Non occorre grande capacità di analisi per capire perché la psichiatria cominci ad essere letteralmente ossessionata dal problema delle resistenze ai trattamenti farmacologici. Questa ossessione, che permette di comprendere il numero di “ricercatori” che si dedicano al problema e i numerosi Congressi ad esso dedicati, ha due diversi aspetti.
Il primo è il “business”, mascherato al solito dal richiamo umanitaristico di non abbandonare a se stessi e alle loro sofferenze un numero rilevante di pazienti.
La depressione a livello mondiale è ormai già al quarto posto nella classifica dell’incidenza delle malattie e, secondo previsioni ragionevoli, nel giro di trenta anni è destinata a scalare questa triste hit parade collocandosi al secondo se non addirittura al primo posto. Si tratta di una previsione che non può non mobilitare l’interesse delle industrie farmaceutiche sia nel senso di proseguire l’affannosa ricerca di nuove sostanze chimiche attive sia in quello di mobilitare gli psichiatri ad utilizzare al massimo grado quelle esistenti. La miscela di psicofarmaci è l’unica dimensione “creativa” di questa ottusa, e quindi nefasta, categoria professionale.
Il secondo motivo, correlato al primo, è di ordine, per così dire, epistemologico. Avendo ricondotto tutte le depressioni nel quadro di una stessa malattia biochimica di origine genetica – il disturbo dell’umore -, la cui genesi coinvolgerebbe sostanzialmente la serotonina e le catecolamine, l’esperienza di un numero rilevante di depressioni che resistono ai trattamenti getta ovviamente un dubbio di grande portata sulla validità dell’ipotesi di base. O si ammette, infatti, che il disturbo dell’umore sia un insieme di diverse malattie con cause biochimiche diverse, o occorre pensare che l’approccio riduzionistico sia errato e che, accanto ai fattori biochimici, si debba tenere conto anche di quelli ambientali e psicodinamici.
È evidente che la psichiatria non può prendere in considerazione questa seconda ipotesi, che richiederebbe una ristrutturazione radicale del suo modello di riferimento biologista, con la prospettiva, di cui fornisco un resoconto in un altro articolo, di pervenire ad un modello integrato psicosomatico che richiede, esso sì, una notevole “creatività” per integrare i dati neurobiologici con quelli psicodinamici.
Ciò significa che il dogma della depressione come malattia biologica va mantenuto ad ogni costo, anche se la sua crescita epidemiologica negli ultimi due decenni e la previsione di una crescita esponenziale nei prossimi la dice lunga sull’incidenza dei fattori ambientali e culturali. Come noto, questo dato è stato interpretato nell’ottica neopsichiatrica dando luogo alla teoria della vulnerabilità costituzionale, che è, per la neopsichiatria, come il prezzemolo che essa sparge a piene mani per colmare lo scarto tra il riduzionismo biologico e i dati clinici.
La nuova teoria ammette l’incidenza dei fattori ambientali, ma ritiene che essi agiscano rivelando una vulnerabilità costituzionale allo stress, che nella popolazione sarebbe distribuita secondo uno spettro pressoché continuo. Se le richieste ambientali aumentano, come accade regolarmente nelle frenetiche società occidentali e in quelle che le seguono sulla via dello sviluppo illimitato, non c’è da sorprendersi che un numero sempre maggiore di persone manifestano disturbi dell’umore.
Non sono ovviamente tutti univocamente difettosi: lo sono in rapporto ad un determinato contesto sociale a determinate richieste dell’ambiente. Il fatto però che altri soggetti, esposti agli stessi fattori ambientali, riescano a mantenere una condizione di equilibrio psichico e psicosomatico, attesterebbe che la normalità comunque esiste.
La teoria della vulnerabilità è ideologicamente inattaccabile perché, data una società, se un numero anche minoritario di persone realizzano un adattamento, questa rappresenta la prova che l’ambiente non è patogeno in sé e per sé. Per essere giudicato tale, infatti, un contesto socioculturale dovrebbe produrre sintomi in tutta la popolazione.
Numerose prove attestano che le società occidentali stanno procedendo in questa direzione. L’obbiettivo, ottimale per le case farmaceutiche, per quanto esso invaliderebbe l’ipotesi biologi sta e la teoria della vulnerabilità, non potrà presumibilmente essere raggiunto. Questa previsione non si basa sulla reificazione di una presunta normalità, che comporterebbe l’adattamento a qualsivoglia ambiente, bensì su di una valutazione più attenta della personalità di coloro che non sviluppano sintomi. Si tratta, infatti, come già rilevato da Fromm, di soggetti integrati nel sistema, il cui equilibrio si fonda sulla messa in atto di meccanismi difensivi che isolano il livello cognitivo da quello emozionale: soggetti, dunque, letteralmente anestetizzati, che vivono come macchine che perseguono gli obbiettivi prescritti dal sistema stesso (status, successo, ricchezza, ecc.).
E’ oltremodo difficile, nonché logorante, opporre ragioni critiche ad un’ideologia – quella neopsichiatrica – che si pone come totalizzante. Nell’immediato sembra addirittura inutile, poiché i numerosi Congressi dedicati alla depressione riecheggiano, per alcuni aspetti, i Concili della Chiesa dei primi secoli, laddove si dibatteva accanitamente su dispute teologiche che riconoscevano però come dato certo e inconfutabile che il Figlio di Dio si era incarnato.
Nei Congressi di psichiatria si parte dal presupposto che la depressione esiste come malattia biologica, una volta che siano stati soddisfatti i criteri diagnostici del DSM-IV, e, mettendo del tutto da parte l’esperienza di coloro che ne soffrono, se ne dibatte sulla base di statistiche, risposte al trattamento farmacologico e via dicendo. I partecipanti, forse, sono convinti di stare mettendo a fuoco le strategie opportune per fronteggiare quella che sembra destinata, dopo vari vaticini, a diventare veramente la malattia del secolo. Il problema è che, non adottando un criterio psicodinamico e funzionalistico, che dà alle espressioni della depressione un significato notevolmente diversificato, e riconducendosi agli schemi nosografici che mortificano tale diversità per avallare il criterio sindromico, ciò di cui si parla, infine, è aria fritta.
Nulla può esemplificare meglio questo discorso del dibattito attualmente in corso sulle depressioni resistenti. Ho già dedicato a tale argomento due articoli. Torno sul tema perché esso è di grande attualità e rivela, quanti altri mai, il vicolo cieco nel quale si trova la psichiatria. Prendo spunto da una serie di articoli pubblicati su Medscape, prodotti in occasione del 160th Annual Meeting of the American Psychiatric Association in San Diego, California, che aggiornano lo stato dell’arte in rapporto al problema della resistenza della depressione agli psicofarmaci.
E’ superfluo rilevare che l’APA, i cui ambigui rapporti con le industrie farmaceutiche sono stati denunciati più volte, è la corporazione psichiatrica più potente al mondo, quella che, a partire dalla pubblicazione del DSM, detta le linee della teoria e della pratica psichiatrica in tutto il mondo.
Ho rilevato in corsivo i punti che ritengo importanti ai fini della discussione.
