Aggiornamento sulla Schizofrenia


1.

Partecipare ai Congressi sulla Schizofrenia o leggere la sempre più abbondante letteratura che viene pubblicate su riviste specialistiche fa uno strano effetto a chi, come me, non aderisce all'ideologia neopsichiatrica. L'effetto è di sentirsi, ad un dipresso, nei panni di coloro che, avendo mantenuto un filo di buon senso, partecipavano, nei primi secoli dell'era cristiana al dibattito sulla consustanzialità o meno del Figlio rispetto al Padre. Il riferimento alla schizofrenia è , ormai, un dato metafisico. La Malattia è disincarnata, è un Oggetto assoluto che viene analizzato indipendentemente dall'esperienza viva di coloro che la sperimentano. La casistica si riduce ai dati computerizzabili (età d'insorgenza, sintomi, decorso, ecc.), senza alcun riferimento alla storia delle persone. Spiegare la malattia si riduce al tentativo di scoprire le alterazioni neurotrasmettitoriali e strutturali che la causerebbero. Curarla verte sull'adozione di protocolli farmaceutici redatti sulla base dell'importanza di una farmacoterapia (ad alte dosi) precoce e della necessità di un trattamento a tempo indeterminato.

Come accadeva ai Concili, anche ai Congressi psichiatrici viene adottato un linguaggio in codice che esclude qualunque possibilità di partecipazione pubblica. La Psichiatria è ormai una scienza esoterica, incomprensibile per l'uomo della strada non meno che per un intellettuale che non abbia competenze neurobiologiche e mediche.

Chi dispone di queste competenze e non rinuncia ad usare la testa e a fare riferimento all'esperienza clinica, si rende subito conto di quanto sia aberrante, anche sotto il profilo strettamente scientifico, l'approccio neopsichiatrico alla Schizofrenia. Si rende anche conto, però, della distanza abissale che c'è tra quell'approccio e l'opinione pubblica, che ha ormai accettato di delegare agli specialisti il problema della malattia mentale.

Come esempio estremo di questa distanza ˝ una vera e propria sconnessione ˝ mi ricondurrei volentieri all'esperienza clinica che ho illustrato in Psicopatologia dinamica e Teoria delle Catastrofi. Al di là della trasparenza dinamica dell'esperienza stessa e di un'evoluzione estremamente significativa (con una scossa psicotica rapidamente rientrata alla quale ha fatto seguito, dopo circa un anno, una situazione di crisi prolungata che ha portato addirittura alla diagnosi di ebefrenia), occorre considerare che il soggetto in questione è figlio di due medici. Pure affidandomelo, dando alla psicoterapia un significato di supporto deputato a scongiurare un distacco dalla realtà, la madre ha consultato (senza trovare alcuna opposizione da parte mia) tutti i "luminari" della psichiatria operanti a Roma all'affannosa ricerca della diagnosi giusta e della cura farmacologica che restituisse al figlio la "ragione". Affanno legittimo e umanamente comprensibile, che però non teneva conto del fatto che la carriera evolutiva del ragazzo ˝ introverso - era esitata in una crisi perché egli aveva troppo accondisceso le aspettative normalizzanti materne.

è inutile dire che le diagnosi formulate sono state le più varie (disturbo dell'umore, sindrome borderline, sindrome dissociativa, schizofrenia incipiente, ebefrenia) e che le cure hanno utilizzato, vanamente, neurolettici di prima e di seconda generazione (sino, naturalmente, all'Abilify, la new entry nel mercato degli psicofarmaci maggiori), stabilizzatori dell'umore, ansiolitici, antidepressivi.

Solo lentamente, e pur rimanendo convinta che nella testa del figlio si sia attivata una malattia, la madre ha preso atto della straordinaria confusione e approssimazione che vige nel campo della neopsichiatria. La sua formazione medica, pur impedendole di affrancarsi dal paradigma della patologia, le ha consentito di capire che se i "luminari" forniscono diagnosi diverse, la malattia in questione deve essere qualcos'altro rispetto alle sindromi di cui si occupa la medicina.

I Congressi e le pubblicazioni scientifiche rimuovono del tutto la realtà clinica, facendo riferimento a categorie diagnostiche chiare e distinte e a protocolli farmaceutici convalidati dall'esperienza. Una mistificazione che copre l'ottusità e la brutalità oggettivante di un approccio rigidamente neurobiologico, che smaschera, tra l'altro, la messa tra parentesi, nella pratica, del modello multidimensionale. Per quanto nessuno neghi che l'evoluzione della malattia dipenda, in qualche misura, anche da circostanze ambientali, il dogma centrale che governa la pratica è che di una malattia vera e propria si tratta: misteriosa, impenetrabile e mal gestibile per alcuni aspetti. Per venirne a capo, però, occorre solo fidare in ulteriori progressi nella conoscenza neurobiologica dei processi che avvengono nel cervello degli schizofrenici e nella ricerca psicofarmacologica.

Questa premessa serve ad introdurre un'analisi critica dello "stato dell'arte" riguardo alla schizofrenia. Per portare avanti tale analisi, prendo spunto da un articolo divulgativo (rivolto ai familiari e agli amici di un paziente schizofrenico) pubblicato sul sito di un'industria farmaceutica e da tre rassegne pubblicate su Medscape: l'una riguardante la neurobiologia della schizofrenia, l'altra la valutazione del trattamento farmacologico, la terza il problema delle forme resistenti, . L'articolo è in italiano, le rassegne sono in inglese e, tra l'altro, rivolte agli addetti ai lavori. Oltre ad avere evidenziato con il grassetto i punti che ritengo più importanti, cercherò di estrapolarne gli aspetti che ritengo essenziali sulla base di un presupposto che farebbe strabuzzare gli occhi ai neopsichiatri: nessuna ideologia (intesa in senso negativo e quale che sia il livello di coscienza di coloro che la costruiscono) riesce a mascherare del tutto la realtà che essa intende mistificare. Utilizzando gli spiragli o meglio le smagliature che essa offre si riesce a risalire ad una qualche verità, non diversamente dall'osservatore di un Concilio nei primi secoli che, al di là della guerra sui termini, avesse capito la posta in gioco: elevare a Dio un uomo morto all'insegna dell'ignominia e sul cui capo pendeva una definizione derisoria della sua presunta potenza.

2.

Il primo articolo è uno dei tanti che circolano sul Web e si rivolgono ai familiari degli schizofrenici al fine di informarli del dramma che è toccato loro e di cooptarli come complici di una strategia incentrata su un trattamento psicofarmacologico costante e duraturo. Quest'ultimo scopo è fondamentale nell'ottica delle industrie farmaceutiche.

Nonostante, infatti, la neopsichiatria abbia inserito tutte le sindromi psicopatologiche in categorie (disturbi di ansia, disturbi dell'umore, ecc.) che implicano un'origine genetica, e dunque la cronicità della malattia una volta che essa sia comparsa e sia stata diagnosticata, tale presupposto, che implica il dovere del paziente di accettare un controllo psichiatrico periodico, anche in assenza di sintomi, non può tradursi in trattamenti psicofarmacologici a tempo indeterminato. I pazienti che, superati gli episodi critici, non hanno più sintomi, infatti, raramente accettano una cura preventiva. Coloro che si curano per anni con psicofarmaci con vantaggi scarsi o relativi finiscono con il demotivarsi e si rivolgono alla medicina alternativa.

Certo, l'industria farmaceutica prefigura nei suoi piani di sviluppo un mondo nel quale tutti i depressi e gli ansiosi assumano quotidianamente almeno una compressa: si tratta, infatti, di una quota imponente della popolazione occidentale (intorno al 20-25%). Anche i manager più ambiziosi, intraprendenti e cinici (il cinismo, in questo caso, essendo mascherato dall'intento umanitaristico di alleviare le sofferenze umane) sanno che si tratta di un sogno che ha poche chances di realizzazione.

Per quanto riguarda la schizofrenia, il discorso è diverso: si tratta, infatti, di "un disturbo mentale devastante, probabilmente il più angoscioso e disabilitante dei disturbi mentali gravi" i cui effetti "disorientano e sconvolgono familiari ed amici", che si manifesta "generalmente nel corso dell'adolescenza e nei primi anni dell'età adulta" e, tranne un quinto di pazienti che guariscono e un decimo che si suicidano, dura tutta la vita invalidando l'individuo sia sotto il profilo lavorativo che affettivo e sociale. Posta una diagnosi di schizofrenia, che peraltro può essere facilmente condivisa dai parenti in nome dell'evidente significato patologico dei sintomi positivi e negativi, i parenti, dunque, devono preparasi ad affrontare un "cancro" psichico, la cui evoluzione, nonostante le cure, è progressiva.

Si tratta, certo di aiutarli a reggere questa terribile prova: essi devono sapere di potersi avvalere della competenza degli psichiatri e dell'aiutoo dei servizi sociali. è ancora più importante, però, che i parenti collaborino alla cura osservando e prendendo nota dei comportamenti del paziente, registrando eventuali incrementi o riaccensioni acute dei sintomi e, soprattutto, facendosi garanti della regolare assunzione degli psicofarmaci: al limite, provvedendo essi stessi a somministrarli.

Il problema centrale, infatti, nella cura della schizofrenia è che i pazienti, nella maggioranza dei casi e in particolare per quanto concerne i soggetti giovanili, non hanno coscienza di malattia e oppongono una resistenza più o meno manifesta nei confronti degli psicofarmaci. Il rifiuto di sostanze chimiche che curano è reso ancora più paradossale dall'appetizione che essi spesso manifestano nei confronti di altre sostanze con effetti psicottivi (tabacco, hashish, alcol, droghe pesanti).

A maggior ragione occorre persuaderli che è un loro interesse assumere i farmaci e, nell'attesa che maturi la loro compliance, sono i parenti a dover esercitare un ruolo attivo, sulla base dei dogmi definiti dalla neopsichiatria:

"La maggior parte delle persone affette da schizofrenia mostra un miglioramento sostanziale in corso di trattamento con farmaci antipsicotici. Alcuni pazienti, tuttavia, non traggono benefici dai farmaci e pochi altri non sembra necessitino di trattamento."

"I farmaci antipsicotici riducono il rischio di episodi psicotici futuri nei pazienti che hanno superato un episodio acuto. Sono stati riscontrati casi di ricaduta anche nei soggetti che hanno continuato il trattamento. Percentuali di ricaduta molto più elevate sono state osservate in caso di interruzione del trattamento. Nella maggior parte dei casi, non sarebbe appropriato asserire che il trattamento continuativo "previene" le ricadute, piuttosto ne riduce l'intensità e la frequenza. Il trattamento dei sintomi psicotici gravi richiede generalmente l'impiego di dosi più elevate rispetto a quelle usate in fase di mantenimento. Se i sintomi si ripresentano anche a dosi minori, può essere utile aumentarle temporaneamente per evitare una ricaduta completa.

Poiché la ricaduta è più probabile nei casi in cui venga sospeso il trattamento antipsicotico o sia assunto in modo irregolare, è molto importante che il paziente collabori con il medico ed i familiari per rispettare il programma terapeutico. Ciò comporta l'assunzione del trattamento prescritto nel dosaggio corretto ed alle ore previste, presentarsi alle visite di controllo e seguire tutte le altre procedure previste dal trattamento."

Sulla base di tali dogmi, si può mettere tra parentesi il problema per cui, oltre che ad una scarsa o assente coscienza di malattia, l'avversione nei confronti dei farmaci è spesso motivata dagli effetti collaterali negativi che essi inducono: è vero: "I farmaci antipsicotici, come ogni altro farmaco, presentano effetti benefici ed effetti indesiderati." Si tratta dei limiti propri della scienza umana. Tali effetti, però, non vanno drammatizzati perché il criterio costi/benefici è comunque spostato dalla parte di questi ultimi.

Riguardo alle cause della schizofrenia, l'articolo, per il suo carattere divulgativo, non approfondisce più di tanto l'argomento: Si tratta, infatti, di una frontiera della ricerca psichiatrica, che coinvolge conoscenze complesse. L'essenziale però non viene omesso:

"Ad oggi non si conoscono tutti i fattori responsabili della schizofrenia, ma gli esperti sono concordi nel ritenere che la malattia sia causata da anomalie della funzione cerebrale, alcune delle quali sono state identificate. La schizofrenia è un disturbo mentale, i cui sintomi sono determinati da anomalie nel trasferimento e nell'elaborazione delle informazioni nel cervello. Le cellule nervose del cervello comunicano tra di loro rilasciando mediatori chimici (neurotrasmettitori) dalle terminazioni nervose. Molti dei sintomi della schizofrenia sono stati associati ad anomalie dell'attività di particolari neurotrasmettitoriÍ

Le ricerche effettuate sulle famiglie indicano che la vulnerabilità alla schizofrenia è ereditariaÍ

La possibilità di esaminare il cervello di soggetti viventi tramite la tomografia assiale computerizzata (TAC) ha consentito di evidenziare che la struttura del cervello di alcuni soggetti con schizofrenia risulta anomalaÍ

Altri studi di diagnostica per immagini effettuati sul cervello di pazienti con schizofrenia hanno confermato la presenza di anomalie in alcune cellule nervose. Le cellule nervose interessate sono quelle che usano due diversi neurotrasmettitori (la dopamina e la serotonina)Í"

Quanto basta, insomma, a suggerire che, se le cause sono complesse e non ancora del tutto note, che la schizofrenia sia una malattia cerebrale la cui matrice è in una predisposizione genetica è un dato di fatto poco o punto confutabile.

Su questa base, è importante che il medico curante, scelto dai familiari, abbia le carte in regola per fronteggiare il "cancro" psichico. E cioè :

" * prenda nota dell'anamnesi dettagliata

* verifichi l'eventuale presenza di problemi causati da altre malattie (fisiche o psichiatriche)

* sia ben informato sui farmaci antipsicotici

* segua il paziente in modo attenti

* effettui aggiustamenti della terapia se necessari

* riveda regolarmente il trattamento

* sia interessato al benessere generale del paziente e segua anche gli aspetti relativi al consulto di uno specialista, alla sistemazione domiciliare, all'assistenza sociale e finanziaria

* illustri chiaramente cosa sta succedendo e cosa è stato pianificato per il trattamento del paziente

* coinvolga la famiglia nel programma terapeutico."

Insomma, è importante che lo psichiatra sia un lacché dell'industria farmaceutica e riesca ad assicurarsi la complicità dei parenti. Infatti,

"Familiari ed amici, se coinvolti nel programma terapeutico, possono essere estremamente utili per verificare che il paziente assuma regolarmente i farmaci, ricordandolo quando se ne dimentica o rammentando i problemi che possono essere insorti nelle occasioni in cui il paziente si sia rifiutato di assumere i farmaciÍ

è estremamente importante che le persone affette da schizofrenia continuino ad assumere i farmaci anche dopo la dimissione dall'ospedale. L'interruzione del trattamento o delle visite di controllo spesso determina la ricomparsa dei sintomi psicotici. Per contribuire alla guarigione del paziente, è importante incoraggiarlo a continuare il trattamento ed assisterlo nel corso del programma terapeutico."

Il programma terapeutico in questione prevede che, naturalmente per il suo bene, ogni paziente renda, vita natural durante, circa 5 euro al giorno all'industria (oltre, eventualmente, i 5 euro per lo psichiatra privato consultato una volta al mese).

La schizofrenia, almeno sulla carta, è la gallina dalle uova d'oro per la psichiatria. Se fosse possibile estendere i benefici della cura urbe ed orbi, considerando che gli schizofrenici bisognosi di farmaci sono all'incirca cinquanta milioni di abitanti del pianeta, il fatturato dell'industria sarebbe di duecentocinquanta milioni di dollari al giorno, cioè poco meno di cento miliardi di dollari ogni anno!

Certo, i farmaci attualmente disponibili non sono miracolosi. Come attestano tutti gli studi riportati nel terzo articolo sugli effetti terapeutici, la remissione della malattia è rara, la discontinuità nel trattamento, dovuta in gran parte agli effetti collaterali, elevata, ed enorme appare la difficoltà di persuadere i pazienti che è benefico per essi attenersi alle prescrizioni psichiatriche. Ciò nonostante, la psichiatria è ottimistica riguardo al futuro. Posto che la schizofrenia è una malattia complessa, un cancro del cervello, nessuno dubita che un giorno o l'altro la scienza riuscirà a sconfiggerla. Nessuno, purtroppo, considera la possibilità alternativa di uno scacco permanente come conseguenza di un modo radicalmente errato di affrontare il problema.

3.

