An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression.

OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of cariprazine, an atypical antipsychotic candidate, in adult patients with acute bipolar I depression. METHOD: This was an 8-week multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in adult patients with bipolar I disorder experiencing a current major depressive episode. Patients were randomly assigned (1:1:1:1) to receive placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day. The primary and secondary efficacy parameters were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity subscale (CGI-S), respectively, analyzed using a mixed-effects model for repeated measures on the modified intent-to-treat population. RESULTS: The intent-to-treat population comprised 571 patients (141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups). Cariprazine at 1.5 mg/day showed significantly greater improvement on MADRS total score change from baseline to week 6 compared with placebo; the least squares mean difference was -4.0 (95% CI=-6.3, -1.6; significant after adjustment for multiple comparisons). Cariprazine at 3.0 mg/day showed greater MADRS score reduction than placebo (-2.5, 95% CI=-4.9, -0.1; not significant when adjusted for multiple comparisons). The 0.75 mg/day dosage was similar to placebo. A similar pattern for significance was observed on the CGI-S (1.5 mg/day: least squares mean difference=-0.4, 95% CI=-0.6, -0.1; 3.0 mg/day: -0.3, 95% CI=-0.5, -0.0). The most common adverse events (≥10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo. CONCLUSIONS: Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting efficacy for the treatment of bipolar I depression.

Low doses of controlled-release paroxetine in the treatment of late-life depression: a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and tolerability of low daily doses of controlled-release (CR) paroxetine in patients with late-life depression. METHOD: This was a 10-week, multicenter, placebo-controlled, double-blind, fixed-dose trial randomly assigning patients >or= 60 years old to daily doses of paroxetine CR 12.5 mg (N = 168), paroxetine CR 25 mg (N = 177), or placebo (N = 180). Patients had major depressive disorder (DSM-IV criteria) and 17-item Hamilton Rating Scale for Depression (HAM-D) total scores of >or= 18. The primary efficacy variable was the change from baseline to study endpoint in total HAM-D scores. The study was conducted from June 2003 to October 2004. RESULTS: The drug/placebo difference in HAM-D change from baseline at study endpoint was -1.8 (95% CI = -3.41 to -0.19, p = .029) for paroxetine CR 12.5 mg, and -3.3 (95% CI = -4.84 to -1.68, p < .001) for paroxetine CR 25 mg. A significantly larger percentage of patients achieved remission (HAM-D total score or= 60 years of age, although effect sizes are relatively smaller with the 12.5 mg/day dose.

Deficiencies in suicide training in primary care specialties: a survey of training directors.

OBJECTIVE: A high percentage of suicide victims have seen a primary care physician in the months before committing suicide. Thus, primary care physicians may play an important role in suicide prevention. METHOD: The authors mailed a survey to directors of training programs in family practice, internal medicine, and pediatrics, and 50.5% responded. Data obtained were analyzed with WebStat. RESULTS: Training directors reported deficiencies in training in suicide and depression. Notably, less than half of the internal medicine and pediatrics training directors who replied reported that teaching about suicide was adequate. The majority of them indicated a need for standardized curricular materials on suicide and depression. CONCLUSIONS: Experts could provide standardized curricula to primary care residencies in the recognition and management of suicide and depression. More robust training about these vital mental health concerns in primary care could reduce morbidity and mortality.

Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy and tolerability of paroxetine in pediatric major depressive disorder. METHOD: Subjects 7 to 17 years old with major depressive disorder received paroxetine (10-50 mg/day) or placebo for 8 weeks from 2000 to 2001. The primary efficacy measure was change from baseline in the Children's Depression Rating Scale-Revised total score at week 8 last observation carried forward). Safety was primarily assessed by spontaneous reporting of adverse events. RESULTS: A total of 206 patients (intent to treat) were randomized to paroxetine (n = 104) or placebo (n = 102). Week 8 Children's Depression Rating Scale-Revised total score adjusted mean changes from baseline for patients receiving paroxetine and placebo were -22.58 (SE 1.47) and -23.38 points (SE 1.60), respectively (0.80, 95% confidence interval -3.09 to 4.69, p = 0.684). Increased cough (5.9% versus 2.9%), dyspepsia (5.9% versus 2.9%), vomiting (5.9% versus 2.0%), and dizziness (5.0% versus 1.0%) occurred in >or=5% of the paroxetine group and at least twice that of the placebo group. Six of 104 (5.8%) paroxetine patients reported serious adverse events compared to 1 placebo patient (1.0%). The incidence of adverse events of suicidal behavior and/or ideation while taking study medication (excluding taper) was 1.92% (2/104) for paroxetine versus 0.98% (1/102) for placebo. CONCLUSIONS: Paroxetine was not shown to be more efficacious than placebo for treating pediatric major depressive disorder.

Analysis of electrocardiographic data following use of paroxetine in pediatric depression and obsessive-compulsive disorder.