Intanto occorre sottolineare che, nonostante se ne parli già da venti anni (da quando cioè – e non è un caso – la nosografia psichiatrica ha ricondotto nell’ambito dei disturbi dell’umore le forme che, essendo considerate in precedenza “psiconevrotiche”, erano ritenute tradizionalmente poco o punto sensibili alle cure farmacologiche), il cosiddetto TRD (treatment-refractory depression) appare ancora lontano da una quantificazione univoca. Le statistiche, infatti, oscillano da ricerca a ricerca, anche se è del tutto evidente che la minimizzazione del fenomeno, valutato venti anni fa intorno al 20%, sta cedendo il passo ad una valutazione più realistica che fa lievitare le percentuali dal 30 al 70%.
Le fluttuazioni nella quantificazione della TRD sono dovute ai diversi criteri con cui si valuta l’efficacia degli antidepressivi. Se essa, infatti, viene ricondotta solo ai casi in cui non si dà risposta alcuna ai vari trattamenti o una risposta minima, la percentuale si attesta intorno al 30%. Se, viceversa, si fanno rientrare nella TRD anche le esperienze di coloro che traggono vantaggio dalle cure farmacologiche rimanendo però affetti da una sintomatologia residua incentrata sull’anedonia, estremamente penosa soggettivamente, ma che non impedisce loro di vivere in modo apparentemente normale, la percentuale si eleva di molto.
E’ evidente che la psichiatria ha tutto l’interesse di limitare la TRD ad un’assenza di risposta al trattamento. Se dovesse, infatti, considerare le esperienze con una residua anedonia, la conclusione sarebbe che gli psicofarmaci sono complessivamente poco efficaci.
Comunque, come ho previsto negli articoli precedenti, i dati di realtà a lungo andare hanno la meglio sulla propaganda. Non più di dieci anni fa, la psichiatria attribuiva agli antidepressivi il potere di guarire l’80% dei disturbi dell’umore; adesso, con una valutazione che, secondo me è ancora per difetto, essa riconosce che non più del 50% dei pazienti hanno consistenti vantaggi.
Sulla base di questa presa d’atto imposta dai fatti, è possibile formulare una previsione che difficilmente sarà smentita. Prima o poi, qualcuno (come è già accaduto per la schizofrenia) proporrà l’esistenza di due forme di depressione. Per le sigle non c’è problema perché la psichiatria dimostra a riguardo una notevole, ancorché sterile, “creatività”. Volendo anticipare i tempi, si può prevedere che si distinguerà una TRD 1 (treatment-responsive depression) e una TRD 2 (treatment-refractory depression). Tra questi due estremi sarà possibile inserire lo spettro di risposte estremamente variabili che affiora dalla pratica clinica.
E’ ovvio anche prevedere che il postulato di fondo – quello per cui il disturbo dell’umore in tutte le sue forme, è comunque una malattia del cervello - non cambierà, almeno finché non sopravverrà una rivoluzione culturale atta a rinnovare profondamente l’interpretazione dei fenomeni psicopatologici.
Questa prospettiva è molto lontana. Nella recensione di Psiche, Dizionario critico di psicologia, psichiatria, psicoanalisi, neuroscienze, ho segnalato la resa sostanziale di colleghi che ritengo validi al pensiero psichiatrico in nome del riconoscimento del fatto che la psicoanalisi ha troppo insistito sulla psicogenesi per opporre resistenza ai dati affiorati negli ultimi anni nell’ambito delle neuroscienze. Ritengo tale resa del tutto ingiustificata. Primo, perché il superamento dell’ingenuo approccio psicogenetico va realizzato nella direzione di un modello psicosomatico (e non comunque somatopsichico), che riesca a dar conto dell’interazione tra fattori biologici e fattori psicodinamici così come essa può essere ricostruita attraverso un assiduo rapporto con soggetti depressi che non ceda alla mistificazione per cui essi stessi “preferiscono” ritenersi “malati”. Secondo, perché la TRD, la cui resistenza al trattamento farmacologico implica una prevalenza dei fattori psicodinamici (per esempio, un bisogno inconscio di soffrire che inattiva l’effetto dei farmaci), dimostra che il superamento della tradizione cui ho fatto cenno, la quale dava per scontato che gran parte delle depressioni nevrotiche era insensibile ai farmaci, non è stata felice.
Se l’obbiettivo implicito nel ricondurre tutte le depressioni ad una malattia biologica era di dimostrare che esse possono essere curate anche solo con i farmaci, tale obbiettivo è fallito. La TRD è la prova più evidente di tale fallimento. Anche assumendo la valutazione media del fenomeno, intorno al 50% dei pazienti, è evidente che una percentuale del genere getta una luce di incredibilità sulle ipotesi eziologiche avanzate dalla psichiatria.
Non meno importante, peraltro, è la sintomatologia anedonica che residua in molti pazienti che rispondono al trattamento con antidepressivi recuperando il sonno, l’appetito, il tono psicofisico, la capacità di svolgere i doveri quotidiani, ma non la partecipazione emotiva e il gusto della vita. Basta parlare con essi per rendersi conto che se ammettono di essere migliorati e sono confortati dal fatto che gli altri li vedono restituiti alla normalità (dato che la vergogna di essere depressi è un vissuto angoscioso), non ritengono di essere guariti. Di fatto, non lo sono.
Tranne che in un numero ridotto di esperienze, che presumibilmente evolverebbero spontaneamente verso la guarigione, i farmaci disattivano le espressioni psicosomatiche della depressione (quelli che un tempo venivano considerati sintomi di “vitalizzazione”: insonnia, inappetenza, astenia, inibizione intellettiva, ecc.), ma non incide sulle dinamiche sottostanti. Essi, dunque, hanno un potere incisivo sui sintomi, non su di una malattia che non esiste se non nella mente degli psichiatri.
Si può essere d’accordo sul fatto che, laddove un disagio psichico assume una configurazione sociologica, coinvolgendo un numero crescente di pazienti, esso richiede anche una valutazione statistica. Tale valutazione, ovviamente, eccede l’osservatorio di cui dispone ogni psichiatra o psicoterapeuta che agisce sul campo.
Se però l’approccio statistico si fonda sul rilievo dei soli sintomi ritenuti essenziali per definire una sindrome, assunti come espressione di un identico disturbo di fondo che si manifesta in varie forme, si entra nell’ambito dell’oggettivazione della condizione umana. In breve, posto che un soggetto manifesti sintomi che rientrano nell’ambito della sindrome, esso scompare nella sua concreta esperienza umana. Al suo posto c’è la malattia di cui è affetto, che la psichiatria isola come fatto dal contesto della sua vita.
Ci si può chiedere se si dia un’alternativa a questa pratica oggettivante che ritiene di portare la psichiatria dalla confusione delle singole storie ricostruite in sede analitica, con l’uso di strumenti interpretativi molteplici e arbitrari, alla chiarezza cartesiana della malattia come fatto empirico.
L’alternativa esiste, ed è stata al centro della mia ricerca. La varietà delle esperienze soggettive può portare facilmente a concepire l’esistenza di una malattia del cervello allorché esse giungono ad esprimere gli stessi sintomi, vissuti e comportamenti. Questo però dipende dall’influenza del paradigma medico sulla psichiatria.