Ma che cosa c'è dietro l'intento missionario della psichiatria di lenire le sofferenze degli schizofrenici e dei loro parenti? Com'è possibile che un'ideologia radicalmente biologista si sia prodotta senza un fondamento scientifico e venga propagandata come un insieme di verità comprovate e inconfutabili?

Per rispondere a queste domande, occorre leggere con attenzione il secondo articolo sulla biologia della schizofrenia che fa riferimento ai dati esposti nel corso dell'annuale meeting dell'APA, l'onnipotente associazione di psichiatri statunitensi che si può ritenere la longa manus dell'industria farmaceutica. Il problema, naturalmente, è che il linguaggio è praticamente inaccessibile per il lettore non dotato di competenze tecniche, al punto che nella sua astrusità può facilmente indurre a pensare che ci sia comunque in atto un autentico sforzo di capire il "mistero" della schizofrenia.

In realtà lo sforzo si esaurisce nel cercare la prova del dogma centrale della psichiatria, secondo il quale le cause della schizofrenia non possono essere che anomalie strutturali e funzionali dei circuiti interneuronali. A tutt'oggi la prova non c'è .

Non è un caso che le insufficienze dell'ipotesi dopaminica (secondo la quale si darebbe un eccesso della molecola a livello di strutture profonde e un difetto a livello di corteccia prefrontale: "an increased formation of presynaptic dopamine, increased release of dopamine from the presynaptic terminal, and a slight increase in dopamine D2 receptors and in prefrontal dopamine D1 receptors"), costringono a battere altre vie. Le ricerche vertono su di una disfunzione del sistema glutamergico ("recent studies that implicate the glutamatergic system in the pathophysiology of the illness. The key receptor system in this case is the n-methyl d-aspartate (NMDA) receptor, which has been shown to be underfunctioning in schizophrenia"). Il problema è che tale disfunzione (posto che il glutammato ha un effetto, per così dire, psicostimolante) spiegherebbe l'iperattività dopaminica a livello profondo, ma non l'ipoattività a livello frontale.

Occorre poi considerare che la fisiologia di tutto il cervello è governata da un equilibrio tra neuroni eccitatori e neuroni inibitori, la cui attività è riconducibile a due sostanze ubiquitarie (rispettivamente il glutammato e il GABA), che agiscono ad un di presso come l'acceleratore e il freno. Ammettere nella schizofrenia una disfunzione del sistema glutamergico rende l'ipotesi di una causalità biochimica estremamente generica.

I dati forniti dalle tecniche di neuroimaging non sembrano più confortanti. Il rilievo di alcune anomalie strutturali (atrofia cerebrale a livello frontale), enfatizzato sino a qualche mese fa, sta perdendo terreno. Esso, infatti, riguarda un numero minimo di pazienti,e non si può escludere che sia docuto ai trattamenti farmacologici.

Sulla scorta di tale rilievo, gli studi sulle disfunzioni cognitive negli schizofrenici, che sarebbero una conseguenza delle anomalie strutturali, sono fioriti come i funghi, per arrivare ad una conclusione che potrebbe significare qualcosa se essa non fosse banalizzata dagli psichiatri. Tale conclusione è che la schizofrenia comporta "an aberrant sense of novelty and an abnormal salience to relatively innocuous stimuli": una significazione, in altri termini, della realtà che segue altre vie rispetto al senso comune, dando un valore "aberrante" alle novità e ipercodificando stimoli insignificanti. Se questo è vero ˝ e in una certa misura lo è ˝ gli schizofrenici adotterebbero lo stesso stile cognitivo da cui nasce la scienza, la letteratura, la filosofia, finendo però in un vicolo cieco. Al di là del senso comune, si danno la follia e il sapere.

Dunque, l'ideologia psichiatrica riferita alla schizofrenia è solo una montatura? L'amore della verità impone di riconoscere che c'è un solo dato che si può ritenere oggettivo e poco confutabile: gli studi sui gemelli monozigoti adottati da famiglia diverse, i quali attestano una concordanza della schizofrenia al 50%. Ciò significa che se uno dei due ammala, l'altro ha una possibilità su due di andare incontro alla malattia.

è inutile sottolineare che questo dato attesta che c'è una predisposizione genetica che facilita il sopravvenire di una sintomatologia schizofrenica, anche se essa, per tradursi in malattia, postula comunque una componente ambientale (altrimenti la concordanza dovrebbe essere del 100%).

A questo dato, che comprova una predisposizione, ma non dice altro riguardo ad essa, ho dedicato grande attenzione in un capitolo di Miseria della neopsichiatria. In un articolo ulteriore affronterò nuovamente il problema, cercando di aggiornarlo sulla base degli sviluppi recenti della genetica.

4.

L'ultimo articolo verte su di un problema che toglie il sonno agli psichiatri e alle case farmaceutiche. Un paziente su cinque, infatti, appare resistente a qualunque trattamento farmacologico, fino al limite estremo della refrattarietà. La resistenza è attestata dalla persistenza dei fenomeni allucinatori e dalla sistematizzazione del delirio.

Il dato, in realtà, è valutato per difetto. Esso fa riferimento ai casi ingovernabili, nel corso del quale le allucinazioni e il delirio si traducono in comportamenti antisociali e in atti autolesivi: in manifestazioni, insomma, socialmente visibili che attestano il fallimento della psichiatria.

Tra gli schizofrenici tranquilli, trattati con dosi farmacologiche elevate e a tempo indeterminato, una stragrande maggioranza continua ad avere fenomeni allucinatori e idee deliranti, mascherati da un comportamento sociale apparentemente adeguato o non del tutto compromesso.

Se si parte dall'ipotesi che la schizofrenia è un "cancro" psichico, i risultati conseguiti dal controllo farmacologico, che mirano ad arginare l'evoluzione del processo morboso, si possono ritenere positivi. Se si prescinde da quell'ipotesi, essi, soprattutto per quanto concerne il 20% dei pazienti resistenti, appaiono viceversa non solo modesti ma fallimentari.

Forme di resistenza al trattamento farmacologico riguardano anche malattie, come il diabete, le cui cause sono accertate definitivamente. Non esiste, però, nell'ambito della medicina, alcuna malattia che manifesti il tasso di resistenza della schizofrenia.

Se i pazienti, come accade spesso, rifiutano i farmaci o li sospendono periodicamente, attribuire loro la responsabilità di un difetto di incidenza dela cura è un gioco da ragazzi. I casi resistenti riguardano, invece, pazienti che, in genere, si sottpongono alle cure senza trarne vantaggio.

Anche questo problema richiederà ulteriori approfondimenti. Per ora, mi limito a rilevare che lo stesso fenomeno riguarda anche la depressione, ritenuta anch'essa una malattia genetica e biochimica.

O c'è qualcosa di sbagliato nella natura o la psichiatria è fuori strada.

Appendici

Che cos'è la schizofrenia

(dal sito di una casa farmaceutica)

Introduzione

La schizofrenia è un disturbo mentale devastante, probabilmente il più angoscioso e disabilitante dei disturbi mentali gravi. I primi segni di schizofrenia si manifestano generalmente nel corso dell'adolescenza e nei primi anni dell'età adulta. Spesso gli effetti della malattia disorientano e sconvolgono familiari ed amici. Le persone affette da schizofrenia hanno difficoltà ad articolare i pensieri. Questa condizione li porta ad avere allucinazioni, deliri, pensieri disarticolati nonché comportamenti ed eloquio inusuali. A causa di questi sintomi, le persone colpite da questa malattia hanno serie difficoltà ad interagire con gli altri e tendono ad isolarsi dal mondo esterno. Al contrario di quanto si creda, le persone colpite da schizofrenia non posseggono "personalità divise" e non sono pericolosi per gli altri. Anzi, è molto più probabile che siano vittime essi stessi, piuttosto che responsabili, di atti di violenza.

La maggior parte delle persone affette da schizofrenia ne soffrono per tutta la vita, senza avere l'opportunità di un'attività lavorativa o di relazioni interpersonali. A causa della scarsa conoscenza della malattia, le persone affette da schizofrenia si sentono spesso isolate e stigmatizzate, e possono mostrarsi riluttanti o incapaci di parlare della propria malattia. Sebbene la disponibilità di nuovi farmaci con effetti collaterali minori abbia migliorato la vita di molti, ancora oggi, solo un paziente su cinque 'guariscè dalla malattia mentre uno su dieci si suicida.

Di tutti i disturbi mentali, la schizofrenia è il più difficile da gestire per chiunque ne sia coinvolto. La malattia sconvolge completamente la vita dei pazienti. La malattia può influire profondamente anche sulla vita dei familiari e degli amici, che vedono gli effetti della malattia nel familiare e si trovano a fronteggiare situazioni impegnative per assistere il paziente. Il dover far fronte ai sintomi della schizofrenia può essere particolarmente difficile per i familiari che ricordano quanto attiva e vivace fosse la persona prima di ammalarsi. Molti ritengono ancora che la schizofrenia sia causata da una cattiva educazione o da una scarsa forza di volontà, nonostante numerose evidenze abbiano dimostrato il contrario. La realtà è molto diversa. La schizofrenia è una malattia complessa che si ritiene sia dovuta a diversi fattori concomitanti. Questi fattori possono includere influenze genetiche, traumi (lesioni) cerebrali che si verificano alla nascita o subito dopo, oltre gli effetti dell'isolamento sociale e/o dello stress. Anche altri effetti possono giocare un ruolo importante, ma non esiste un fattore specifico che possa essere identificato come causa della schizofrenia. è probabile invece che ciascuno di questi fattori aumenti il rischio di sviluppo dei sintomi della malattia.

La schizofrenia colpisce una percentuale che varia dall'1% al 2% della popolazione. La malattia è diffusa in tutto il mondo con percentuali pressoché equivalenti nei vari paesi. La schizofrenia è la malattia più devastante che possa colpire i giovani. La malattia colpisce indifferentemente sia uomini che donne. Mentre nel sesso maschile la malattia tende a manifestarsi nella fascia di età tra i 16 ed i 25 anni, nel sesso femminile i sintomi tendono a presentarsi tra i 25 e i 30 anni. I farmaci e gli altri tipi di trattamento, se impiegati regolarmente come da prescrizione medica, possono aiutare a ridurre ed a controllare i sintomi più angoscianti della malattia. Tuttavia, alcune persone non traggono grandi benefici dalle terapie disponibili o interrompono prematuramente il trattamento a causa degli spiacevoli effetti collaterali o per altre ragioni. Anche nei casi in cui il trattamento si riveli efficace, le conseguenze a lungo termine della malattia (perdita di opportunità, ostracismo, sintomi residui ed effetti collaterali dei farmaci) possono essere difficili da tollerare e comunque possono impedire al paziente di vivere una vita normale.

L'abuso di sostanze è un problema che affligge molte delle famiglie dei pazienti schizofrenici. Poiché alcuni soggetti che abusano di droghe mostrano sintomi simili a quelli della schizofrenia, gli schizofrenici possono essere scambiati per "drogati". Spesso gli schizofrenici abusano di sostanze alcoliche e/o di droghe e possono presentare reazioni particolarmente negative a certi tipi di droghe. Inoltre, l'abuso di sostanze può ridurre l'efficacia terapeutica dei farmaci da assumere Le sostanze stimolanti (ad esempio, le anfetamine e la cocaina) possono provocare ai soggetti con schizofrenia seri problemi, così come la PCP o la marijuana. In effetti, alcuni pazienti manifestano un peggioramento dei sintomi quando assumono queste sostanze. L'abuso di sostanze riduce inoltre la possibilità che i pazienti seguano i trattamenti prescritti.

La forma più diffusa di disturbo da abuso di sostanze nei pazienti affetti da schizofrenia è la dipendenza da nicotina, derivata dal fumo di sigarette. La prevalenza del fumo di sigarette nei soggetto con schizofrenia è circa tre volte superiore a quella della popolazione generale. Tuttavia, la relazione tra fumo e schizofrenia è complessa. Sebbene i soggetti con schizofrenia tendano a fumare per lenire i sintomi, è stato osservato che il fumo interferisce con la risposta ai trattamenti farmacologici, per cui coloro che fumano possono necessitare di dosi maggiori di farmaco antipsicotico.

Sintomi della schizofrenia

Al contrario di quanto si creda, i pazienti schizofrenici non hanno una "personalità divisa". Tuttavia, percepiscono la realtà in modo completamente diverso dagli altri. Spesso, soffrono di sintomi terribili: sentono voci che provengono dall'interno che nessun altro sente, credono che gli altri possano leggere il loro pensiero, controllare i loro pensieri o stiano tramando contro di loro. Poiché vivono in una realtà distorta da allucinazioni e deliri, possono sentirsi spaventati, ansiosi, confusi e tendono ad isolarsi. Il loro eloquio ed il comportamento possono diventare così disorganizzati da essere incomprensibili o da suscitare timore negli altri. Possono anche comportarsi in modo diverso in occasioni diverse, a causa modo distorto in cui vivono la realtà. A volte sembrano distanti, assenti o preoccupati e possono stare seduti per ore immobili, senza pronunciare una sola parola. Altre volte, si muovono continuamente, perennemente impegnati in qualche attività, apparentemente all'erta e vigili.

I soggetti con schizofrenia manifestano generalmente due tipi di sintomi.

Sintomi "positivi"

Questi sintomi rappresentano caratteristiche psicologiche "ulteriori",che compaiono a seguito del disturbo, ma che non sono presenti nelle persone sane

* allucinazioni

* deliri

* pensiero disorganizzato

* agitazione.

Le allucinazioni sono disturbi della percezione comuni nelle persone affette da schizofrenia. Si tratta di percezioni che non hanno alcun riscontro nella realtà. Sebbene le allucinazioni possano interessare qualsiasi senso (udito, vista, tatto, gusto ed olfatto), la forma più comune di allucinazione in corso di schizofrenia è data dal sentire le voci. Le voci possono descrivere le attività del paziente, conversare con lui, avvertirlo di eventuali pericoli o impartirgli degli ordini. I deliri sono costituiti da convinzioni personali irrazionali ed erronee che non hanno alcun riscontro nella realtà, che vengono mantenute nonostante l'evidenza di prove contrarie e che non possono essere spiegatesulla base del background culturale del paziente. I pazienti che soffrono di sintomi di tipi paranoide (circa un terzo dei pazienti) manifestano deliri di persecuzione, o credono irrazionalmente di essere vittima di inganni, minacce, avvelenamenti o cospirazioni. In alcuni casi sono presenti deliri di grandezza, a causa dei quali la persona ritiene di essere un personaggio famoso o importante. Alcuni pazienti manifestano deliri bizzarri, come credere che un vicino li stia controllando tramite onde magnetiche o che i personaggi della televisione stiano inviando loro messaggi o ancora che i loro pensieri vengano divulgati ad altri.

Pensiero disorganizzato. I soggetti con schizofrenia spesso non presentano una normale fluidità dei pensieri. I pensieri vanno e vengono rapidamente, la persona non è in grado di concentrarsi su un unico pensiero per molto tempo e tende a distrarsi ed a perdere la concentrazione. I soggetti con schizofrenia possono non essere in grado di decidere cosa sia importante, e cosa non lo sia, in una situazione. A volte non riescono a collegare i pensieri in sequenze logiche al punto che questi diventano disorganizzati e frammentari. Questa assenza di continuità logica dell'ideazione, definita con il termine "disturbo del pensiero", rende la conversazione con questi pazienti molto difficile e può provocarne l'isolamento sociale. Se chi lo ascolta non riesce a dare un senso a ciò che il paziente sta dicendo, si sente a disagio e tende ad isolarlo.

Sintomi "negativi"

Si tratta di capacità psicologiche che la maggior parte delle persone possiedono, ma che i soggetti con schizofrenia "hanno perso"

* mancanza di iniziativa

* isolamento sociale

* apatia

* insensibilità emotiva ("appiattimento")

Spesso, i pazienti con schizofrenia manifestano un "appiattimento" dell'affettività. Ciò è dovuto ad una grave riduzione della capacità di esprimere emozioni. I soggetti affetti da schizofrenia possono non mostrare i segni caratteristici delle normali emozioni (parlano con un tono monotono, mostrano una ridotta mimica facciale e sembrano estremamente apatici). Inoltre, possono allontanarsi dagli altri evitando ogni tipo di contatto e quando sono obbligati ad interagire possono non avere nulla da dire, come riflesso del loro "pensiero impoverito".

