Clinical Trial Issues

Trials for novel antipsychotic drugs usually employ the randomized double blind placebo-controlled design and focus on a reduction in acute psychotic symptoms and the prevention of relapse as primary outcomes.52 Trials usually average 50-60 participants, but large studies have been reported with sample sizes ranging from 200 up to 2000 subjects. Typical trial length is 6 weeks or less, but trials lasting for more than 6 months have provided valuable information on long-term treatment. Several issues are apparent in generalizing the results obtained from clinical trials to the general population of schizophrenics, and to clinical practice. Most large clinical trials for novel antipsychotic medications are carried out in a population of acute exacerbated schizophrenic patients, or in patients that are resistant to available treatments. The trials typically exclude individuals with comorbid psychiatric disorders or those that require continued use of antidepressants or mood stabilizers. In addition, patients with a history of substance abuse, violent behavior, or suicidal tendencies are usually excluded. These criteria are largely necessitated by the need to gather a large population of subjects with a relatively homogeneous disease state. While this approach aids in trial recruitment, it raises several important caveats. First, the selection process obviously favors a subgroup of patients that may not be representative of the whole population. Second, the individuals in the chosen population likely have a history of antipsychotic drug use that could alter response to an NCE. Lastly, the clinical trial conditions are not representative of the actual clinical situation in which comorbidity and polypharmacy are the rule rather than the exception.

In an attempt to improve the signal-to-noise ratio, many trials initiate with a short washout period during which the subject is treated with placebo. This serves several purposes beyond insuring a medication-free starting point. It allows for a more accurate identification of the actual response to the novel treatment and an enhanced ability to detect side effect liabilities. Furthermore, it provides an opportunity to screen out subjects that respond to placebo as well as noncompliant subjects. An alternative to the placebo washout is found in trials that selectively enroll first-episode schizophrenics. This design provides an opportunity to study efficacy in a drug-naive population. Unfortunately, this represents a significant challenge in subject recruitment resulting in relatively small sample size.

To date, most clinical trials for novel antipsychotic drugs have focused on amelioration of positive symptoms, or in some cases a combination of positive and negative symptoms. The tools typically employed are the Brief Psychiatric Rating Scale (BPRS), and the Positive and Negative Syndrome Scale (PANSS).2'4 Additional scales are usually employed to assess extrapyramidal side effects, including the Simpson-Angus Extrapyramidal Symptom Scale, and the Abnormal Involuntary Movement Scale. This focus on a single aspect of core symptoms and potential adverse effects associated with known treatments in part explains the state of modern antipsychotic medication, which tends to primarily act to reduce positive symptoms with an improved therapeutic index for EPS. While claims have been made for improved efficacy in treating negative and cognitive symptoms, these claims are almost always based on secondary outcome measures that are by nature multiple comparisons and therefore lack the statistical rigor necessary to make firm statements that can be carried into clinical practice.

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