In medicina è ovvio che una malattia – per esempio una broncopolmonite -, posto che riconosca lo stesso fattore causale, ha manifestazioni sintomatiche più o meno costanti che, in larga misura, sono indipendenti dall’esperienza personale.
Applicare questo modello ai fenomeni psicopatologici, però, trascura un dato di estrema importanza. Se si ammette, infatti, che i conflitti dinamici sottostanti hanno una struttura costante, in quanto riconducibile alla scissione dei bisogni intrinseci e delle funzioni che si edificano su di essi, non ci si sorprende che le loro espressioni rappresentino una sorta di via finale comune delle esperienze soggettiva. Tale via finale comune rappresenta un tentativo che la mente opera, solitamente a livello inconscio, di risolvere i problemi cui fanno riferimento i conflitti. Le difese adottate spontaneamente dall’inconscio sono ovviamente inadeguate: esse richiedono di essere decifrate come indizi di problemi che il soggetto deve risolvere sulla base della riflessione sulla sua vicenda. In difetto di questa consapevolezza, la coscienza interagisce con i sintomi interpretandoli in maniera disastrosa, per esempio ricavando dallo stato attuale una previsione di fine della vita che si estende a tutto l’orizzonte futuro: previsione classicamente erronea, dato che le depressioni hanno di solito una natura episodica.
Il punto di vista dinamico e strutturale può spiegare, con un’eleganza molto maggiore rispetto a quello nosografico, il mistero della varietà delle esperienze soggettive che si trasforma nell’invarianza dei sintomi, dei vissuti e dei comportamenti.
Esso non ha neppure difficoltà a spiegare la quota di depressioni refrattarie ai trattamenti farmacologici. In alcuni casi, infatti, è in gioco un bisogno inconscio di soffrire che nessuna medicina riesce a modificare in quanto corrisponde a esigenze intrinseche di una determinata personalità governata, inconsciamente dai sensi di colpa. In altri casi, le inibizioni funzionali prodotte dalla depressione sono mirate a disattivare un rapporto con la realtà giunto a configurarsi come troppo doloroso o problematico o ad impedire l’esplosione “maniacale” dei bisogni frustrati.
Il punto di vista struttural-dialettico e quello nosografico sono dunque antitetici: questo vede nei sintomi solo l’espressione di una malattia del cervello, quello li assume come indiziari al tempo stesso di problemi da risolvere e di difese contro il carattere emotivamente critico assunto da tali problemi a livello inconscio: in breve, come un tentativo maldestro della mente di “guarire” in difetto della consapevolezza soggettiva dei problemi in questione.
Non vedo quale altro approccio possa contrapporsi alla sterile egemonia della neopsichiatria se non quello che riprende e approfondisce il punto di vista che, in passato, è stato definito antipsichiatrico. Certo, oggi la psicodinamica non può trascurare i dati forniti dalla neurobiologia. Posto però che essi non sono affatto rivoluzionari se non per chi ha ritenuto che la sofferenza psicologica non coincidesse con un coinvolgimento cerebrale, essi, come ho cercato di argomentare altrove, possono essere interpretati in maniera meno enfatica e più coerente adottando un modello psicosomatico che uno riduzionista.
Augmentation/Combination Therapy in the STAR*D Trial CME/CE
Maurizio Fava, MD Jennifer M. Covino, MPA
According to the Global Burden of Disease Study, the public health implications of depression are vast; depression currently ranks as the 4th leading global disease burden and is projected to rise to the number 2 disease burden worldwide in 2020, second only to ischemic heart disease. Antidepressants are the mainstay of treatment for depression and depressive episodes; however, these treatments are often incomplete or inadequate. Indeed, approximately 2 million individuals in the United States will experience an inadequate response to treatment for depression during their lives. Clinicians are therefore presented with the challenge of tailoring and adjusting treatments to the individual patient, as they work to find the best matched treatment to not only achieve, but also to sustain remission.
In an effort to provide relief to those suffering from such a debilitating illness, clinicians rely on a variety of augmentation and combination strategies. New research presented at the 160th Annual Meeting of the American Psychiatric Association in San Diego, California, examined many of these strategies with a major focus on the recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.
Treatment-Refractory Depression and STAR*D
The definition of treatment-refractory depression (TRD) is the subject of debate. TRD is described variously as depression that does not remit with 1 or more adequate antidepressant trials, or 2 or more acute treatment trials; or failure to respond to 4 or more different antidepressant approaches including augmentation, combination, and electroconvulsive therapy (ECT). TRD can be related to a variety of factors including poor efficacy, intolerable adverse effects, drug-drug interactions, comorbid medical illness, and nonadherence.
When considering the treatment of depression, one important limiting factor is the paucity of literature surrounding TRD, which is further complicated because published studies often have excluded many of the 'sickest' patients, precisely the patients that most clinicians face in daily practice. The STAR*D study was designed to conduct research that mirrored clinical practice, providing options to patients seeking treatments as they moved through each step of the trial.
The STAR*D project enrolled 4041 patients with a broad range of symptoms and severity from 25 participating sites. The study involved 4 possible 'steps' for treatment, and any patient who failed to meet remission criteria at each step was then asked to move to the next level. Of note, the study revealed what is often seen in clinical practice; patients tended to choose an option based on their experiences with the initial antidepressant. If they experienced a partial response, they chose augmentation; if they were not responding, they preferred to switch, and so forth.
Level 1: The first treatment level consisted of citalopram at maximally tolerated doses titrated as quickly as could be achieved (dropout rate was approximately 8%). Patients were encouraged to continue the treatment for up to 12 weeks. A total of 3671 patients participated in level 1 treatment with citalopram monotherapy.
Level 2: After 12 weeks, if patients failed to reach remission in level 1, they were randomized to the next level, depending on their preference to switch to a different medication (bupropion SR, N = 239; sertraline, N = 238; or venlafaxine XR, N = 250), switch to cognitive therapy (N = 62), augment citalopram with another medication (bupropion SR, N = 279; or buspirone, N = 286), or augment citalopram with cognitive therapy (N = 85). Participants who chose to switch to or augment with cognitive therapy were randomized separately.
Level 3: Participants who did not achieve remission after 12 weeks in level 2 were randomized to: switch to mirtazapine (N = 110); switch to nortriptyline (N = 116); or augment level 2 treatment with lithium (N = 63) or thyroid medication (N = 70).
Level 4: To remain in the study, patients who did not achieve remission after 12 weeks in level 3 were required to switch to the nonhydrazine monoamine oxidase inhibitor, tranylcypromine (N = 55); or switch to a combination of venlafaxine XR and mirtazapine (N = 50).
This study used 3 methods of evaluation: HAM-D scales administered over the phone (single-blind) by those who did not know which treatment a patient was receiving; interactive voice response (IVR) system and self-reports with pencil; and paper Quick Inventory of Depressive Symptoms -- self-report (QIDS) scale.
Augmentation and Combination in STAR*D
For purposes of this report, we will focus on the pharmacologic augmentation and combination results of those who remained on pharmacotherapy throughout the study.