La motivazione risulta molto ridotta come l'interesse o la gioia di vivere. Nei casi più gravi, il paziente può trascorrere giorni interi senza fare niente ed addirittura senza occuparsi dell'igiene della propria persona. Questi problemi correlati all'incapacità di esprimere le emozioni o la propria motivazione, estremamente problematici per familiari ed amici, rappresentano i sintomi della schizofrenia e non devono essere considerati difetti del carattere o debolezze personali.

Episodi psicotici

L'improvvisa manifestazione di sintomi psicotici gravi identifica un episodio psicotico acuto. La 'psicosi' rappresenta uno stato mentale che provoca allucinazioni (disturbi della percezione) e/o deliri (convinzioni personali false ma fermamente mantenute, che sono determinate dall'incapacità di distinguere le esperienze reali da quelle irreali). I sintomi negativi della schizofrenia, come l'isolamento sociale, l'eloquio, i pensieri o i comportamenti inusuali, possono essere meno evidenti dei sintomi positivi e possono manifestarsi prima, in concomitanza o dopo l'insorgenza dei sintomi psicotici positivi.

Durante l'episodio psicotico, i pazienti non sono in grado di pensare in modo logico e possono perdere ogni percezione di se stessi e degli altri. Per i soggetti con schizofrenia, le attività di tutti i giorni come articolare i pensieri in modo logico, controllare le emozioni, prendere decisioni e interagire con gli altri diventano difficili. La gravità dei sintomi ed il pattern prolungato e cronico della malattia determinano spesso un alto livello di compromissione del funzionamento.

I sintomi della malattia variano generalmente nel tempo e tendono a peggiorare durante i periodi di ricaduta ed a migliorare durante i periodi di remissione. Alcuni pazienti manifestano solo un episodio psicotico, altri ne manifestano molti durante la vita, ma conducono una vita relativamente normale fra un episodio e l'altro, mostrandosi emotivamente sani e stabili. Tuttavia, i soggetti affetti da schizofrenia "cronica" o che manifestano un pattern di malattia continuo o ricorrente, spesso non recuperano completamente la funzionalità normale e richiedono trattamenti a lungo termine, che comprendono generalmente l'assunzione di farmaci, per controllare i sintomi.

I mezzi di comunicazione ed il mondo dello spettacolo tendono ad associare i disturbi mentali a comportamenti violenti. In realtà i soggetti con schizofrenia non sono particolarmente inclini alla violenza, ad eccezione dei soggetti che già mostravano una tendenza violenta prima di ammalarsi o di quelli con problemi di alcolismo e di abuso di sostanze. La maggior parte dei soggetti con schizofrenia non sono violenti. Piuttosto, tendono ad isolarsi socialmente e preferiscono restare soli. L'abuso di sostanze può aumentare il rischio di reazioni violente nei soggetti con schizofrenia come in qualsiasi altra persona sana. Anche i pazienti che soffrono di sintomi paranoidei o psicotici, che possono peggiorare se il trattamento viene interrotto, sono a rischio di comportamento violento. Quando si verifica una reazione violenta, molto frequentemente essa è mirata a familiari ed amici e spesso avviene in ambito domestico. Il suicidio rappresenta un serio pericolo per questi soggetti. Se il paziente tenta di suicidarsi o minaccia di farlo, è consigliabile rivolgersi immediatamente ad un medico.

La percentuale di suicidi è molto più elevata tra i soggetti con schizofrenia che nella popolazione generale. Circa il 10% delle persone affette da schizofrenia (soprattutto giovani adulti di sesso maschile) si suicidano. Sfortunatamente, è piuttosto difficile riuscire in questi casi a prevedere l'atto suicidario

Quali sono le 'causè della schizofrenia?

Non esiste un'unica causa. Molte malattie, come ad esempio quelle cardiache, sono determinate da numerosi fattori genetici, comportamentali e di altro tipo, e ciò potrebbe essere anche il caso della schizofrenia. Ad oggi non si conoscono tutti i fattori responsabili della schizofrenia, ma gli esperti sono concordi nel ritenere che la malattia sia causata da anomalie della funzione cerebrale, alcune delle quali sono state identificate. La schizofrenia è un disturbo mentale, i cui sintomi sono determinati da anomalie nel trasferimento e nell'elaborazione delle informazioni nel cervello. Le cellule nervose del cervello comunicano tra di loro rilasciando mediatori chimici (neurotrasmettitori) dalle terminazioni nervose. Molti dei sintomi della schizofrenia sono stati associati ad anomalie dell'attività di particolari neurotrasmettitori.

Le ricerche effettuate sulle famiglie indicano che la vulnerabilità alla schizofrenia è ereditaria. Un bambino con un genitore affetto da schizofrenia ha circa il 10% di probabilità di manifestare la malattia. Diversamente, il rischio di contrarre la schizofrenia nella popolazione generale è pari a circa 1%. Tuttavia, nel caso dei gemelli monozigoti, che presentano un patrimonio genetico identico, la probabilità che entrambi i gemelli manifestino la malattia è solo del 50%. Ciò indica che la schizofrenia non è predeterminata dalla genetica. Altri studi hanno dimostrato che anche le influenze ambientali (che si verificano forse nei primi anni di vita o addirittura durante la gravidanza) possono avere effetto sul cervello e predisporre il soggetto ad ammalarsi. è probabile che il disturbo derivi da una combinazione di fattori di rischio.

La possibilità di esaminare il cervello di soggetti viventi tramite la tomografia assiale computerizzata (TAC) ha consentito di evidenziare che la struttura del cervello di alcuni soggetti con schizofrenia risulta anomala. Una scoperta rilevante è che le cavità (ventricoli) del cervello hanno dimensioni maggiori nelle persone affette da schizofrenia. è stato provato che tali dimensioni sono dovute ad anomalie nella struttura di particolari aree del cervello. Tuttavia, queste anomalie sono impercettibili e non si riscontrano in tutti i pazienti, né si verificano esclusivamente nei soggetti con questa malattia. Nei soggetti con schizofrenia le valutazioni al microscopio di tessuto cerebrale post-mortem hanno rilevato anche lievi variazioni nella distribuzione o nella quantità di cellule cerebrali. Apparentemente la maggior parte di queste variazioni (anche se probabilmente non tutte) sono presenti prima che il soggetto si ammali. Quindi, la schizofrenia potrebbe essere in parte un disturbo nello sviluppo del cervello.

Altri studi di diagnostica per immagini effettuati sul cervello di pazienti con schizofrenia hanno confermato la presenza di anomalie in alcune cellule nervose. Le cellule nervose interessate sono quelle che usano due diversi neurotrasmettitori (la dopamina e la serotonina). Il trattamento della schizofrenia si basa sull'uso di farmaci (cioè i neurolettici o gli antipsicotici) che modificano gli effetti di questi neurotrasmettitori sul cervello.

 

Diagnosi di schizofrenia

La maggior parte dei disturbi psichiatrici sono molto difficili da diagnosticare e la schizofrenia non fa eccezione. Poiché non esistono test che siano in grado di diagnosticare con assoluta certezza la presenza di schizofrenia, la diagnosi si basa essenzialmente sull'esclusione di altre cause che possono provocare sintomi simili, quali l'uso di stupefacenti, l'epilessia, i tumori celebrali e la disfunzione tiroidea. è importante escludere altre malattie, poiché a volte le persone soffrono di gravi sintomi mentali o di psicosi a causa di altre condizioni mediche non diagnosticate. Per questo motivo, è necessario effettuare un'anamnesi, una visita obiettiva e test di laboratorio per escludere eventuali altre cause prima di concludere che il soggetto è affetto da schizofrenia. Inoltre, poiché l'abuso di sostanze provoca sintomi simili a quelli della schizofrenia, si possono effettuare anche esami del sangue e delle urine per rilevare l'eventuale presenza di droghe.

Dopo aver escluso le altre cause, il medico deve effettuare una diagnosi unicamente sulla base dei sintomi manifestati dal paziente e segnalati dal paziente stesso e dalla sua famiglia. Questa procedura potrebbe creare problemi e ritardi perché alcuni dei sintomi diventano evidenti solo quando la malattia è in fase avanzata. Anche in questo caso, è necessario che i sintomi siano presenti da almeno 6 mesi per poter effettuare una diagnosi formale.

Farmaci per la cura della schizofrenia

I primi farmaci efficaci per il trattamento della schizofrenia furono sviluppati verso la metà degli anni 50. Vi sono numerosi farmaci antipsicotici 'convenzionali', quali aloperidolo, clorpromazina, flufenazina, droperidolo, pimozide, sulpiride e tioridazina. Questi farmaci sembrano agire prevalentemente riducendo gli effetti del neurotrasmettitore dopamina sul cervello. I farmaci sono per lo più efficaci nel trattamento dei sintomi positivi della schizofrenia e permettono a molti pazienti di non essere ospedalizzati e di condurre una vita normale. Tuttavia, non sono altrettanto efficaci nei confronti dei sintomi negativi o dei disturbi dell'umore (sintomi affettivi). Inoltre, alcuni pazienti rispondono scarsamente o per niente a questi farmaci. I neurolettici convenzionali presentano molti effetti collaterali spiacevoli al punto che i pazienti devono assumere altri farmaci per eliminarli. Gli effetti collaterali possono determinare la sospensione del trattamento (non aderenza alla terapia), che a sua volta può causare una nuova insorgenza dei sintomi.

Nell'ultimo decennio sono stati sviluppati numerosi trattamenti efficaci, con effetti collaterali minori e meno gravi rispetto ai farmaci tradizionali. Gli antipsicotici più recenti (quali clozapina, risperidone e olanzapina) bloccano gli effetti sia della serotonina sia della dopamina e risultano quindi efficaci in una gamma più ampia di sintomi. Questi farmaci sono efficaci nel trattamento delle psicosi, compresi allucinazioni e deliri, e possono essere utili per curare i sintomi negativi della malattia, come la scarsa motivazione o l'appiattimento affettivo. Clozapina è efficace in una gamma di sintomi, ma l'effetto collaterale potenzialmente grave della agranulocitosi (riduzione di un certo tipo di globuli bianchi) ha limitato il suo impiego, in molti paesi, ai pazienti che non rispondono ad altri trattamenti.

La maggior parte delle persone affette da schizofrenia mostra un miglioramento sostanziale in corso di trattamento con farmaci antipsicotici. Alcuni pazienti, tuttavia, non traggono benefici dai farmaci e pochi altri non sembra necessitino di trattamento. è difficile stabilire quali pazienti rientrino in questi due gruppi e distinguerli dalla maggior parte dei pazienti che invece traggono beneficio dal trattamento con farmaci antipsicotici.

Spesso i pazienti e le famiglie hanno qualche riserva sui farmaci antipsicotici usati nel trattamento della schizofrenia. Oltre alla preoccupazione per gli effetti collaterali, ci sono riserve sulla possibile dipendenza. Tuttavia, i farmaci antipsicotici non determinano un comportamento euforico o dipendenza nelle persone che li assumono. è sbagliata anche la credenza che i farmaci antipsicotici effettuino una sorta di controllo della mente, o si rivelino una specie di "camicia di forza chimica". Se assunti alle dosi adeguate, i farmaci antipsicotici non 'annullanò le persone né la loro volontà. Sebbene abbiano un effetto sedativo, che può essere particolarmente utile all'inizio del trattamento, soprattutto se il paziente è particolarmente agitato, l'utilità di questi farmaci non è dovuta a questa caratteristica, ma alla capacità di ridurre allucinazioni, agitazione confusione e deliri tipici degli episodi psicotici. In questo modo i farmaci antipsicotici dovrebbero aiutare il paziente ad affrontare la realtà in modo più razionale.

I farmaci antipsicotici riducono il rischio di episodi psicotici futuri nei pazienti che hanno superato un episodio acuto. Sono stati riscontrati casi di ricaduta anche nei soggetti che hanno continuato il trattamento. Percentuali di ricaduta molto più elevate sono state osservate in caso di interruzione del trattamento. Nella maggior parte dei casi, non sarebbe appropriato asserire che il trattamento continuativo "previene" le ricadute, piuttosto ne riduce l'intensità e la frequenza. Il trattamento dei sintomi psicotici gravi richiede generalmente l'impiego di dosi più elevate rispetto a quelle usate in fase di mantenimento. Se i sintomi si ripresentano anche a dosi minori, può essere utile aumentarle temporaneamente per evitare una ricaduta completa.

Poiché la ricaduta è più probabile nei casi in cui venga sospeso il trattamento antipsicotico o sia assunto trattamento. Malgrado tutto ciò possa risultare difficile da gestire per i pazienti, può essere reso più semplice grazie a numerose strategie e portare ad una migliore qualità della vita.

Effetti collaterali

I farmaci antipsicotici, come ogni altro farmaco, presentano effetti benefici ed effetti indesiderati. Nelle fasi iniziali del trattamento, i pazienti possono manifestare effetti collaterali quali sonnolenza, irrequietezza, spasmi muscolari, tremore, secchezza delle fauci o vista annebbiata. Molti di questi effetti collaterali possono essere ridotti abbassando il dosaggio o possono essere controllati da altri farmaci. I pazienti presentano risposte diverse e diversi effetti collaterali nei confronti dei vari farmaci antipsicotici. Un paziente può rispondere meglio ad un farmaco piuttosto che ad un altro.

Gli effetti collaterali a lungo termine dei farmaci antipsicotici pongono problemi ben più gravi. La discinesia tardiva (TD) è un disturbo caratterizzato da movimenti involontari che interessano prevalentemente la bocca, le labbra, la lingua e, in alcuni casi, il busto e altre parti del corpo quali braccia e gambe. Questo effetto collaterale colpisce il 15-20% dei pazienti ai quali sono stati somministrati per molti anni i farmaci antipsicotici più vecchi. Tuttavia, questo disturbo è stato rilevato anche in pazienti trattati con questi farmaci per periodi più brevi. Nella maggior parte dei casi, i sintomi della TD sono lievi ed il paziente può non essere consapevole di questi movimenti. I farmaci antipsicotici più recenti sono meno rischiosi dei farmaci più vecchi, rispetto alla TD. Tuttavia, il rischio non è nullo poiché anche questi farmaci possono produrre effetti collaterali quali l'aumento di peso. Inoltre, se somministrati a dosi troppo elevate, i nuovi farmaci possono determinare problemi correlati all'isolamento sociale e sintomi simili a quelli del morbo di Parkinson, un disturbo che influisce sulla capacità di movimento. Ciò nonostante, gli antipsicotici più recenti offrono grandi vantaggi. Sono ancora in corso studi per rilevare l'uso ottimale di questi farmaci nei pazienti con schizofrenia.

 

Interventi psicosociali

Il trattamento con farmaci antipsicotici è utile per alleviare i sintomi psicotici della schizofrenia ma ha mostrato benefici variabili in termini di sintomi comportamentali tipici del disturbo. Anche nei casi in cui i pazienti non presentino sintomi psicotici, molti hanno grosse difficoltà in termini di comunicazione, motivazione, cura di sé o nello stabilire e mantenere relazioni con gli altri. Poiché i pazienti con schizofrenia spesso si ammalano negli anni critici per la crescita professionale,(cioè nell'età compresa tra i 18 ed i 35 anni), questi soggetti non sempre sono in grado di completare la formazione richiesta per determinate professioni. Di conseguenza, oltre ad avere disturbi del pensiero e della sfera emotiva, molti pazienti mancano di professionalità e di esperienza lavorative .

Gli interventi psicosociali sono particolarmente utili nel risolvere i problemi psicologici, sociali ed occupazionali. Mentre l'approccio psicosociale ha una scarsa influenza sui pazienti affetti da psicosi gravi (ossia quelli estraniati dalla realtà o affetti da allucinazioni o deliri evidenti), può comunque essere utile nei pazienti che presentino sintomi meno gravi o i cui sintomi psicotici siano sotto controllo. I pazienti con schizofrenia possono ricevere varie forme di intervento psicosociale. Gran parte di tali interventi mirano a migliorare il funzionamento sociale del paziente, sia in ospedale che in comunità, a casa e nel lavoro.

Riabilitazione

La riabilitazione dei soggetti con schizofrenia comprende una vasta gamma di interventi non di carattere medico. I programmi di riabilitazione si focalizzano sulla formazione attitudinale e sociale al fine di aiutare i pazienti e gli ex-pazienti a superare le difficoltà in queste aree specifiche. I programmi possono includere interventi di consulenza attitudinale, formazione professionale, tecniche per la gestione dei problemi e delle risorse finanziarie, uso dei mezzi di trasporto pubblico e attività di interazione sociale. Questi approcci sono particolarmente importanti per garantire il successo dei trattamenti della schizofrenia in comunità, perché permettono ai pazienti dimessi di acquisire le capacità necessarie per condurre una vita produttiva al di fuori dei confini protetti del ricovero ospedaliero.

