, scarsamente curata nell’aspetto e nella
persona. Il tono dell’umore appare lievemente orientato
verso le basse polarità con una sintomatologia ansiosa
psichica e somatica di grado moderato. Non emergono
disturbi della forma e del contenuto del pensiero, né delle senso-percezioni. Analogamente, non si rilevano significativi deficit delle funzioni mnestiche e cognitive. La
paziente riferisce una lieve alterazione del ritmo sonnoveglia con insonnia prevalentemente iniziale.
Indagini di approfondimento diagnostico
Al fine di valutare la gravità della dipendenza, la presenza di sintomi astinenziali, il craving, la sintomatologia
psichiatrica e il livello globale di funzionamento è stata
impiegata una batteria di reattivi psicometrici: Alcohol
Dependence Scale (ADS): 13; Clinical Institute Withdrawal Assessment of Alcohol - Revised Scale (CIWA-Ar): 8;
Obsessive Compulsive Drinking Scale (OCDS): 20; Visual
Analogue Scale for craving (VASc): 7; Hamilton Depression Rating Scale (HDRS): 12; Hamilton Anxiety Rating
Scale (HARS): 16; Clinical Global Impression-Severity index (CGI-S): 4.
Con il diario di assunzione alcolica (Timeline Followback, TLFB) è stato ricostruito retrospettivamente un livello di consumo di alcol (Drinking Risk Level, DRL) a
elevato rischio (> 40 g/die per una donna) nelle quattro
settimane precedenti. Inoltre, è stato chiesto alla paziente
di registrare il consumo alcolico nelle settimane successive mediante il TLFB.
Sono state effettuate indagini strumentali e di laboratorio,
quali ECG (nei limiti della norma), parametri di funzionalità epatica [AST: 18 UI/l (10-31); ALT 21 UI/l (9-36);
γ-GT: 49 UI/L (7-33)] e analisi di routine risultate nella
norma a eccezione di: glicemia: 116 mg/dl (70-110); co85
I. Maremmani et al.
lesterolo LDL: 141 mg/dl (< 130); trigliceridi: 155 mg/dl
(35-135).
Diagnosi finale
Mediante le Structured Clinical Interviews for DSM IV
Axis I and II Disorders (SCID I, SCID II) è stata formulata
la diagnosi di Dipendenza da Alcol ed esclusa la presenza di comorbilità psichiatriche.
Trattamento farmacologico
Dopo due settimane, la paziente presentava ancora livelli di consumo alcolico a elevato rischio (Total Alcohol
Consumption, TAC: 90 g/die; HDD: 25) e un craving di
grado moderato (OCDS: 20; VASc: 7) ma, in assenza di
sintomi fisici da sospensione (CIWA-Ar: 8), non richiedeva interventi immediati di disintossicazione.
Dopo avere informato la paziente circa l’opportunità
di intraprendere un percorso di cura basato sulla riduzione del consumo alcolico come passaggio intermedio
verso la completa astensione, a novembre 2013 è stato
iniziato il trattamento farmacologico con nalmefene 18
mg cp, 1 cp secondo necessità, congiuntamente a un
supporto psicosociale continuativo secondo il modello
BRENDA, con l’obiettivo di rafforzare la motivazione a
ridurre il consumo di alcol e di favorire l’aderenza alla
terapia.
Risposta al trattamento
Nella visita di follow-up dopo quattro settimane di trattamento, la paziente ha riferito di aver assunto 16 compresse di nalmefene. Rispetto al basale, è stata riscontrata una
riduzione del consumo alcolico [TAC: 60 g/die (-33,4%);
HDD: 14 (-44%)] e dei punteggi alle scale per il craving
[OCDS: 14 (-30%); VASc: 6 (-14,3%)].
Nella visita di follow-up dopo otto settimane di trattamento, la paziente ha riportato di aver assunto 12 compresse di nalmefene. Rispetto al basale, è stata registrata una riduzione del consumo alcolico [TAC: 45 g/die
(-50%); HDD: 12 (-52%)] e dei punteggi alle scale per
il craving [OCDS: 12 (-40%); VASc: 5 (-28,6%)], oltre a
un miglioramento degli indici di funzionamento globale
(CGI-S: 2; CGI-I: 2).
è stata ripetuta l’analisi dei parametri di funzionalità
epatica [AST: 16UI/l (10-31); ALT 19 UI/l (9-36); γ-GT:
41 UI/L (7-33)] e degli altri esami ematochimici risultati
nella norma a eccezione di: colesterolo LDL: 135 mg/dl
(< 130); trigliceridi: 140 mg/dl (35-135).
Nel corso del trattamento, non è stato rilevato alcun effetto collaterale o evento avverso. è stata programmata una
valutazione clinica, degli indicatori di esito e del profilo
di sicurezza e tollerabilità della terapia con frequenza
mensile fino a 24 settimane.
86
Commento
Nel caso della signora S., il trattamento farmacologico
con nalmefene (1 cp secondo necessità) associato alla terapia di supporto psicosociale si è rivelato ben tollerato e
ha consentito di raggiungere una riduzione del consumo
alcolico, come obiettivo intermedio nel percorso verso
l’astensione, e di modulare la terapia in base alle esigenze della paziente favorendone l’aderenza.
Case Report 2: Signor M.
A.G.I. Maremmani, I. Maremmani
Caratteristiche generali
Il signor M. è un maschio caucasico di 36 anni. Pesa
95 kg, BMI = 28,4 kg/m2 e ha una pressione arteriosa di
150/100 mmHg.
Sintesi anamnestico-clinica
All’anamnesi familiare veniva evidenziata una familiarità
negativa per ‘potus’ e positiva per depressione in linea
materna e paterna.
Dall’anamnesi fisiologica si è appreso che il paziente è
nato da parto eutocico, ha presentato uno sviluppo psicofisico nella norma, è stato affetto dalle comuni malattie
esantematiche dell’infanzia, non ha presentato allergie a
farmaci, ha avuto un regolare profilo alimentare, ipnico
e neurovegetativo.
All’età di 20 anni il paziente ha iniziato l’abuso di alcol,
negando un concomitante abuso di sostanze psicoattive
(neurodislettici, sedativi, stimolanti).
Dall’anamnesi patologica remota si è appreso che il paziente ha iniziato il potus (vino rosso da tavola), all’età
di 19-20 anni e che questo si è protratto fino a 25 anni
a scopo primariamente ricreazionale e disinibente sul
piano sessuale. In concomitanza all’interruzione della
prima relazione sentimentale, il signor M. interrompeva completamente l’uso di alcol per un periodo di circa
4 anni, senza incorrere in complicanze astinenziali sul
piano fisico. In seguito riprendeva l’assunzione di alcol,
superalcolici esclusi, con modalità di consumo di tipo
stabile (senza disadattamento sociale e lavorativo), ma,
successivamente, le condotte potatorie si andavano intensificando e il paziente si presentava reattivo agli eventi ambientali e sensibile agli eventi vitali stressanti con
conseguenti molteplici episodi di intossicazione acuta.
L’uso dell’alcol generalmente iniziava ai pasti (mai di
mattina) e si intensificava nel pomeriggio fino a tarda sera, raggiungendo un introito alcolico di circa 3-4 l al giorno, mantenendo una tolleranza diretta e non mostrando
mai episodi di violenza nelle fasi di intossicazione acuta.
Nel 2009 il paziente presentava criticità di tipo ansioso
e conseguente strutturazione agorafobica; nel 2012, era
Nalmefene: profilo clinico e real world evidence nel trattamento della dipendenza da alcol
ospedalizzato per una pancreatite acuta alcol-correlata.
Sul piano della comorbidità psichiatrica era possibile evidenziare, durante la storia clinica del paziente, episodi di
attacchi di panico e fasi opposte dell’umore (depressive
ed eccitatorie) tipiche del disturbo bipolare.
Indagini di approfondimento diagnostico
All’inizio del trattamento con nalmefene, per la valutazione dell’introito giornaliero di alcol, è stato utilizzato il
metodo TLFB (Timeline Follow-Back).
Dal punto di vista ematochimico è stata indagata la funzionalità cardiaca, epatica, pancreatica e emocromo.
Diagnosi finale
Disturbo da uso di alcol, gravità severa (DSM-5). Diabete
mellito di tipo 2, ipertensione arteriosa, eiaculazione precoce, pancreatite acuta esotossica.
Trattamento farmacologico
Per la dipendenza da alcol il paziente è stato, inizialmente, trattato con sodio oxibato (fino a 60 ml/die) dall’aprile
2013 all’ottobre 2013, quando è stato aggiunto, per il
permanere di un consumo alcolico ad alto rischio, nalmefene 18 mg 1 cpr al bisogno. Tale terapia è stata continuata fino al momento attuale (dicembre 2013).
Dall’inizio del trattamento (aprile 2013) il paziente
ha assunto anche sali di litio (450 mg/die), gabapentin (1200 mg/die), trimipramina (20 mg/die), imipramina (20 mg/die), paroxetina (20 mg/die), delorazepam
(0,5 mg/die) per la concomitante comorbidità psichiatrica caratterizzata da disturbo bipolare e disturbo di
panico.
Dall’inizio del trattamento (aprile 2013) il paziente ha
assunto anche pantoprazolo (20 mg/die), nebivololo
(5 mg/die), enalapril + lercanidipina (20 mg+10 mg/
die), doxazosin (2 mg/die), sitagliptin + metformina
(100 mg+1700 mg/die), metformina (500 mg/die) per le
comorbidità internistiche (diabete mellito tipo 2 e ipertensione arteriosa).
