The NIMH-CATIE Schizophrenia Study: What Did We Learn?
2011; American Psychiatric Association; Volume: 168; Issue: 8 Linguagem: Inglês
10.1176/appi.ajp.2011.11010039
ISSN1535-7228
AutoresJeffrey A. Lieberman, T. Scott Stroup,
Tópico(s)Treatment of Major Depression
ResumoBack to table of contents Previous article Next article PerspectivesFull AccessThe NIMH-CATIE Schizophrenia Study: What Did We Learn?Jeffrey A. Lieberman, M.D., and T. Scott Stroup, M.D., M.P.H.Jeffrey A. Lieberman, M.D., and T. Scott Stroup, M.D., M.P.H.Published Online:1 Aug 2011https://doi.org/10.1176/appi.ajp.2011.11010039AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail Everyone said, loud enough for the others to hear: "Look at the Emperor's new clothes."—The Emperor's New Clothes, by Hans Christian AndersonIt has been over 10 years since the initiation of the National Institute of Mental Health (NIMH) Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study and 5 years since the first publication of its primary results (1). In this period, the initial report has been cited in the literature over 1,600 times (2) while more than 80 articles from the study's extensive database (Table 1), as well as a book serving as an archive of the study's results and implications (3), have been published. In the meantime, several more randomized trials comparing the effectiveness of antipsychotics have been completed (4–6), meta-analyses that bear on the findings of the CATIE study have been performed (7, 8), and commentaries on CATIE's findings and critiques of its methodology have been published (9–11). All of these help us to view the CATIE study in a broader context and enable us to determine what we really learned from it.TABLE 1. Key Published Articles on the CATIE StudyaTopicStudyAuthorsPublicationPhase 1 effectivenessEffectiveness of antipsychotic drugs in patients with chronic schizophreniaLieberman et al.N Engl J Med 2005; 353:1209–1223Phase 2E effectivenessEffectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatmentMcEvoy et al.Am J Psychiatry 2006; 163:600–610Phase 2T effectivenessEffectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia after discontinuing a previous atypical antipsychoticStroup et al.Am J Psychiatry 2006; 163:611–622Cost-effectivenessCost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophreniaRosenheck et al.Am J Psychiatry 2006; 163:2080–2089Switching effects on medication treatment outcomesEffectiveness of switching antipsychotic medicationsEssock et al.Am J Psychiatry 2006; 163:2090–2095Phase 1B effectivenessEffectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE studyStroup et al.Am J Psychiatry 2007; 164:415–427Treatment effects on neurocognitionNeurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE trialKeefe et al.Arch Gen Psychiatry 2007; 64:633–647Treatment effects on psychosocial functioningEffects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE studySwartz et al.Am J Psychiatry 2007; 164:428–436Metabolic effects of treatmentsAntipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia studyDaumit et al.Schizophr Res 2008; 105:175–187Metabolic effects of treatmentsChange in metabolic syndrome parameters with antipsychotic treatment in the CATIE schizophrenia trial: prospective data from phase 1Meyer et al.Schizophr Res 2008; 101:273–286Extrapyramidal side effects of treatmentsExtrapyramidal side effects of antipsychotics in a randomized trialMiller et al.Br J Psychiatry 2008; 193:279–288Genome-wide association studyGenome-wide association for schizophrenia in the CATIE study: results of stage 1Sullivan et al.Mol Psychiatry 2008; 13:570–584Phase 3 effectivenessResults of phase 3 of the CATIE schizophrenia trialStroup et al.Schizophr Res 2009; 107:1–12aArticles presented are from a total of more than 80 published articles on the CATIE study.TABLE 1. Key Published Articles on the CATIE StudyaEnlarge tableWhen the CATIE study was designed in 1999–2000, the prevailing opinion of researchers and clinicians alike was that the newer (second-generation) antipsychotic drugs were vastly superior to the older (first-generation) antipsychotic drugs in efficacy and safety. This largely reflected the results of studies sponsored by the manufacturers of the new drugs (12, 13), marketing messages of pharmaceutical