Psicoterapia individuale

La psicoterapia individuale comprende una serie di colloqui regolari tra il paziente ed uno psichiatra, uno psicologo, un assistente sociale o un assistente sanitario. I colloqui possono essere incentrati su problemi, esperienze, pensieri, sensazioni o relazioni attuali o passati. Condividendo le proprie esperienze con un professionista empatico (parlando dei propri problemi con una persona non coinvolta), i pazienti riescono progressivamente a comprendere molto circa il proprio sé e i propri problemi. Inoltre, i pazienti possono imparare a distinguere ciò che è reale da ciò che è irreale e distorto. Gli studi evidenziano che una psicoterapia di sostegno individuale ed orientata alla realtà e un approccio cognitivo-comportamentale, in grado di insegnare al paziente a gestire e risolvere i problemi, possono essere utili soprattutto ai pazienti ambulatoriali.. La psicoterapia non può tuttavia sostituire l'uso di farmaci antipsicotici e si dimostra più utile una volta che il trattamento farmacologico ha alleviato i sintomi psicotici del paziente.

Educazione familiar

Molto spesso i pazienti affetti da schizofrenia vengono dimessi dall'ospedale ed affidati alle cure dei familiari. Per questo è importante che i membri della famiglia imparino a conoscere la schizofrenia e comprendano le difficoltà e i problemi associati al disturbo. è utile che i membri della famiglia imparino a ridurre al minimo le possibilità di ricaduta, ad esempio utilizzando strategie di adesione al trattamento, e vengano informati di tutti i servizi ambulatoriali e di sostegno familiare disponibili. La "psicoeducazione" familiare, che comprende l'apprendimento di varie strategie e tecniche per la gestione e la risoluzione dei problemi, può aiutare le famiglie a gestire in modo efficace il paziente e influire positivamente sul suo andamento clinico.

 

Contributo della famiglia e degli amici

Se a uno dei familiari è stata fatta diagnosi di schizofrenia, gli altri membri della famiglia possono aiutare il paziente in modo significativo, assistendolo ed aiutandolo a ricevere le cure appropriate. è molto importante conoscere tutti gli aspetti della malattia. Il medico che assiste il paziente deve essere pronto a rispondere a qualsiasi domanda sulla schizofrenia e sulle terapie disponibili.

è probabile che il medico chieda un colloquio con i membri della famiglia per avere maggiori informazioni sul comportamento del paziente. In alcuni casi infatti le persone affette da schizofrenia non sono in grado di fornire molte informazioni durante la visita. In certi casi solo i familiari o le persone vicine al paziente si rendono conto dei comportamenti o delle idee inusuali manifestati dal paziente. Poiché i pazienti possono non essere in grado di fornire queste informazioni volontariamente durante la visita medica, è consigliabile che i familiari o gli amici chiedano di parlare con la persona che visita il paziente in modo che possano essere prese in esame tutte le informazioni necessarie. è necessario preparare tutte le informazioni da fornire al medico nonché le eventuali domande. è utile fornire al medico informazioni sull'anamnesi della famiglia e sul tipo di farmaci assunti dal paziente. Il medico potrà fornire informazioni sul trattamento, sugli effetti collaterali, sui rischi a lungo termine e sulla necessità di ricovero. è utile preparare in anticipo le domande e disporre di carta e penna per prendere eventuali appunti.

 

Cosa attendersi dal medico responsabile della cura del paziente

La procedura per la diagnosi e il trattamento del paziente prevede che lo psichiatria:

* prenda nota dell'anamnesi dettagliata

* verifichi l'eventuale presenza di problemi causati da altre malattie (fisiche o psichiatriche)

* sia ben informato sui farmaci antipsicotici

* segua il paziente in modo attenti

* effettui aggiustamenti della terapia se necessari

* riveda regolarmente il trattamento

* sia interessato al benessere generale del paziente e segua anche gli aspetti relativi al consulto di uno specialista, alla sistemazione domiciliare, all'assistenza sociale e finanziaria

* illustri chiaramente cosa sta succedendo e cosa è stato pianificato per il trattamento del paziente

* coinvolga la famiglia nel programma terapeutico.

A causa della natura stessa del disturbo, alcuni pazienti con schizofrenia possono negare di aver bisogno di un trattamento, rifiutandosi di assumere i farmaci prescritti o interrompendo la terapia a causa degli effetti collaterali Per questi pazienti è difficile ricordare di assumere i farmaci a causa della disorganizzazione del pensiero di cui soffrono. Familiari ed amici, se coinvolti nel programma terapeutico, possono essere estremamente utili per verificare che il paziente assuma regolarmente i farmaci, ricordandolo quando se ne dimentica o rammentando i problemi che possono essere insorti nelle occasioni in cui il paziente si sia rifiutato di assumere i farmaci.

è estremamente importante che le persone affette da schizofrenia continuino ad assumere i farmaci anche dopo la dimissione dall'ospedale. L'interruzione del trattamento o delle visite di controllo spesso determina la ricomparsa dei sintomi psicotici. Per contribuire alla guarigione del paziente, è importante incoraggiarlo a continuare il trattamento ed assisterlo nel corso del programma terapeutico. Se non trattati, alcuni pazienti diventano così psicotici e disorganizzati al punto da non riuscire a prendersi cura delle proprie necessità di base, quali l'alimentazione, il vestirsi e l'assicurarsi un riparo. Molto spesso, le persone affette da gravi disturbi mentali come la schizofrenia finiscono per strada o in carcere, dove raramente ricevono le cure necessarie.

Le persone vicine ai pazienti con schizofrenia spesso non sono in grado di rispondere alle affermazioni strane o realmente infondate che essi formulano. Al paziente con schizofrenia, le convinzioni bizzarre o le allucinazioni sembrano reali e non fantasie immaginarie. Anziché tentare di "assecondare" i deliri del malato, i familiari o gli amici possono fargli notare che non vedono le cose allo stesso modo o che non sono d'accordo con le sue conclusioni, pur dando atto del fatto che la realtà può apparire diversa al paziente.

In alcuni casi, è utile che le persone che conoscono il paziente prendano nota del tipo di sintomi manifestati, dei farmaci assunti (compresi i dosaggi) e degli effetti della terapia. La conoscenza dei sintomi che si sono già manifestati aiuta i familiari a prevedere cosa tenere sotto controllo in futuro. Le famiglie possono anche essere in grado di identificare, in modo migliore e prima del paziente stesso, i primi segni di avvertimento di possibili ricadute, come ad esempio un'eccessiva tendenza all'isolamento o variazioni nel pattern del sonno. In questo modo, è possibile prevedere con un certo anticipo il ritorno della psicosi e il trattamento tempestivo può impedire la ricaduta completa. Inoltre, conoscendo quali farmaci sono stati vantaggiosi e quali invece hanno causato effetti collaterali problematici, la famiglia può aiutare lo specialista che ha in cura il paziente ad identificare più rapidamente il trattamento migliore.

Oltre ad aiutare il paziente a richiedere assistenza, i familiari, gli amici o i gruppi di sostegno possono fornirgli un supporto ed incoraggiarlo a recuperare le proprie capacità. è importante che gli obiettivi siano raggiungibili, in quanto i pazienti che si sentono sotto pressione e/o ripetutamente criticati dagli altri tendono a subire un ulteriore stress, che può peggiorare i loro sintomi. Le persone affette da schizofrenia, come chiunque altro, devono sapere quando agiscono correttamente. Ai fini dei risultati a lungo termine, è più utile adottare un approccio positivo anziché critico. Questo consiglio si applica a tutti coloro che interagiscono con i pazienti.

The Biology of Schizophrenia

Zubin Bhagwagar, MD, PhD John M. Kane, MD

Introduction

Although the weather in Toronto was chilly and capricious, delegates to the 2006 Annual Meeting of the American Psychiatric Association were treated to heartwarming news about recent advances in the understanding of the biological basis of schizophrenia. Scattered throughout the meeting were a number of presentations that gave the weary clinician hope for improved treatment of this severe, chronic, and disabling condition. The main focus of these advances centered on the interaction between glutamate and dopamine, and also recent findings from genetic studies of patients with schizophrenia.

Molecular Mechanisms

In a symposium entitled, "Not Just Dopamine Any More: Emerging Glutamatergic Therapies for Schizophrenia," Professor Joseph Coyle from Harvard Medical School, Cambridge, Massachusetts, and Editor of the Archives of General Psychiatry, described molecular mechanisms that had recently been identified as being of interest in schizophrenia.[1] These mechanisms are predominantly glutamatergic, and he described in some detail the 2 classes of ionotropic glutamate receptors, namely the AMPA/kainate receptors (AMPAR) and the n-methyl d-aspartate receptors (NMDAR).

The AMPAR (GluR 1-4) are the primary mediators of excitatory postsynaptic currents (EPSCs). The NMDAR (NR1; NR2A-D) contribute to the EPSC and play a more fundamental role in coincidence detection. EPSCs and coincidence detection are believed to be important mediators of neuroplasticity in mechanisms such as learning and memory, and these may be disrupted in schizophrenia. At the resting membrane potential, the NMDAR channel is blocked by Mg2+, which is removed upon depolarization. The NMDAR channels are sufficiently large to readily transduce Ca2+, which activates the intracellular kinases that ultimately regulate gene expression. The recruitment of NMDAR during high presynaptic glutamatergic activity results in the permanent increase in synaptic efficacy known as long-term potentiation (LTP).[2] Influx of Ca2+ through the NMDAR during LTP causes the recruitment of AMPAR from intracellular stores to the synapse. Persistent hyperactivity through a glutamatergic pathway can cause sprouting of postsynaptic spines via NMDAR activation, further strengthening synaptic connections. NMDAR activation has trophic effects, especially during development, with inactivity of NMDAR resulting in neuronal apoptosis.

Another unique characteristic of the NMDAR is that, in addition to the binding site for the agonist, glutamate, there is a glycine modulatory site (GMS) to which glycine and/or d-serine bind. The GMS needs to be occupied for glutamate to open the channel. The availability of d-serine depends upon the activities of serine racemase (SR) and the degrading enzyme d-amino acid oxidase (DAAO),[3] whereas the availability of glycine is determined by the activity of the glycine transporter, GlyT-1.[4] Notably, both SR and GlyT1, as well as the glutamate transporters that protect against excitotoxicity (EAAT 1 and 2), are expressed exclusively in astrocytes, indicating a vital role of astroglia in modulating glutamatergic neurotransmission.

Dr. Coyle concluded that regulation of the availability of glycine/d-serine at the GMS plays a critical role in optimal NMDAR function.

Insights From Neuroimaging

Anissa Abi-Dargham, Professor of Clinical Psychiatry and Radiology at Columbia University College of Physicians & Surgeons in New York, NY, continued this line of thought, presenting a thorough overview of the neurochemistry of schizophrenia during the symposium, "Advances in Schizophrenia."[5] She described the conventional model of schizophrenia in which hyperfunction of the dopaminergic system in subcortical regions is postulated to cause the positive symptoms of the illness while a relative hypofunction of the dopaminergic system in the prefrontal cortical region is believed to be responsible for negative symptoms. The key difference between the dopaminergic systems in these 2 regions is that the frontal regions lack the dopamine transporter, the protein that clears released dopamine from the synapse, and thus relies on catechol-O-methyl transferase (COMT; the enzyme that catabolizes dopamine) to clear dopamine from the synapse.[6]

Professor Abi-Dargham gave a clear account of a large number of neuroimaging studies that use molecular imaging with positron emission tomography (PET) or single photon emission computerized tomography (SPECT), and further informed us regarding the pathophysiology of the illness. She described how these studies had nearly unanimously shown an increased formation of presynaptic dopamine,[7] increased release of dopamine from the presynaptic terminal,[8-11] and a slight increase in dopamine D2 receptors[12] and in prefrontal dopamine D1 receptors.[13] The latter finding has been shown to relate to the concept of working memory (the ability to store relevant pieces of information, such as a telephone number, for a short time),[13] which has also been shown to be impaired in patients with schizophrenia.

Professor Abi-Dargham also described recent studies that implicate the glutamatergic system in the pathophysiology of the illness. The key receptor system in this case is the n-methyl d-aspartate (NMDA) receptor, which has been shown to be underfunctioning in schizophrenia.[14] This property was demonstrated in human studies in which the anesthetic agent, ketamine, an NMDA receptor antagonist, produced positive and negative symptoms, and cognitive distortions in healthy subjects very similar to those seen in schizophrenia.[15] Chronic ketamine users exhibit a regionally selective upregulation of D1 receptor availability in the dorsolateral prefrontal cortex, a phenomenon observed following chronic dopamine depletion in animal studies.[16] She also described how these abnormalities may be caused by glutamatergic projections from the prefrontal cortex to the striatum and cited recent unpublished data that support this proposition. Of interest, patients with a diagnosis of substance abuse and schizophrenia may have 2 levels of pathology, with NMDA receptor dysfunction and dopaminergic receptor abnormalities, which may feed into each other and worsen the situation.

Dopamine and Motivational Salience

Although Professor Abi-Dargham shed light on the intricate connections between glutamate and dopamine, Shitij Kapur, MD, PhD, Professor of Psychiatry and Chief of Research at the University of Toronto, provided a tantalizing twist to the dopaminergic hypothesis of schizophrenia.[17] Dr. Kapur expanded on his view of dopamine in psychosis.[18] Drawing from previous work, he spoke of dopamine not only mediating the phenomenon of hedonia[19] but of dopamine release preceding the hedonic event[20] and also mediating adverse events.[21] He contended that dopamine may be responsible for the phenomenon of "motivational salience,"[18] a process whereby neutral events and representations grow to be attention-grabbing, capturing thoughts and behavior. He described psychosis as resulting from an aberrant sense of novelty and an abnormal salience to relatively innocuous stimuli, which are mediated through a dysfunctional dopaminergic system.

He discussed how psychotic phenomena arise when the patient develops a cognitive scheme to explain aberrant salience. When this aberrant salience captures behavior or causes distress, it attracts attention, subsequent hospitalization, and treatment with appropriate antidopaminergic agents. In support of this, he challenged the widely held belief that there is a lag in the onset of antipsychotic effect following treatment, citing a recent meta-analysis conducted by his group.[22] In a subsequent study,[23] factor analysis showed that an independent change in psychosis (which included conceptual disorganization, hallucinatory behavior, and unusual thought content) was evident within the first 24 hours after receiving antipsychotic medications. This improvement in core psychosis was not mediated unidirectionally by changes in nonspecific behavioral effects or other psychopathology.[23]

Neurocognition in Schizophrenia

In an industry-supported symposium, "New Developments in Schizophrenia: From Neurobiology to Public Health," Robert Bilder PhD, Professor of Psychology at UCLA, Los Angeles, California,[24] reminded us of the ongoing cognitive deficits in patients with schizophrenia and quantified the effect size of this dysfunction as being around 1 (effect sizes of greater than 0.8 are considered large[25]). He also described a study (in press) that showed that the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) composite score of neurocognitive function was 1.59 standard deviation units lower in the patient population.[26] He related these deficits to problems with connectivity of neural networks, especially the fronto-striato-pallido-thalamic and fronto-striato-cerebellar. He reminded participants that enduring and long-lasting changes in cognitive function are likely in patients with schizophrenia. In a recent study,[27] he showed that, in the subset of patients for whom Scholastic Aptitude Test (SAT) scores were available, WAIS-R Full Scale IQ was 11.5 points lower than predicted from earlier SAT scores, suggesting a substantial decline in cognitive ability accompanying the initial episode of illness.[27] These findings suggest that schizophrenia is marked by substantial cognitive deficits in the first grade, that additional, subtle declines may precede the overt onset of psychotic symptoms, and that the initial episode of illness is marked by additional decline. He also related these deficits to polymorphisms of the COMT gene, where the allele with methionine has low activity and results in higher prefrontal dopamine levels and, perhaps, better cognitive performance.[6,28]

Genetics of Schizophrenia

Patrick F. Sullivan, MD, Professor of Psychiatry at University of North Carolina, Chapel Hill, gave an enlightening and highly informative lecture regarding the genetic basis of schizophrenia.[29] Clearly the disorder cannot be explained by a single gene or Mendelian genetics, and most likely results from multiple genes of small effect. He reminded us that the human genome comprises 3,300,000,000 base pairs that form approximately 30,000 genes, of which 6% are conserved throughout various species. Among the many pieces of evidence, work from the Institute of Psychiatry in London suggests that, of all risk factors, a family history of schizophrenia has the highest odds ratio (close to 10) and provides the most compelling data for the genetic basis of schizophrenia.