Risposta al trattamento
Il paziente è stato trattato dall’aprile 2013 con sodio oxibato (60 ml/die) riducendo il consumo alcolico di circa il
50-75% (considerando un’assunzione iniziale di 3-4 l di
vino rosso al giorno). Il paziente ha mostrato un miglioramento clinico con un parziale controllo delle condotte
potatorie senza tuttavia riuscire a estinguere i comportamenti di abuso, mossi dal sottostante craving, che hanno portato il paziente ad assumere alcolici soprattutto di
sera nel proprio ambiente domestico e nelle occasioni
sociali. Nel corso dei mesi il paziente ha identificato nei
fine-settimana i momenti di rischio maggiore con episodi
di intossicazione acuta su base impulsiva, comportamen-
ti a rischio (guida dell’automobile sotto effetto dell’alcol),
scadimento del funzionamento sociale e familiare con
un peggioramento del quadro clinico che è culminato in
un grave episodio di intossicazione acuta con comparsa
di sopore a fine settembre 2013. Nonostante, quindi, la
terapia praticata, il paziente ha mantenuto un consumo
alcolico a elevato rischio. A questo punto si è pensato di
introdurre in terapia nalmefene 18 mg al fine di ridurre
il quantitativo di alcol assunto. Poiché dopo 2 settimane
dalla proposta di modifica del trattamento, il paziente riportava un consumo alcolico ancora a elevato rischio,
come testimoniato dalla compilazione del TLFB, e il paziente non presentava sintomi fisici da sospensione, è
stato inserito nalmefene 18 mg secondo necessità. Per
una settimana il paziente, percependo il rischio di bere tutti i giorni, ha assunto una compressa di nalmefene
ogni mattina. In seguito, il paziente ha assunto la terapia
3-4 volte/settimana, concentrate nel fine settimana. Allo
stesso tempo, si è intensificato il supporto psicosociale
mirato all’aderenza al trattamento. Nelle prime 2 settimane il paziente ha riferito la comparsa di abbondante
sudorazione, tremore fine agli arti superiori, capogiro e
lieve irrequietezza. Tale sintomatologia si è mostrata più
intensa nella mattinata e della durata di 2-3 ore con completa risoluzione spontanea. La sintomatologia descritta
non è mai stata tale da compromettere il funzionamento
del paziente. Dall’introduzione di nalmefene il paziente
ha mostrato un netto miglioramento clinico con riduzione delle condotte di potus ed estinzione degli episodi di
intossicazione acuta. Rispetto al livello di alcol assunto
nel momento dell’introduzione di nalmefene, il paziente
ha ridotto il potus di un ulteriore 25-50%, raggiungendo
periodi di astensione dall’alcol e un controllo del bere
nel fine settimana (massimo 2 unità alcoliche) senza alterazioni comportamentali. Nei 30 giorni successivi all’inizio del trattamento con nalmefene, il paziente non ha
più presentato episodi di intossicazione alcolica acuta,
ha riferito assenza di craving mostrando un completo recupero psicoaffettivo con buon funzionamento globale.
Nelle occasioni in cui assumeva alcol, il signor M. ha
mostrato un recupero del controllo sul bere riferendo di
non percepire più quell’euforia e quel piacere legato al
bere che aveva provato nel passato. Al contemporaneo
miglioramento dell’assunzione alcolica ha fatto riscontro
la possibilità di ridurre la posologia di sodio oxibato (fino
a 30 ml/die).
Commento
In conclusione l’uso del nalmefene nel signor M. ha permesso di ridurre il suo bere da un livello altamente a
rischio a un livello lieve-moderato. L’uso del Nalmefene sembra quindi essere indicato anche in soggetti che
soddisfano i criteri di inclusione al trattamento dopo
87
I. Maremmani et al.
parziale risposta ad altri farmaci indicati nell’alcolismo
e miranti a raggiungere e mantenere uno stato di sobrietà nel paziente.
Case Report 3: Signora A.
S. Presta
Caratteristiche generali
44 anni, donna, peso 51,200 kg, altezza 163 cm, BMI
19,2 kg/m2.
Sintesi anamnestico clinica
Anamnesi familiare
Familiarità positiva per disturbi dell’umore dello spettro
bipolare II, per uso di sostanze (alcol e cocaina) e per
suicidio.
Anamnesi fisiologica
Primogenita, nata a termine da parto eutocico, allattamento al seno. Sviluppo psicofisico regolare, primi
atti della vita di relazione in età fisiologica. Scolarità
universitaria. Casalinga. Sposata, ha un figlio. Alimentazione irregolare con craving per i carboidrati. Fino a
settembre 2013 assunzione quotidiana di due aperitivi,
vino ai pasti e non (circa un litro al giorno) e superalcolici. Ha fumato dai 14 anni 20-30 sigarette/die, ora
ridotte a 10. Beveva 7-8 caffè/die, ora ridotti a 2. Alvo
stitico. Diuresi regolare.
Esame obiettivo
Condizioni generali discrete. Sensorio integro. Decubito
attivo, indifferente. Cute e mucose trofiche e ben umidificate. Sottocutaneo scarsamente rappresentato ma distribuito in maniera armonica. Masse muscolari ipotoniche
e ipotrofiche. Apparato osteoarticolare indenne. Articolazioni non dolenti né dolorabili ai movimenti attivi e passivi. Lingua ben sporta sulla linea mediana, rosea, umida
ma patinosa. Apiretica. Polso ritmico, 72 bpm. Pressione
arteriosa 145/85.
Anamnesi patologica internistica
Comuni esantemi. Appendicectomia. Ipertensione arteriosa in trattamento con ACE-inibitori (perindopril). Ipercolesterolemia familiare in trattamento con statine (atorvastatina). Steatosi epatica. Gastrite cronica con reflusso
gastro-esofageo e esofagite da reflusso, in trattamento
con inibitori di pompa protonica (lansoprazolo).
Anamnesi psichiatrica premorbosa
Incostante, instabile, labile, volubile, ipersensibile alla
critica, al giudizio, al commento, al rifiuto, facilmente re88
attiva e irritabile, con presenza di deficit attentivi; e occasionali agiti aggressivi autodiretti (tagli cutanei). Ha avuto
esperienze, pur se non continuative a eccezione dell’alcol, con varie tipologie di sostanze (THC, allucinogeni).
I dati anamnestici orientano verso la presenza di un temperamento ciclotimico e tratti borderline di personalità.
Anamnesi psichiatrica remota
In età giovanile, in coincidenza della comparsa di ripetuti episodi critici d’ansia, le condotte potatorie si intensificano, forse configurando una modalità autoterapica nei
confronti delle crisi di panico.
Nel tempo compaiono periodi caratterizzati da oscillazioni timiche in senso depressivo e stati misti attenuati.
Nel post-partum (periodo autunnale) compare grave flessione del tono timico, elevazione dei livelli di angoscia,
ruminazione su temi di inadeguatezza, labilità emotiva
con crisi di pianto, insonnia. Il quadro esita in un tentativo autolesivo per flebotomia. A. viene ricoverata in
ambiente specialistico dove, diagnosticata anche la condizione di alcoldipendenza, le viene proposto un trattamento con disulfiram, decisamente rifiutato.
Nella primavera seguente si assiste a un probabile switch
ipomaniacale, con nuovo incremento delle condotte potatorie. La terapia farmacologica suggerita alla dimissione viene spontaneamente abbandonata.
Nell’autunno successivo A. va incontro a un nuovo viraggio depressivo, ma rifiuta ancora il trattamento farmacologico e si rifugia in terapie ‘alternative’: non abbandona
però il consumo di alcolici, divenuto oramai abituale.
Negli anni successivi l’andamento del disturbo dell’umore oscilla tra periodi di relativa eutimia, fasi a tonalità
depressiva, e probabili microswitch espansivi. Ciò che
rimane costante è l’assunzione di alcol, oramai strutturata nella quotidianità.
In coincidenza con un evento di perdita, A. presenta una
profonda flessione timica, temi olotimici e di abbandono
invadono il campo di coscienza, compaiono anedonia,
apatia, chiusura, ritiro sociale, riduzione della cura di sé,
elevazione della quota ansiosa con occasionali crisi di
panico. Il consumo di alcolici si intensifica e gli episodi
di ebbrezza acuta si fanno più frequenti e si associano a
una tinta sempre più disforica dell’umore. Solo la ricomparsa degli episodi di panico convince A. ad accettare un
consulto e poi il ricovero in una struttura specializzata.
Alla dimissione viene prescritta una terapia specifica a
base di SSRI (escitalopram), timoregolatori (sali di litio
e topiramato 32), anticraving specifici (acamprosato), ma
A. non si rivolge più ad alcun specialista e prosegue in
autogestione l’assunzione dei farmaci. Dopo breve periodo ‘sceglie’ di abbandonare acamprosato e sali di litio,
proseguendo piccole dosi di fluoxetina (inserita autonomamente al posto di escitalopram) e topiramato. Nei due
Nalmefene: profilo clinico e real world evidence nel trattamento della dipendenza da alcol
anni seguenti l’umore si mantiene più stabile, ma le condotte potatorie proseguono invariate.
Anamnesi psichiatrica prossima
Di recente, A. presenta un episodio importante di reflusso gastro-esofageo. Una EGDS evidenzia una gastrite
iperemica con esofagite erosiva da reflusso, che vengono correlate alle condotte potatorie e al tabagismo e caffeinismo cronici. Viene prescritta terapia con inibitori di
pompa protonica (lansoprazolo) e consigliata una rivalutazione psichiatrica.
Viene modificata la terapia timoregolatoria e ansiolitica
(inserimento di pregabalin), programmati accertamenti ematochimici (che evidenziano un incremento delle
gamma-GT a 248 UI/L e del MCV a 100.1 fL), valutazione cardiologica (che non evidenzia significative alterazioni del ritmo, della struttura e dell’emodinamica cardiaca), ecografia addominale (che evidenzia la presenza
di steatosi epatica moderata).
A Settembre 2013, mantenendo A. livelli di consumo di
alcol a elevato rischio, dopo aver somministrato la Clinical Institute Withdrawal Assessment of Alcohol Scale,
Revised (CIWA-Ar) 33 per escludere la presenza di sintomi
astinenziali (punteggio: 7), viene proposto il trattamento
con nalmefene 18 mg, illustrando la strategia relativa alla
possibilità di introduzione di un passaggio intermedio nel
percorso verso l’astensione e la possibilità di assumere il
farmaco secondo una modalità ‘as needed’.
Diagnosi finale lifetime (DSM-5) 34
Asse I: disturbo bipolare II; disturbo di panico; disturbo da
uso di sostanze (alcol, THC, allucinogeni, caffeina, nicotina).
