Mortality risk in patients with schizophrenia participating in premarketing atypical antipsychotic clinical trials.

OBJECTIVE: 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.

Psychiatric diagnosis and clinical trial completion rates: analysis of the FDA SBA reports.

Completion rates may affect the safety and efficacy evaluations of psychotropics. We assessed completion rates in clinical trials evaluating psychotropics for five psychiatric disorders. We also examined differences in completion rates between psychotropics and placebo in each diagnostic category. We reviewed clinical data in the Food and Drug Administration summary basis of approval reports for 20 psychotropics evaluated for the treatment of depression, schizophrenia, obsessive compulsive disorder (OCD), generalized anxiety disorder (GAD), or panic disorder, consisting of 19 710 patients. Patients with OCD had the highest completion rates (78.0%), followed by patients with panic disorder (74.4%), GAD (69.2%), depression (64.7%) and schizophrenia (49.0%). Patients assigned to placebo had significantly lower completion rates in antipsychotic clinical trials. Patients assigned to psychotropics in OCD trials had significantly lower completion rates compared to the placebo group. A greater number of early terminations relating to a lack of efficacy was seen among patients assigned to placebo (17.4%) compared with patients assigned to psychotropics (12.2%). A greater number of early terminations relating to adverse events was seen among patients assigned to psychotropics (10.4%) compared with patients assigned to placebo (4.8%). Our findings suggest that psychiatric diagnosis and treatment assignment (placebo vs psychotropic) were associated with completion rates in clinical trials. These findings may help in the design of future psychopharmacology clinical trials.

Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports.

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.

BMI, sex, and antidepressant response.

BACKGROUND: Investigators have examined potential mechanisms for the observed differences between men and women in antidepressant response. However, to date no studies have measured the impact of body mass index (BMI) on men's and women's response to selective serotonin re-uptake inhibitors or placebo. METHODS: We evaluated the response to antidepressants and placebo of 274 non-obese (BMI<30) and obese (BMI>30) depressed outpatients participating in Phase II-IV clinical trials. After categorizing men and women into their respective BMI groups, we measured the amount of change each group experienced from baseline to the final visit using the HAM-D-17 and MADRS ratings scales. RESULTS: Compared to women, men assigned to an antidepressant had a significantly lower mean total change on both the HAM-D-17 [non-obese, F(1,88)=5.292, p=0.024; obese, F(1,39)=7.040; p=0.012] and the MADRS [non-obese, F(1,66)=4.049, p=0.048; obese, F(1,27)=8.631, p=0.007]. In fact, obese men showed the smallest difference in antidepressant-placebo response. The results of the ANCOVAs indicated significant main effects of treatment (placebo vs. antidepressant), sex of the patient, and BMI category as well as a significant interaction between all three variables. LIMITATIONS: Patients participating in clinical trials are not necessarily representative of the entire depressed population. In addition, our results include only SSRIs, not other antidepressants. CONCLUSION: Compared to the rest of the depressed sample the subgroup of depressed obese men (n=40) showed little or no therapeutic benefit with SSRI antidepressants. Although our findings may have important clinical implications, replication and further research is warranted in order to understand their underlying mechanisms and their pertinence to dosing strategies.

Relationship between depression severity entry criteria and antidepressant clinical trial outcomes.

BACKGROUND: We assessed whether increasing the minimum prerandomization Hamilton Depression Rating Scale (HAM-D) score to enrich the severity of the depressed sample affects antidepressant trial outcome. METHODS: Using the Food and Drug Administration Summary Basis of Approval reports, we examined outcome data from 51 clinical trials (11,270 depressed patients) evaluating 10 investigational antidepressants. RESULTS: Using four categories of trials with increasing minimum HAM-D entry trial criteria, we found no statistically significant relationship between prerandomization categories and trial outcome overall. Although there were minor differences in trial outcome among the three categories with the lowest entry criteria (mean 49%, range, 44.4%-50.0%), the antidepressant trials requiring the highest prerandomization HAM-D score (> or = 20 HAM-D 17) had the lowest frequency of positive outcomes (20%), chi(2) = 4.04, df =1, p = .04. Paradoxically, high entry criteria requirements failed to increase reliably actual mean total prerandomization HAM-D scores, although mean total prerandomization HAM-D scores and use of flexible dosing were associated with higher rates of positive outcome. A greater placebo response was seen in trials requiring higher prerandomization depressive symptoms. CONCLUSIONS: In summary, requiring higher prerandomization depressive symptoms was not associated with an increased rate of favorable outcomes among these 51 antidepressant trials.