Dr. Sullivan elucidated previous family, adoption, and twin studies, which provide support for theoretical notions of the genetic basis of the illness. He then explained the 3 strategies employed in current research. The first is to study copy number changes in genes (insertions, deletions, etc). This strategy suggests involvement of the area 22q11, which is implicated in the DiGeorge or velocardiofacial syndrome. The other major finding from analysis of copy number changes is the gene called "Disrupted in Schizophrenia 1" (DISC1), which was identified at the breakpoint on chromosome 1 of the balanced translocation (1;11)(q42.1;q14.3) that co-segregated in a large Scottish family with a wide spectrum of major mental illnesses.

Dr. Sullivan suggested that the second strategy, linkage analysis (studying the segregation of genetic markers with illness in large pedigrees), has not contributed to our understanding of the illness because no gene was implicated in more than 4 studies and many in not more than a single study.[30]

Dr. Sullivan contended that the third strategy, association studies (case control studies), are productive with the accumulated data providing particular support for DISC1, DTNBP1 (the gene encoding dystrobrevin binding protein 1, or dysbindin), neuregulin 1 (NRG1), and regulator of G-protein signaling 4 (RGS4). He suggested that each of these genes has received support from multiple lines of evidence with imperfect consistency. For example, the case for each of these as a candidate gene for schizophrenia is supported by linkage studies. The preponderance of association study findings provides further support for a role of these genes in schizophrenia. mRNA from each gene is expressed in the prefrontal cortex and in other areas of the brain, lending face and construct validity, and additional neurobiological data link the functions of these genes to biological processes thought to be related to schizophrenia: DISC1 modulates neurite outgrowth[31]; other evidence supports the involvement of NRG1 in the development of the CNS[32]; and RGS4 may modulate intracellular signaling for many G-protein-coupled receptors.[33] Moreover, DTNBP1 and RGS4 have been reported to be differentially expressed in postmortem brain samples of individuals with schizophrenia. In conclusion, he suggested small sample size, diagnostic heterogeneity, and other parsimonious explanations as the main reasons for the nonreplication of various studies, but proposed that the field will advance dramatically in the next 2-5 years.

Novel Treatments for Schizophrenia

Although considerable work has advanced our understanding of the illness, no conclusions can be drawn until these findings are translated from the laboratory to the clinic. Although early attempts may not have met with unqualified success, progress is being made.

Most of the work in this area builds on the glutamatergic interactions described by Dr. Coyle and Dr. Abi-Dargham. Indeed, glutamatergic-modulating agents have been assessed in randomized controlled trials. Donald Goff, MD,[34] presented the results of a clinical trial of an AMPA receptor-positive modulator (AMPAkine) CX516 that had been compared with placebo in a recently concluded randomized clinical trial in combination with clozapine.[35] In the initial study, CX516 was tolerated well and was associated with moderate to large, between-group effect sizes, compared with placebo, involving improvements in measures of attention and memory. However, Dr. Goff presented data from a recently concluded larger trial, which found that the drug did not differ from placebo in terms of efficacy measures or improved cognition. Nevertheless, this is a good example of how preclinical science identifies new molecules that may have therapeutic benefit. Dr. Goff also discussed why the trial may not have found efficacy and suggested specific actions of the molecule that were likely responsible for the lack of effect. He asserted that the line of inquiry was scientifically valid and expressed optimism about the potential for future trials.

Similarly, Daniel Javitt, MD, from the Nathan Kline Institute for Psychiatric Research in New York, NY, presented results of a clinical trial comparing glycine, d-serine, and placebo in schizophrenia.[36] Again, although this study found no clear benefit from either of the 2 active treatments, a subgroup of inpatients responded to glycine, which was moderately encouraging, as was its effect when used in conjunction with typical antipsychotic agents. He noted that previous trials have suggested a role for glycine in the treatment of schizophrenia[37] and that this line of inquiry was encouraging. Dr. Javitt also described the potential role of glycine transport inhibitors as future treatments as similar to the way selective serotonin reuptake inhibitors act in the treatment of depression.

In contrast to the outcomes reported by Dr. Javitt, Scott Woods, MD, from Yale University School of Medicine, New Haven, Connecticut, reported encouraging preliminary results from an open-label study of glycine treatment in prodromal patients, and the initiation of a placebo-controlled trial based on these initial findings.[38]

In an industry-supported symposium, John M. Kane, MD, from the Albert Einstein College of Medicine, Bronx, New York, discussed the current understanding of the role of atypical antipsychotics in the treatment of schizophrenia.[39,40] Citing recent meta-analyses, he clarified the role these drugs take in the acute and chronic management of schizophrenia, and also showed that only 9 patients need to be treated with atypicals to produce 1 additional responder, compared with low-potency antipsychotics.[41] To put this "number needed to treat" (NNT) in perspective, the recently published Collaborative Atorvastatin Diabetes Study (CARDS)[42] showed that atorvastatin markedly reduced vascular events in patients with type 2 diabetes mellitus. The NNT with atorvastatin was 27 for 4 years to prevent 1 event.[43]

Results From the CATIE Trial

It was difficult to find a talk on schizophrenia at the conference that did not mention the results from the recently concluded CATIE trial.[44] In the same symposium, Dr. Kane[39] briefly outlined the design of the CATIE study. Phase 1 was a 57-site, double-blind, randomized treatment assignment of approximately 1500 patients with schizophrenia (not first episode or treatment resistant) to olanzapine, quetiapine, risperidone, ziprasidone, or the typical agent perphenazine. In phase 2, patients who discontinued phase 1 were allowed to choose either clozapine or ziprasidone as an alternative to randomization to quetiapine, olanzapine, or risperidone. In phase 3, patients who discontinued phase 2 were allowed to choose open-label treatments.

As reported elsewhere, results of phase 1 showed that the majority of patients in each group discontinued their assigned treatment because of inefficacy or intolerable side effects, or for other reasons. Rates of discontinuation were lowest for olanzapine, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with more weight gain and increases in measures of glucose and lipid metabolism.

Other presentations also brought out results from the other stages of the CATIE study. For example, 99 patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1-B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (n = 49) or blinded treatment with another, newer atypical antipsychotic the patients had not previously received in the trial (olanzapine [n = 19], quetiapine [n = 15], or risperidone [n = 16]). The results showed that for these patients, clozapine was more effective than switching to another, newer atypical antipsychotic.[45]

Conclusion

We can be optimistic about the future development of novel treatments for schizophrenia. Studies like CATIE have begun to inform rational pharmacotherapy and will also influence study design for future therapeutic molecules.

References

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21. Salamone JD. The involvement of nucleus accumbens dopamine in appetitive and aversive motivation. Behav Brain Res 1994;61:117-133.

22. Agid O, Kapur S, Arenovich T, Zipursky RB. Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry. 2003;60:1228-1235. Abstract

23. Kapur S, Arenovich T, Agid O, Zipursky R, Lindborg S, Jones B. Evidence for onset of antipsychotic effects within the first 24 hours of treatment. Am J Psychiatry. 2005;162:939-946. Abstract

24. Bilder RM. Cognitive functioning in schizophrenia: cognitive impairments as clues for improvements. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Symposium ISS14.

25. Cohen J. Statistical Power Analysis for the Behavioural Sciences (2nd ed). Hillsdale, NJ: Lawrence Earlbaum Associates; 1988.

26. Keefe RS, Bilder RM, Harvey PD, et al. Baseline neurocognitive deficits in the CATIE schizophrenia trial. Neuropsychopharmacology. 2006; April 19 [Epub ahead of print].

27. Bilder RM, Reiter G, Bates J, et al. Cognitive development in schizophrenia: follow-back from the first episode. J Clin Exp Neuropsychol. 2006;28:270-282. Abstract

28. Glatt SJ, Faraone SV, Tsuang MT. Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. Am J Psychiatry. 2003;160:469-476. Abstract

29. Sullivan PF. A review of the genetics of schizophrenia. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Symposium A05.

30. Lewis CM, Levinson DF, Wise LH, et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, Part II: Schizophrenia. Am J Hum Genet. 2003;73:34-48. Abstract

31. Ozeki Y, Tomoda T, Kleiderlein J, et al. From the cover: disrupted-in-schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc Natl Acad Sci U S A. 2003;100:289-294. Abstract

32. Law AJ, Shannon Weickert C, Hyde TM, Kleinman JE, Harrison PJ. Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. Neuroscience. 2004;127:125-136. Abstract

33. De Vries L, Zheng B, Fischer T, Elenko E, Farquhar MG. The regulator of G protein signaling family. Annu Rev Pharmacol Toxicol. 2000;40:235-271. Abstract

34. Goff DC. AMPA agonists (AMPAkines) in schizophrenia. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Symposium S027.

35. Goff DC, Leahy L, Berman I, et al. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia. J Clin Psychopharmacol. 2001;21:484-487. Abstract

36. Javitt DC. The PCP model of schizophrenia: 45 years and counting. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Symposium S027.

37. Heresco-Levy U, Ermilov M, Lichtenberg P, Bar G, Javitt DC. High-dose glycine added to olanzapine and risperidone for the treatment of schizophrenia. Biol Psychiatry. 2004;55:165-171. Abstract

38. Woods S. NMDA glycine site agonists in the treatment of the schizophrenia prodrome. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Symposium S027.

39. Kane JM. Pharmacologic treatment of schizophrenia; state of the art. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Symposium ISS14.

40. Leucht S, Barnes TRE, Kissling W, Engel RR, Correll C, Kane JM. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry. 2003;160:1209-1222. Abstract

41. Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet. 2003;361:1581-1589. Abstract

42. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696. Abstract

43. Lee JD, Morrissey JR, Mikhailidis DP, Patel V. CARDS on the table: should everybody with type 2 diabetes take a statin? Curr Med Res Opin. 2005;21:357-362.

44. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223. Abstract

45. McEvoy J. Comparison of clozapine versus other atypical drugs in prospectively defined, unresponsive patients. Effectiveness of antipsychotic drugs in chronic schizophrenia: complete results of the CATIE Trial. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Symposium ISS21.

American Psychiatric Association 2006 Annual Meeting

Schizophrenia

Peter J. Weiden, MD John M. Kane, MD

Introduction

This year's 159th Annual Meeting of the American Psychiatric Association (APA) in Toronto had a greater international participation than previous meetings, and the scientific agenda was enhanced by the contributions of psychiatrists from outside the United States and Canada. Some of the zeitgeist of the meeting will be presented in this selective review of new findings and new perspectives on the integration of pharmacologic and psychosocial treatments for psychosis. Many of the sessions on psychosocial and pharmacologic treatments of schizophrenia were particularly relevant in light of the results from the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study, which were published and became widely known to many of the APA participants before the meeting.

One year ago, at the 2005 APA meeting, Scott Stroup, MD, presented the CATIE design but not the primary findings. Psychiatrists learned that the intent of CATIE was to study a treatment cohort that would in many ways reflect those patients seen in "real-world" clinical practice. Therefore, the CATIE investigators enrolled patients with active medical or substance abuse comorbidities, as well as patients treated with other, ongoing adjunctive [non-antipsychotic] psychopharmacologic treatments.

By this year, the top-line results of the phase 1 CATIE study were already well known -- namely, that almost three quarters of 1460 patients enrolled either stopped or switched their assigned antipsychotic medication within the 18-month follow-up period. Regarding the comparative effectiveness of the medications studied, to the surprise of many, the mid-potency conventional antipsychotic perphenazine performed relatively well compared with the other [nonclozapine] first-line atypical antipsychotics. In the comparison of the second-generation antipsychotics, olanzapine performed somewhat better than risperidone, quetiapine, and ziprasidone in terms of the primary outcome of all-cause treatment discontinuation (ACTD), but olanzapine was also burdened by much higher rates of weight gain and metabolic problems. Phase 2 involved the cohort who discontinued their assigned medication and agreed to try another antipsychotic -- one of the second-generation antipsychotics that had not yet been given to the individual during phase 1 of CATIE. The ACTD results for phase 2 showed that for the subsequent switch trial, those who switched for tolerability remained on risperidone or olanzapine longer than on the other first-line [nonclozapine] atypical agents. The phase 2 results also showed that the impact of the second medication change on reducing (or increasing) side-effect burden was at least as great as shown in the phase 1 results.[1,2]

The Post-CATIE Era in Schizophrenia Research in the United States

One question that frequently arose throughout the sessions pertaining to schizophrenia treatment was, "What are the implications of CATIE for other psychosocial and pharmacologic research for patients with schizophrenia?" Although some areas of contention remain, participants throughout the other presentations almost universally agreed on what the CATIE results showed:

* First, the overall outcome measure of ACTD was promising but in need of further refinement and replication in other studies involving schizophrenia cohorts.

* Second, it is becoming clear that large numbers of schizophrenia patients do not achieve full remission during maintenance treatment with antipsychotic medications, and further research in this area needs to differentiate unequivocally bad outcomes (eg, relapse) and identify treatments that lead to unequivocally good outcomes (eg, remission).

* Third, future pharmacologic treatments should incorporate medication adherence or medication persistence (eg, willingness to remain on the current treatment instead of trying an alternate treatment) as a major outcome in addition to control of schizophrenia symptoms or relapse prevention.

* Finally, effectiveness outcomes research for schizophrenia conducted in the United States may benefit from greater attention to psychotherapeutic interventions as well as psychopharmacologic therapies.

Do the New Medications Help Achieve Remission Status? A Post-CATIE Analysis of a Pre-CATIE Maintenance Study

One of the concerns of the CATIE study is that the length of time that the patients received the antipsychotics may have been too short to detect differences between medications that could be small in magnitude but large in clinical importance. Very few maintenance studies have compared newer antipsychotics with first-generation agents and followed patients beyond a 1-year or, at most, 2-year outcome.

As mentioned, the CATIE results show that large numbers of schizophrenia patients do not go into full remission during maintenance antipsychotic treatment. Further research on duration of antipsychotic therapy that includes time until discontinuation also needs to differentiate patients who are discontinuing medication because of unequivocally bad outcomes from those whose treatment was associated with an unequivocally good outcome. It is theoretically possible that both outcomes may occur in an individual patient, and that is a very different kind of treatment result than that of a patient who never responded well for the entire time he or she received a given medication.

Is this kind of data available? One valuable approach is to reevaluate some longitudinal results of extension studies that followed patients on antipsychotic monotherapy for long periods of time, before the specific medication was approved by the US Food and Drug Administration (FDA). The merits of this approach are that the restricted access to the specific medication becomes an effectiveness outcome measure, and has been a part of other effectiveness studies that were conducted during times of restricted medication access.[3,4] The access constraint allows a longitudinal assessment of individuals who are self-selected (by themselves or by their doctors) as "winners" on the study medication. The trajectory of what symptom changes are attainable during the follow-up period can be estimated from this kind of data.

One study, presented in an APA poster session, followed patients who had been randomized to either ziprasidone or haloperidol for up to 3 years, providing one of the longest follow-up periods of any long-term maintenance study comparing a newer and an older antipsychotic.[5] The study evaluated the effectiveness of 2 dose regimens of ziprasidone (80-160 mg/d given twice daily [n = 72] or 80-120 mg/d given once daily [n = 67]) with haloperidol (5-20 mg/d [n = 47]) for the long-term treatment of schizophrenia. A total of 186 patients who had already completed a 40-week, double-blind study comparing ziprasidone and haloperidol continued their assigned antipsychotic medication in a 156-week (3 years) double-blind continuation study. Efficacy evaluation was based on recently proposed remission criteria for schizophrenia. Patients on ziprasidone treatment were more likely than those on haloperidol to meet full remission criteria (P < .05) during the 6 months preceding the last visit. Longitudinal assessment of cross-sectional remission and quality of life in the continuation phase demonstrated superior improvements (slope of trends) for patients who received ziprasidone when compared with those who received haloperidol. These superior temporal trends were concurrent, and the correlation was statistically significant (P < .001).

Using CATIE Outcome Criteria for First-Episode Patients

One of the constraints of CATIE is that it was designed to recruit patients who, for the most part, already had long histories of medication exposure and thus were probably known to be at least partially treatment-resistant to antipsychotic medications.

At the Scientific and Clinical Report session, "Treatment of Schizophrenia," Diana Perkins, MD, Professor of Psychiatry at University of North Carolina, Chapel Hill, presented the results of a large multicenter trial known as the Comparison of Atypicals for First-Episode Psychosis (CAFé) study.[6] Other first-episode studies have compared the newer antipsychotics with one of the first-generation agents.[7] The goal of the CAFé study was to compare 3 first-line atypical antipsychotics for the treatment of first-episode schizophrenia. The endpoint -- time until all-cause discontinuation -- was similar to that used in the CATIE trial. In fact, this trial was, in many ways, a deliberate attempt to reproduce the CATIE methods, but instead of a chronically ill patient population, this trial enrolled a first-episode schizophrenia population.