Asse II: disturbo borderline.
Asse III: gastrite cronica; esofagite da reflusso; steatosi
epatica; ipertensione arteriosa; dislipidemia familiare.
Trattamento farmacologico e risposta
al trattamento
Sorprendentemente, sarà proprio la non richiesta di interruzione immediata dell’assunzione di alcol, nonché
la sensazione di non ‘intrappolamento’ in uno schema
terapeutico costrittivo, a convincere A. ad assumere il
nalmefene in modo regolare, dato il rischio quotidiano
di eccessi alcolici. A. inizia nalmefene secondo una modalità ‘as-needed’ e già dalle prime assunzioni avverte
una netta riduzione del desiderio di assumere alcol, in
assenza di effetti collaterali di rilievo. Decide così, dopo
appena due settimane, di sperimentare una assunzione
quotidiana, che prosegue a Dicembre 2013, cioè a distanza di circa tre mesi da inizio trattamento.
A. ha ridotto in modo consistente il consumo di alcolici, che si attesta ora su circa 400 cc di vino al giorno,
avendo del tutto eliminato gli aperitivi e quasi del tutto
i superalcolici. Prosegue una terapia psicofarmacologica
(fluoxetina, pregabalin) e, più recentemente, ha iniziato
il percorso psicoterapico già suggerito all’inizio del trattamento con nalmefene.
Case report 4: Signora M.
A. Petracca
Sintesi anamnestico-clinica
M. è una donna di 35 anni, che vive da pochi mesi con
un nuovo compagno, ma ha alle spalle diversi rapporti sentimentali, con un figlio nato da una relazione con
un uomo che si è allontanato senza occuparsi, se non in
modo saltuario, del bambino. Lavora come impiegata.
Ha una familiarità psichiatrica per disturbi dell’umore e
per alcoldipendenza. Non riferisce malattie di rilievo di
interesse internistico o chirurgico, con un esame obiettivo
nella norma, a eccezione di valori in anamnesi lievemente
alterati per quanto concerne la funzionalità epatica. Fuma
circa trenta sigarette al giorno e nell’anamnesi giovanile
sono presenti abuso di cannabinoidi e in alcuni periodi
di cocaina. All’età di venti anni comparsa di un episodio
con attacchi di panico e comportamenti di evitamento
di tipo agorafobico insorto in relazione a un evento abbandonico sul piano sentimentale. Dopo un trattamento
con sertralina e benzodiazepine riferisce un progressivo
miglioramento clinico, con la sospensione dopo pochi
mesi del trattamento farmacologico. Abbandona comunque gli studi universitari da poco iniziati e svolge diverse
attività lavorative. All’età di 23 anni la paziente presenta
un primo episodio espansivo dell’umore, con iperattività,
insonnia, logorrea, aggressività verbale e disinibizione sessuale. Trattata con neurolettici e benzodiazepine ha una
remissione clinica in breve tempo, ma rifiuta la proposta
di un qualsiasi trattamento con stabilizzatori dell’umore
per mancanza di insight. Si accentua il consumo di alcolici, già iniziato anche in rapporto all’attività lavorativa,
con eccessi soprattutto nel fine settimana e nelle situazioni
conviviali. Nel tempo vengono riferite varie riacutizzazioni del disturbo bipolare dell’umore, con prevalenza di episodi espansivi trattati nella fase acuta, ma senza l’adozione
di terapie preventive per il rifiuto della paziente. Il consumo di alcolici si fa nel tempo più abituale, soprattutto birra
e vino, con quantità sempre crescenti. I tentativi di disassuefazione basati sull’assunzione di farmaci avversativi,
quando il quadro clinico comprende alterazioni, anche
se di lieve entità, della funzionalità epatica o in seguito a
problemi legali (sospensione della patente), vengono abbandonati dopo periodi variabili e comunque non oltre
i sei mesi. Nell’ultimo anno, da quando ha l’attuale rapporto di convivenza, l’assunzione di alcolici è stata pressoché quotidiana, comprendente in genere uno-due spritz
al mattino, un paio di aperitivi prima di cena, una bottiglia
89
I. Maremmani et al.
di vino durante la cena e quasi sempre uno-due superalcolici nella serata, soprattutto se trascorsa in compagnia. Il
peggiorare della condizione clinica sul piano internistico e
una compromissione delle capacità prestazionali lavorative e domestiche hanno spinto la famiglia a un’azione tesa
a modificare le abitudini della paziente, con la richiesta di
un aiuto medico.
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Diagnosi finale
La diagnosi posta è disturbo bipolare II dell’umore e dipendenza da alcol.
Trattamento farmacologico e risposta
al trattamento
È stata adottata una terapia con sali di litio, senza l’impiego di altri farmaci timolettici per non favorire l’insorgenza di rapida ciclicità. Per quanto riguarda il trattamento dell’alcoldipendenza, il rifiuto da parte della donna a
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Conflitto di interessi
I. Maremmani ha partecipato a Board nazionali e internazionali
per Reckitt Benckiser Pharmaceuticals, Mundipharma, D&A
Pharma e Lundbeck.
S. Presta non ha ricevuto alcun grant.
A. Petracca non ha ricevuto alcun grant.
M. Di Nicola non ha ricevuto alcun grant.
A.G.I. Maremmani non ha conflitto di interessi.
F. Ruggeri non ha ricevuto alcun grant.
L. Janiri ha ricevuto grant di ricerca da Bruno Farmaceutici,
Lundbeck e Pfizer e ha partecipato ad Advisory Board nazionali
e internazionali per Bruno Farmaceutici e Lundbeck.
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91
Clinical psychopharmacotherapy
Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura
e la ricerca
Bipolar mixed states: evolution of the concept and implications for the treatment and research
C. Vampini, F. Nifosì
2° Servizio di Psichiatria, Ospedale Civile Maggiore, Verona, Dipartimento per la Salute Mentale, Verona
Summary
Objectives
Bipolar mixed states remain a nosologic dilemma, diagnostic
challenge and neglected area of therapeutic research. Mixed
episodes are reported to occur in up to 40% of acute bipolar
admissions and are associated with more severe manic and
general psychopathology, more catatonic symptoms, more comorbidity, a higher risk of suicide and a poorer outcome than
pure manic episodes. Kraepelin was the first to emphasize the
clinical relevance of mixed states. In recent years, several authors have contributed to promove a greater awareness of this
issue, considering the (DSM-IV-TR) definition of mixed states
extremely narrow and inadequate. The nomenclature for the cooccurrence of manic and depressive symptoms has been revised
in the new DSM-5 version to accommodate a mixed categorical–dimensional concept. The new classification will capture
subthreshold non-overlapping symptoms of the opposite pole
using a “with mixed features” specifier to be applied to manic
episodes in bipolar disorder I, hypomanic, and major depressive
episodes experienced in bipolar disorder I, bipolar disorder II,
bipolar disorder not otherwise specified, and major depressive
disorder. The revision will have a substantial impact in several
fields: epidemiology, diagnosis, treatment, research, education,
and regulations.
Methods
Findings are based upon review of the current literature. We
searched the Medline and Pubmed databases using combinations of the keywords: “mixed states”, “with mixed features”,
Introduzione
Benché la mania e la depressione siano comunemente viste come polarità opposte, esse sono strettamente collegate tra loro e possono di frequente coesistere nelle manifestazioni psicopatologiche del disturbo bipolare (DB). Con
il termine di stato misto bipolare si intende un’alterazione
patologica del tono dell’umore nella quale sono presenti
contemporaneamente sintomi maniacali e depressivi per
periodi di tempo prolungati. La coesistenza di sintomi
“bipolar”, “manic”, “depressive, “hypomanic”, “manic depression”, “bipolar depression”, “DSM-5” and all the medications
we described.
Results
Overall, there were very few double-blind, placebo-controlled
studies specifically designed to treat manic-depressive mixed
states. Rather, patients with mixed states comprised a sub-group
of the examined patient cohorts. Nevertheless, the data show
that acute mixed states do not respond favourably to lithium.
Instead, valproate and olanzapine are drugs of first choice. Carbamazepine may play a role in the prevention of mixed states.
Antidepressants should be avoided, because they may worsen
intraepisodic mood lability. Lamotrigine may be useful in treating
mixed states with predominantly depressive symptoms. With the
emergence of second-generation antipsychotics, which in some
cases have both antimanic and antidepressant effects, monotherapy options in the treatment of mixed states may increase.
Conclusions
However, assessing their comparative effectiveness in the treatment of the newly defined mixed states will require specific and
prospectively designed clinical trials. The medications that are
effective in treating mixed episodes per the DSM-IV-TR definition
may also be effective in treating mixed features per the DSM-5,
but new studies are needed to demonstrate it.
Key words
Mixed States • Mixed Features • Bipolar Disorder • Mania • Depression
• Pharmacological Treatment
di opposta polarità si manifesta nel tono affettivo, negli
aspetti formali e di contenuto del pensiero, nelle alterazioni della psicomotricità, dando luogo a quadri clinici
eterogenei e mutevoli. Dopo le descrizioni originarie del
IX secolo e un lungo periodo di relativo disinteresse, gli
Stati Misti (SM) sono ridiventati nell’ultimo decennio oggetto di studio e di ricerca sia per quanto riguarda una
opportuna ridefinizione nosografica e clinica, sia per l’individuazione di trattamenti farmacologici adeguati. La
mancanza di criteri diagnostici validi e specifici per lo SM
Correspondence
C. Vampini, 2° Servizio di Psichiatria, Ospedale Civile Maggiore, piazzale A. Stefani, 37121 Verona, Italy • E-mail: claudio.vampini@gmail.com
92
Journal of Psychopathology 2014;20:92-106
Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca
ha reso più difficile lo studio dei rapporti fra queste condizioni e le altre polarità degli episodi affettivi, soprattutto quando la mania si presenta con umore disforico o la
depressione si caratterizza per l’agitazione psicomotoria.
