Assessments of suicidality in double-blind, placebo-controlled trials of ziprasidone.

OBJECTIVE: A pooled analysis was conducted to identify possibly suicide-related adverse events in Pfizer-sponsored, phases 2-4, placebo-controlled, double-blind, adult and pediatric completed randomized controlled trials of ziprasidone and to evaluate the risk of suicidality with ziprasidone versus placebo. METHOD: The trials included were initiated as early as June 1992, and the cutoff date for selection of the placebo-controlled trials in the Pfizer database was October 2, 2009. The US Food and Drug Administration (FDA)-defined search methodology was used to identify possibly suicide-related adverse events, and the Columbia Classification Algorithm of Suicide Assessment (primary outcome measure) was used to categorize them. The incidences of possibly suicide-related adverse events were calculated for individual classifications and for the predefined combined categories of suicidality (comprising classification codes 1-4) and suicidal behavior (comprising classification codes 1-3), along with the ziprasidone versus placebo relative risks and corresponding 95% CIs. Exact binomial 95% CIs were calculated for the individual treatment group incidences. RESULTS: Suicidality events were identified in 52 among 5,123 subjects treated with either ziprasidone or placebo in 22 trials. No cases of completed suicide occurred in this analysis. There were no statistically significant differences between ziprasidone and placebo in any of the individual classification categories, combined suicidal behavior category (ziprasidone vs placebo relative risk = 0.67; 95% CI, 0.206-2.201), or combined suicidality risk category (ziprasidone vs placebo relative risk = 0.90; 95% CI, 0.514-1.563). CONCLUSIONS: Results of our analyses, performed in accordance with the FDA-specified search strategy, reveal no significant differences in treatment-emergent suicidality risk in ziprasidone versus placebo subjects treated in controlled clinical trials.

A pooled analysis of suicidality in double-blind, placebo-controlled studies of sertraline in adults.

OBJECTIVE: The analyses were conducted to identify possibly suicide-related adverse events in Pfizer-sponsored, phases 2 through 4, placebo-controlled, completed studies of sertraline in adult patients and evaluate the risk of suicidality with sertraline versus placebo. METHOD: U.S. Food and Drug Administration (FDA)-defined search methodology was used to identify possibly suicide-related adverse events in short-term, all-duration/all-indication, and psychiatric studies of sertraline. Categorization of possibly suicide-related adverse events was based on the approach developed by the Columbia group for the FDA's analysis of pediatric suicide risk with antidepressants. The incidences of possibly suicide-related adverse events were calculated for individual classifications and for the predefined combined category of suicidality along with the sertraline versus placebo relative risks and corresponding 95% CI limits. Exact binomial CI limits were calculated for the individual treatment group incidences. Age group analyses were also performed using the age limits defined by the FDA. RESULTS: Ninety-nine suicidality events were identified among 19,923 sertraline- and placebo-treated subjects participating in 126 studies conducted between the mid-1980s and the mid-2000s. Four cases of completed suicides among 10,917 sertraline-treated subjects yielded an incidence of 0.04% (95% CI = 0.01 to 0.09) and 3 cases among 9,006 placebo treated subjects yielded an incidence of 0.03% (95% CI = 0.01 to 0.10). There were no statistically significant differences between sertraline and placebo in any of the individual categories or combined suicidality risk category across all performed analyses. CONCLUSION: Results of short-term, all-duration, and psychiatric studies analyses, as well as age-group analyses, performed in accordance with the FDA-specified search strategy, show no significant increase in suicidality risk in adult sertraline- versus placebo-treated patients.

From the Bench to the Trench: A Comparison of Sertraline Treatment of Major Depression in Clinical and Research Patient Samples.

BACKGROUND: New medications that enter the marketplace have been tested almost exclusively in controlled clinical trials conducted in specialty research settings. There is some concern that these carefully selected patient samples may not provide information generalizable to the "real world" clinical population. The purpose of this investigation was to compare results from a large, open-label study of sertraline in the treatment of major depression in the clinical practice setting with pooled results from 2 multicenter, double-blind, placebo-controlled studies conducted in specialty research settings. METHOD: Clinical practice patients (N = 1482), aged 21 to 65 years, from 228 psychiatric clinical practice sites across the United States participated in the open-label treatment study (Clinical Practice sample). Patients who met DSM-III-R criteria for moderate-to-severe unipolar major depression (i.e., had pretreatment Hamilton Rating Scale for Depression [HAM-D] scores >/= 18) were treated for 8 weeks with sertraline in a flexible dosing fashion (50-200 mg daily). Outcomes on the HAM-D and Clinical Global Impressions-Improvement scale (CGI-I) were compared with the pooled results from 2 previously published placebo-controlled, multicenter treatment studies of sertraline in outpatients with major depression (N = 280). The overall response to sertraline in the Clinical Practice sample was compared with the outcome from the research study patient sample (Clinical Research sample). Additionally, comparison of outcomes of patients with common depressive subtypes (double depression, anxious depression, and melancholic ["endogenous"] depression) were examined. RESULTS: The percentage of sertraline-treated patients rated as responders on the CGI-I was significantly higher in the Clinical Practice sample compared with the Clinical Research sample (87% vs. 73%; p <.001). Sertraline was also much better tolerated in the Clinical Practice sample than in the Clinical Research sample as evidenced by significantly lower overall reports of adverse events (9.4% vs. 13.2%; p <.05) and lower patient dropout rates (17.5% vs. 34.3%; p <.01). Among clinical practice patients, sertraline was found to be equally effective in treating endogenous/melancholic and anxious subtypes and only mildly less effective in achieving a response in patients with double depression (chronic low-grade depression with a superimposed major depression). A regression analysis identified older age and double depression as being predictors of a slower time to response. More than 70% of patients who reported nonresponse to previous treatment with fluoxetine or a tricyclic antidepressant responded to sertraline. CONCLUSION: The effectiveness and tolerability of sertraline treatment was found to be significantly better in the Clinical Practice sample, suggesting that the results from controlled studies in research settings may represent an underestimate of the benefits of a drug. More effectiveness research is needed to confirm and extend these findings.