"First-episode" is more accurately described as first presentation, given that the mean duration of psychosis in the patient sample was over a year.[8-10] Also, as with other first-episode studies, more men than women comprised the patient sample. The dosing equivalencies for this trial were selected to reflect the needs of a first-episode treatment cohort, which, relative to chronically ill patients, tend to respond to lower doses yet also be more sensitive to side effects. The dosage equivalent was 2.5 olanzapine = 100 mg quetiapine = 0.5 mg risperidone. The actual doses achieved (mean modal dose) were 11.7 mg/day of olanzapine, 500 mg/day of quetiapine, and 2.5 mg/day of risperidone. Of note, the risperidone and olanzapine doses were lower than doses in the CATIE study, whereas the quetiapine dose of 500 mg was similar to the 543 mg/day quetiapine dose in the CATIE study. The main finding was that regardless of medication used, roughly 70% of patients stopped their assigned medication within the first year of treatment. Secondary outcomes related to symptom improvements showed equivalent efficacy for all medications, including overall severity of illness, positive and negative symptoms of schizophrenia, and comorbid depressive symptoms in schizophrenia.

Dr. Perkins mentioned that the CAFé study included a proactive effort to elicit common and distressing side effects to learn whether any of them might explain factors that contribute to medication adherence. Unlike standard efficacy trials in which many of the common side effects are only compiled if they are spontaneously reported by the study subject, side effects were systematically assessed with an interview during which patients were asked about common and distressing side effects typically associated with antipsychotic treatments. In addition to clinician-estimated severity, this measure also rated the degree of distress and whether the side effect might lead to medication discontinuation. At the doses used, extrapyramidal symptoms were well controlled for all medication groups. More surprising to the investigators was the relatively high rate of distress from sedation, which was common in all 3 medication groups.

Although all 3 agents were associated with weight gain, not surprisingly, the olanzapine group showed significantly greater weight gain than the quetiapine or risperidone treatment groups. Most striking was the absence of any association between these side effects and likelihood of medication nonadherence. Rather, 2 general patterns of nonadherence were apparent among these first-episode patients. In the first pattern, patients who did not respond well to their antipsychotic medication became nonadherent; thus, the study showed an interaction between medication nonresponse and nonadherence. The second pattern of delayed medication discontinuation involved the subgroup of patients who responded best to their medication. Upon achieving remission, these individuals would feel "cured" and stop their medication to "get on with life." These patients often would experience devastating sequelae to their relapse. Dr. Perkins concluded that more work needs to be done in capturing this kind of outcome endpoint, and that although the ACTD measure was a good start, future studies should attempt to better capture the interactions between psychology and psychopharmacology.

Clinical Trials of Newer Medications

What CATIE and other research reinforce is that we have an enormous unmet need in treating patients with schizophrenia. We still don't have sufficient impact on negative symptoms, cognitive dysfunction, nonadherence to treatment, or comorbid substance abuse. Fortunately, there is still considerable activity in the pipeline of new antipsychotic medications. One example of a new antipsychotic under review by the FDA is paliperidone, which is the 9-hydroxyrisperidone metabolite of risperidone. Kane and colleagues, from Albert Einstein College of Medicine, Bronx, New York, presented results of a large phase 3 trial of paliperidone .[11] The study included 630 patients with schizophrenia who were randomly assigned for 6 weeks of treatment with 6 mg, 9 mg, or 12 mg of paliperidone; or olanzapine 10 mg (to determine assay sensitivity only); or placebo. Paliperidone was given in an oral extended-release formulation, which allows once-daily dosing immediately, without any uptitration period, and provides less variability in plasma levels during a 24-hour dosing period. All 3 doses of paliperidone were superior to placebo as determined by outcomes on the Positive and Negative Syndrome Scale (PANSS) and the Personal and Social Performance Scale (PSP). The PSP is a clinical rating of personal and social functioning which adds another domain of outcome beyond the PANSS assessments.

Modified Cognitive-Behavioral therapy (CBT) for Patients With Schizophrenia

CBT has been used in the United States primarily for affective and anxiety disorders, not psychotic conditions such as schizophrenia. This is changing. A growing body of evidence shows that adding a course of CBT interventions to antipsychotic medication benefits these patients. Until recently, most of the research on CBT for psychotic disorders took place in the United Kingdom.[12]

Challenges for Implementation

An Issue Workshop on new work on CBT for psychosis in the United States entitled, "But can we do it here?: Challenges for implementing a CBT for schizophrenia program in the US," was featured at the APA meeting.[13] Chaired by Page Burkholder, MD, of Brooklyn New York, the workshop panelists included investigators across the United States who have begun pilot studies or dissemination work pertaining to CBT for schizophrenia.

The level of activity in the pilot studies across the United States and Canada reflects the growing awareness of the importance of studying CBT as an adjunct to antipsychotic medication for the treatment of schizophrenia. Scott Temple, PhD, of the University of Iowa, discussed his efforts to introduce this technique to a rural treatment environment in Iowa, a state with a limited number of mental health clinicians trained in CBT techniques (only 2 for the entire state!). His approach is to develop training programs, and in the last year he has focused on introducing CBT techniques to assertive community treatment (ACT) team members.

Narisimha R. Pinniniti, MD, from the University of Medicine and Dentistry of New Jersey, works as a community psychiatrist and medical director of the Steininger Mental Health Center in Camden, New Jersey. He described his own experience of getting involved in CBT for psychotic patients. He works in a busy International Center for Mental Specialties (ICMS) program with 600 to 800 patients and 30 case managers. After attending a workshop 5 years ago on adding CBT to pharmacotherapy for patients with schizophrenia, he started behavioral experiments with patients who had suffered very severe positive experiences. He then sought out additional training at the Beck Institute for Cognitive Therapy and Research in suburban Philadelphia, Pennsylvania, and began researching CBT techniques in his community mental health setting. After initial skepticism, he found that the case manager staff was "energized" and more engaged in work. He recommended that when introducing new approaches such as CBT for psychotic patients, to "Start small, within the resources of your service; and lead by example; once you start doing good work and getting good results, that is when you can ask for administrative support for adding a CBT program." Dr. Pinniniti received a NARSAD Young Investigator Award to study the potential additional benefits of providing CBT to schizophrenia patients who are taking newer antipsychotic medication.

Yulia Landa, PhD, is another NARSAD Young Investigator who described a pilot study evaluating the possible changes in paranoid ideation resulting from a group therapy approach using CBT principles. She hopes to study neuroimaging changes associated with clinical improvements, in collaboration with David Silbersweig, MD, at Cornell University Medical School.

David Kingdon, MD, Professor of Mental Health Care Delivery at the University of Southampton, United Kingdom, was the discussant for this workshop. He noted that this was the first US workshop on CBT for psychosis that focused solely on implementation, which seemed to reflect the growing interest in moving CBT for psychosis forward in the United States. He also noted the cascade effects of implementing CBT for his patients after they experienced initial treatment success. From a funding perspective, participants noted that NARSAD is taking a leadership role in providing funding in this area, which is especially noteworthy given the historical reluctance of NIMH to fund individual psychotherapy research for patients with schizophrenia.

Basic Techniques

The rising interest in CBT for schizophrenia was seen in a striking change in attendance in a yearly workshop on this topic that is given by Dr. Kingdon and Douglas Turkington, MD, of the University of Newcastle-upon-Tyne, United Kingdom.[14] Previous workshops were attended by a fairly small group of individuals who seemed particularly enthusiastic or interested in this specific treatment modality. This year, the workshop attracted an overflow, standing-room-only crowd, and the audience seemed to represent a much broader range of attendees who wanted to learn more about integrating CBT techniques into other mental health services. One of the participants who had attended this workshop every year commented that a "tipping point" in American psychiatry had been reached. Whether this is, indeed, the case remains to be seen; meanwhile, the workshop faculty provided some references for attendees interested in learning more about the research evidence and the principles and techniques of using CBT for patients with schizophrenia.[15-18]

Dr. Turkington reviewed some of the key techniques that differentiated CBT from other psychoeducational approaches to schizophrenia. One important difference is that a CBT-oriented interviewer will be very interested in the patient's own personal interpretation of the psychotic experience. According to Dr. Turkington, "For so long in psychiatry, we have avoided trying to understand the meaning of 'the voices'." He gave as an example a technique that involves homework assignments to do "research on the voices." He might ask the patient to try to record the voices the patient hears, and bring back the recording to the next session so that the patient and clinician can listen to the tapes together in an effort to hear the voices together. This technique permits patients to build up an interest in their experiences in a safe manner that was formerly terrifying and avoided. The idea is to disrupt the vicious cycle of trying not to think about the psychotic experiences. Dr. Turkington gave the example of "think of an elephant and now stop thinking about that elephant!" as an example of how experiences can become amplified by the avoidance process.

CBT to Prevent Relapse

Shanaya Rathod, MD, Hampshire Partnership NHS Trust, Mulfords Hill Centre, Hampshire, UK, presented long-term follow-up outcome data on a CBT effectiveness trial conducted in the United Kingdom.[19] The primary study was a multicenter, randomized trial that compared a brief course of CBT delivered by mental health nurses trained in CBT techniques with treatment as usual (TAU). Twelve-month follow-up data of this cohort showed that the CBT intervention delayed the time to rehospitalization (OR 1.84, CI 1.11-3.04, P < .02), but the symptom improvements seen acutely following the CBT intervention were not sustained during this follow-up period compared with the TAU group. The most recent findings of this study support the feasibility of using CBT-trained but nonexpert clinicians, which may provide enduring relapse prevention beyond the acute phase.

Dr. Turkington, the lead investigator of the original study,[20] was asked whether the relapse benefits were potentially related to better medication adherence in the CBT group. He noted that the benefits of the CBT intervention over TAU also were observed in patients whose adherence was known because they were receiving long-acting medication. In fact, Dr. Turkington noted their preliminary analyses seemed to show that second-generation antipsychotics did not offer additional benefits. Because this study was conducted before the availability of a long-acting atypical formulation (long-acting risperidone microspheres), Dr. Turkington said, "We think that a possible explanation for favorable relapse results from our long-term follow-up of the Insight Trial may be because the patients on the first-generation antipsychotics were receiving them in depot formulation. While this is not yet confirmed, the benefits of a brief CBT program may be made more durable when the medication is administered regularly and reliably."

Conclusion

Schizophrenia research is alive and well, as evidenced at the first post-CATIE APA meeting. Promising inroads are being made into understanding the relatively new ACTD measures, and refining them further. Evidence that the newer medications may be more likely to help patients achieve remission status than the first-generation medications is accumulating, and duration of medication treatment may be a key factor. First-episode patients seem to respond well on the newer medications, but the atypical antipsychotics -- even with a reduced side-effect burden -- will not by themselves solve the high rates of medication discontinuation seen among first-episode patient populations.

Other pharmacologic strategies (eg, route of drug delivery) and psychosocial strategies (eg, adding CBT) need to be considered in the first-episode population. Finally, we are beginning to see a "tipping point" of interest in the potential benefits of adjunctive CBT for patients with schizophrenia who have persistent symptoms, comorbid depression, or who are likely to become nonadherent to their antipsychotic medication.

References

1. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600-610. Abstract

2. Stroup TS, Lieberman JA, McEvoy JP, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. Am J Psychiatry. 2006;163:611-622. Abstract

3. Essock S, Hargreaves W, Covell N, Goethe J. Clozapine's effectiveness for patients in state hospitals: Results from a randomized trial. 1996;32:683-697.

4. Essock S, Hargreaves WA, Dohm FA, Goethe J, Carver L, Hipshman L. Clozapine eligibility among state hospital patients. Schizophrenia Bulletin. 1996;22:15-25. Abstract

5. Loebel AD, Warrington L, Siu C, Lieberman JA. Remission in schizophrenia: a comparison of 2 dose regimens of ziprasidone vs haloperidol treatment in a 40-week core and 3-year double-blind extension study. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Abstract NR395.

6. Perkins D. Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of first-episode psychosis: a randomized, double-blind, 52-week comparison. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Session SCR27.

7. Schooler N, Rabinowitz J, Davidson M, et al. Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial. Am J Psychiatry. 2005;162:947-953. Abstract

8. Robinson DG, Woerner MG, McMeniman M, Mendelowitz A, Bilder RM. Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry. 2004;161:473-479. Abstract

9. Robinson D, Woerner MG, Alvir J, Bilder R, Hinrichsen GA, Lieberman JA. Predictors of medication discontinuation by patients with first-episode schizophrenia and schizoaffective disorder. Schizophr Res. 2002;57:209-219. Abstract

10. Robinson D, Woerner MG, Alvir J, et al. Predictors of relapse following response from a first-episode of schizophrenia or schizoaffective disorder. Arch Gen Psych. 1999;56:241-247.

11. Kane J, Kramer M, Ford L, Gassmann-Mayer C, Lim P, Eerdekens M. Patients with acute schizophrenia: treatment with 3 fixed dosages of oral paliperidone extended-release tablets in an international 6-week placebo-controlled study. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Abstract NR375.

12. Turkington D, Kingdon D, Weiden PJ. Cognitive behavioral therapy for schizophrenia. Am J Psychiatry. 2006;163:365-373. Abstract

13. Burkholder P, Weiden PJ, Kingdon DJ, Landa Y, Temple S, Pinniniti NR. But can we do it here?: Challenges for implementing a CBT for schizophrenia program in the US. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Abstract IW008.

14. Rathod S, Kingdon DG, Turkington D. Cognitive-behavior therapy for psychosis: basic techniques for psychiatrists. Program and abstracts of the American Psychiatric Association 2006 Annual Meeting; May 20-25, 2006; Toronto, Ontario, Canada. Abstract IW023.

15. Turkington D, Kingdon D, Chadwick P. Cognitive-behavioural therapy for schizophrenia: filling the therapeutic vacuum. Br J Psychiatry. 2003;183:98-99. Abstract

16. Kingdon DG, Turkington D. Treatment Manual for Cognitive Behavior Therapy of Schizophrenia. New York, NY: The Guilford Press; 2005.

17. Turkington D, Siddle R. Cognitive therapy for the treatment of delusions. Psychiatric Rehabilitation Skills. 1998;4:300-320.

18. Chadwick P, Birchwood M, Trower P. Cognitive Therapy for Delusions, Voices and Paranoia. New York, NY: John Wiley & Sons; 1996.

19. Rathod S, Kingdon D, Smith P, Turkington D. Insight into schizophrenia: the effects of cognitive behavioural therapy on the components of insight and association with sociodemographics -- data on a previously published randomised controlled trial. Schizophr Res. 2005;74:211-219. Abstract

20. Turkington D, Kingdon D, Turner T. Effectiveness of a brief cognitive-behavioral therapy intervention in the treatment of schizophrenia. Br J Psychiatry. 2002;180:523-527. Abstract

Treatment-Resistant Schizophrenia

Introduction

Psychopharmacologic treatment can suppress psychotic symptoms in most patients with schizophrenia, but about 20% remain "treatment-resistant" to the antipsychotic effects of neuroleptic therapy and continue to manifest delusions and hallucinations as well as formal thought disorder. This resistance to therapy occurred even in the era when positive symptoms were considered the hallmark of this brain disease, and patients who responded poorly to 1 or more courses of antipsychotic therapy continued to be institutionalized rather than discharged into community care.

Defining Treatment Resistance

In the Clozapine Registration Trial, Kane and colleagues proposed rigorous criteria for defining treatment resistance in schizophrenia patients, which included a patient's failure to respond to 3 different antipsychotics at high doses.[1] In a subsequent investigation, however, it was shown that failure to respond to 2 antipsychotics at usual doses is predictive of an inadequate response to further nonclozapine medication.[2] Although poor functioning was a criterion in the original Kane definition, treatment resistance in the usual clinical context implies persistent positive symptoms despite adequate medication. Given that negative and cognitive deficits are common and often persist despite the resolution of positive symptoms, a majority of treatment-resistant patients with schizophrenia could fit into a definition of treatment resistance that included those domains. Patients and families might argue that poor occupational and social functioning, often the consequence of persistent negative and cognitive symptoms, are devastating. If poor recovery of function were added to the criteria, many more people with schizophrenia would then be defined as resistant to the currently available pharmacotherapeutic treatments that focus mainly on dopamine receptor D2 (DRD2) antagonism.