Poco chiara è pure la relazione con alcuni aspetti evolutivi dei disturbi dell’umore, quali la cronicità e la rapida
ciclicità. Inoltre, la frequente contaminazione psicotica
della condizione mista, già sottolineata dagli autori classici, pone problemi di diagnosi differenziale dalle manifestazioni psicotiche proprie di altri ambiti nosografici,
come la schizofrenia ed i disturbi schizoaffettivi. La definizione del DSM-IV TR di ”stato misto”, inteso come la
concomitanza di mania e depressione in senso categoriale, è stata rivista nel nuovo DSM-5, che presenta un
concetto misto categoriale-dimensionale volto a superare
i problemi derivanti dalla definizione eccessivamente ristretta del DSM-IV-TR. Il trattamento farmacologico degli
SM rappresenta a tutt’oggi una sfida clinica per la scarsità
di studi controllati che possano sostenere dei protocolli
condivisi. I nuovi studi clinici dovranno valutare l’effetto
dei trattamenti in pazienti reclutati per la presenza o l’assenza di “aspetti misti” secondo il DSM-5 e i composti
che si sono dimostrati efficaci nel trattamento degli SM
secondo il DSM-IV-TR dovranno dimostrare, in nuovi
RCT, di esserlo anche rispetto alla nuova definizione. Lo
scopo di questo lavoro è quello di presentare una revisione critica della letteratura, sia riguardo all’evoluzione
dei criteri diagnostici, sia in merito agli aspetti clinici e di
trattamento degli SM, con particolare attenzione al trattamento degli SM maniacali.
Diagnosi e quadri clinici
La prima descrizione formale degli SM si deve a Kraepelin,
il quale osservò come uno o più dei principali aspetti
psicopatologici della mania (umore, cognizione, motricità) potessero essere sostituiti da uno o più degli aspetti
principali della depressione e viceversa 1-4. In base alle
diverse combinazioni tra queste oscillazioni indipendenti, Kraepelin distinse schematicamente alcuni sottotipi di
SM: 1) depressione agitata, caratterizzata da umore depresso e da agitazione psicomotoria; 2) stupor maniacale,
nel quale l’euforia e la sensazione di aumentata capacità
e potenza si accompagnano ad inibizione psicomotoria
ed ideativa; 3) depressione con fuga delle idee, caratterizzata da deflessione timica e inibizione psicomotoria
uniti però ad accelerazione ed affollamento di pensieri;
4) mania improduttiva, con euforia e affaccendamento
associati a rallentamento del pensiero; 5) mania depressiva, con umore orientato in senso depressivo, ma anche
notevole irritabilità, intolleranza e reattività; 6) mania
acinetica, con elevazione dell’umore, distraibilità, fuga
delle idee associate ad inibizione motoria 5 (Tab. I).
Kraepelin descrisse inoltre alcune caratteristiche specifi-
che degli SM, quali la tendenza alla cronicizzazione e la
frequente presenza di aspetti psicotici. La classificazione
proposta da Kraepelin, criticata in passato per una eccessiva schematizzazione, è stata rivalutata in anni recenti per la conferma della sua corrispondenza alla realtà
clinica. Berner et al. 6 hanno in seguito proposto criteri
specifici (Vienna Research Criteria), che delineano un
“sottotipo misto” del DB, in cui una persistente instabilità
emotiva viene considerata il radicale fondamentale ed è
associata a disturbi della percezione, sensazione di interferenze esterne e depersonalizzazione. Vi è sempre maggiore concordanza in letteratura sul fatto che gli SM bipolari non sono semplicemente un verificarsi simultaneo
o rapidamente sequenziale di sintomi affettivi di polarità
opposta. Essi corrispondono a quadri clinici complessi, fluttuanti e instabili, con elevata frequenza di aspetti
quali perplessità emotiva, ansia, agitazione, irritabilità, e,
meno costanti, confusione, comportamenti disorganizzati, impulsività e sintomi psicotici 4. Queste caratteristiche
vengono considerate tipiche e specifiche degli SM e ricondurrebbero all’ipotesi di una loro autonomia quale
“terza polarità” dei disturbi dell’umore 5 7 8. Nei moderni
sistemi di classificazione ufficiali gli SM non hanno ricevuto una caratterizzazione nosografica specifica. Prima
della recente edizione del DSM-5 9, i criteri diagnostici
Tabella I. Gli stati misti secondo il modello di Kraepelin. Mixed states
according to the model of Kraepelin.
Mania depressiva/irritabile
Depressione agitata
Mania improduttiva
Stupor maniacale
Depressione con fuga delle idee
Mania con inibizione motoria
Umore
-
Motricità
+
Ideazione
+
Umore
-
Motricità
+
Ideazione
-
Umore
+
Motricità
+
Ideazione
-
Umore
+
Motricità
-
Ideazione
-
Umore
-
Motricità
-
Ideazione
+
Umore
+
Motricità
-
Ideazione
+
93
C. Vampini, F. Nifosì
per la mania mista del DSM-IV TR 10 e del DSM-IV-TR 11
richiedevano che i pazienti soddisfacessero contemporaneamente i criteri di un episodio depressivo e maniacale
completi. La classificazione ICD-10 12 fornisce una descrizione leggermente meno rigida, che comprende anche la possibilità di depressione più ipomania ma al pari
della classificazione DSM-IV TR richiede che la diagnosi
di disturbo bipolare misto sia effettuata solo se le due
serie di sintomi sono entrambe rilevanti per la maggior
parte dell’episodio in corso. Nessuna delle serie di criteri
dei sistemi diagnostici descritti prende in considerazione
casi in cui gli elementi espansivi e depressivi siano combinati senza soddisfare appieno i criteri relativi all’uno
o all’altro tipo di episodio, né pone l’attenzione sull’estrema variabilità del quadro clinico e sulle rapide variazioni umorali proprie degli SM. Inoltre, la classificazione
ICD-10 prevede che per una diagnosi di stato misto esista
almeno un episodio affettivo pregresso e pertanto non riconosce che la sintomatologia mista rappresenti spesso
la prima espressione del disturbo dell’umore. Il DSM-IV
TR indica, come criterio di esclusione, il fatto che la sintomatologia mista non sia “dovuta agli effetti fisiologici
diretti di una sostanza o a una condizione medica generale”. Valutare se un episodio misto sia una conseguenza
diretta di un danno cerebrale, dell’abuso di sostanze e/o
di tossicità può rivelarsi piuttosto difficile nella pratica
clinica. Per di più, tali condizioni sono spesso riportate
nell’anamnesi personale dei pazienti con SM 13 14.
I risultati degli studi effettuati negli ultimi 10 anni sulla
valutazione dimensionale della mania hanno confermato e integrato la riconcettualizzazione nosografica degli
stati misti maniacali (SSM), ribadendo l’esistenza di una
dimensione depressiva nella mania pura 15- 18. Numerosi
autori, sulla base di una valutazione di ampie coorti di
pazienti, hanno proposto una nuova nosografia degli SM
basata su differenti criteri che vanno da una definizione
categoriale intermedia a più ampi approcci dimensionali 1 5 19‑21. Secondo tale revisione, che si rifà in parte a
concetti kraepeliniani, la soglia del DSM-IV TR per la depressione sindromica nel corso della mania è considerata
troppo restrittiva e basterebbero invece pochi sintomi
depressivi per convalidare la diagnosi clinica di mania
mista. I criteri di Cincinnati richiedono la presenza di ≥
3 sintomi depressivi associati per porre diagnosi di mania mista 19 22 23, mentre i criteri di Pisa-San Diego sono
basati sulla presenza di 2 su 5 caratteristiche cliniche e
temperamentali 1 5.
Classificazioni ancora più ampie richiedono un solo sintomo depressivo o un temperamento in opposizione allo
stato maniacale (Duke/ROC criteria) 24. è stato proposto
che i criteri per la diagnosi di episodio misto dell’umore
in ambito clinico dovrebbero essere basati sulla presenza di > 3 sintomi non in sovrapposizione della polarità
opposta, mentre in ambito di ricerca dovrebbero esse94
re considerati dei cut-off specifici nel punteggio delle
scale di valutazione (ad esempio un punteggio ≥ 10 alla
Hamilton Depression Rating Scale per un episodio misto ipomaniacale o un punteggio ≥ 8 alla Schedule for
Affective Disorders and Schizophrenia per un episodio
misto depressivo) 18. Sulla base di queste considerazioni,
gli SMM sono stati variamente denominati “mania disforica”, “mania mista”, “mania mista disforica”, “mania
depressiva” e “disturbo bipolare misto” 1 5 23 25-27.
Contrariamente agli SMM, l’esistenza di stati misti depressivi (SMD), che includano un episodio depressivo
maggiore completo con presenza di sintomi maniacali,
non è stata sinora considerata negli attuali sistemi di classificazione ufficiali e, fino a non molto tempo fa, è stata
ampiamente trascurata in letteratura. Le forme depressive
degli SM originariamente delineate da Kraepelin appaiono caratterizzate dall’aggiunta ai sintomi depressivi di
elementi di eccitazione psicomotoria 2 3. Secondo le osservazioni cliniche descrittive, il profilo sintomatologico
degli SMD consiste in una depressione agitata, spesso
psicotica, con umore irritabile, eloquio accelerato e fuga
delle idee 28 29. Successivamente Benazzi 30 e Benazzi
e Akiskal 21, applicando i criteri DSM-IV TR in pazienti ambulatoriali con depressione bipolare II e unipolare,
hanno definito gli SMD come la presenza di tre o più sintomi ipomaniacali concomitanti durante la depressione
maggiore. Un importante contributo è stato fornito da Perugi et al. 13, che, in uno studio condotto su 195 pazienti
bipolari I, hanno validato gli SMD caratterizzandoli clinicamente rispetto alla depressione maggiore bipolare
“pura”. Rispetto a quest’ultima gli SMD presenterebbero
episodi meno numerosi e più lunghi, un episodio indice
più spesso misto, con una minor remissione interepisodica. L’identificazione di condizioni cliniche definibili
come SMD ha implicazioni fondamentali per la pratica
clinica. Perugi et al. 44 osservano come tali condizioni
vengano spesso confuse con numerosi altri disturbi psichiatrici, quali la depressione psicotica, la schizofrenia
e il disturbo di personalità borderline e trattati in modo
inadeguato, con elevata probabilità di non risposta e/o di
destabilizzazione del DB.
