Conceptual and Methodological Issues in the Design of Clinical Trials of Antipsychotics for the Treatment of Schizophrenia
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Schizophrenia is one of the most severe and disabling psychiatric disorders. Antipsychotic drugs offer considerable benefits in controlling symptoms and preventing relapse. The strategy for the present review of clinical trials was to ask ‘What are the features of schizophrenia and the existing treatments of the illness that have implications for future clinical trials’ ? Six key facts were identified.
First, schizophrenia is genetically ‘complex’. Trials may benefit from designs including genetically related illnesses, by focussing on cross-cutting aspects of the phenotype such as psychosis or cognitive dysfunction, and by collecting information on possible moderators and mediators of treatment response.
Second, schizophrenia affects multiple neurotransmitter systems. Mutiple signalling pathways may need to be considered, with different time courses of response. Outcome measures from clinical trials could be collected at more frequent intervals, particularly in the early phase of response.
Third, the clinical features used to define the illness are a mix of symptoms and social-occupational dysfunction, yet treatment response is often defined only by changes in symptoms. Multiple measures of functioning need to be collected at baseline and at the endpoint of trials. Consensus definitions for response, remission, relapse, recovery and recurrence need to be developed.
Fourth, schizophrenia is often highly disabling. Linking treatment response in clinical trials to measures of quality-adjusted life-years will allow comparison with other medical illnesses using common metrics.
Fifth, the general health and care of individuals with schizophrenia is often poor. ‘Complex’ interventions, which include, but are not limited to, antipsychotic medications, need to be designed and tested for the problems facing these patients.
Finally, large gaps exist between clinical trials, practice guidelines and patterns of practice. Trials need to be designed to investigate widely used approaches such as antipsychotic polypharmacy, where actual practice diverges from evidence-based guidelines.
KeywordsSchizophrenia Clozapine Risperidone Antipsychotic Drug Negative Symptom
Support was provided by the Michael Smith Foundation for Health Research and the BC Mental Health and Addictions Services.
Dr Honer reports receiving consulting or advisory board fees from In Silico, Janssen, AstraZeneca and Solvay; lecture fees from AstraZeneca and Janssen; and grant support from Eli Lilly, Janssen and AstraZeneca.
Drs Thornton, Sherwood and Barr have no financial ties to the industry.
Dr MacEwan reports receiving consulting or advisory board fees from AstraZeneca, Janssen, Eli Lilly and Novartis; lecture fees from GlaxoSmithKline; and grant support from AstraZeneca.
Dr Ehmann reports receiving grant support from Pfizer.
Dr Williams reports receiving consulting or advisory board fees from AstraZeneca, GenPharm, Janssen, Eli Lilly and Prestwick Pharmaceuticals; lecture fees from AstraZeneca, GenPharm, Janssen, Eli Lilly, Novartis, Pfizer and Prestwick Pharmaceuticals; and grant funding from AstraZeneca, Janssen and Pfizer.
Dr Kopala reports receiving consulting or advisory board fees from AstraZeneca, Pfizer, Solvay and Janssen; and receiving lecture fees as well as grant support from AstraZeneca and Janssen.
Dr Procyshyn reports receiving consulting or advisory board fees and lecture fees from AstraZeneca, Janssen, Eli Lilly and GlaxoSmithKline.
- 2.Murray CJL, Lopez AD. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge (MA): Harvard School of Public Health, 1996Google Scholar
- 11.Risch N. Linkage strategies for genetically complex traits: I. Multilocus models. Am J Hum Geneti 1990; 46: 222–8Google Scholar
- 31.Caspi A, Moffitt TE, Cannon M, et al. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 2005; 57: 1117–27PubMedCrossRefGoogle Scholar
- 59.Lieberman JA, Phillips M, Gu H, et al. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacol 2003; 28: 995–1003Google Scholar
- 66.Leucht S, Davis JM, Engel RR, et al. Defining “response” in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs. Neuropsychopharmacol. In pressGoogle Scholar
- 84.Lohr K, Skillman S. Glossary: health outcomes methodology. Med Care 2000; 38(SII): 7–13Google Scholar
- 85.Weiss AP. Measuring the imapct of medical research: moving from outputs to outcomes. Am J Psychiatry 2007; 164: 204–14Google Scholar
- 97.McEvoy JP, Meyer JM, Goff DC, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005; 80: 19–32PubMedCrossRefGoogle Scholar