OBJECTIVE: This retrospective analysis of electrocardiographic (ECG) data investigated the cardiovascular effects of paroxetine 10-50 mg/day in pediatric patients (7-18 years of age). Data were collected from three 8- to 10-week, randomized, placebo-controlled, double-blind trials of paroxetine in pediatric patients with major depressive disorder or obsessive-compulsive disorder. METHOD: Electrocardiograms (ECGs) were retrospectively retrieved from 63 study sites in the United States and Canada. Only patients with at least one screening and one on-treatment ECG were included. ECGs were analyzed for heart rate, QT interval corrected using Bazett's formula (QTcB) and Fridericia's formula (QTcF), at screening and while being treated. PR, R-R, and QRS intervals and the maximum change in QTcB and QTcF from screening to endpoint were determined. Clinically significant thresholds were defined a priori. RESULTS: A total of 1,451 ECGs from 449 patients receiving placebo (n = 207), paroxetine (n = 200), or imipramine (n = 42) were analyzed. Treatment with paroxetine did not significantly increase QTcB or QTcF or any ECG parameters compared with placebo. Treatment with imipramine significantly increased heart rate and QTcB, R-R, and QRS intervals compared with either paroxetine or placebo. CONCLUSIONS: Data from this retrospective study indicate that paroxetine (10-50 mg/day) is unlikely to be associated with significant ECG changes in medically healthy pediatric patients.

Evaluation of suicidal thoughts and behaviors in children and adolescents taking paroxetine.

OBJECTIVE: The aim of this study was to summarize results of a blinded review of potential suicidal events and analyses comparing incidence rates between paroxetine- and placebo-treated pediatric patients. METHOD: One thousand one hundred ninety-one (1191) children and adolescents received paroxetine (n = 642) or placebo (n = 549) during placebo-controlled portions of all acute double-blind trials of paroxetine (n = 5). An expert panel blindly reviewed and categorized all identified cases detected by electronic and manual search of adverse events (AEs), serious AEs, and selected cases as suicidal or non-suicidal behavior. Incidence rates were calculated for suicide-related events and for rating scale items assessing suicidality. RESULTS: Suicide-related events occurred more often in paroxetine (22 of 642, 3.4%) than placebo groups (5 of 549, 0.9%); odds ratio (OR) 3.86 (95% CI 1.45, 10.26; p = 0.003). All suicide-related events occurred in adolescents of at least 12 years, except for 1 of 156 paroxetine-treated children. All suicide attempts occurred in major depressive disorder (MDD); few suicide-related events occurred in patients with a primary anxiety disorder. Suicide item analyses did not reveal significant differences between paroxetine and placebo. CONCLUSIONS: Adolescents treated with paroxetine showed an increased risk of suicide-related events. Suicidality rating scales did not show this risk difference. The presence of uncontrolled suicide risk factors, the relatively low incidence of these events, and their predominance in adolescents with MDD make it difficult to identify a single cause for suicidality in these pediatric patients.

Efficacy and tolerability of controlled-release paroxetine in the treatment of severe depression: post hoc analysis of pooled data from a subset of subjects in four double-blind clinical trials.

OBJECTIVES: The aims of this work were to assess the efficacy and tolerability of controlled-release paroxetine (paroxetine CR) in the treatment of outpatients with severe major depressive disorder (MDD). METHODS: This was a retrospective analysis of pooled data from 4 previously published, double-blind, randomized, placebo-controlled, 8- to 12-week outpatient studies of paroxetine CR (12.5-62.5 mg) in MDD. However, the studies were designed to assess the efficacy of paroxetine CR overall, rather than specifically in those with severe MDD. Subjects were categorized according to their baseline mean 17-item Hamilton Depression Rating Scale (HAMD-17) total score as having severe (> or =25) or nonsevere (<25) depression. Changes in depressive symptomatology were assessed, based on the mean change from baseline in HAMD-17 total scores and the proportion of responders (> or =50% reduction from baseline in HAMD-17 total scores or Clinical Global Impression [CGI] of Improvement scores of 1 or 2), for each study and pooled across the studies. The pooled analysis of data also assessed the proportion of patients achieving remission (HAMD-17 total score < or =7 or CGI-Improvement score of 1) at last-observation-carried-forward end point. RESULTS: A total of 1083 subjects participated in the 4 studies; 303 had severe MDD (paroxetine CR, n = 174; placebo, n = 129). Among the patients with severe MDD, most were women, had a mean HAMD-17 score between 26.3 and 27.7, and had a mean CGI of Severity score between 4.5 and 4.9. In 3 studies, the mean age of such participants was between 35 and 43 years. However, the fourth study was an evaluation in late-life depression in which the mean age was 71.3 years in the paroxetine CR group and 70.0 years in the placebo group. In the overall pooled sample, significantly greater improvements in depressive symptoms were observed among those with severe MDD who were treated with paroxetine CR compared with those who received placebo (HAMD-17 total treatment difference, -4.37 [95% CI, -6.31 to -2.42; P < 0.001]). The odds of CGI-Improvement response were also significantly higher for patients receiving paroxetine CR than those receiving placebo, regardless of baseline depressive symptomatology (severe MDD: odds ratio [OR], 2.42 [95% CI, 1.50-3.91; P < 0.001]; nonsevere MDD: OR, 1.63 [95% CI, 1.21-2.19; P < 0.002] ). Withdrawal rates due to adverse events were 9.8% versus 5.4% (severe) and 5.2% versus 4.5% (nonsevere), paroxetine CR versus placebo, respectively. CONCLUSIONS: This post hoc analysis of pooled data suggests that paroxetine CR was effective and well tolerated in these outpatients with severe MDD.

Determination of precipitating events in the suicide of psychiatric patients.

Data from therapists who were treating patients when they killed themselves were used to provide information about precipitating events that was missing from accounts obtained from suicide victims' relatives and friends. Among 26 patient suicides studied, the therapists identified a precipitating event in 25 cases; in 19 of these, supporting evidence linked the identified event to the suicide. A schema was developed that identifies nine types of evidence provided by therapists in determining that an event precipitated the suicide. Use of the schema is likely to improve accurate identification of events that precipitate patient suicides, and distinguish them from unrelated coterminous events or suicide risk factors.