Gli stati misti nel DSM-5
La definizione di ”stato misto” secondo il DSM-IV TR è
stata rivista nel nuovo DSM-5, che presenta un concetto
misto categoriale-dimensionale, con l’obiettivo di superare i problemi di un’eccessiva restrittività e di una scarsa
corrispondenza alla pratica clinica. Nella nuova definizione è stata ridefinita la nomenclatura degli episodi di alterazione dell’umore: è stata mantenuta la presenza degli
episodi depressivi, maniacali e ipomaniacali, mentre è
stata abolita la categoria di “episodio misto dell’umore”,
così come previsto e definito nel DSM-IV-TR. è stato inve-
Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca
ce introdotto il termine “episode with mixed features specifier”, che si applica qualora almeno tre sintomi sottosoglia
della polarità opposta siano presenti durante un episodio
dell’umore e che può essere di conseguenza attribuibile
all’episodio maniacale nel DB I, all’episodio ipomaniacale nel DB I, all’episodio depressivo maggiore nel DB I, II,
NAS e nel disturbo depressivo maggiore (DDM). Si configurano dunque le seguenti categorie diagnostiche:
• episodio depressivo maggiore con caratteristiche miste (Tab. II);
• episodio maniacale con caratteristiche miste (Tab. III);
• episodio ipomaniacale con caratteristiche miste
(Tab. IV).
La possibilità di includere alcuni sintomi della polarità
opposta in gruppi diagnostici differenti è strettamente
collegata al concetto kraepeliniano, descritto in precedenza, secondo il quale, al posto di “categorie dell’umore” (la dicotomia unipolare-bipolare), vi è uno “spettro dell’umore” che vede ai due estremi la depressione
unipolare e la mania pura, riconoscendo per la prima
volta il legame tra DB e DDM 31. Secondo Vieta e Valentì 32 una tale revisione, per la sua maggiore aderenza
alla realtà clinica del DB, avrà un profondo impatto su
diversi ambiti, dall’epidemiologia, alla diagnosi, al trattamento, alle prospettive sulla ricerca, sino alla normativa delle agenzie regolatorie internazionali. Non mancano critiche rispetto a questo nuovo approccio classificatorio, Murru et al. 33 sottolineano come esso non
sia di aiuto nel chiarire i confini tra il DB e le diagnosi
correlate (ad es. il disturbo schizoaffettivo). Diversi au-
tori osservano come rimanga irrisolto il problema della dicotomia bipolare-unipolare, dal momento che un
episodio depressivo maggiore associato a una bipolarità sottosoglia “con aspetti misti”, secondo i criteri del
DSM-5, viene tuttora considerato un DDM e non incluso nello spettro bipolare 34 35. Da un’analisi preliminare
della definizione di stati misti del DSM-5, secondo Koukopoulos e Sani 36, i nuovi criteri per gli stati depressivi
misti sarebbero esplicitamente errati e condurrebbero a
un mancato riconoscimento della condizione clinica o
ad un suo fraintendimento.
Epidemiologia
Una diretta conseguenza delle diverse definizioni di SM
è che i tassi di prevalenza riportati variano significativamente da studio a studio. La prevalenza media della
mania mista è pari al 31% 23, ma utilizzando i criteri più
ristretti dello ICD-10 o del DSM-IV TR i tassi riportati
vanno dal 9 al 13% 37-39. Le stime di prevalenza degli
SMD appaiono alquanto scarse in letteratura, come conseguenza della non inclusione di queste forme nelle diagnosi categoriali degli attuali sistemi diagnostici. Un dato
importante appare quello riportato nello studio di Azorin
et al. 40, secondo il quale il 23,8% di una coorte di 493
pazienti affetti da DDM soddisferebbero i criteri allargati per stato misto depressivo. La ricollocazione nell’ambito dello spettro bipolare di pazienti tradizionalmente
considerati affetti da depressione unipolare, rappresenta
un’ipotesi di lavoro di grande attualità e riveste una note-
Tabella II. Episodio depressivo maggiore con caratteristiche miste. Major depressive episode with mixed features.
New DSM-5 mood episode DSM-5 Criteria for an episode “with mixed features” specifier
classification
Major depressive
Full criteria for a major depressive episode and at least 3 of following symptoms present:
Applicability of “mixed
features” specifier
MDE in BD 1, BD 2,
BDNOS and MDD
• Elevated, expansive mood
• Inflated self-esteem or grandiosity
• More talkative than usual or pressure to keep talking
• Flight of ideas or subjective experience that thoughts are racing
• Increase in energy goal directed activity (either socially, at work or
school, or sexually)
• Increase or excessive involvement in activities that have a high
potential for painful consequences (e.g., engaging in unrestrained
buying sprees, sexual indiscretions, or foolish business investments
• Decreased need for sleep (feeling rested despite sleeping less than
usual (to be contrasted from insomnia))
MDE: major depressive episode; BD 1: bipolar 1 disorder; BD 2: bipolar 2 disorder; MDD: major depressive disorder.
95
C. Vampini, F. Nifosì
Tabella III. Episodio maniacale con caratteristiche miste. Manic episode with mixed features.
New DSM-5 mood episode DSM-5 Criteria for an episode “with mixed features” specifier
classification
Applicability of “mixed
features” specifier
Manic
Manic episodes in BD 1
Full criteria for a manic episode and at least 3 of following symptoms present:
• Prominent dysphoria or depressed mood as indicated by either
subjective report (e.g., feels sad or empty) or observation made by
others (e.g., appears tearful)
• Diminished interest or pleasure in all, or almost all, activities (as
indicated by either subjective account or observation made by
others)
• Psychomotor retardation nearly every day (observable by others,
not merely subjective feelings of being slowed down)
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or inappropriate guilt (not
merely self-reproach or guilt about being sick)
• Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a
specific plan for committing
BD 1: bipolar 1 disorder.
Tabella IV. Episodio ipomaniacale con caratteristiche miste. Hypomanic episode with mixed features.
New DSM-5 mood episode DSM-5 Criteria for an episode “with mixed features” specifier
classification
Applicability of “mixed
features” specifier
Hypomanic
Hypomanic episodes in
BD 1 and BD 2
Full criteria for hypomanic episode and at least 3 of following symptoms present:
• Prominent dysphoria or depressed mood as indicated by either
subjective report (e.g., feels sad or empty) or observation made by
others (e.g., appears tearful)
• Diminished interest or pleasure in all, or almost all, activities (as
indicated by either subjective account or observation made by
others)
• Psychomotor retardation nearly every day (observable by others,
not merely subjective feelings of being slowed down)
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or inappropriate guilt (not
merely self-reproach or guilt about being sick)
• Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a
specific plan for committing
BD 1: bipolar 1 disorder; BD 2: bipolar 2 disorder.
vole rilevanza pratica per quanto riguarda la scelta terapeutica più corretta. Indipendentemente dalle definizioni
diagnostiche, lo stato misto maniacale è decisamente più
rappresentato nel sesso femminile, con prevalenza del
63-69% 37 41, mentre, per quanto riguarda gli SMD, la
96
maggior parte degli studi concorda che non vi è differenza di genere 13 16 40. Le differenze di genere negli SMM
risultano più significative quando viene applicata la definizione categoriale secondo i criteri DSM o ICD, con un
rapporto femmine-maschi pari a 1,9:1, mentre impiegan-
Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca
do criteri che comportano un minor numero di sintomi
depressivi il rapporto si riduce (da 0.6:1 a 1.8:1) 42.
Decorso e prognosi
Gli SM presentano caratteristiche di decorso del disturbo e di risposta al trattamento sostanzialmente diverse
rispetto agli episodi depressivi e maniacali. Il decorso e
la prognosi della mania mista sono peggiori delle forme
maniacali pure nel medio-lungo termine, con un tasso
di cronicizzazione pari a 15% in cinque anni 18 22 23. In
confronto agli episodi di mania pura, gli SMM tendono a
presentare un maggior numero di episodi di malattia, episodi di durata maggiore ed una più grave compromissione funzionale 43. Inoltre, i pazienti con SMM presentano
tassi più elevati di riospedalizzazione, maggiore comorbilità con abuso di sostanze e maggior rischio di tentativi
di suicidio 44-46. Il decorso e la prognosi degli SMD sono
stati a tutt’oggi scarsamente studiati 47. Gli SMD sarebbero caratterizzati, rispetto alla depressione bipolare, da un
tasso più elevato di ricadute depressive o ipomaniacali,
di rapid cycling, di sintomi psicotici, di caratteristiche
atipiche e di tentativi di suicidio. Vengono riportate una
maggiore comorbilità ed un più frequente temperamento
ipertimico o ciclotimico, oltre alla maggiore presenza di
precedenti episodi misti. L’età di insorgenza risulta in genere più precoce. La familiarità per DB, per alcoolismo e
per suicidalità è risultata altresì più frequente nei soggetti
con SDM 13 16 17 40. è riportato in letteratura che la polarità
dell’episodio indice appare predittiva della polarità delle recidive in campioni eterogenei di soggetti bipolari 48.
Gli episodi misti appaiono, in studi retrospettivi e prospettici, predittivi di recidive di tipo depressivo o misto,
a conferma degli aspetti depressivi che li sottendono e a
sostegno di una loro autonomia clinica 44 49 50.
Trattamento farmacologico
Nel trattamento degli SM vanno considerati tre aspetti
chiave:
a. porre una corretta diagnosi;
b. iniziare precocemente la terapia;
c. considerare non solo la fase acuta ma anche il trattamento di mantenimento e gli esiti a lungo termine.