companies and the hopes of many who wanted better treatments. Indeed, the hypothesis and expectation of the CATIE study investigators was that the first-generation antipsychotic perphenazine would be inferior to the newer agents. Consequently, the finding that perphenazine was similar in effectiveness to most other medications had a profound effect that extended beyond the scientific and psychiatric communities to the lay public and various stakeholder groups. Somewhat sensational news reports decried the preferential use and greater cost of the newer medications and the marketing practices that led to them. For example, the September 21, 2005, editorial page of The New York Times opined, "A government-financed study has provided the strongest evidence yet that the system for approving and promoting drugs is badly out of whack. The study compared five drugs used to treat schizophrenia and found that most of the newest, most heavily prescribed drugs were no better than an older drug that is far cheaper. The nation is wasting billions of dollars on heavily marketed drugs that have never proved themselves in head-to-head competition against cheaper competitors" (14).But what did we really learn from the CATIE study? In this commentary, we summarize its major implications and their relevance to clinical practice. We will also address some of the study's most relevant critiques.Results of the CATIE StudyThe most striking result of the CATIE study, which enrolled almost 1,500 individuals with chronic schizophrenia, was the high rate of treatment discontinuation (up to 74%) over the 18-month period of the trial and the short median time to discontinuation of treatment (about 6 months) in all phases of the trial. Treatment discontinuation in CATIE reflected the desire of patients and their clinicians to switch their medications or patients' nonadherence to treatment. These findings were surprising to some but are consistent with those observed in administrative databases that document antipsychotic prescribing patterns in state Medicaid programs (15, 16), in Québec (17), and in the U.S. Veterans Health Administration (18). In fact, the mean duration of treatment for persons with schizophrenia spectrum disorders who started new antipsychotics in these analyses of administrative data was shorter than that for participants in CATIE.The most controversial finding of the CATIE study was the lack of significant differences in effectiveness between most of the second-generation antipsychotics and perphenazine, the proxy for the first-generation antipsychotics. It has been argued that olanzapine was the most effective antipsychotic medication in the first phase of the study in spite of the lack of a statistically significant advantage over perphenazine or ziprasidone (19). However, olanzapine had the most adverse metabolic effects and highest discontinuation rate as a result of intolerability. Moreover, the other second-generation antipsychotics were similar to perphenazine in effectiveness. In addition, there were no advantages in efficacy for any of the second-generation antipsychotics with regard to negative symptoms or cognitive impairment. The most robust differences observed between drugs were in the rates of side effects, particularly weight gain and laboratory measures of cholesterol, triglycerides, and prolactin. Extrapyramidal symptoms were similar across treatment groups, although more patients receiving perphenazine discontinued treatment because of this side effect.The CATIE study showed that each drug might be most useful in particular situations. For patients whose symptoms did not improve with first-line treatment, clozapine was most effective. Olanzapine was effective in all phases of the study, but it and clozapine had the greatest side effect liabilities. For patients who switched medications because of side effects, the best alternative depended on the type of the individual side effects and the severity of the patient's illness. Risperidone was effective overall for people who discontinued prior medications as a result of intolerability (and is now available as a generic). Quetiapine worked well for people who did not tolerate perphenazine. Ziprasidone demonstrated the most favorable metabolic profile. Perphenazine, because