Suicide risk analysis among patients assigned to psychotropics and placebo.

Based on available data, it is unclear if the suicide risk is significantly different among clinical trial patients assigned to psychotropics compared with patients assigned to placebo, among patients with various psychiatric diagnoses. This study was to investigate whether patients assigned to psychotropics would have a similar suicide risk as measured by the frequency of completed suicides and suicide attempts, compared to those patients assigned to placebo. The U.S. Food and Drug Administration database of controlled clinical trials for 9 antidepressants, 3 antipsychotics, and 7 anxiolytics provided data for comparing suicides and suicide attempts among 46,575 patients assigned to psychotropics or placebo. The Poisson Regression analysis suggested that there were no significant differences in rates of suicide and suicide attempts among patients assigned to the psychotropics or placebo. These findings suggest that the high suicide risk among clinical trial participants is not significantly affected by psychotropics.

Sex differences in antidepressant response in recent antidepressant clinical trials.

Some previous reports suggest that women respond differently than men to antidepressant treatment. Much of this literature compares men and women's response to tricyclics to that of newer antidepressants (SSRIs, SNRI), or only examines one particular antidepressant. This study compares men and women's responses to 6 newer antidepressants. A total of 15 randomized, placebo-controlled trials that included 323 depressed patients were examined for sex differences in antidepressant treatment response. Women had a significantly greater response than men to SSRI antidepressants. A similar trend was seen for those assigned to an SNRI antidepressant, although not to the same extent as with SSRI antidepressants. Although these gender differences in treatment response are not large enough to suggest that gender should guide the clinical use of SSRI and SNRI antidepressants, the results do have implications for the design and interpretation of antidepressant clinical trials. These findings also raise the possibility that antidepressants may work somewhat differently in men and women.

Magnitude of placebo response and drug-placebo differences across psychiatric disorders.

BACKGROUND: Placebo response, drug response, and drug-placebo differences appear to vary among psychiatric conditions. METHOD: We evaluated the Food and Drug Administration (FDA) Summary Basis of Approval (SBA) reports to compare the magnitude of placebo response, magnitude of psychotopic drug response, and drug placebo differences among various diagnostic groups such as depression, anxiety, and psychotic disorders. RESULTS: Six diagnostic groups (psychosis, obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), depression, post-traumatic stress disorder, panic) varied in response to both placebo and active drug treatments. Response to placebo was high among patients participating in GAD, depression, and panic disorder clinical trials. Conversely, patients participating in psychotic disorder and OCD trials experienced low response to placebo. CONCLUSION: Our findings indicate that the magnitude of placebo response and drug response were heterogeneous and were statistically significantly different among various psychiatric disorders. Although a noticeable degree of heterogeneity was detected in the drug-placebo ratio among various disorders, the differences did not reach statistical significance. This finding suggests that placebo use should be continued for newer agents being tested for all of the psychiatric disorders. These findings may help in the development of psychopharmacology trial designs and in the deliberations of ethics committees.

Severity of depressive symptoms and response to antidepressants and placebo in antidepressant trials.