Level 2: Augmentation With Bupropion SR and Buspirone
Alan Schatzberg, MD, Professor of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, discussed some of the advantages and disadvantages of both bupropion SR and buspirone augmentation. First, Dr. Schatzberg noted that one advantage of bupropion SR is that it may assist with the treatment of SSRI-induced sexual dysfunction; but a disadvantage is that we lack double-blind placebo-controlled trials of bupropion, and the metabolism of this agent can inhibit metabolism of some SSRIs. By contrast, buspirone monotherapy has been studied in 5 double-blind trials with the composite data set showing efficacy; moreover, several open label trials have shown buspirone to be a useful augmentation agent. The largest disadvantage of buspirone augmentation is that this agent has generally failed in double-blind studies of refractory depression.
Dr. Schatzberg, specifically discussed the resulting data from the STAR*D level 2 treatment arm that involved augmentation with sustained release bupropion (up to 400 mg/day; N = 279) or buspirone (up to 60 mg/day; N = 286). Remission rates based on the Hamilton Rating Scale for Depression (HRSD-17) were 29.7% for bupropion and 30.1% for buspirone. Remission rates based on QIDS-SR-16 were 39.0% for bupropion and 32.9% for buspirone.
Trivedi and colleagues evaluated the use of bupropion and buspirone in the STAR*D study and found that bupropion led to greater reduction in the number and severity of symptoms, with fewer side effects and adverse events. In this analysis, the group that received sustained-release bupropion demonstrated greater reductions in QIDS-SR-16 scores than buspirone (25.3% vs 17.1% from baseline, P < .04); a lower QIDS-SR-16 score (8.0 vs 9.1, P < .02); and lower dropout rates related to intolerance (12.5% vs 20.6%, P < .009).
Level 3: Lithium and Triiodothyronine Augmentation
Dr. Schatzberg also discussed lithium and thyroid augmentation. He began by summarizing the highlights of the literature on lithium. At least 50 trials have used lithium as an augmentation agent and yielded mostly positive results; these studies have most frequently used lithium in conjunction with tricyclic antidepressants; levels of 0.4 mg to 0.6 mg are often effective; there is a low therapeutic index; and patients sometimes require monitoring of thyroid and renal function, an additional burden. With regard to augmentation with thyroid hormone, there have been at least 25 mostly positive trials; studies have indicated that thyroid augmentation may help with energy and weight; it is well tolerated when compared with lithium; it may work less well in men; it can cause bone demineralization; and thyroid levels must be monitored, adding a burden to patients.
Timothy Petersen, PhD, Assistant Professor of Psychiatry at Harvard Medical School in Cambridge, Massachusetts, summarized the level 3 augmentation options of either lithium (N = 69) or T3 (N = 73). Based on HRSD-17, remission rates were 15.9% for lithium and 24.7% for T3; based on the QIDS-SR-16, remission rates were 13.2% for lithium and 24.7% for T3. These results indicate that failure to achieve response or remission at level 2 (bupropion SR or buspirone) predicts lower response/remission rates at level 3. Despite the low numbers, a limited number of patients will experience benefit with lithium or T3, indicating that using all available options is sometimes necessary because we currently cannot predict who might respond to which medication and/or augmentation strategy.
STAR*D Augmentation/Combination Summary
Dr. Petersen concluded that when one looks at the STAR*D, data pertaining to remission based on the augmentation/combination trials (levels 2-4), one sees that remission rates drop from 35% at level 2 to 19% at level 3 and 16% at level 4, which, according to Dr. Petersen, indicates that failure to achieve remission with one agent at level 1 does not substantially reduce the chances of remission with a next-step augmentation trial. However, failure to achieve remission with 2 consecutive treatments is associated with very low remission rates with subsequent treatments. Dr. Shatzberg concluded that although remission rates were relatively low in all phases, buspirone, bupropion SR, and thyroid appear to offer considerable benefit. He also noted that low remission rates across all trials indicate that many patients still require additional treatment.
The STAR*D trial was designed to mirror the methods clinicians use in practice, and the results of this large multicenter trial mirror what many clinicians have seen for years -- challenges in understanding and deciding upon the best treatment options for the individual patient in an effort to achieve and maintain response with the ultimate goal of remission. STAR*D shows that, as additional augmentation/combination strategies are used, the response and remission rates of patients decreased; however, a small population of patients did respond and/or remit with these additional strategies. Thus, clinicians must use an array of pharmacotherapies as they work to alleviate depression in patients through what becomes an individualized 'trial and error' mechanism. Of importance, the STAR*D study also highlights that despite our best efforts, and given our current treatment options, a vast number of individuals remain without relief from their depression. Clearly further research is warranted as we work to understand the underlying causes of depression and best treatment modalities for individuals suffering from this illness.
Switching Treatments Following Nonresponse to an Initial Antidepressant: Summary of STAR*D Level 2 Findings CME/CE
Michael E. Thase, MD
A large number of effective treatments are available for major depressive disorder yet, aside from electroconvulsive therapy (which is generally reserved for use with only the most severely ill or difficult-to-treat), only about one-half of those who begin a course of antidepressant medication or depression-focused time-limited psychotherapy, will respond to the initial course of treatment. Moreover, remission rates following 8 to 12 weeks of treatment with first-line antidepressants typically hover around 33% in controlled clinical trials.[1,2] Response without remission, in turn, is not an acceptable response because of high rates of relapse,[3,4] persistent psychosocial disability, and impairments of health and quality of life. Thus, the decision to begin a course of antidepressant therapy for depression clearly carries with it the obligation to monitor outcomes closely and, as often as not, the need to change to alternate therapies in a timely manner for those who do not respond or do not remit fully.
Commonly used second-step treatment options for depressed outpatients include various add-on or augmentation strategies and switching strategies. For additional background, the interested reader may wish to read more recent narrative and quantitative reviews. A number of switching and augmenting/combining treatment options were studied at length in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project, a large, multicenter, multistage investigation sponsored by the National Institute of Mental Health. The results of the augmentation and combination approaches in STAR*D are discussed here by Maurizio Fava, MD, and Jennifer M. Covino, MPA.[9,10] The results of the STAR*D level 2 switching strategies were discussed at an industry-sponsored symposiom "Insights from STAR*D: Are Our Patients' Needs Being Met?" at the 2007 American Psychiatric Association Meeting.
Switching Antidepressants: The STAR*D Experience
In an era in which the selective serotonin reuptake inhibitors (SSRIs) are widely considered to be the first-line antidepressants of choice, the first decision clinicians usually must face following SSRI nonresponse is whether to switch 'within' the class or to switch to a different type of antidepressant. For clinicians in the United States, the most widely prescribed non-SSRI antidepressants are bupropion, a dopamine-norepinephrine reuptake inhibitor (NDRI), and the 2 serotonin-norepinephrine reuptake inhibitors (SNRIs), venlafaxine and duloxetine. Outside the United States, the tricyclic antidepressants, which are predominantly norepinephrine reuptake inhibitors, and the tetracyclic compound mirtazapine -- which is not a monoamine reuptake inhibitor but enhances serotonin and norepinephrine neurotransmission via other receptor effects -- also are still widely used for SSRI nonresponders. These options were reserved for the more advanced levels of treatment resistance in STAR*D.