it was priced as a generic, was the most cost-effective drug in the study's main phase.The essential import of the CATIE study can be summarized as follows. Antipsychotic drugs, both old and new, are clearly effective and have been a boon to the treatment of schizophrenia. However, they have substantial limitations in efficacy and safety, which lead clinicians and consumers to seek better results by switching or adding medications. The numerous antipsychotic drugs, however they might be classified, are more similar to than different from each other. To the extent that antipsychotics differ, it is more in their side effects than therapeutic effects. Nevertheless, there is variation in the effectiveness of antipsychotic drugs, which for individual patients can be substantial, and what works for one person may not work for another. Consequently, treatments for schizophrenia must be individualized.Critiques of the CATIE Study"There is only one thing worse than being talked about and that is not being talked about."—Oscar WildeThe CATIE study has not suffered from lack of attention. Of all the issues raised in the commentary and critiques of the CATIE study, we believe that three are most salient. CATIE used an innovative outcome measure to capture the overall effectiveness of the medications and to reflect the input of patients and clinicians on their efficacy and tolerability: time to "all-cause treatment discontinuation." It is important to emphasize that discontinuation did not mean that patients stopped treatment and left the study but that they and/or their clinicians elected to switch or stop the medication to which they had been randomly assigned. This measure was criticized as being not sufficiently specific or clinically valid (11). However, treatment discontinuation is a discrete event that may have many clinically important causes that are not mutually exclusive or specifically identified. For example, in everyday practice when patients "drop out" of treatment or are "noncompliant," this is often because of problems with psychotic symptoms and/or adverse effects. The measure's simplicity and comprehensiveness make it an attractive primary outcome for effectiveness studies. Patients in CATIE who discontinued treatment for any cause had lower quality of life scores than those who completed the study, and their quality of life scores at the time of discontinuation were decreased from baseline (20).A second criticism was that the dose ranges of the study drugs were not equivalent. However, the doses selected were based on those used in clinical practice. Moreover, no studies at the time of the trial, or subsequently, have demonstrated clear differences in dose response from those used in the trial. In addition, the dose of the first-generation drug, perphenazine, was administered at the low end of the recommended dose range. This was done to minimize the potential extrapyramidal side effects, but the drug still proved to be therapeutically comparable to the second-generation medications.A more cogent criticism is that the study was not powered for noninferiority. This is accurate but does not negate the results. The fact that the study was powered for superiority reflects the investigators' a priori belief that the second-generation drugs would prove superior. The fact that the new drugs did not show statistical superiority (or even numerical superiority in all cases except olanzapine) over perphenazine indicates that if there were an effectiveness difference, which the study did not reveal because of power limitations, the magnitude of the effect must be small. In addition, the confirmatory pattern of results from subsequent studies and meta-analyses further supports the validity of the CATIE results.Effect of the CATIE StudyGiven its startling results and the extraordinary attention that it attracted, one might have expected the CATIE study to have had a profound effect on clinical practice. However, prescribing patterns have not markedly changed in the ways suggested by the CATIE study's results. For example, since 2006, among New York State Medicaid recipients with schizophrenia or schizoaffective disorder, clozapine use is flat, olanzapine use has declined, quetiapine use is up, and risperidone use has declined—even