I pazienti con SM, a causa della gravità e della complessità della sintomatologia, rappresentano spesso delle
acuzie cliniche. Le terapie farmacologiche devono essere, pertanto, rapidamente efficaci e in grado di controllare la concomitanza di sintomi di eccitamento e di
depressione, la labilità emotiva, le rapide fluttuazioni
umorali, gli eventuali sintomi psicotici, l’ansia/angoscia,
l’irrequietezza e l’impulsività a elevato potenziale autolesivo. Dal momento che nessun farmaco è generalmente
in grado di soddisfare tutti questi requisiti, nel trattamen-
to degli SM la polifarmacoterapia rappresenta la regola,
piuttosto che l’eccezione. Alcuni farmaci comunemente impiegati nella cura delle forme maniacali o depressive “pure” possono peggiorare i sintomi ed il decorso
degli SM, per l’elevato rischio di viraggio contropolare,
rispettivamente depressivo o (ipo)maniacale 51 52. L’individuazione di criteri “evidence-based” per il trattamento
degli SM è resa difficoltosa dalla carenza di dati di buona
qualità. La letteratura disponibile risulta infatti gravata da
alcuni importanti limiti, comuni ad altre condizioni psichiatriche gravi e/o acute. A tal proposito vanno citati:
a) l’inclusione negli studi di pazienti non gravi, che non
sono in genere rappresentativi della popolazione cui verrà prescritto, nella pratica clinica, il trattamento oggetto
di studio. Il problema riguarda particolarmente, per gli
SM, gli studi in monoterapia; b) gli studi in doppio cieco
placebo-controllati con stabilizzatori dell’umore (litio e
anticonvulsivanti) o antipsicotici di II generazione non
sono disegnati in modo specifico per il trattamento degli SM, bensì di episodi maniacali puri; c) nella maggior
parte di questi studi i pazienti con SM rappresentano una
quota modesta dell’intero campione e, quindi, i risultati
delle sub-analisi che li riguardano devono essere interpretati con cautela; d) data l’inadeguatezza dei criteri
diagnostici formali proposti da DSM e ICD, molti studi
hanno impiegato nella definizione di SM diverse rating
scales o criteri diagnostici alternativi, rendendo difficile
il confronto tra i risultati dei trattamenti; e) le misure di
esito impiegate nella maggior parte degli studi sono state
la riduzione del punteggio della YMRS e della HAM-D
(o della MADRS), confermando il modello di SM come
somma di sintomatologia maniacale e depressiva e non
intercettandone, quindi, la complessità clinica e l’estrema variabilità fenomenologica; f) rispetto alla profilassi
delle ricadute, gli studi a lungo termine hanno una numerosità inferiore a quelli in acuto e la quantità di dati
disponibili sugli SM è, a tutt’oggi, alquanto scarsa 53 54.
Una considerazione correlata all’interpretabilità di questi
risultati è che in questo articolo si è focalizzata l’attenzione sull’efficacia in acuto dei singoli composti sugli SM,
senza affrontare l’argomento del trattamento di mantenimento. I dati a tutt’oggi disponibili sul trattamento farmacologico degli SM riguardano esclusivamente gli SMM,
mentre gli SMD, non identificati dai tradizionali sistemi
diagnostici, non sono stati sinora oggetto di studi controllati. Alcune considerazioni sull’impiego degli antidepressivi negli SMD possono essere, peraltro, estrapolate
da studi sulla depressione bipolare “classica”, nei quali
è stato osservato come i trattamenti con antidepressivi
possano, sul medio-lungo termine, peggiorare il decorso
di malattia inducendo un’accelerazione dei cicli e/o la
comparsa di SM cronici, specie in presenza di sintomi
maniacali alla valutazione basale 17. L’effetto destabilizzante degli antidepressivi, solo attenuato dalla co-terapia
97
C. Vampini, F. Nifosì
con stabilizzatori dell’umore, sarebbe confermato con
tutti i tipi di composti, maggiore con i triciclici rispetto
agli SSRI e costituirebbe, insieme ad un’efficacia terapeutica inferiore rispetto alla depressione unipolare, il motivo per un impiego cauto e conservativo degli antidepressivi nei pazienti bipolari 51 55 56. Qualora, nel trattamento
di una depressione bipolare, si decida di associare allo
stabilizzatore dell’umore un antidepressivo, è opportuno monitorare la comparsa di sintomi di attivazione
psicomotoria, considerando in tal caso la sospensione
dell’antidepressivo in favore di un secondo stabilizzatore dell’umore (ad. es. litio più anticonvulsivanti) o di
un antipsicotico atipico (ad. es. litio o anticonvulsivanti
più asenapina, olanzapina o quetiapina). Nel trattamento
degli SMD l’impiego degli antidepressivi è decisamente
sconsigliato per l’elevato rischio di peggiorare l’instabilità umorale intraepisodica, oltre alla totale assenza di
dati a sostegno di una loro efficacia, mentre è indicato
l’impiego di stabilizzatori dell’umore e antipsicotici di II
generazione, preferibilmente in combinazione, anche se
i criteri di scelta e di associazione rimangono a tutt’oggi
empirici 42 53. In generale, gli antipsicotici di II generazione risultano indicati in presenza di irritabilità e impulsività, nonché di sintomi psicotici. Quando gli SMD non
rispondano adeguatamente alle terapie farmacologiche
e persistano quadri di grave agitazione psicomotoria o
inibizione, aspetti psicotici, catatonia, alto rischio di suicidio, ecc., dovrebbe essere presa in considerazione la
terapia elettroconvulsivante 57.
A tutt’oggi è naturalmente troppo presto e di conseguenza difficile poter prevedere quali ricadute si verificheranno, dal punto di vista dei trattamenti farmacologici, con
l’introduzione del DSM-5. Si può ipotizzare che un possibile contributo del DSM-5, che per la prima volta ha introdotto in un sistema classificatorio ufficiale il concetto
di bipolarità sottosoglia, sarà quello di fornire una nuova
cornice concettuale alla ricerca e all’applicazione clinica
di strategie terapeutiche per gli SM. Appare lecito ipotizzare che la nuova concettualizzazione potrà affinare le
capacità in termini di specificità e sensibilità nel riconoscimento degli stati misti, verosimilmente a scapito delle
diagnosi delle opposte polarità maniacali e depressive
“pure”. In un futuro molto prossimo ci potremo attendere
una maggiore quantità e qualità di studi specificamente
dedicati agli SMM, e soprattutto agli SMD, a proposito
dei quali la letteratura è storicamente molto carente. Una
modifica, decisamente sostanziale, della concettualizzazione diagnostica non potrà non avere ricadute sul
trattamento, farmacologico e non, degli stati misti. Al
momento una possibilità concreta molto promettente è
quella di utilizzare la grande quantità di dati già esistenti,
derivati dagli RCT o dagli studi naturalistici condotti su
soggetti bipolari, per effettuare sub-analisi post-hoc impiegando la definizione del DSM-5. L’obiettivo di queste
98
analisi è quello di valutare l’utilità clinica di trattamenti
farmacologici, già sperimentati su campioni selezionati
con criteri diagnostici tradizionali, su sottopopolazioni di
pazienti ridefinite “a posteriori” mediante il nuovo criterio del “mixed specifier” 54.
Farmaci studiati negli stati misti maniacali
Litio
Il litio è stato valutato per lo più in piccoli sottogruppi di
pazienti con SMM, come parte di studi a gruppi paralleli
finalizzati alla registrazione di altri composti. La re-analisi
del database originale registrativo del valproato ha evidenziato che la presenza di sintomi depressivi all’interno
di stati misti/maniacali riduce l’efficacia del litio, ma non
quella del valproato 20. Nell’unico studio di confronto randomizzato controllato il litio è risultato inferiore al valproato in presenza di sintomi depressivi, benché gli stessi siano stati valutati con strumenti non specifici 58. Al contrario,
Goldberg et al. 26, in uno studio retrospettivo di confronto
tra pazienti maniacali puri e misti, non ha riscontrato differenze tra litio, carbamazepina e valproato rispetto al tasso di remissione. Inoltre, il litio è risultato equivalente ad
aripiprazolo nel trattamento degli SMM 50. Il ruolo del litio
nel trattamento degli SMM appare attualmente controverso. La sua efficacia nei confronti dell’impulsività, della
suicidalità ne suggerisce l’impiego nei confronti di alcune
manifestazioni cliniche degli SMM, anche se mancano dati controllati in proposito 59 60.
Anticonvulsivanti
Valproato. Gli studi di confronto a gruppi paralleli
tra valproato e litio sono stati citati in precedenza. ll
valproato è risultato superiore al placebo in uno studio
randomizzato controllato a tre settimane condotto in 364
pazienti ospedalizzati, maniacali o misti 61. Il grado di
miglioramento sintomatologico è risultato sovrapponibile
nei due sottogruppi. Due studi in aperto hanno confermato
l’efficacia del valproato nella mania mista, il primo
condotto in soggetti anziani, il secondo in pazienti rapid
cyclers. 62 63. Inoltre, a conferma di una certa efficacia
del composto nei confronti dei sintomi depressivi, una
metanalisi dei quattro principali studi sul trattamento
della depressione bipolare ha evidenziato una superiorità
del valproato nei confronti del placebo 64. Nel complesso,
i dati disponibili suggeriscono che il valproato è efficace
nel trattamento a breve termine degli SMM.
Carbamazepina. In due studi randomizzati placebocontrollati a 3 settimane, dal disegno sovrapponibile,
la carbamazepina è risultata superiore al placebo nella
mania acuta, sia pura che mista 65 66. In un’analisi post-
Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca
hoc di questi due studi Weisler et al. 67 hanno analizzato
separatamente i dati relativi ai due sottogruppi. La
carbamazepina è risultata più efficace del placebo nel
ridurre il punteggio alla YMRS nei due sottogruppi ed il
punteggio alla HAM-D nei pazienti con mania mista. Per
i problemi connessi all’elevato potenziale di interazioni
farmacocinetiche la carbamazepina è considerata
attualmente un’opzione di seconda scelta, in soggetti
intolleranti o non responder a precedenti trattamenti 42.
Oxcarbazepina. Il vantaggio potenziale di oxcarbazepina,
un ketoderivato di carbamazepina, rispetto al composto
madre, è l’assenza di interazioni farmacocinetiche. Allo
stato attuale, non sono disponibili studi controllati di
oxcarbazepina negli SM.
Lamotrigina. La lamotrigina ha dimostrato, in una
metanalisi di 5 studi, un’efficacia di poco superiore al
placebo in pazienti con depressione bipolare acuta 68.