The investigators who designed the STAR*D study wanted to prospectively document the treatment course, in part to ensure that each patient who was said to be an antidepressant nonresponder had actually received an adequate course of antidepressant therapy. Citalopram was chosen as the first course of therapy in STAR*D (level 1) for several reasons. Citalopram was (and still is) a 'perfectly good' SSRI and, because it was one of the first members of this class to lose patent protection in the United States, the STAR*D investigators correctly anticipated that insurance benefit providers and managed care pharmacy formularies would eventually favor the less expensive generic compounds over 'branded' compounds, unless there were clear-cut differences in efficacy and/or tolerability. Beyond this economic factor, citalopram has little effect on the hepatic cytochrome P450 isoenzymes involved in drug-drug interactions and a good track record of use in late-life depressive disorders, all of which were advantages, considering the wide age range and medical complexity of the STAR*D patient population. Last, because citalopram was prescribed less frequently than fluoxetine, sertraline, and paroxetine when the study was conceived in 2000, fewer potential study participants would have to be excluded from the first phase of the study because of past treatment experiences with the study medication. To ensure that the initial treatment trial was indeed adequate in dose and duration, citalopram therapy could be titrated to a maximum daily dose of 60 mg if tolerated and the trial could extend for up to 12 weeks. As reported by Trivedi and colleagues, approximately 50% of the more than 2800 patients who received an adequate course of citalopram therapy responded -- as defined by a 50% reduction in Hamilton Rating Scale for Depression (HAM-D) scores -- and roughly 60% of the responders had remitted by the end of the initial course of acute phase therapy.
Approximately 60% of the 1100+ outpatients who entered STAR*D level 2 opted for switch strategies. Patients who only accepted medication switches tended to have experienced more side effects during the initial course of citalopram therapy and had higher symptom levels than patients who opted only for augmentation options. The switch options employed in STAR*D level 2 included sertraline, bupropion SR, and venlafaxine ER. The rationale for selecting these particular medications is that all 3 were in wide use when the study was designed and they permitted several clinically meaningful options: sertraline represented a switch within the SSRI class, bupropion SR was the most widely prescribed 'nonserotoninergic' antidepressant, and venlafaxine was the only member of the SNRI class at the time that the study was undertaken. Venlafaxine also was the most extensively studied newer antidepressant for treatment-refractory depression at the time and there was some evidence from randomized controlled trials that it may have greater therapeutic efficacy than the SSRIs.
Level 2 therapies were randomly assigned and administered 'open label' (both doctors and their patients knew which treatments were being prescribed). The primary measure of efficacy -- the HAM-D -- was administered by telephone by a centralized group of independent clinical evaluators without knowledge of the treatment assignment. Again, the study design permitted treatment in level 2 for up to 12 weeks; and all 3 antidepressants could be titrated to maximum approved therapeutic doses.
Rush and colleagues reported results of the level 2 medication switch study. Overall, there were no statistically significant differences in efficacy of the 3 medications on any of the continuous or categorical measures of outcome. Remission rates (a final HAM-D score of 7 or less) were relatively low: approximately 18% for sertraline; 21% for bupropion SR; and 25% for venlafaxine XR. The 3 medications also were comparably well tolerated in terms of the incidence of side effects and attrition rates.
Interpreting the Results
When looking across levels, the response and remission rates of the 600+ patients who participated in the second medication trial were not quite as high as in the initial course of citalopram therapy. This 'therapeutic decrement' no doubt reflects patients who were at level 2 because their depression was more difficult-to-treat or treatment-refractory than the cohort that began the initial course of therapy, and probably results from the declining impact of placebo-expectancy factors across sequential courses of therapy. Even greater drop-offs in remission rates were observed in the level 3 and level 4 treatment trials.
One might argue that the magnitude of the numeric difference in remission rates between the groups treated with venlafaxine XR and sertraline is comparable to those reported by Thase and colleagues in a meta-analysis of individual patient data from 8 randomized controlled trials comparing the SNRI with SSRIs and that the lack of statistical significance in STAR*D is what is called a type II error (a 'false negative' conclusion resulting from insufficient statistical power). Indeed, that analysis reported an effect size for the SNRI vs SSRI difference -- calculated as an odds ratio -- of 1.52, compared with 1.50 in STAR*D. With respect to the 2 previous comparisons of SSRI vs venlafaxine in patients who had not responded to previous treatment with antidepressants, the difference in remission rates observed in STAR*D is much smaller than reported by Poirer and LeBoyer but comparable to that observed by Baldomero and colleagues. Of note, as with the STAR*D study, the Baldomero study was a very large, multicenter outpatient trial that employed random assignment but open-label administration of medication. By contrast, the trial by Poirer and Boyer was a smaller double blind study conducted in inpatient and partial hospital settings. From this, one might speculate that the overall advantage for the SNRI over a second SSRI may be small in an unselected population of SSRI nonresponders, but larger among patients with more severe depressive symptoms.
The intermediate performance of bupropion SR following nonresponse to citalopram was less surprising. Numerous double-blind, head-to-head trials have shown that the NDRI provides efficacy comparable to the SSRIs. Likewise, bupropion and venlafaxine were reported to have comparable overall efficacy in the 2 previous head-to-head studies in the published literature, including 1 study of bipolar depression and 1 study of a somewhat younger group of sexually active depressed outpatients. The apparent absence of significant differences in sexual side effects observed in STAR*D is curious, as this is a consistent advantage for the NDRI in controlled studies vs both SSRIs and venlafaxine. The most parsimonious explanation is that the method used for side effect reporting in STAR*D may not have been sufficiently sensitive to detect differences in sexual activity or behavior. Additional, more finely grained analyses of the STAR*D data set also will be needed to determine whether bupropion and sertraline were differentially effective in subsets of patients with anergia and reverse neurovegetative features or pronounced anxiety. One might think that the NDRI may have an advantage for the former symptom cluster, with the SSRI favored for the latter group.
Disappointments and Challenges
One disappointment of the STAR*D trial was that too few patients accepted randomization to either the switch or augmentation arms of the study to permit a meaningful comparison of outcomes across the full range of Level 2 options. In particular, the field needs empirical evidence gauging the efficacy of switching antidepressants versus combining medications. Looking across the switch and augmentation arms of STAR*D,[16,21] there appears to be a modest advantage favoring the combination of citalopram and bupropion over switching to either venlafaxine or bupropion as monotherapies. However, as the large majority of patients in each arm were not at equipoise for randomization, and because there were a number of differences in clinical and treatment characteristics, this comparison is likely to be subject to bias.
In summary, results of the STAR*D level 2 switching study challenge widely held clinical beliefs about selection of antidepressants following nonresponse to an initial course of antidepressant medications. Remission rates were relatively low in all 3 medication switch arms and the observed differences among the 3 switch options -- sertraline, bupropion SR, and venlafaxine XR -- were small and below the threshold of statistical significance. Although it is possible that there are larger advantages for switching across classes of antidepressants for some subgroups of SSRI nonresponders, results also supported the use of the within-class switch option.
Augmentation/Combination Strategies for Residual Symptoms of Treatment Refractory Depression CME/CE
Maurizio Fava, MD Jennifer M. Covino, MPA
As researchers work to uncover new treatment approaches through advances in neuroimaging techniques and the use of genetic information, clinicians continue to use an array of pharmacologic treatments to alleviate symptoms of depression. Despite advances in our understanding of pharmacotherapy and the ongoing development of new agents, reported remission rates in clinical trials remain low, varying from 30% to 50%. Thus, many individuals are left without relief or only partial relief from this debilitating illness.
