Mortality Risk in Patients With Schizophrenia Participating in Premarketing Atypical Antipsychotic Clinical Trials

Arif Khan, M.D.; Kelly Schwartz, M.S.; Chelsea Stern; Nick Redding, M.S.; Russell L. Kolts, Ph.D.; Walter A. Brown, M.D.; and Donald S. Robinson, M.D.

Objectives: Given the concern that mortality rates may be increased in geriatric patients exposed to atypical antipsychotic agents, we assessed mortality rates for adult patients with schizophrenia assigned to an investigational antipsychotic (olanzapine, quetiapine, risperidone, or ziprasidone), a control antipsychotic (haloperidol or chlorpromazine), or placebo in preapproval clinical development programs to assess relative risk with atypical antipsychotics as compared to typical antipsychotics or placebo.

Method: We reviewed safety data (from clinical trials conducted from approximately 1982 to 2002) for 16,791 adult patients with schizophrenia (DSM-III or DSM-IV criteria) in U.S. Food and Drug Administration (FDA) Summary Basis of Approval (SBA) reports for 6 antipsychotic drugs. Mortality rates were calculated for each treatment group (investigational agent, active control, or placebo) on the basis of patient exposure years (PEY) and gross mortality. We compared the differences in mortality rates between placebo and investigational agents, active controls, and all antipsychotic drugs combined using odds ratios.

Results: By PEY analysis, the mortality rate for patients assigned to placebo treatment was significantly higher (p < .05) than for either the investigational antipsychotic (OR = 0.23, 95% CI = 0.13 to 0.45) or the active control group (OR = 0.19, 95% CI = 0.08 to 0.45). Although rates based on gross mortality were also higher with placebo treatment, statistical significance was only seen when comparing patients assigned to placebo with those assigned to the active control antipsychotic group (OR = 0.35, 95% CI = 0.15 to 0.82).

Conclusions: Despite reported excess mortality with antipsychotic use in elderly patients with dementia, SBA data did not reveal a similar increased risk of antipsychotics in adult patients with schizophrenia. However, methodological limitations of the FDA SBA reports may affect the generalizability of these findings.

(J Clin Psychiatry 2007;68:1828-1833)

Received Dec. 20, 2006; accepted Mar. 12, 2007. From the Northwest Clinical Research Center, Bellevue, Wash. (Dr. Khan, Mss. Schwartz and Stern, and Mr. Redding); the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, N.C. (Dr. Khan); Department of Psychology, Eastern Washington University, Cheney, Wash. (Dr. Kolts); Department of Psychiatry, Brown Medical School, Providence, R.I., and Department of Psychiatry, Tufts University School of Medicine, Boston, Mass. (Dr. Brown); and Worldwide Drug Development, Burlington, Vt. (Dr. Robinson).

The Northwest Clinical Research Center in Bellevue, Wash., supported this research from private funds. No support was provided by any pharmaceutical companies or other funding agencies.

Dr. Khan, principal investigator of over 200 trials sponsored by more than 40 pharmaceutical companies, has done no consulting or speaking on their behalf. Ms. Schwartz, Ms. Stern, and Mr. Redding have been employees of the Northwest Clinical Research Center. Dr. Kolts has had no support from either pharmaceutical companies or other agencies and is a full-time employee of Eastern Washington University. Dr. Brown is the cofounder and President of Clinical Research Centers International, a company that develops and manages clinical trials sites overseas. These sites carry out research sponsored by drug companies. Dr. Robinson is a consultant to the pharmaceutical industry and has published extensively on clinical methodology and drug development in psychopharmacology.

Corresponding author and reprints: Arif Khan, M.D., 1900 116th Ave. N.E., Bellevue, WA 98004 (e-mail: akhan@nwcrc.net).