Inoltre ha dimostrato efficacia nella profilassi del DB,
maggiormente nei confronti degli episodi depressivi
che di quelli maniacali, ma non vi è alcun dato da studi
controllati a sostegno della sua efficacia negli SM 69.
Antipsicotici di II generazione
Una recente meta-analisi dei risultati ottenuti da nove
RCT (Randomized Controlled Trial) dimostra una efficacia superiore degli antipsicotici di II generazione rispetto
al placebo nel trattamento degli SMM, sia in monoterapia, sia in combinazione con stabilizzatori dell’umore 70.
I campioni studiati erano tutti eterogenei, composti da
pazienti affetti da mania pura o mista e l’effect size è risultato sovrapponibile per i due gruppi (pari rispettivamente
a 0,56 e 0,44), collocabile nel range “medio” di efficacia.
I sintomi maniacali degli episodi misti rispondono agli
antipsicotici di II generazione, in particolare asenapina,
aripiprazolo, paliperidone ER, risperidone e ziprasidone.
Nessun dato è a tutt’oggi disponibile per quetiapina, amisulpride e clozapina. Asenapina e olanzapina sembrano
efficaci anche nel trattamento dei sintomi depressivi nel
corso di SMM, ma ulteriori studi sono necessari per confermare tali osservazioni preliminari.
I dati relativi ai singoli antipsicotici di II generazione, per
quanto riguarda gli RCT condotti su pazienti con SMM,
sono qui di seguito riassunti.
Aripiprazolo. L’efficacia di aripiprazolo negli SMM è
stata valutata in un’analisi cumulativa post-hoc di due
studi randomizzati controllati vs. placebo, a tre settimane,
condotto in pazienti con mania acuta 31. All’endpoint
il composto ha evidenziato un’efficacia comparabile
nei due gruppi al punteggio della YMRS. Suddividendo
il campione in tre sottogruppi a seconda dal punteggio
basale alla MADRS, aripiprazolo è risultato ugualmente
efficace nella riduzione del punteggio MADRS. Lo studio
non riporta alcun dato di efficacia rispetto ai sintomi
depressivi.
Asenapina. L’efficacia di asenapina in soggetti bipolari I
con episodio maniacale o misto è stata documentata in
due RCT vs. placebo a tre settimane, identici nel disegno,
nei quali olanzapina è stata inclusa come controllo
attivo, e in una loro estensione a 9 settimane 71‑73.
Asenapina (5 o 10 mg due volte al giorno) è risultata
più efficace del placebo nel ridurre la sintomatologia
maniacale nell’intero campione ed ha soddisfatto i
criteri di non inferiorità vs. olanzapina. Gli Autori hanno
condotto un’analisi separata post-hoc della variazione
del punteggio alla YMRS nei sottogruppi pazienti con
mania pura vs. mista. Nel primo sottogruppo la riduzione
del punteggio all’endpoint è risultata statisticamente
significativa, mentre nel secondo gruppo la variazione
di punteggio alla YMRS ha sfiorato la significatività
statistica senza raggiungerla. In un’ulteriore analisi posthoc dei due studi a 3 settimane sopra citati, Szegedi et
al. 74 hanno valutato l’efficacia di asenapina sui sintomi
depressivi in pazienti maniacali/misti. La popolazione
in studio è stata suddivisa in modo indipendente in tre
sottogruppi a seconda che fossero presenti al baseline:
a) un punteggio alla MADRS ≥ 20 (n = 132); b) un
punteggio di gravità alla Clinical Global Impression for
Bipolar Disorder-Depression (CGI-BP-D) ≥ 4 (n = 170),
c) una diagnosi di episodio misto secondo il DSM-IVTR (n = 302). In ciascuno dei sottogruppi così definiti
asenapina ha evidenziato, al giorno 7, una riduzione
significativa nel punteggio totale alla MADRS rispetto al
basale. Al giorno 21 la variazione dal basale nel gruppo
trattato con asenapina è risultata superiore al placebo
nelle sottopopolazioni a) e b) (Fig. 1).
L’efficacia complessiva di asenapina, nel trattamento degli episodi misti, è stata ribadita in una recente analisi
post-hoc dei due medesimi studi a tre settimane e della loro estensione a 9 settimane 40. Alla terza settimana,
la riduzione del punteggio alla YMRS ed alla MADRS è
risultata significativamente maggiore rispetto al placebo
nei pazienti trattati con asenapina, ma non con olanzapina, mentre nell’estensione a 9 settimane asenapina e
olanzapina hanno dato risultati sovrapponibili nella riduzione del punteggio di entrambe le scale (Figg. 2, 3).
Nel trattamento dei pazienti con SM la non induzione di
viraggi di fase rappresenta un valore aggiunto, rispetto
all’obiettivo primario di una stabilizzazione del DB. Una
conferma delle favorevoli caratteristiche di asenapina, in
tal senso, viene dalla già citata estensione a 9 settimane
nei due studi nella mania acuta 72. In questo studio, i soggetti che hanno presentato una variazione del punteggio
99
Day 7
0
Day 21
Manic symptoms significantly reduced in patients
with mixed episodes
-5
-10
-15
Week 3
-8
Week 12
-10
*
†
*
-20
Asenapine (n = 45)
Placebo (n = 33)
Olanzapine (n = 54)
LS mean YMRS change
from baseline
LS mean (±SE) change
from baseline
MADRS total score
C. Vampini, F. Nifosì
-12
-14
*
-16
-18
-20
-22
-24
MADRS: Montgomery-Asberg Depression Rating Scale.
Post-hoc analysis; * p ≤ 0.01 vs. placebo; † p = 0.02 vs. olanzapine.
-26
Asenapine
Figura 1.
Modificazione del punteggio MADRS al giorno 21 (da Szegedi
et al., 2011, mod.) 74. Modification of the MADRS score at day
21 (from Szegedi et al., 2011, mod.) 74.
100
Olanzapine
ITT/OC; * p < 0.05 vs. placebo
YMRS: Young Mania Rating Scale.
Figura 2.
Efficacia sui sintomi maniacali (da Azorin et al., 2012,
mod.) 40. Effectiveness on manic symptoms (from Azorin et al.,
2012, mod.) 40.
Depressive symptoms significantly reduced in patients
with mixed episodes (I)
Week 3
0
LS mean MADRS change
from baseline
alla MADRS, da ≤ 8 al basale a ≥ 16 all’endpoint, sono
risultati il 2,3% con asenapina e il 5,0% con olanzapina.
Nel complesso, i dati disponibili confermano l’efficacia
di asenapina nel trattamento della sintomatologia maniacale e depressiva di pazienti bipolari con episodio misto e un basso potenziale del farmaco di indurre viraggi
depressivi. Nell’ambito di una valutazione di outcome
allargata, un’analisi post-hoc di due degli studi fondamentali sulla mania acuta ha evidenziato che pazienti
con DB tipo I, con episodi misti dell’umore, presentavano una riduzione considerevole della qualità della
vita legata allo stato di salute (HRQoL: Health Related
Quality of Life), misurata utilizzando la SF-36v2 (36-item
Short-Form Health Survey), rispetto ai pazienti con episodi di mania pura. Al termine delle 3 settimane di studio,
nei pazienti con episodi misti l’asenapina ha dimostrato
di indurre un significativo miglioramento della qualità di
vita confrontata con olanzapina e placebo 75. Un contributo sostanziale alla miglior comprensione dell’efficacia
di asenapina nel trattamento degli SMM è stato recentemente fornito da McIntyre et al. 54, che hanno condotto
un’analisi post-hoc di due degli studi fondamentali di
confronto con olanzapina e placebo condotti sulla mania
acuta. L’originalità dello studio, il primo nel suo genere,
consiste nel fatto che al campione totale di 960 pazienti
è stato applicato il “mixed features specifier” secondo il
DSM-5, selezionando in tal modo una sottopopolazione
di pazienti diversa da quella definita nel protocollo dello
studio, che prevedeva la tipizzazione dell’episodio misto secondo i criteri del DSM-IV-TR. L’obiettivo primario
Placebo
Week 3
-2
-4
-6
-8
*
-10
-12
-14
Asenapine
Placebo
Olanzapine
* p < 0.01 vs. placebo
MADRS: Montgomery-Asberg Depression Rating Scale.
Figura 3.
Efficacia sui sintomi depressivi (da Azorin et al., 2012, mod.) 40.
Effectiveness on depressive symptoms (from Azorin et al., 2012,
mod.) 40.
Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca
dell’analisi post-hoc è stato quello di valutare l’outcome
dei trattamenti sui sintomi maniacali e depressivi in pazienti bipolari I, che presentavano un episodio maniacale
con aspetti depressivi, così come definito nel DSM-5. A
tal scopo è stata studiata una griglia di selezione che corrispondesse in modo approssimativo ai “mixed features
specifier”, utilizzando alcuni item della MADRS e uno
della PANSS, stabilendo alcuni cut-off, nei punteggi e
nel numero di sintomi, per definire la gravità della depressione. Per quanto riguarda il tasso di remissione alla
MADRS, lo studio evidenzia che, al crescere del numero
dei sintomi depressivi al basale, asenapina mantiene la
stessa efficacia mentre olanzapina e placebo la riducono
entrambi (Fig. 4).
Per quanto riguarda la variazione media del punteggio alla
YMRS, lo studio evidenzia che la differenza tra asenapina
e placebo si incrementa con l’incremento dei sintomi depressivi. Nei pazienti più gravi (MADRS item ≥ 3; PANSS
item ≥ 4), l’efficacia di asenapina è statisticamente superiore a olanzapina al secondo e quarto giorno di trattamento e numericamente in tutte le altre rilevazioni (Fig. 5).
