Meta-analysis of efficacy and treatment-emergent suicidality in adults by psychiatric indication and age subgroup following initiation of paroxetine therapy: a complete set of randomized placebo-controlled trials.

OBJECTIVE: This meta-analysis of placebo-controlled paroxetine trials examines suicidality incidence in adults, focusing on disorder and age as potential risk factors. The findings are put in context with an efficacy meta-analysis of the same trial datasets. DATA SOURCES: GlaxoSmithKline paroxetine clinical trial database(s). STUDY SELECTION: All double-blind, randomized, placebo-controlled, parallel-group studies of paroxetine therapy in adults enrolling at least 30 patients total were included in the analysis. The dataset comprised 14,911 patients from 61 trials. DATA EXTRACTION: Possible cases of suicidality were identified and blindly categorized by an expert panel, using methodology previously used by the US Food and Drug Administration. Incidences of suicidal behavior (preparatory act, suicide attempt, or completed suicide) and any suicidality (suicidal behavior or ideation) were compared between paroxetine and placebo. Efficacy assessments were based on standard depression rating scales (eg, Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale) and Clinical Global Impressions Improvement scale (CGI-I) scores. RESULTS: In the primary dataset, ie, all disorders combined, there were no significant differences between paroxetine and placebo for overall suicidality (suicidal behavior or ideation: n/n = 83/8,958 [0.93%] vs n/n = 65/5,953 [1.09%], respectively; OR = 0.9 [95% CI, 0.7-1.3]; P = .649) or for suicidal behavior specifically (n/n = 50/8,958 [0.56%] vs n/n = 40/5,953 [0.67%], respectively; OR = 1.2 [95% CI, 0.8-1.9]; P = .483). However, in patients with major depressive disorder (MDD), a greater incidence of suicidal behavior occurred in paroxetine-treated patients than in placebo-treated patients (n/n = 11/3,455 [0.32%] vs n/n = 1/1,978 [0.05%], respectively; OR = 6.7 [95% CI, 1.1-149.4]; P = .058). Across all indications, a higher incidence of suicidal behavior occurred in paroxetine-treated versus placebo-treated adults aged 18 to 24 years (n/n = 17/776 [2.19%] vs n/n = 5/542 [0.92%], respectively; OR = 2.4 [95% CI, 0.9-7.3]). In older age groups, no increase in suicidality was observed. Efficacy was demonstrated in all disorders evaluated, including MDD. CONCLUSIONS: Across all disorders, overall suicidality incidence was similar between paroxetine and placebo. However, a higher frequency of suicidal behavior occurred with paroxetine in MDD, which was largely explained by the higher incidence in young adults. These data support the efficacy of paroxetine therapy; however, they also highlight the need for careful monitoring of suicidality during antidepressant therapy, particularly in younger adults.

Clinical features of patients with treatment-emergent suicidal behavior following initiation of paroxetine therapy.

BACKGROUND: Understanding suicidal behavior is an important component of assessing suicidality in psychiatric patients. GlaxoSmithKline (GSK) conducted a meta-analysis of randomized, placebo-controlled trials to compare suicidality in adult patients treated with paroxetine vs. placebo. The goal was to identify emergent clinical characteristics of patients with definitive suicidal behavior (DSB: preparatory act, suicide attempt, completed suicide). METHODS: The dataset comprised 14,911 patients from 57 placebo-controlled paroxetine trials. Possible cases of suicidality were identified and were blindly reviewed by an expert panel, which categorized cases as suicidal or non-suicidal. DSB incidences were compared between paroxetine and placebo. Clinical narratives and case report forms for major depressive disorder (MDD) and anxiety disorder patients with DSB were reviewed. For MDD, rating scale items relating to suicidality, insomnia, agitation, and anxiety were examined. RESULTS: Overall (all indications) there were no differences between paroxetine and placebo for DSB (50/8958 [0.56%] vs. 40/5953 [0.67%], respectively; OR=1.2 [CI 0.8, 1.9]; p=0.483). However, in patients with major depressive disorder (MDD), the incidence of DSB was greater for paroxetine (11/3455 [0.32%] vs. 1/1978 [0.05%], OR=6.7 [CI 1.1, 149.4]; p=0.058). Review of the 11 paroxetine MDD cases revealed common clinical features: symptomatic improvement; younger age (18-30 years); psychosocial stressors; overdose as method; and absent/mild suicidal ideation at the visit prior to the event. There was no evidence for a consistent adverse event profile or onset of akathisia/agitation or a manic/mixed state. Anxiety disorder patients with DSB had a heterogeneous clinical picture. LIMITATIONS: Limitations to the study include the relatively small number of cases and the retrospective nature of the study. CONCLUSIONS: DSB incidence was similar between paroxetine and placebo overall, but a higher frequency of DSB was found for paroxetine in MDD patients, driven by young adults aged < or =30 years. Most MDD patients with DSB improved prior to the attempt and experienced a psychosocial stressor. Patients should receive careful monitoring for suicidality during paroxetine therapy.