The definition of treatment-refractory depression (TRD) remains a hot issue. TRD has been described as depression that does not remit with 1 or more adequate antidepressant trials, or 2 or more acute treatment trials; or failure to respond to 4 or more trials of different antidepressant therapies including augmentation, combination, and electroconvulsive therapy (ECT).
Given the desire to maximize outcome based on current treatment options, clinicians have turned to a variety of augmentation and combination strategies. Research presented at the 160th Annual Meeting of the American Psychiatric Association in San Diego, California, on May 19th-24th, focused on several such strategies.
Maurizio Fava, MD, Professor of Psychiatry at Harvard Medical School, Cambridge, Massachusetts, presented data on the use of augmentation and combination strategies. Dr. Fava highlighted a number of factors that contribute to lower remission rates with antidepressant monotherapy. In addition to nonresponders and those who are unable to tolerate treatment, many 'responders' experience residual symptoms (including problems with mood, interest, weight, sleep, psychomotor slowing, fatigue, guilt, concentration, and suicidal ideation) and cognitive symptoms (including difficulties with focus, recall, word-finding, and mental activity). Moreover, psychiatric comorbidity (eg, substance abuse, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, post-traumatic stress disorder), medical comorbidity (eg, hypothyroidism), depressive subtypes (eg, anxious, melancholic, lethargic), worsening symptoms, and adverse events can hinder patient recovery and require the use of augmentation and combination strategies.
Dr. Fava specifically looked at strategies targeting melancholic/severe depression; anxious depression; depression with fatigue and/or sleepiness; and depression with insomnia (Table 1).
Table 1. Treatment Options According to Depression TypeDepression Type/Subtype Treatment Options
Melancholic/severe depression SSRI plus NRI (eg, SNRI)
Mirtazapine plus SSRI or SNRI
Atypical antipsychotic augmentation
Anxious depression SSRI plus NRI (eg, SNRI)
Buspirone/pindolol plus SSRIs
Atypical antipsychotic augmentation
Depression with fatigue and/or sleepiness Modafinil augmentation
Bupropion plus SSRIs or SNRIs
SSRI plus NRI (eg, SNRI)
SAMe* or methylfolate augmentation
Depression with insomnia Eszopiclone or zolpidem augmentation
Trazodone plus SSRIs or SNRIs
Mirtazapine plus SSRIs or SNRIs
TCAs plus SSRIs
SSRI = selective serotonin reuptake inhibitor; NRI = norepinephrine reuptake inhibitor; SNRI = selective norepinephrine reuptake inhibitor; SAMe = S-adenosyl-L-methionine; TCA = tricyclic antidepressant; *not approved by US Food and Drug Administration
Depression With Fatigue and/or Sleepiness
Fatigue and/or sleepiness is a frequent complaint of patients suffering from depression. As noted, suggested augmentation/combination strategies include: modafinil augmentation; bupropion plus selective serotonin reuptake inhibitors (SSRIs) or selective norepinephrine reuptake inhibitors (SNRIs); psychostimulant augmentation; SSRI plus norepinephrine reuptake inhibitor (NRI; eg, SNRI); S-adenosyl-L-methionine (SAMe) or methylfolate augmentation; and thyroid augmentation.
Fava and colleagues examined the efficacy of modafinil augmentation in patients receiving SSRI treatment who continued to suffer from major depressive disorder (MDD) along with symptoms of fatigue and excessive sleepiness. In this 8-week study, 311 patients (18-65 years; DSM-IV diagnosis of MDD; partial response to SSRI monotherapy [8 weeks or longer]; baseline 31-item Hamilton Rating Scale for Depression [HAM-D] scores of 14 to 26, Epworth Sleepiness Scale [ESS] scores ≥ 10, and Fatigue Severity Scale [FSS] scores ≥ 4) were randomly assigned to augmentation with 200 mg of modafinil daily (N = 158) or to placebo (N = 153). Assessments included the ESS, Clinical Global Impressions-Improvement scale (CGI-I), 31- and 17-item HAM-D, FSS, Brief Fatigue Inventory (BFI), and Montgomery-Asberg Depression Rating Scale (MADRS). Based on their final visit, the group assigned to the modafinil augmentation treatment showed significant improvements in overall clinical condition compared with placebo (based on CGI-I scores; P = .02), with trends toward greater mean reductions in ESS, 31- and 17-item HAM-D, and MADRS scores vs placebo. In addition, modafinil significantly reduced BFI scores for worst fatigue at final visit (P < .05 vs placebo); however, no significant differences between modafinil and placebo were found at final visit in FSS or BFI total scores.
Dr. Fava also discussed a smaller open label study by Ninan and colleagues, which consisted of 29 patients (DSM-IV MDD), free from antidepressant therapy (≥ 4 weeks) who were administered modafinil (titrated to 200 mg daily) and fluoxetine or paroxetine (20 mg daily) for 6 weeks. Results showed significant reduction of fatigue (FSS score reduction from baseline = 0.7 at week 1, P < .01) and improved wakefulness (ESS score reduction from baseline = 3.6 at week 1, P < .01); indicating that modafinil, when combined with an SSRI at initiation may enhance the onset and degree of symptom benefit in patients with MDD and fatigue.
In both studies, modafinil as an adjunct therapy was well tolerated, and most adverse events were mild/moderate in severity. Side effects were significantly more common during modafinil treatment when compared with placebo, with nausea (9% vs. 2%; P = .01) and feeling jittery (4% vs 1%; P = .03) most common in Dr. Fava's study and nausea and headache most common in Dr. Ninan's study.
Bupropion is another adjunctive treatment that is commonly used to treat residual symptoms; it appears to significantly affect dopaminergic neurotransmission and may help with fatigue and sexual dysfunction. A study by Papakostas and associates examined the impact of bupropion vs SSRIs on sleepiness and fatigue in patients with MDD. The investigators pooled data from 6 double-blind, randomized clinical trials (bupropion [n = 662]; SSRI [n = 655]) and found greater improvements in fatigue scores among both bupropion-treated (P < .0001) and SSRI-treated groups (P = .0005) than placebo-treated patients, and greater improvements in fatigue scores among bupropion-treated than SSRI-treated patients (P = .0078).
The literature regarding the use of the psychostimulant methylphenidate as an augmentation strategy for depression is sparse. Patkar and colleagues randomized 60 patients who were either nonresponders or partial responders to antidepressant therapy to receive osmotic-release methylphenidate (OROS-MPH; N = 30) or placebo (N = 30). Results failed to show separation of methylphenidate from placebo based on the 21-item Hamilton Depression Rating Scale scores (drug, -6.9; placebo, -4.7) from baseline to the end of treatment (F1,47 = 1.24, P = .22). However, the overall responder rate was numerically higher in the methylphenidate (40%) vs placebo group (23.3%), with the most common adverse events being loss of appetite, nausea, headache, and anxiety.
