Elsevier

Biological Psychiatry

Volume 62, Issue 4, 15 August 2007, Pages 345-354
Biological Psychiatry

Original Article
Seizure Incidence in Psychopharmacological Clinical Trials: An Analysis of Food and Drug Administration (FDA) Summary Basis of Approval Reports

https://doi.org/10.1016/j.biopsych.2006.09.023Get rights and content

Background

Clinical trial data provide an approach to the investigation of the effects of psychopharmacological agents, and psychiatric disorders themselves, on seizure threshold.

Methods

We accessed public domain data from Food and Drug Administration (FDA) Phase II and III clinical trials as Summary Basis of Approval (SBA) reports that noted seizure incidence in trials of psychotropic drugs approved in the United States between 1985 and 2004, involving a total of 75,873 patients. We compared seizure incidence among active drug and placebo groups in psychopharmacological clinical trials and the published rates of unprovoked seizures in the general population.

Results

Increased seizure incidence was observed with antipsychotics that was accounted for by clozapine and olanzapine, and with drugs indicated for the treatment of OCD that was accounted for by clomipramine. Alprazolam, bupropion immediate release (IR) form, and quetiapine were also associated with higher seizure incidence. The incidence of seizures was significantly lower among patients assigned to antidepressants compared to placebo (standardized incidence ratio = .48; 95% CI, .36- .61). In patients assigned to placebo, seizure incidence was greater than the published incidence of unprovoked seizures in community nonpatient samples.

Conclusions

Proconvulsant effects are associated with a subgroup of psychotropic drugs. Second-generation antidepressants other than bupropion have an apparent anticonvulsant effect. Depression, psychotic disorders, and OCD are associated with reduced seizure threshold.

Section snippets

Summary Basis of Approval (SBA) Reports

An SBA report is a review of the pre-clinical and clinical data from the New Drug Application (NDA) for a new drug or new drug indication. The FDA staff includes physicians, pharmacologists, and toxicologists, who prepare reviews of the NDA research data that are then compiled into an SBA report. After the senior FDA staff physician signs off on the completed SBA report, it is made available to the public under the Freedom of Information Act (US Department of Justice 1996), and a subset of the

Results

In Table 1, we rank ordered all of the active compounds based on total seizure incidence unadjusted for PEY for each diagnostic category, and included corresponding PEY and placebo data where it was available.

Discussion

The synthesis and extraction of relevant conclusions from this data set involves recognition of its limitations, evaluation of analyses within indication categories and between active treatment and placebo arms, and interpretation of the results in the context of existing clinical, experimental, and epidemiological evidence.

The clinical trial data reviewed in this study indicated that a relatively high rate of seizures occurred in patients assigned to placebo, which suggests that psychiatric

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