Multicenter, randomized, double-blind, active comparator and placebo-controlled trial of a corticotropin-releasing factor receptor-1 antagonist in generalized anxiety disorder.

BACKGROUND: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). METHOD: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. RESULTS: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). CONCLUSIONS: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.

Sheehan Suicidality Tracking Scale (Sheehan-STS): Preliminary Results from a Multicenter Clinical Trial in Generalized Anxiety Disorder.

OBJECTIVE: Accurate and prospective assessments of treatment-emergent suicidal thoughts and behaviors are essential to both clinical care and randomized clinical trials. The Sheehan Suicidality Tracking Scale is a prospective, patient self-report or clinician-administered rating scale that tracks both treatment-emergent suicidal ideation and behaviors. The Sheehan Suicidality Tracking Scale was incorporated into a multicenter, randomized, double-blind, placebo-controlled, and active comparator study examining the efficacy of an experimental corticotropin-releasing factor antagonist (BMS-562086) for the treatment of generalized anxiety disorder. METHOD: The Sheehan Suicidality Tracking Scale was administered to subjects at baseline, Week 2, Week 4, and Week 8 or early termination. Subjects completed theSheehan Suicidality Tracking Scale by self report. The Sheehan Suicidality Tracking Scale was designated as an exploratory outcome measure in the study protocol, and post-hoc analyses were performed to examine the performance of the Sheehan Suicidality Tracking Scale. RESULTS: A total of 82 subjects completed the Sheehan Suicidality Tracking Scale during the course of the study. Altogether, these subjects provided 297 completed Sheehan Suicidality Tracking Scale ratings across the study time points. Sixty-one subjects (n=25 placebo, n=24 BMS-562086, and n=12 escitalopram) had a baseline and at least one post-baseline Sheehan Suicidality Tracking Scale measurement. The mean change from baseline at Week 8 in the Sheehan Suicidality Tracking Scale total score was -0.10, -0.02, and -0.06 for escitalopram, placebo, and BMS-562086 groups, respectively. The sensitivity of the Sheehan Suicidality Tracking Scale and HAM-D Item #3 (suicide) for identifying subjects with suicidal thoughts or behaviors was 100 percent and 63 percent, respectively. CONCLUSIONS: The Sheehan Suicidality Tracking Scale may be a sensitive psychometric tool to prospectively assess for treatment-emergent suicidal thoughts and behaviors. Despite the small sample size and low occurrence of suicidal ideation during the course of this clinical trial, the self-reported Sheehan Suicidality Tracking Scale demonstrated increased sensitivity over the rater administered HAM-D Item #3 in identifying suicide related ideations and behaviors. Further research in larger study samples as well as in other psychiatric disorders are needed.

Antimanic response to aripiprazole in bipolar I disorder patients is independent of the agitation level at baseline.

OBJECTIVE: To examine the antimanic efficacy of the relatively nonsedating antipsychotic aripiprazole in patients with bipolar I disorder and high or low baseline levels of agitation. METHOD: Data were pooled for this post hoc analysis from two 3-week, placebo-controlled trials of aripiprazole in acute mania (DSM-IV). Patients randomly assigned to aripiprazole 30 mg/day (N = 259) or placebo (N = 254) were classified as having either high (Positive and Negative Syndrome Scale [PANSS] Excited Component [PEC] score of >or=14 and a score of >or= 4 on at least one PEC item) or low (PEC < 14) levels of agitation at baseline. Efficacy measures were changes in Young Mania Rating Scale (YMRS) scores, Clinical Global Impressions-Bipolar (CGI-BP) scores, and PEC scores. Efficacy and agitation measurements were assessed by analysis of covariance. RESULTS: From the first week of therapy onward, aripiprazole-treated subjects had significantly greater reduction from baseline in YMRS total scores than placebo-treated subjects in both the high- and low-agitation groups (p < .05 for both groups) and significantly improved CGI-BP scores vs. placebo at end point (p < .05 for both). In highly agitated patients receiving aripiprazole, PEC scores were significantly decreased versus placebo at end point (p < .05). In patients with low agitation receiving aripiprazole, no increases in PEC scores were seen, and a significant reduction in agitation symptoms was apparent after adjustment for baseline PEC scores. CONCLUSIONS: Aripiprazole was superior to placebo in reducing the severity of both mania and agitation in highly agitated patients with bipolar I disorder and showed significant antimanic activity in patients with low levels of agitation without increasing agitation. These findings suggest that aripiprazole's antimanic effect is specific and not limited to control of agitation through sedation.