The use of tri-iodothyronine (T3) to enhance the onset of antidepressant response has received mixed reviews. A meta-analysis conducted by Altshuler and colleagues in 2001 identified 6 studies that combined T3 with a tricyclic antidepressant (TCA). The analysis supported the efficacy of T3 in accelerating the clinical response to TCAs; 5 of the 6 studies found T3 to be significantly more effective than placebo in accelerating the clinical response. (The pooled, weighted effect size index was 0.58, and the average effect was highly significant.)
A more recent study by Appelhof and colleagues in 2004 examined the efficacy of adding T3 to paroxetine in an 8-week study of 113 patients with MDD. Patients were randomly assigned to double-blind outpatient treatment with low-dose T3 (25 micrograms [mgm] once daily), high-dose T3 (25 mgm twice daily), or placebo, in addition to paroxetine 30 mg daily. Response rate (based on a 50% reduction in HAM-D score from baseline) after 8 weeks was 46% in all 3 treatment arms (P = .99). The study also examined the data for sex differences and found no separation in T3 vs placebo for women or men. Of note, patients receiving T3 augmentation experienced higher rates of adverse events.
Jonathan Alpert and colleagues examined the efficacy of oral S-adenosyl-L-methionine (SAMe) as an antidepressant adjunct among partial and nonresponders to SSRIs or venlafaxine. SAMe is a dietary supplement that has been marketed as an antidepressant and antiarthritic, and as a remedy for chronic liver disease. Outpatients with MDD (n = 30) who were currently taking antidepressant treatment received 800 mg to 1600 mg of SAMe during a 6-week trial. The intent-to-treat analyses indicated that augmentation with SAMe led to a 50% response rate and a 43% remission rate (based on the Hamilton Depression Rating Scale); gastrointestinal symptoms and headaches were the most common side effects.
Low folate has been associated with poorer response to SSRIs in patients with MDD. Alpert and colleagues assessed the efficacy of methylfolate as an adjunctive treatment among adults with MDD and inadequate response to an SSRI. They enrolled 22 adults with DSM-IV MDD who had experienced partial or nonresponse to an SSRI after at least 4 weeks of treatment in an 8-week, prospective, open-label trial. Methylfolate was added (as a folinic acid form) to SSRIs at 15-30 mg daily. Folate levels rose from 28 ± 19 ng/mL to 301 ± 203 ng/mL (P < .001). HAM-D-17 scores among the 16 completers decreased from 19.1 ± 3.9 to 12.8 ± 7.0 (P < .01). A double-blind, placebo-controlled study of methylfolate in refractory depression is ongoing.
Depression With Insomnia
Insomnia is another common complaint associated with the use of SSRI therapy. Dr. Fava presented research on the use of eszopiclone augmentation of fluoxetine in patients with MDD. The investigators randomized 545 patients who received morning doses of fluoxetine to either 3 mg eszopiclone (nightly) or placebo, and assessed subjective sleep and daytime function weekly for 8 weeks. The overall results indicated that combination therapy was relatively well tolerated and associated with rapid, substantial, and sustained improvements in sleep, a faster onset of antidepressant response on the basis of CGI, and an increased magnitude of the antidepressant effect. Specifically, patients who received the combination of fluoxetine and eszopiclone reported significantly shortened sleep latency and wake time after sleep onset, longer total sleep time, and improved sleep quality and depth of sleep at all double-blind time points (P < .05). Significantly greater changes in HAM-D-17 scores at week 4 (P = .01), with progressive improvement at week 8 (P = .002), and significantly improved CGI-I and CGI-S scores at all time points following week 1 (P < .05) were observed. Rates of response and remission at week 8 for combination fluoxetine/eszopiclone vs placebo were significant at 59% vs 48% (P = .009) and 42% vs 33% (P = .03), respectively.
Dr. Fava also discussed a study by Asnis and colleagues that investigated zolpidem augmentation of SSRI therapy in a randomized, double-blind, parallel-group study. This study enrolled 190 patients (score ≤ 12 on HAM-D) receiving stable SSRI treatment (fluoxetine ≤ 40 mg/day), sertraline (≤ 100 mg/day), or paroxetine (≤ 40 mg/day) who had experienced symptoms of insomnia for longer than 2 weeks. All participants began with a 1-week single-blind placebo period before inclusion and then received either zolpidem 10 mg (N = 94) or placebo (N = 96) for 4 weeks, followed by single-blind placebo for 1 week. Results based on weekly physician visits and daily sleep questionnaires indicated that self-rated sleep and daytime functioning improved in the SSRI + zolpidem group. Specifically, zolpidem was associated with improved sleep, longer sleep times (weeks 1 through 4, P < .05), greater sleep quality (weeks 1 through 4, P < .01), and reduced number of awakenings (weeks 1, 2, and 4; P < .05). Patient reports included feeling significantly more refreshed, less sleepy, and more able to concentrate after using zolpidem when compared with placebo. In addition, following placebo substitution, the SSRI + zolpidem group showed significant worsening relative to pretreatment sleep, but no evidence of dependence or withdrawal from zolpidem was noted.
A large population of individuals seeking treatment for depression and relief of myriad associated symptoms frequently do not achieve the results they are striving for. The ability to alleviate residual symptoms and medication side effects (eg, fatigue or insomnia) play an important role in the long-term treatment of the patient. The use of monotherapy in the treatment of these disorders is often not enough and can cause the patient to become more frustrated. Despite the relatively small literature, augmentation and combination strategies provide clinicians with an armament of tools that, in collaboration with the patient, must be used to provide relief not only from the depression, but also from residual symptoms and treatment-emergent side effects. This approach gives clinicians the opportunity to enhance remission through broader mechanisms of action and can potentially retain those who may choose not to continue treatment because of adverse side effects and/or lack of response.
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From Medscape Psychiatry & Mental Health
Antidepressants in Bipolar Depression: Data From STEP-BD: An Expert Interview With Andrew Nierenberg, MD
Does adding an antidepressant to mood stabilizer put patients with bipolar depression at risk of mania? A new and comprehensive study from the NIH yields some results that may change the way you prescribe.
Medscape: Recently Gary Sachs, MD, you, and colleagues conducted some research that created a buzz. Could you briefly set the stage for the rationale and need for this study?
Andrew Nierenberg, MD: One of the interesting things you find when you review the literature is the remarkable dearth of studies that carefully and rigorously look at whether antidepressants per se are effective in bipolar depression. Very few studies have ever been done, and many are either small, or short, or they include patients who aren't really representative of the types of patients who would usually be seen in clinical care. So the need was to try to establish: (1) whether antidepressants are helpful if they are added to ongoing treatment with mood stabilizers, and (2) to assess the safety of antidepressants. There is the idea, not supported by a lot of data, that the modern antidepressant might actually exacerbate the course of bipolar disorder, that they could cause either rapid cycling or a switch from depression into mania, hypomania, or a mixed state.
Medscape: Would you also describe what the current state of the art is in terms of the role antidepressants play in bipolar disorder?
Dr. Nierenberg: Many of the guidelines do include antidepressants as part of the treatment. They are consistent also in saying, well, if you are going to use an antidepressant, it's probably best if you avoid using tricyclic antidepressants because there is a robust literature that shows you could make a course of bipolar disorder worse. So that being said, there are actually very little data that looks at the whole modern generation of antidepressants; even with that limited data, there have been a few meta-analyses -- although they're not really meta-analyses because they included so few patients, and so few studies that suggest that, in fact, antidepressants may be helpful.
