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.
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