though it became generic during this time—while its branded metabolite, paliperidone, has gained considerable use. Meanwhile, use of perphenazine and all other mid- and low-potency first-generation antipsychotic drugs remains rare (Figure 1).FIGURE 1. Antipsychotic Prescriptions Filled for New York Medicaid Recipients With Schizophrenia Spectrum Disorders (2006–2009)aa Antipsychotic prescriptions filled indicates the number of patients who filled at least one prescription for a specified drug in the calendar year.On the other hand, the CATIE results have clearly affected the debate about the relative effectiveness of antipsychotic drugs and our understanding of the true value and real role of the different types of antipsychotics. Moreover, the CATIE study has dramatically demonstrated the value and importance of independently sponsored and conducted comparative effectiveness trials to inform clinicians, consumers, and policy makers of the relative value of marketed treatments for medical disorders. In particular, policy makers need information to make rational decisions about whether to adopt expensive new treatments that have not been compared with cheaper existing ones. The importance of comparative effectiveness research is evident in recent legislation. In 2009, the American Recovery and Reinvestment Act provided for the development of an infrastructure for the ongoing generation and dissemination of information on comparative effectiveness. In 2010, the Patient Protection and Affordable Care Act established the Patient-Centered Outcomes Research Institute to identify national priorities for research and to establish, update, and carry out a national comparative outcomes research project agenda.CATIE helped to demonstrate that, although the introduction of second-generation antipsychotic drugs brought new options for the treatment of psychosis, the major advance many had hoped for remains elusive. By revealing the truth about the emperor's new clothes, CATIE has helped to refocus efforts on the need for truly innovative treatments and strategies that can make significant advances for persons with schizophrenia and related psychoses.Address correspondence to Dr. Stroup ([email protected]columbia.edu).Editorial accepted for publication April 2011.Dr. Lieberman serves on the advisory boards of Bioline, Intracellular Therapies, Pierre Fabre, and PsychoGenics; he receives grant support from Allon, Eli Lilly, F. Hoffman-La Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, LTD, Sepracor (Sunovion), and Targacept; and he holds a patent with Repligen. Dr. Stroup has received research support from the National Institute of Mental Health and the Foundation for the National Institutes of Health; in the last 3 years, he has received consulting fees from Janssen and Lilly. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.References1. Lieberman JA , Stroup TS , McEvoy JP , Swartz MS , Rosenheck RA , Perkins DO , Keefe RS , Davis SM , Davis CE , Lebowitz BD , Severe J , Hsiao JK: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353:1209–1223Crossref, Medline, Google Scholar2. Google Scholar: http://scholar.google.comGoogle Scholar3. Stroup TS , Lieberman JA: Antipsychotic Trials in Schizophrenia: The CATIE Study. New York, Cambridge University Press, 2010Crossref, Google Scholar4. Sikich L , Frazier JA , McClellan J , Findling RL , Vitiello B , Ritz L , Ambler D , Puglia M , Maloney AE , Michael E , De Jong S , Slifka K , Noyes N , Hlastala S , Pierson L , McNamara NK , Delporto-Bedoya D , Anderson R , Hamer RM , Lieberman JA: Double-blind comparison of first- and second-generation antipsychotics in early onset-schizophrenia and schizoaffective disorder: findings from the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study. Am J Psychiatry 2008; 165:1420–1431 (Erratum in Am J Psychiatry 2008; 165:1495)Link, Google Scholar5. McEvoy JP , Lieberman JA , Perkins DO , Hamer RM , Gu H , Lazarus A , Sweitzer D , Olexy C , Weiden P , Strakowski SD: Efficacy and tolerability of olanzapine, quetiapine, and risperidone in the treatment of early psychosis: a randomized, double-blind, 52-week comparison. Am J Psychiatry 2007; 167:1050–1060Crossref, Google Scholar6. Kahn RS , Fleischhacker WW , Boter H , Davidson M , Vergouwe Y , Keet