I risultati dello studio, che richiedono una conferma con
MADRS items ≥ 1
MADRS remission rate (%)
70
Olanzapina. L’efficacia di olanzapina nella mania
acuta è stata ben documentata in studi randomizzati
controllati 76. Due studi di Tohen et al. 77 78 sono stati
rianalizzati da Baker et al. 79 per valutare in modo specifico
l’impiego di olanzapina nella “mania disforica”, definita
come la presenza al basale di un punteggio alla MADRS
≥ 20. In un campione di 68 pazienti si è evidenziata con
olanzapina una significativa riduzione del punteggio sia
alla YMRS sia alla HAM-D, con un’ampiezza dell’effetto
sui sintomi maniacali indipendente dalla presenza di
sintomi depressivi. Successivamente, Baker et al. 80
hanno condotto uno studio randomizzato controllato
a 6 settimane vs. placebo in pazienti con mania pura/
disforica trattati con una combinazione di litio o
valproato e olanzapina. Nel gruppo con mania disforica
MADRS items ≥ 2
70
*
RCT appositamente disegnati, evidenziano come composti di comprovata ed equivalente efficacia nella mania,
quali asenapina e olanzapina, non abbiano un’efficacia
sovrapponibile nel ridurre sia i sintomi maniacali, sia
quelli depressivi, in soggetti maniacali che soddisfano i
criteri del DSM-5 per il “mixed specifier”.
**
MADRS items ≥ 3
70
60
60
60
50
50
50
40
40
40
30
30
30
20
20
20
10
10
10
0
0
0
*
Asenapine (n = 113)
Asenapine (n = 56)
Asenapine (n = 12)
Placebo (n = 89)
Placebo (n = 40)
Placebo (n = 12)
Olanzapine (n = 132)
Olanzapine (n = 66)
Olanzapine (n = 16)
Post-hoc analysis; * p ≤ 0.05, ** p ≤ 0.01 vs. placebo.
MADRS: Montgomery-Asberg Depression Rating Scale.
Figura 4.
Tassi di remissione alla MADRS al crescere del numero di sintomi depressivi (da McIntyre et al., 2013, mod.) 54. MADRS remission
rates to increases in the number of depressive symptoms (from McIntyre et al., 2013, mod.) 54.
101
C. Vampini, F. Nifosì
Mean change in YMRS total score in patients with severe severity of depressive symptoms
≥ 3 depressive features (MADRS items ≥ 3 and PANSS items ≥ 4)
Mean change from baseline
in YMRS total score
0
Asenapine (n = 13)
-3
Placebo (n = 12)
-6
Olanzapine (n = 16)
-9
**
†
†
-12
*
-15
-18
0
2
4
7
14
21
EP
Day
Post-hoc analysis; * p ≤ 0.05, ** p ≤ 0.01 vs. placebo; † p ≤ 0.01 vs. olanzapine.
MADRS: Montgomery-Asberg Depression Rating Scale; YMRS: Young Mania Rating Scale.
Figura 5.
Variazione media del punteggio alla YMRS al crescere della gravità dei sintomi depressivi (da McIntyre et al., 2013, mod.) 54. Mean
change in YMRS score with increasing severity of depressive symptoms (from McIntyre et al., 2013, mod.) 54.
il punteggio medio totale alla HAM-D, così come quello
alla YMRS è risultato significativamente maggiore con
la co-terapia con olanzapina rispetto al placebo. In
uno studio randomizzato controllato a 47 settimane di
confronto tra olanzapina e valproato in pazienti affetti da
mania mista, Tohen et al. 48 hanno riscontrato un tasso di
remissione sindromica nel 50% dei pazienti trattati con
olanzapina e nel 38% dei pazienti trattati con valproato.
Come gli stessi Autori fanno osservare, lo studio presenta
alcune limitazioni, tra cui un sottodosaggio del valproato
e l’assenza dei valori esatti delle concentrazioni
plasmatiche del valproato. Per quanto riguarda gli studi
più recenti, nei quali olanzapina è stata confrontata ad
asenapina e placebo nel trattamento degli SMM, si veda
quanto riportato nella sezione dedicata ad asenapina.
Paliperidone. L’efficacia di paliperidone nella mania
acuta, pura o mista, è stata dimostrata in due studi
randomizzati controllati vs. placebo a 3 settimane, uno
al dosaggio di 12 mg/die, l’altro a dose flessibile 39 81. Lo
studio a dose fissa non ha evidenziato con paliperidone
una riduzione statisticamente significativa nel punteggio
alla MADRS nei due sottogruppi. Lo studio a dose
102
flessibile ha evidenziato un’efficacia di paliperidone
sui sintomi maniacali sovrapponibile nella mania pura
e mista, mentre per quanto riguarda i sintomi depressivi
vengono riportati solo i dati relativi all’intero campione.
Quetiapina. Gli studi registrativi di quetiapina nel
trattamento della mania acuta escludevano i pazienti con
SM 82 83. Un successivo studio randomizzato controllato
di quetiapina a rilascio prolungato (RP) ha dimostrato
l’efficacia del composto in pazienti bipolari con mania
pura o mista, anche se non è stata riportata un’analisi
separata dei due sottogruppi 84.
Risperidone. In uno studio randomizzato controllato a
tre settimane condotto su 290 pazienti con mania acuta,
pura o mista, risperidone è risultato significativamente
superiore al placebo nella riduzione del punteggio alla
YMRS e alla MADRS 85. Va segnalato che la percentuale
di soggetti con mania mista reclutati in questo studio era
alquanto esigua (3 e 6%, rispettivamente, nei gruppi in
risperidone e placebo).
Ziprasidone. L’efficacia di ziprasidone nella “mania
Gli stati misti bipolari: evoluzione del concetto e implicazioni per la cura e la ricerca
disforica”, definita secondo i criteri di McElroy et al. 23
(punteggio ≥ 2 in almeno due dei seguenti otto items
della HAM-D: umore disforico, preoccupazione, autoriprovazione, autovalutazione negativa, scoraggiamento,
tendenza suicidaria, senso di affaticamento, perdita di
interessi) è stata dimostrata in un’analisi cumulativa posthoc dei dati di due studi randomizzati controllati a tre
settimane, effettuati in pazienti affetti da mania acuta, dal
disegno sovrapponibile, tranne per la rapidità di titolazione
del farmaco 86. Ziprasidone ha evidenziato un’efficacia
superiore al placebo nel ridurre il punteggio sia alla HAM-D
(misura di esito primaria), sia alla Mania Rating Scale.
Considerazioni conclusive
Gli SM bipolari costituiscono una manifestazione clinica
comune all’interno del DB e rimangono a tutt’oggi un
dilemma nosologico, una sfida diagnostica ed un’area
trascurata dalla ricerca. è nozione sempre più condivisa
che, a differenza di quanto espresso dei criteri diagnostici degli attuali sistemi nosografici, gli SM non equivalgono ad una somma di sintomatologia maniacale e
depressiva ma rappresentano una condizione clinica
autonoma e complessa, venendo a costituire una “terza
polarità dell’umore”. La presenza contemporanea di elementi contropolari, di perplessità e di instabilità affettiva
comporta una presentazione polimorfa ed una difficile
identificazione e differenziazione diagnostica, soprattutto quando vi è una contaminazione di sintomi psicotici. La formulazione di criteri specifici e meno restrittivi
per la diagnosi di stato misto, può costituire un punto di
partenza per ricerche future, soprattutto in relazione allo
studio delle basi biologiche e delle condotte terapeutiche 5. Il DSM-5 ha proposto di soppiantare la definizione
di episodio misto del DSM-IV-TR con quella di “mixed
specifier”, che consentirà di includere la sintomatologia
sottosoglia della polarità opposta e superare, almeno in
parte, i limiti ristretti imposti dai precedenti sistemi nosografici, a vantaggio di una maggiore adesione alla realtà
clinica. è prevedibile che questa evoluzione concettuale
avrà importanti ripercussioni per la clinica e per la ricerca, anche se la specificità e sensitività del nuovo costrutto diagnostico andranno confermate in successivi studi.
Il trattamento degli SM rappresenta a tutt’oggi un’”area
grigia” della psicofarmacologia clinica, suscettibile quindi di ampio miglioramento. I dati disponibili riguardano
esclusivamente gli SMM e derivano per lo più da analisi post-hoc di sottogruppi da RCT effettuati in pazienti
maniacali, mentre gli SMD costituiscono, a tutt’oggi, una
dimensione negletta della ricerca. Vi è una qualche evidenza, da studi datati, che gli SMM rispondono meglio
agli anticonvulsivanti che non al litio, anche se studi recenti, che impiegano il litio come controllo attivo, non
confermano del tutto questo dato 50 87. Il valproato e, in
misura minore, la carbamazepina, possono essere impiegati in monoterapia o in combinazione con il litio. Gli
studi attuali lasciano tuttora irrisolta la questione dell’impiego degli antidepressivi negli SM. Molte linee guida
e recenti revisioni della letteratura scoraggiano i clinici
dall’impiego degli antidepressivi negli SM diagnosticati
secondo il DSM-IV-TR, per la possibilità di un peggioramento della sintomatologia, benché nessun studio randomizzato controllato sia stato sinora condotto in proposito 47 87. Alla luce dei dati disponibili, alcuni, ma non
tutti gli antipsicotici di II generazione risultano efficaci
negli SMM, sia in monoterapia sia in combinazione con
litio o valproato. Alcuni dati recenti, ottenuti applicando
a posteriori il “mixed specifier” del DSM-5 al database di
studi controllati con antipsicotici di II generazione, suggeriscono che l’efficacia nei confronti degli SMM, definiti
secondo il DSM-IV, non è direttamente estrapolabile a
costrutti clinici più ampiamente comprensivi, in particolare per quanto concerne la dimensione depressiva. Data
la rilevanza epidemiologica e clinica degli SM all’interno
del DB, vi è estrema necessità di RCT specifici, che prendano in considerazione sia gli SMM che gli SMD e che
testino composti appartenenti a classi farmacologiche
diverse, in monoterapia e in combinazione, utilizzando
nella selezione dei pazienti criteri diagnostici condivisi e
maggiormente aderenti alla pratica clinica.
Conflitto di interessi
C. Vampini ha avuto i seguenti rapporti con soggetti portatori di
interessi commerciali in campo sanitario: è stato speaker e/o ha
realizzato materiale scientifico per Bristol-Myers Squibb, Servier, Innova Pharma, Lundbeck, Janssen Cilag, Sanofi Aventis,
AstraZeneca, Eli Lilly, Pfizer.
F. Nifosì non ha avuto rapporti con soggetti portatori di interessi
commerciali in campo sanitario.
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