Although increased pre-treatment severity of depressive symptoms is thought to suggest better outcome with tricyclic antidepressants, it is unclear if such a pattern exists among those depressed patients treated with newer antidepressants. If such a pattern with newer antidepressants were observed, it would have implications for the design and conduct of future antidepressant trials. We reviewed the data from 329 depressed adult patients that were part of 15 multi-center, randomized, double blind, placebo-controlled antidepressant clinical trials at our center. Based on patients' pre-treatment scores on the 17-item Hamilton Depression Rating Scale (HAM-D), patients were sub-grouped to one of four severity of depression groups: low moderate, high moderate, moderately severe, and severe. The effect size was 0.51 in the low moderate group, 0.54 in the high moderate group, 0.77 in the moderately severe group and 1.09 in the severe group. An analysis of variance revealed a statistically significant interaction between treatment and severity of depressive symptoms. A correlational analysis revealed that in the group of depressed patients assigned to antidepressants, higher levels of pre-treatment depressive symptoms were significantly associated with greater changes in response to antidepressant treatment. Although a similar pattern was seen among the depressed patients assigned to placebo, it did not reach statistical significance. The results of this study suggest that antidepressant-placebo differences may be larger among those depressed outpatients with higher pre-treatment HAM-D scores compared to those depressed outpatients with lower pre-treatment scores. These findings may help in the design of future antidepressant clinical trials.

Research design features and patient characteristics associated with the outcome of antidepressant clinical trials.

OBJECTIVE: The authors examined which, if any, research design features and patient characteristics would significantly differ between successful and unsuccessful antidepressant trials. METHOD: Clinical trial data were reviewed for nine antidepressants approved by the Food and Drug Administration between 1985 and 2000. From the antidepressant research programs on these medications, 52 clinical trials were included in the study. The authors evaluated trial design features, patient characteristics, and difference in response between placebo and antidepressant. RESULTS: Nine trial design features and patient characteristics were present in the research programs for all nine of the antidepressants. The severity of depressive symptoms before patient randomization, the dosing schedule (flexible versus fixed), the number of treatment arms, and the percentage of female patients were significantly associated with the difference in response to antidepressant and placebo. The duration of the antidepressant trial, number of patients per treatment arm, number of sites, and mean age of the patients were similar in successful trials (with a greater antidepressant-placebo difference) and less successful trials (with a smaller antidepressant-placebo difference). CONCLUSIONS: These findings may help in the design of future antidepressant trials.

Relative sensitivity of the Montgomery-Asberg depression rating scale, the Hamilton depression rating scale and the Clinical Global Impressions rating scale in antidepressant clinical trials: a replication analysis.

The present study replicates a previous study in which we found that the less frequently used Montgomery-Asberg Depression Rating Scale (MADRS) is as sensitive an instrument in detecting antidepressant-placebo differences in antidepressant clinical trials as the more widely used Hamilton Depression (HAM-D) rating scale. The Clinical Global Impressions Rating Scale for Severity (CGI-S) was also similar to the other two scales. A retrospective chart review was performed on the records of 139 depressed adult patients who participated in six randomized, placebo-controlled, double-blind antidepressant clinical trials at the North-west Clinical Research Centre between 1996 and 2003. The effect size (measured as the mean change in rating with antidepressants minus the mean change for placebo divided by the pooled SD of change) was 0.68 with MADRS, 0.54 with CGI-S and 0.57 with HAM-D. A correlation analysis also revealed a significant positive relationships between baseline MADRS and HAM-D and final MADRS and HAM-D for the total sample, placebo group, and antidepressant group (P<0.01). Further research is needed to examine which scale is the most appropriate to use for each particular antidepressant clinical trial.

The relationship of sociotropy and autonomy to posttraumatic cognitions and PTSD symptomatology in trauma survivors.

The current study examined relationships between sociotropic and autonomous personality styles and posttraumatic stress disorder (PTSD) symptomatology following trauma as well as specific posttraumatic cognitions that have been shown to characterize individuals with PTSD. Self-report data were collected in a sample of 156 college students indicating a history of traumatic experience. Significant relationships were found between symptoms of PTSD and depression and measures of sociotropy, autonomy, and negative posttraumatic beliefs about self and world. Additionally, measures of autonomy and negative posttraumatic thoughts improved prediction of PTSD symptom level after controlling for depressive symptoms.