IP , Gheorghe MD , Rybakowski JK , Galderisi S , Libiger J , Hummer M , Dollfus S , López-Ibor JJ , Hranov LG , Gaebel W , Peuskens J , Lindefors N , Riecher-Rössler A , Grobbee DE; EUFEST study group: Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomized clinical trial. Lancet 2008; 371:1085–1097Crossref, Medline, Google Scholar7. Leucht S , Komossa K , Rummel-Kluge C , Corves C , Hunger H , Schmid F , Asenjo Lobos C , Schwarz S , Davis JM: A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166:152–163Link, Google Scholar8. Leucht S , Corves C , Arbter D , Engel RR , Li C , Davis JM: Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009; 373:31–41Crossref, Medline, Google Scholar9. Tandon R , Belmaker RH , Gattaz WF , Lopez-Ibor JJ , Okasha A , Singh B , Stein DJ , Olie JP , Fleischhacker WW , Moeller HJ; Section of Pharmacopsychiatry, World Psychiatric Association: World Psychiatric Association Pharmacopsychiatry Section statement on comparative effectiveness of antipsychotics in the treatment of schizophrenia. Schizophr Res 2008; 100:20–38Crossref, Medline, Google Scholar10. Kane JM: Commentary on the clinical antipsychotic trials of intervention effectiveness (CATIE). J Clin Psychiatry 2006; 67:831–832Crossref, Medline, Google Scholar11. Kraemer HC , Glick ID , Klein DF: Clinical trials design lessons from the CATIE study. Am J Psychiatry 2009; 166:1222–1228Link, Google Scholar12. Lewis S , Lieberman JA: CATIE and CUtLASS: can we handle the truth? Br J Psychiatry 2008; 192:161–163Crossref, Medline, Google Scholar13. Heres S , Davis J , Maino K , Jetzinger E , Kissling W , Leucht S: Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry 2006; 163:185–194Link, Google Scholar14. New York Times: Comparing Schizophrenia Drugs (editorial). New York Times, Sept 21, 2005Google Scholar15. Rothbard AB , Kuno E , Foley K: Trends in the rate and type of antipsychotic medications prescribed to persons with schizophrenia. Schizophr Bull 2003; 29:531–540Crossref, Medline, Google Scholar16. Chen L , McCombs JS , Park J: Duration of antipsychotic drug therapy in real-world practice: a comparison with CATIE trial results. Value Health 2008; 11:487–496Crossref, Medline, Google Scholar17. Moisan J , Gregoire JP: Patterns of discontinuation of atypical antipsychotics in the province of Québec: a retrospective prescription claims database analysis. Clin Ther 2010; 32(suppl 1):S21–S31Crossref, Medline, Google Scholar18. Kilzieh N , Todd-Stenberg JA , Kennedy A , Wood AE , Tapp AM: Time to discontinuation and self-discontinuation of olanzapine and risperidone in patients with schizophrenia in a naturalistic outpatient setting. J Clin Psychopharmacol 2008; 28:74–77Crossref, Medline, Google Scholar19. Davis JM , Leucht S , Glick ID: CATIE findings revisited. Psychiatr Serv 2009; 60:125–126Link, Google Scholar20. Davis SM , Stroup ST , Koch GG , Davis CE , Rosenheck RA , Lieberman JA: Time to all-cause treatment discontinuation as the primary outcome in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Study. Stat Biopharmaceut Res 2011; 3:253–265Crossref, Google Scholar FiguresReferencesCited byDetailsCited byEffectiveness of Switching to Long-acting Injectable Aripiprazole in Patients with Recent-onset and Chronic SchizophreniaClinical Psychopharmacology and Neuroscience, Vol. 21, No. 1Potential Mechanisms for Why Not All Antipsychotics Are Able to Occupy Dopamine D3 Receptors in the Brain in vivo24 March 2022 | Frontiers in Psychiatry, Vol. 13Using Nonhuman Primate Models to Reverse-Engineer Prefrontal Circuit Failure Underlying Cognitive Deficits in Schizophrenia7 January 2023Psychiatrist and Psychiatric Pharmacists Beliefs and Preferences for Atypical Antipsychotic Treatments in Patients With Schizophrenia and Bipolar Disorders25 June 2019 | Journal of Pharmacy Practice, Vol. 34, No. 1Translational medicine in psychiatry: challenges and imaging biomarkersTargeting Serotonin 5-HT2A Receptors to Better Treat Schizophrenia: Rationale and Current Approaches11 August 2020 | CNS Drugs, Vol. 34, No. 9The association between a free medicine program and functioning in people with schizophrenia: a cross-sectional study in Liuyang, China24 April 2020 | PeerJ, Vol. 8Concentration–Effect Relationships of Psychoactive Drugs and the Problem to Calculate