Medscape: Could you describe the study design?
Dr. Nierenberg: This was an embedded placebo-controlled randomized trial. The study design was unique because it was part of the systematic treatment enhancement program for bipolar disorder. Notice it doesn't say the systematic treatment enhancement study. And it was a program because it was a comprehensive system of care, of recordkeeping, of collaborative care for patients. So the whole idea was that you would have patients across the country in centers of excellence, where there were experts in bipolar disorder who could be relied upon to provide guideline-informed care. So any patient in any of the mood states that are associated with bipolar disorder, ranging from being fine to being quite ill, could come into the study.
Entry into the study was through outpatient settings, but included patients who had been hospitalized. It included patients who were bipolar I, bipolar II, or specified schizoaffective bipolar, or patients who have had psychosis, as well as those who could have the full range of psychiatric and medical comorbid conditions usually excluded in run of the mill studies. We had a large population of over 4000 patients, across 22 sites who were followed over time and treated with a philosophy of collaborative care. The patient was informed of what was going on; the measurement and management of their care was shared with the patients and their families. Many of these patients were invited to come into the study if they met the reasonable inclusion and exclusion criteria.
Now what I mean by reasonable is that for example, the study included bupropion (Wellbutrin) and also paroxetine (Paxil). And if a patient was previously exposed to those medications and had a bad reaction, or wouldn't take it, they would be excluded.
Medscape: Could you describe the randomization strategy, specifically the use of equipoise stratification.
Dr. Nierenberg: Equipoise stratification is very well described in an article by Philip Lavori in Biological Psychiatry, and is actually quite a simple idea. In this particular case, the patient and the doctor would have to be in equipoise, would have to be even about whether or not a patient got an antidepressant, because quite frankly we didn't know if the antidepressants help or hurt. The other thing that the patient and doctor would have to be in equipoise about is which medication they got randomized to. So, for example, you could have a patient who didn't care, and didn't think that it mattered which one they got randomized to. That patient would either get the bupropion or bupropion placebo, or they would get paroxetine or paroxetine placebo. So even though they could get randomized to either one, there might be some patients who had had a bad experience with paroxetine, for example, so they would get randomized to bupropion or bupropion placebo, and similarly, if somebody had had a bad experience with bupropion, they were randomized to paroxetine or paroxetine placebo. This was designed to make entry into the study easy and that's why there were actually 2 medications. We thought that there wouldn't be a difference between those medications so it wouldn't matter.
Medscape: Can you comment on the outcome measure used in the study?
Dr. Nierenberg: If you look at most studies, all you have to do is either reach remission or response. Remission usually means getting completely better, while if you reach response, you're at least 50% better without getting all the way better. What we did was we had a definition of durable recovery, which meant that if somebody got better they had to sustain that for 8 weeks and then they were declared to have a durable recovery. And what's remarkable in this particular study is you're talking about between 23% and 27% of patients who met those criteria during the study. So it's clear that there's room for improvement and it's clear that there are other things that we can do. Again, this study doesn't address the use of quetiapine or lamotrigine or the olanzapine/fluoxetine combinations, so at least we do have those evidence-based alternatives.
Medscape: 4360 patients were enrolled in the STEP BD program but only 10% of patients in the program were recruited into the study. What does that say about the generalizability of these results?
Dr. Nierenberg: It's not so much that such a small proportion of patients went into the study, because actually a large proportion of the patients had a prospectively observed depressive episode. The second part is that there were plenty of people who had been exposed to both of those medications who didn't want to come into the study. So there is a clear description in the manuscript itself of who came in and who didn't come into the study. But I think it's a little bit of an exaggeration to say that it actually limits the generalizability because the study is really designed to maximize generalizability.
Medscape: The article suggests that approximately 24.6% in the antidepressant arm, and 28.9% in the placebo arm, did not receive an adequate dose of a mood stabilizer during the study. Does that reflect on how poorly we treat patients with bipolar disorder?
Dr. Nierenberg: No, actually, if you play by the rules of a randomized clinical trial and you say, you have to have an operationally defined adequate dose, what happens to the people for whom that dose was the maximum dose they could take? So it's not necessarily, oh, we were treating them badly, it was that's what they were taking and they wouldn't take more. That was one part of it. The other part is not so much that they wouldn't take it, it's that they would have intolerable side effects or had a previous experience where they wouldn't take any more so it was important that for those who were randomized, we just looked at those who took the adequate dose that was operationalized.
Medscape: Less than 1% of patients in each group attempted suicide. Can you comment on the issue of suicide in bipolar disorder in the context of antidepressant treatment?
Dr. Nierenberg: Remember, at least in this particular study and that's all I could really comment on in terms of what you're asking, we were not just adding an antidepressant to no treatment. These were patients who were taking inadequate antimanic medication. I think once you get into whether the selective serotonin reuptake inhibitors can exacerbate suicidal thoughts, suicidal behavior, it becomes a much more complicated issue that I don't think we should get into.
Medscape: The Gijsman and colleagues meta-analysis found that antidepressants did have an effect on bipolar depression. How would you reconcile those findings with those of this study?
Dr. Nierenberg: The Gijsman and colleagues meta-analysis looked at a few studies and from that they concluded that antidepressants actually worked. The problem with that meta-analysis is that the largest study included in it was the olanzapine/fluoxetine combination, not fluoxetine alone, and that heavily weighs the entire small meta-analysis toward the results of that study. But what's remarkable is, even in that study, the number of patients who were exposed to the combination of olanzapine and fluoxetine was around 86, and that's it. The other studies were substantially smaller than that. So one thing that's really rather amazing is that the STEP-BD study is the largest placebo-controlled study of antidepressants for bipolar disorder ever published.
Medscape: In terms of switch rates, you found no difference between the 2 groups. However, a certain proportion of each of the 2 groups (38% and 42%) had experienced the switch in the past. So if one assumes that these patients may have an underlying neurobiologic vulnerability, was there any difference in switch rates between these subgroups?
Dr. Nierenberg: I don't know if that subanalyses was done yet. We are working on the mediator and moderator analyses.
Medscape: If the National Institutes of Health were in a position to fund another follow-up study, what would you be thinking of?
Dr. Nierenberg: Well, the National Institute of Mental Health (NIMH) is thinking of looking at another study to evaluate the use of adjunct moderate doses of lithium to really see how that works over the long term. This is an important issue that hasn't been looked at.
Medscape: Based on your reading of the literature and specifically the current study, when would you advocate the use of an antidepressant in bipolar depression?
Dr. Nierenberg: Well, the current study really suggests several things. One is that, there was no apparent benefit to adding an antidepressant to an ongoing adequate dose of a mood stabilizer. It doesn't address who should get an antidepressant or who responds to it or who doesn't. Again, we have to do further analyses to understand that. This study also doesn't suggest that if a patient's doing well on an antidepressant, you should stop it. I would also like to add that we are very grateful to the NIMH for having the courage to fund this really innovative study that informs care. We'll see what happens in the future.