Even though this review will focus on treatment-resistant positive symptoms, there is good evidence that psychosocial treatments, such as vocational rehabilitation and social skills training, can contribute to recovery of function once the debilitating psychotic, or positive, symptoms are adequately treated.[3] If a patient has persistent positive symptoms despite the application of approaches suggested in this article, then he or she should be considered treatment refractory, which, fortunately, represents only a small proportion of the treatment-resistant population.

Prevalence of Treatment Resistance

The prevalence of treatment resistance varies by patient characteristics. Men with both first-episode[4] and multi-episode "chronic" schizophrenia[5] usually don't respond as well to treatment as do women. Further, the duration of untreated psychosis (DUP) may predict a subsequent treatment response. As shown in a meta-analysis, a longer DUP significantly correlated with the risk of "no remission" in schizophrenia.[6] An 8-year prospective study also found that there was a positive correlation between persistent positive symptoms and DUP.[7]

Chronic patients seem to have a higher prevalence of resistance. For instance, one study of state-hospital patients in Connecticut found that almost half met the investigators' criteria for resistance, which included both medication nonresponse and 24 months of inpatient care over 5 years.[8]

Because the definition of treatment resistance is not standardized, the precise prevalence of treatment resistance is not known. In one study of outpatients with schizophrenia and schizoaffective disorder at a public clinic in California, investigators found that if they applied less rigorous criteria of treatment resistance than what Kane had proposed, they reported a prevalence of 43% vs only 13% using Kane. Their criteria included nonresponse to two 4-week antipsychotic trials at doses equivalent to at least 600 mg chlorpromazine.[9]

Comprehensive estimates, however, predict that at least 25% of chronic patients are resistant[10] and that resistance is less common in patients early in the course of illness when positive symptoms are usually more responsive to antipsychotic medication. However, the disorganized subtype of schizophrenia, also known as hebephrenia, may have a poor treatment response early in its course and a worse long-term prognosis than other types.[11]

Neurobiology of Treatment Resistance

Some neuroimaging studies have found that treatment-resistant patients more often have cortical atrophy than do other patients with schizophrenia.[12] In a case-controlled magnetic resonance study of 40 persons with schizophrenia, 95% of treatment-resistant patients in that sample had atrophy as determined by a global measurement of cerebral volume compared with 60% of treatment-responsive patients.[13] Two of the treatment-resistant and none of the other patients had cerebellar atrophy. Patients with a history of perinatal complications have poorer responses to treatment.[4,14] Likewise, a history of obstetric complications is associated with neuroimaging evidence of volumetric brain change.[15] Prenatal events, such as infections, may also correlate with such findings.[16] An hypothesis meriting further investigation is that prenatal and perinatal insults associated with the loss of cerebral volume contribute to poor treatment responsiveness.

A pharmacologic hypothesis is that treatment resistance in schizophrenia represents a form of neurochemical adaptation to antipsychotic medication, related to the phenomenon called "supersensitivity psychosis."[17] This could result from heightened dopamine activity in the mesocortical and mesolimbic dopamine pathways in response to chronic DRD2 blockade, which some investigators have postulated is similar to heightened dopamine activity or receptor upregulation in the nigrostriatal pathway, a possible cause of tardive dyskinesia. In one study where 35% of the treatment-resistant patients studied had tardive dyskinesia, supersensitivity psychosis, determined by an increase in positive symptoms over 4 weeks after antipsychotic discontinuation, did not positively correlate.[18] Furthermore, some investigators have suggested that supersensitivity psychosis is actually more common in patients with good-prognosis schizophrenia.[17]

Neuroscience research is not conclusive on the issue of D2 upregulation during treatment with antipsychotics. Some postmortem studies of brain tissue from schizophrenia patients chronically treated with antipsychotics have shown increases in D2 receptor density[19] whereas others have not.[20] In nonhuman primates, chronic exposure to the D2 receptor antagonist, raclopride, caused significant increases in D2 receptors in the basal ganglia and cingulate cortex, as detected by in vivo neuroimaging.[21] In a recent study of both antipsychotic-naive and antipsychotic-exposed patients with schizophrenia which used single-positron emission computed tomography and a raclopride-congener probe, there was no mean difference in D2 receptor density between the 2 groups.[22] The question remains unresolved because of methodologic differences among studies, such as the type of D2-receptor ligand used as a probe.

In a small study of Finnish patients with schizophrenia, those who had an inadequate response to first-generation antipsychotics were significantly more likely to have low activities of monoamine oxidase A (MAO-A) and catechol-O-methyltransferase (COMT).[23] The researchers examined the subjects' genotypes for alleles related to low-activity-enzyme phenotypes. A high rate of nonresponse to antipsychotics correlated with homozygotes for low-activity COMT compared with homozygotes for high-activity COMT. Compared with responders, nonresponders had a 6-fold greater likelihood of having a genotype for both low-activity MAO-A and low-activity COMT. The investigators speculate that a lower ability to metabolize dopamine and norepinephrine, associated with COMT and MAO-A, may either impair medication response or may be associated with a more severe kind of schizophrenia.

The role of other neurotransmitters is less certain. Faber[24] has hypothesized a model of psychosis that involves the hypofunctioning of the NMDA-glutamate receptor with a resulting decrease in GABA-mediated inhibition of excitatory cortical projections. Antagonists of NMDA receptors, such as phencyclidine, cause psychotic thought, perceptions, and behavior that do not fully respond to D2 antagonists. A recent in vivo magnetic resonance study of patients with a mean of 6 years of paranoid schizophrenia demonstrated elevated glutamate in prefrontal and hippocampal regions compared with controls.[25] This is compatible with NMDA receptor hypofunction, which could cause compensatory increase in presynaptic glutamate. All of these patients were treated with antipsychotics, but the severity of their psychosocial dysfunction during the 2 years prior to the study correlated with higher glutamate in both brain regions.

Finally, on the basis of an evolving understanding of the neurobiology of schizophrenia, treatment resistance may represent a subset of early-onset schizophrenia with more severe neurodevelopmental and neurodegenerative impairments that fail to respond to antipsychotic pharmacotherapy. This may be so even during the first episode, when responsiveness is usually prompt and remission is achievable in many patients.

Clinical Management

"Pseudo-resistance" in Schizophrenia Treatment

A working definition of treatment resistance hinges on an assumption that a patient is resistant if he or she fails to respond to an adequate trial of pharmacotherapy. Patients who remain psychotic and impaired over the course of treatment should be considered resistant to therapy only after sufficiently high doses and long duration of medication have been administered. This situation may be called "pseudo-resistance" and may be related to several factors, as described below.

Antipsychotic Dosing

Each medication has its own effective dose range, which traditionally has been standardized according to chlorpromazine or haloperidol equivalents. Davis and colleagues have called this concept into question when they surveyed existing randomized, placebo-controlled studies to determine dose-response curves for first- and second-generation antipsychotics.[26]

In some circumstances, the antipsychotic dose may need upward adjustment because of pharmacokinetic interactions with other prescription or recreational drugs the patient is receiving. According to a recent worldwide review, the point prevalence of tobacco smoking among patients with schizophrenia is 71% in males and 44% in females.[27] Tobacco smokers have lower serum concentrations of haloperidol, olanzapine, and clozapine at a given dose than nonsmokers because the polycyclic hydrocarbons in smoke induce certain hepatic cytochrome P450 enzymes that metabolize these drugs.[28,29] Smokers may therefore require a 50% higher dose of olanzapine and clozapine because of greater CYP1A2 activity. Other agents that induce CYP1A2 activity are omeprazole, rifampin, ritonavir, carbamazepine, and phenytoin.

Rifampin, carbamazepine, and phenytoin also induce CYP3A, which metabolizes quetiapine. Quetiapine may need to be increased 5-fold when coadministered with these medications. This enzyme also metabolizes risperidone and aripiprazole, which may need a 2-fold dosage increase, and, to a lesser extent, ziprasidone, which may require a 50% dosage increase.[30] Fewer data are available on the anticonvulsants oxcarbazepine and topiramate, which may also induce CYP1A2 and CYP3A.[30] Chronic use of St. John's wort, however, does significantly induce CYP3A.[31]

Many drugs, including serotonin reuptake inhibitors and bupropion, inhibit cytochrome P450 enzymes, requiring a lower dose of the coadministered antipsychotic.[30] When these drugs are discontinued, an increase in the metabolism of antipsychotics may occur, which can lead to a decrease in antipsychotic serum levels and a spurious loss of efficacy, all of which can be misperceived as treatment resistance.[32]

Another consideration is superimposed iatrogenic delirium, or psychosis, which can confound treatment of the underlying schizophrenia and may be misinterpreted as treatment resistance. Most psychiatry textbooks provide a list of such medications, which includes anticholinergics, stimulants, steroids, and others. When patients do not respond to antipsychotic treatment adequately or when response diminishes, clinicians should carefully review patients' medication regimens, including over-the-counter and herbal remedies, and recent medication discontinuations, with an eye toward iatrogenic psychosis and pharmacokinetic interactions.

A less common pharmacokinetic consideration in an apparently treatment-resistant patient is a predisposition for rapid metabolism that occurs in individuals with certain alleles of CYP2D6.[33] This enzyme is important in the elimination of haloperidol, zuclopenthixol, risperidone, thioridazine, and perphenazine. The causative allelic variants occur more often in certain ethnic groups: 3% of white northern Europeans may have a duplication of the CYP2D6 gene, as may as many as 10% of white southern Europeans, 16% of Saudi Arabians, and 29% of Ethiopians.[33,34] In patients with poor responses and lower than expected serum levels, genotyping can in some, but not all, cases confirm that the presence of these alleles is the cause.[35] Although this is an uncommon condition, it may explain a proportion of apparent treatment resistance among patients with schizophrenia. In a study of 749 white patients with schizophrenia, investigators found that patients who were rapid metabolizers were more likely to have had multiple hospitalizations and polypharmacy compared with other patients.[36]

Adequate Treatment Trial Duration

Another consideration in treatment resistance is the adequacy of the duration of an antipsychotic trial. Recent analyses of clinical trials call into question the previously established idea that antipsychotic effects are delayed in onset. As measured by standard instruments such as the Positive and Negative Symptoms Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS), more improvements occurred during the first 2 weeks of treatment than during the second 2 weeks.[37] Furthermore, 70% of the total improvement obtained at 1 year may be obtained by the end of the first 4 weeks of treatment.[38] Nonetheless, a "full response" may require several months in many patients. Although the precise time course of an individual's response cannot be predicted, lack of any response whatsoever within 2 weeks, given evidence of adequate serum levels, would suggest the need for different medication. Some response by that time indicates continuing treatment for at least 4-6 weeks, which is the standard recommendation for an adequate trial.[39]

Adherence to Treatment

Full adherence to medication is a crucial determinant of treatment outcome. In a British study, partial or complete nonadherence was associated with a 60% increased need for inpatient services over the course of 1 year.[40] The rate of nonadherence in patients with psychotic disorders has been estimated to be as high as 80%,[41] but a recent large study of people with schizophrenia within the U.S. Veterans' Administration system found that 40% of outpatients had poor compliance, defined as a medication possession ratio of ? 0.8 during a 1-year period.[42] African Americans and younger patients were poorly adherent more often than other patients.

In another study of recently hospitalized patients followed as outpatients, 42% discontinued medication within 2 years.[43] According to the literature, documented factors associated with poor adherence to antipsychotic medication include poor insight, negative attitude toward medication, substance abuse, shorter illness duration, cognitive dysfunction, amotivation, and poor therapeutic alliances.[44]

Studies strongly implicate intolerable side effects in nonadherence, chiefly extrapyramidal symptoms (EPS), such as Parkinsonism and akathisia, and antipsychotic-induced dysphoria, often concomitant with EPS.[41] Given that second-generation antipsychotics cause fewer EPS, clinicians might expect patients to be more willing to take them. A review of the effectiveness of second-generation antipsychotics in treatment-resistant schizophrenia found that study subjects assigned to these agents compared with first-generation agents were more likely to complete a clinical trial.[45]

However, studies in clinical populations suggest this may not translate into better adherence. In the large Veterans Administration study discussed above, the rate of poor adherence among patients on second-generation agents was 41.5%, slightly more than the 37.8% of patients on first-generation agents.[42] Similarly, in a smaller study of medication adherence among patients 40 years of age or older with psychotic disorders who were receiving both antipsychotics and other medications, there was no difference in adherence rates between those administered first-generation agents and those receiving second-generation agents. It should be noted, however, that nonadherence to antipsychotics was no worse than nonadherence to nonpsychiatric treatments such as antihypertensive, antidiabetic, or lipid-lowering medications.[46]

Psychiatric Comorbidity

Psychiatric comorbidity is a complex issue in patients with schizophrenia. Most often it involves substance use disorders (SUD), which occur in approximately half of patients with schizophrenia,[47] and depressive symptoms, which pose a lifetime risk that may affect up to 81% of patients with schizophrenia.[48] SUD and depressive symptoms are also associated with each other. In a prospective Canadian study of patients with schizophrenia and related disorders, those patients with SUD typically used alcohol and cannabis, and had more psychotic, anxiety, and depressive symptoms at baseline compared with those who did not. During 12 months of treatment, their psychotic symptoms abated more than those of patients without concurrent SUD, but their depressive symptoms remained greater as long as their substance use persisted.[49] Even though their persistent positive symptoms may not necessarily be greater than those in the general population of psychotic patients without concurrent SUD, a study of 1843 US patients with schizophrenia or related disorders demonstrated that there is an association between SUD and poor psychosocial functioning.[50]

The poor outcome in patients with comorbidity may be due, in part, to poor treatment adherence. A recent multicenter study of people with schizophrenia or related disorders found that mood symptoms, especially feeling "emotionally numb," were associated with poor adherence, as were substance abuse, loss of interest, suicidal ideation, and relocation in the past 30 days.[51] Antipsychotic medication may cause neurologic adverse effects that can mimic depression, so-called secondary negative symptoms or neuroleptic-induced akinesia, or cause agitation, ie, antipsychotic-induced akathisia.[52] If not recognized, such effects may cause poor treatment response or may lead to medication discontinuation by the patient. Clinicians must actively screen for such iatrogenic effects, distinguish them from other conditions, and ameliorate them promptly. Whether or not second-generation agents more effectively treat primary negative symptoms such as alogia, avolition, and affective flattening remains controversial, but the lower prevalence of parkinsonism and akathisia seen in atypicals[45] may be associated with a decrease in secondary negative symptoms, such as apathy and anhedonia, that are concurrent with bradykinesia.

Some illicit substances may induce or exacerbate psychotic symptoms, even in patients with schizophrenia who are taking antipsychotic medication, giving the appearance of treatment resistance. In a review of published studies, both experimental and naturalistic, investigators found strong evidence suggesting that exposure to amphetamines and cocaine is associated with psychotic symptoms in people both with and without preexisting psychotic illness.[53] The presence of positive symptoms at baseline in people with a psychotic illness puts them at increased risk for temporarily worsened psychosis even after 1 experimental illicit stimulant dose.[53]

Methamphetamine use is associated with a psychosis indistinguishable from paranoid schizophrenia. These psychotogenic (psychosis-generating) effects may not only persist for months, but they are also likely to recur with re-exposure, even after several years of abstinence, and may recur under stress, even without re-exposure in severe cases.[54] The risk of psychosis increases with duration of methamphetamine use.

Use of stimulants may cause transient psychotic symptoms to be superimposed upon the already existing psychosis of schizophrenia. There is also the possibility that stimulants can make the psychosis of schizophrenia more persistent, ie, treatment resistant. It is challenging for clinicians who treat patients who use illicit stimulants to sort out the influences on persistent psychosis of the drug, nonadherence to treatment, and the natural course of illness.

People with schizophrenia drink caffeinated beverages, as do most people in North America. The difference may be in the amount taken. Some studies have found that caffeine intake in patients with schizophrenia may be as high as 500 mg per day compared with a mean of 210 mg per day in the general population.[55] Caffeine acts on adenosine receptors in the central nervous system to dopamine neurotransmission. Using standardized rating instruments, there is evidence in enhance some published work that caffeine intake positively, but weakly, correlates with hostility and positive symptoms.[55] An experimental study of intravenous caffeine administration in people with schizophrenia found a resultant robust increase in positive symptoms and a decrease in negative symptoms,[56] which suggests that patients may use caffeine to alleviate the subjective experience of negative symptoms. With sustained high intake, it appears that caffeine intake could adversely affect treatment response.