Therapeutic Reference RangesTherapeutic Drug Monitoring, Vol. 41, No. 2Preventing discrimination based on psychiatric risk biomarkers6 April 2018 | American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, Vol. 180, No. 2Pharmacology Research & Perspectives, Vol. 7, No. 3Schizophrenia Research, Vol. 206Metabolic Side Effects in Patients Using Atypical Antipsychotic Medications During HospitalizationJournal of Psychosocial Nursing and Mental Health Services, Vol. 56, No. 4Association between serum levels of glutamate and neurotrophic factors and response to clozapine treatmentSchizophrenia Research, Vol. 192Psychosis: Schizophrenia and Related Disorders25 January 2018DOES OLANZAPINE HAVE ADVANTAGE OVER ILOPERIDONE IN EARLY AMELIORATION OF SYMPTOMS IN SCHIZOPHRENIA? A RANDOMISED PARALLEL GROUP TRIAL24 April 2017 | Journal of Evidence Based Medicine and Healthcare, Vol. 4, No. 33Behavioural Brain Research, Vol. 323Drug Discovery Today, Vol. 22, No. 7EBioMedicine, Vol. 26Treating refractory mental illness with closed-loop brain stimulation: Progress towards a patient-specific transdiagnostic approachExperimental Neurology, Vol. 287Journal of Psychiatric Research, Vol. 90Using model systems to understand errant plasticity mechanisms in psychiatric disorders26 October 2016 | Nature Neuroscience, Vol. 19, No. 11Journal of Autism and Developmental Disorders, Vol. 46, No. 4Journal of Contemporary Psychotherapy, Vol. 46, No. 1Drugs - Real World Outcomes, Vol. 3, No. 3Palliative and Supportive Care, Vol. 14, No. 1New England Journal of Medicine, Vol. 375, No. 15International Clinical Psychopharmacology, Vol. 31, No. 4Journal of Pharmacology and Experimental Therapeutics, Vol. 356, No. 3Journal of Psychology & Clinical Psychiatry, Vol. 6, No. 2Health care resource utilization and direct medical costs for patients with schizophrenia initiating treatment with atypical versus typical antipsychotics in Tianjin, China9 April 2015 | BMC Health Services Research, Vol. 15, No. 1Early Intervention for Better Mental Health Services20 February 2015Translational Medicine in PsychiatryJournal of Child and Adolescent Psychopharmacology, Vol. 25, No. 8Schizophrenia Bulletin, Vol. 41, No. 2Antipsychotic patterns of use in patients with schizophrenia: polypharmacy versus monotherapy30 November 2014 | BMC Psychiatry, Vol. 14, No. 1Changes in Physician Antipsychotic Prescribing Preferences, 2002–2007Julie Donohue, Ph.D., A. James O'Malley, Ph.D., Marcela Horvitz-Lennon, M.D., M.P.H., Anna Levine Taub, Ph.D., Ernst R. Berndt, Ph.D., and Haiden A. Huskamp, Ph.D.1 March 2014 | Psychiatric Services, Vol. 65, No. 3Journal of Neuroscience Research, Vol. 92, No. 12Pharmacology & Therapeutics, Vol. 143, No. 1The Humanistic Psychologist, Vol. 42, No. 2Children & Society, Vol. 28, No. 3Journal of Biomechanical Engineering, Vol. 136, No. 3BMC Medicine, Vol. 12, No. 1Journal of Psychology & Clinical Psychiatry, Vol. 1, No. 4Current and future treatment modalities in schizophrenia: novel antipsychotic drugs and cognitive therapy2 December 2013 | Expert Review of Neurotherapeutics, Vol. 14, No. 1Frontiers in Psychiatry, Vol. 5Review of Schizophrenia Research Using MEG8 August 2014Generic atypical antipsychotic drugs in Belgium: their influence and implicationsJournal of Comparative Effectiveness Research, Vol. 2, No. 6Can authorities take advantage of the availability of generic atypical antipsychotic drugs? Findings from Sweden and potential implications25 June 2013 | Journal of Pharmaceutical Health Services Research, Vol. 4, No. 3Peptide POP inhibitors for the treatment of the cognitive symptoms of schizophreniaFuture Medicinal Chemistry, Vol. 5, No. 13Neuroscience, Vol. 251International Journal of Neuropsychopharmacology, Vol. 16, No. 6Early Intervention in Psychiatry, Vol. 7, No. 3International Journal of Clinical Practice, Vol. 67, No. 2Expert Review of Pharmacoeconomics & Outcomes Research, Vol. 13, No. 4People living with psychosis: The good news and the bad news6 September 2012 | Australian & New Zealand Journal of Psychiatry, Vol. 46, No. 9Nature Reviews Drug Discovery, Vol. 11, No. 7 Volume 168Issue 8 August 2011Pages 770-775 Metrics PDF download History Accepted 1 April 2011 Published online 1 August 2011 Published in print 1 August 2011
Referência(s)