Aripiprazole effects in patients with acute schizophrenia experiencing higher or lower agitation: a post hoc analysis of 4 randomized, placebo-controlled clinical trials.

OBJECTIVE: Patients with acute schizophrenia who are agitated typically manifest worse overall symptomatology and are generally more challenging to treat than nonagitated patients. In order to determine whether baseline agitation level influences treatment response, the effects of oral aripiprazole in acute patients with schizophrenia experiencing either higher or lower levels of agitation were examined. METHOD: A post hoc analysis of pooled data from the first 4 or 6 weeks of 4 randomized, double-blind, placebo-controlled aripiprazole trials was conducted. Patients with a DSM-IV diagnosis of acute schizophrenia randomly assigned to treatment with either aripiprazole 10, 15, 20, or 30 mg/day (N = 790) or placebo (N = 397) were divided into groups experiencing higher or lower agitation at baseline. Higher agitation was defined as a baseline Positive and Negative Syndrome Scale (PANSS)-Excited Component (PEC) score of > or = 14 and a score of > or = 4 on at least 1 PEC item (excitement, hostility, tension, uncooperativeness, or poor impulse control). Analysis of covariance was used to evaluate PANSS total, Clinical Global Impressions-Improvement scale (CGI-I), and PEC scores between aripiprazole and placebo within the higher and lower agitation groups. RESULTS: In both the higher and lower agitation groups, aripiprazole treatment produced significantly lower PANSS total, CGI-I, and PEC scores at weeks 2 to 6, compared with placebo (p < .05 for each measure). Percentage of concomitant benzodiazepine use was similar at end point for aripiprazole and placebo, and adverse events were generally mild across groups. CONCLUSIONS: Aripiprazole significantly improved the core symptoms of acute schizophrenia regardless of baseline agitation level. In particular, agitation symptoms were significantly decreased in patients with higher baseline agitation. Improvements appeared to be independent of benzodiazepine use or excessive sedation effects. These results suggest that oral aripiprazole is an effective and safe treatment option for patients with acute schizophrenia who manifest agitation symptoms.

Does cognitive function improve with quetiapine in comparison to haloperidol?

Recent evidence suggests that schizophrenia patients taking atypical antipsychotic medications may perform better on some tests of cognitive function than those treated with older antipsychotics. The current study compared the effects of quetiapine and haloperidol on measures of executive function, memory and attention. Subjects were 58 stable outpatients with schizophrenia (DSM III-R) who received a battery of cognitive tests as part of a randomized, double-blind, multi-site clinical efficacy study conducted by AstraZeneca Pharmaceuticals. Cognitive assessments were conducted prior to randomization when patients were receiving < or =30 mg haloperidol or equivalent (mean: 9.2mg/day haloperidol equivalents), and again after 24 weeks of fixed-dose treatment with either quetiapine 600 or 300 mg/day or haloperidol 12 mg/day. Analyses of covariance with planned comparisons were used to compare scores on cognitive measures at the end of 24 weeks by treatment group with baseline cognitive function scores used as covariates. Patients receiving quetiapine 600 mg/day improved to a greater extent than patients receiving haloperidol on overall cognitive function (p<0.02). Specific differences were found for executive function (Verbal Fluency Test, p<0.04), attention (Stroop Color Word Test, p<.03) and verbal memory (Paragraph Recall Test, p<0.02). Treatment group differences were not solely due to benztropine use, medication side effects, or changes in symptomatology. Treatment with quetiapine at higher doses (600 mg/day) relative to haloperidol appears to have a positive impact on important domains of cognitive performance that have been found to predict role function and community outcomes in patients with schizophrenia.