Another comorbidity that may contribute to treatment resistance is obsessive-compulsive disorder (OCD). Among 118 outpatients with schizophrenia, 8.8% of patients had clinically significant obsessive-compulsive symptoms as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).[57] The higher the Y-BOCS score, the higher the positive symptoms measured by the PANSS, especially delusions. Some studies have found a higher prevalence of obsessive-compulsive symptoms in schizophrenia, up to 25%.[58] Treatment of this comorbidity may be complicated by the fact that, according to a series of case reports, atypical antipsychotics in monotherapy may be associated with the de novo appearance of, or the aggravation of, preexisting obsessive-compulsive symptoms in a small proportion of patients with schizophrenia.[59] On the other hand, the addition of atypicals to selective serotonin reuptake inhibitors (SSRIs) has been shown to increase the response of OCD patients who had failed to respond adequately to SSRIs.

Finally, certain medical illnesses may present with schizophrenia-like psychoses. These include Wilson's disease, metachromatic leukodystrophy, basal ganglia calcification, and systemic lupus erythematosus. While uncommon in mental-health treatment settings, patients with these conditions may respond partially or poorly to standard therapy and usually would require concurrent evaluation and management by other medical specialists.

Managing Treatment-Resistant Schizophrenia

Address Possible "Pseudo-resistance"

The following steps can help clinicians to exclude the possibility of pseudo-resistance, as opposed to true treatment resistance:

* Optimize the dose of antipsychotic medication, which includes upward titration, and check serum levels if there are concerns about pharmacokinetic interactions.

* Optimize the duration of antipsychotic therapy, typically a 4- to 6-week trial, given optimal dosing.

* Monitor adverse effects of psychiatric and other medications that may mimic worsening positive (akathisia, delirium) or negative (hypokinesia) symptoms.

* Screen for comorbid conditions such as substance use disorders, excessive caffeine intake, depression, and OCD.

* Rule out a general medical or neurologic condition that may be presenting with psychotic symptoms by conducting a complete physical and neurologic examination, laboratory workup, and specialist consultations, as appropriate.

* Assess medication compliance by using several techniques, such as asking patient and relatives about compliance, pill counting, measuring serum levels, and checking pharmacy refill dates.

Further steps that can be helpful include establishing the adequacy of, and response to, previous medication trials. This may require obtaining records from other providers or institutions, calling previous clinicians, and interviewing the patient's family or care provider. Before embarking on medication trials, the clinician should choose specific target symptoms in collaboration with the patient, family, and case manager, if possible. These may include characteristic delusions, frequency of hallucinations, or level of hostility or bizarre behavior. Using standardized rating instruments to quantify a patient's symptom severity at baseline and during medication trials can improve the clinician's ability to monitor and document improvements. Commonly used instruments for assessing schizophrenia are the PANSS[60] and the Clinical Global Impression Scale.[61] For monitoring depression, the Calgary Depression Scale has been found to be reliable in patients with schizophrenia.[62]

Ensuring adherence is a challenge to any physician treating a chronic illness. In several studies of schizophrenia, a leading correlate of medication adherence is the therapeutic alliance between clinician and client.[63] This should be reassuring as it means that every provider has a basic clinical tool to use with difficult patients. Still, this alliance can be especially challenging with treatment-resistant patients in whom persistent positive symptoms may be accompanied by hostility and aggression.[64]

Another common-sense approach to nonadherence is simplifying medication regimens. In a study from Japan, investigators treating patients with chronic schizophrenia eliminated unnecessary medications and consolidated all psychotropics to 1 dose in the evening. They found no mean effects on patients' symptoms, although several individuals worsened or improved, but 65% of patients preferred the new regimen despite a trend toward greater morning sedation.[65] Although no study has proved that simplifying treatment will improve compliance in schizophrenia, studies of other chronic conditions have found greater adherence with lower-complexity medication regimens.[66] Various specific interventions to improve adherence in patients with schizophrenia have been tested, and psychoeducation is usually not effective without concomitant problem-solving and behavioral interventions.[63]

If treatment adherence is the major barrier to effective pharmacotherapy, and a patient had previously responded to first-generation agents or risperidone, a trial of long-acting injectable medication should be considered. In a review of the literature on first-generation antipsychotics, Schooler and colleagues[67] estimated the 1-year relapse rate to be 27% among patients treated with depot antipsychotics compared with 42% among patients treated with oral antipsychotics. What contributes to improved outcome with use of such preparations as fluphenazine decanoate, haloperidol decanoate, or long-acting injectable risperidone microspheres are such factors as consistent, reliable drug delivery and more regular clinic visits so that a clinician can closely follow a patient's response.[68] Furthermore, nonadherence can be immediately detected when a patient does not show up for an injection.

Pharmacologic Strategies for Treatment Resistance

Switching Antipsychotics. When a patient has received the highest tolerated dose of one antipsychotic for an appropriate duration but positive symptoms persist, the next step should be a trial of a medication with a different pharmacologic profile. If the first failed trial was with a first-generation agent, a second-generation agent would be appropriate because the likelihood of a positive response to another first-generation agent is < 5%.[39] In a naturalistic study of 135 outpatients switched because of poor efficacy or adverse effects from a first-generation agent to either olanzapine, quetiapine, or risperidone, 60% had an adequate response and tolerated the new medication.[69] Little evidence supports switching from a second-generation agent to a first-generation agent in the event of a failed trial of a second-generation agent. In fact, in a systematic review of randomized controlled trials (RCTs) of ? 6 months' duration that compared relapse prevention with first- vs second-generation agents, a significant advantage was shown for risperidone, olanzapine, and sertindole compared with haloperidol.[70]

In most cases, the second medication trial will be with a second-generation agent. The choice of medication will depend on a patient's medical history and vulnerability to specific adverse effects such as weight gain, EPS, hyperglycemia, or dysrhythmia. In the randomized and double-blinded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), switching to second-generation antipsychotic agents occurred in three quarters of cases.[71] In an analysis of the time until treatment discontinuation for lack of efficacy, patients remained on olanzapine significantly longer than on quetiapine or risperidone; the difference with ziprasidone was not significant. Nonetheless, 64% of patients assigned to olanzapine discontinued it during the 18-month trial compared with 74% to 82% of patients assigned to the other medications. However, it should be noted that the mean modal dose of olanzapine (20.1 mg/day) was optimal for the chronic schizophrenia sample in CATIE, but the dose was less optimal for risperidone (3.9 mg/day), quetiapine (543 mg/day) and ziprasidone (113 mg/day), which underscores the importance of optimizing doses as discussed earlier in this article.

A study of 38 inpatients with rigorously defined treatment-resistant schizophrenia that involved 2 failed 6-week medication trials provides some perspective on the effects of a third trial of monotherapy. In randomized, double-blind fashion, the subjects received either risperidone, quetiapine, or fluphenazine. Discontinuations were significantly more common in the fluphenazine group (64%) than in the second-generation antipsychotic group (31%) and were largely due to lack of response.[72] These findings provide further evidence that treatment-resistant patients are unlikely to benefit from a first-generation agent; however, according to the investigators, the second-generation agents provided only "marginal improvements."

A meta-analysis of RCTs comparing olanzapine with first-generation agents in treatment-resistant schizophrenia and related disorders found a mean reduction in the BPRS score of 13%. This falls short of the 20%-30% reduction considered the standard for response.[45] The same analysis examined trials of clozapine compared with first-generation agents and found a mean BPRS reduction of 19%. The positive-symptom BPRS scores did not improve in the olanzapine trials, whereas they decreased by a mean of 15.6% in the clozapine trials. These data suggest that a third trial of any monotherapy other than clozapine would likely delay recovery. The results of phase 2 of the CATIE trial confirmed that patients who failed to respond to an atypical in phase 1 were more likely to respond to clozapine than to another first-line atypical.[73]

Pharmacologic Augmentation. After fully or partially failing a second medication trial, a patient is considered treatment resistant. At that point, the decision is whether to initiate a clozapine trial or to use another agent to augment the antipsychotic the patient is taking, which may have resulted in limited benefit. Apart from available evidence of efficacy, the decision depends on a number of individual factors, such as target symptoms, vulnerability to adverse effects, and patient preference.

If a patient has had a partial response to a medication with few adverse effects, augmenting with an agent that acts on a neurotransmitter other than dopamine can be justified. Lamotrigine is an anticonvulsant and mood stabilizer that affects glutamate neurotransmission. A randomized, placebo-controlled trial of 38 inpatients with treatment-resistant schizophrenia who were assigned to either a first- or a second-generation antipsychotic found a significant reduction in the mean total PANSS score and its positive-symptom subscale.[74] The mean scores on the total BPRS and the PANSS negative-symptom subscale showed no significant change. Whether the patient was taking a first- or second-generation agent (7 were on olanzapine, 3 on risperidone, 1 on clozapine) made no difference in outcome. These data corroborate a case series of adjunctive lamotrigine treatment with first- and second-generation agents,[75] indicating that it is well tolerated when gradually increased to doses of 50 mg to 400 mg per day.

Since some patients with chronic psychotic disorders have mood symptoms or cycling, and because GABA modulates dopamine activity in the central nervous system, clinicians may consider valproate to augment an antipsychotic. A rigorous review of the 5 available RCTs of valproic acid added to haloperidol, olanzapine, or risperidone found no significant reduction in overall psychopathology compared with placebo in trials of ? 12 weeks' duration.[76] The subjects in the trials had schizophrenia or schizoaffective disorder but were not necessarily treatment resistant. Two studies, however, have documented a specific improvement in hostility among patients with schizophrenia taking haloperidol, olanzapine, or risperidone and adjunctive valproic acid, an important finding requiring further research.[77]

The long-chain omega-3 and omega-6 polyunsaturated fatty acids are major constituents of the human brain. The predominant omega-3, docosahexaenoic acid, is found in cell membranes and plays a role in neurotransmission and enzyme regulation; it or its precursors must be obtained from the diet.[78] Evidence exists that the proportional amounts of long-chain polyunsaturated fatty acids and their precursors are abnormal in brains of people with schizophrenia compared with controls.[79] Clinical trials of omega-3 and omega-6 fatty acid supplementation in chronic psychosis lack uniformity in the specific kind of fatty acid administered and are of short duration. A Cochrane Library systematic review of RCTs of patients with schizophrenia and related disorders receiving both an omega-3 fatty acid supplement and an antipsychotic medication found short-term improvement on mean PANSS scores, but no evidence of long-term improvement.[80] In one positive short-term study, the participants were not necessarily treatment resistant at baseline, although they were symptomatic despite receiving antipsychotic treatment.[81] The reviewers concluded that although the supplements are well tolerated, omega-3 fatty acids should still be considered experimental for adjunctive treatment of schizophrenia.

Because there are cognitive deficits inherent in schizophrenia and some evidence of a decrease in muscarinic cholinergic receptors in the brain,[82] the adjunctive therapy of a cholinergic agent such as donepezil was studied. However, none of the 3 published RCTs of donepezil (administered at doses of 5 to 10 mg per day) demonstrated improvement in psychopathology or cognition.[83] In the largest study, patients received 10 mg/day, had significant positive and negative symptoms at baseline despite treatment with risperidone or olanzapine, but were not specifically identified as treatment refractory.[84] Hence, adjunctive donepezil should be low on the list of alternatives.

Clozapine. Clozapine is the only drug specifically indicated for treatment-resistant schizophrenia, and clinicians must consider it as a next step for the patient with an established resistance to treatment. A meta-analysis of RCTs confirmed its superiority in this patient population compared with other antipsychotics, both first- and second-generation.[45] Certain serious clinical conditions in schizophrenia are particularly responsive to clozapine, including persistent auditory hallucinations, persistent hostility, suicide risk, and tardive dyskinesia.[39] Drawbacks include the complications of weekly venipuncture during the first 6 months of treatment, then biweekly thereafter, to monitor for agranulocytosis, which affects 1% of patients. Other adverse effects include seizures, myocarditis, weight gain, and hyperglycemia, as well as early mortality from cardiovascular disease.[84]

Despite these perils, patients with schizophrenia taking clozapine may have better adherence to treatment than other patients because of improved functional status and more frequent contact with providers.[63] Some patients, however, do not have an adequate response to clozapine. As with other medications, adherence and pharmacokinetic matters must be addressed. If response is poor or if adverse effects are severe, it is important to check serum levels, which should be > 250 ng/mL.[85] Adjunctive strategies that have been tested and found safe and possibly effective include lamotrigine[86] and electroconvulsive therapy (ECT).[87]

Nonpharmacologic, Psychological, and Somatic Adjunctive Strategies

Psychotherapy. Psychosocial treatments are essential once acute psychotic symptoms are controlled with pharmacotherapy. These treatments include psychoeducation, social skills training, family therapy, and vocational rehabilitation. Certain manualized psychotherapeutic techniques have been well documented in depression and anxiety, such as cognitive-behavioral therapy (CBT), which has been shown to be a feasible intervention for patients with schizophrenia. A recent review succinctly described the evidence base and technique of CBT in schizophrenia, which differs from that used in depression.[88] Patients with persistent delusions are the most appropriate candidates for this type of intervention. Most studies have been conducted in the United Kingdom, and some have included patients identified as treatment resistant. However, a Cochrane Library review showed that the variability in study design and lack of long-term outcome data precluded definitive evidence of a benefit compared with other approaches at this time.[89]

A recently published pilot study of CBT in schizophrenia from the United States involved 38 patients who had "severe and persistent psychotic symptoms" after 3 months on antipsychotic medication.[90] The control condition was treatment as usual, but subjects were not randomly assigned to their treatments. Independent raters evaluated patients at baseline and at 6 months with standardized instruments. The CBT group had a significant mean reduction in total symptom severity and in delusions, and significant mean improvement in global psychosocial functioning compared with controls. With select patients and skilled clinicians, this therapy may be a beneficial approach to managing treatment-resistant schizophrenia.

Repetitive Transcranial Magnetic Stimulation (rTMS). rTMS at 1 Hertz applied once on consecutive days to the temporoparietal region may reduce auditory hallucinations.[91] Two randomized, double-blind, sham-controlled trials of treatment-refractory auditory hallucinations in patients with well-defined, treatment-resistant schizophrenia produced conflicting results. In one, investigators administered 10 actual or sham treatments to the left hemisphere of 30 patients, who remained on a stable dose of antipsychotic medication.[92] No significant improvement occurred in total mean PANSS score or its positive- or auditory-hallucination subscales among active-treatment patients compared with controls. In the other trial, involving 39 subjects, investigators randomized patients to receive 10 stimulations to the right or to the left temporoparietal region. The report did not indicate whether patients continued on antipsychotic medication. A significant improvement in the mean PANSS positive subscale score occurred in active-treatment patients, regardless of which hemisphere was stimulated, compared with controls.[93]

Most patients tolerate the treatment well; the most common adverse effects are headache and dizziness. Although not yet approved for treatment of schizophrenia by the US Food and Drug Administration or Health Canada, physicians may use rTMS off-label and in approved clinical trials. Select patients may benefit from rTMS, but before widespread application in treatment-resistant schizophrenia, further investigation of its efficacy is necessary.

Electroconvulsive Therapy. Treatment of schizophrenia with ECT was introduced in 1938. A review of studies of combined ECT and antipsychotics for schizophrenia did not necessarily address whether this approach is effective for treatment resistance.[87] The 8 controlled and blinded studies of nonclozapine combined treatment did not include well-defined treatment-resistant patients. These trials suggest the approach is most helpful in patients with a short duration of illness. The majority of studies were nonblinded, although some were randomized and controlled, and treatment resistance was not well defined. Most patients received a first-generation antipsychotic. The reviewers concluded that combination therapy is generally safe and is more effective than medication alone. Although solid research on its application in treatment-resistant schizophrenia is deficient, ECT has well-recognized efficacy in certain clinical situations, such as in patients with catatonia or severe depression.

Conclusions

The challenge of treatment-resistant schizophrenia continues despite the advent of a second-generation class of antipsychotics. The widespread off-label use of combination therapies of 2, 3, or even 4 antipsychotic drugs is an indication that many clinicians still encounter a substantial number of patients who do not adequately respond to the approved doses of antipsychotic medications. It is vital that patients be properly classified as treatment resistant by excluding many confounding factors that may impede clinical response and by ascertaining that treatment optimization is achieved before nonevidence-based interventions are implemented. Further research in treatment-resistant schizophrenia is clearly needed to address the needs of patients who remain substantially symptomatic and disabled even with the use of currently available antipsychotic agents. Many of the suggestions made in this article need further validation by controlled trials, and effective novel interventions are sorely needed to help persons afflicted with treatment-resistant schizophrenia.

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