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.

Dynamics of ribulose 1,5-bisphosphate carboxylase/oxygenase gene expression in the coccolithophorid Coccolithus pelagicus during a tracer release experiment in the Northeast Atlantic.

We report a pronounced diel rhythm in ribulose 1,5-bisphosphate carboxylase/oxygenase (RubisCO) gene expression in a natural population of the coccolithophorid Coccolithus pelagicus sampled during a Lagrangian experiment in the Northeast Atlantic. Our observations show that there is greater heterogeneity in the temporal regulation of RubisCO expression among planktonic chromophytes than has been reported hitherto.

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.

Efficacy of controlled-release paroxetine in the treatment of late-life depression.

BACKGROUND: Depression is the second most common neuropsychiatric disorder in older Americans, with significant clinical and public health costs. Despite advances in treatment, late-life depression remains a clinical challenge. Although the selective serotonin reuptake inhibitors (SSRIs) are the most common pharmacologic intervention for late-life depression, few placebo-controlled trials have assessed the efficacy of SSRIs for this condition. METHOD: In this 12-week, multicenter, placebo-controlled, flexible-dose, double-blind, randomized trial, 319 elderly patients (mean age = 70 years) were treated with controlled-release paroxetine (paroxetine CR) up to 50 mg/day (N = 104), immediate-release paroxetine (paroxetine IR) up to 40 mg/day (N = 106), or placebo (N = 109). Patients met DSM-IV criteria for major depressive disorder and had a total score of 18 or more on the 17-item Hamilton Rating Scale for Depression (HAM-D). The primary efficacy measure was change from baseline to endpoint in HAM-D total score. RESULTS: The primary efficacy analysis showed an adjusted difference between change from baseline in HAM-D score for paroxetine CR and placebo of -2.6 (95% confidence interval [CI] = -4.47 to -0.73, p = .007) at the week 12 last-observation-carried-forward (LOCF) endpoint. The adjusted difference between paroxetine IR and placebo was -2.8 (95% CI = -4.65 to -0.99, p = .003) at week 12. Paroxetine CR and IR were more effective than placebo, with mean +/- SD endpoint HAM-D total scores of 10.0 +/- 7.41 and 10.0 +/- 7.10, respectively, for the active treatments compared with 12.6 +/- 7.34 for placebo. Response, defined as a score of 1 or 2 on the Clinical Global Impressions-global improvement scale, was achieved by 72% of paroxetine CR patients (LOCF; p < .002 vs. placebo), 65% of paroxetine IR patients (p = .06 vs. placebo), and 52% of placebo patients. Remission, defined as a HAM-D total score < or = 7, was achieved by 43% of paroxetine CR patients (LOCF; p = .009 vs. placebo), 44% of paroxetine IR patients (p = .01 vs. placebo), and 26% of placebo patients. In a post hoc analysis, mean HAM-D improvement for paroxetine CR and paroxetine IR was greater than for placebo in both chronically depressed patients (duration > 2 years) and those with short-term (< or = 2 years) depression. Dropout rates due to adverse events were 12.5% for paroxetine CR, 16.0% for paroxetine IR, and 8.3% for placebo. CONCLUSION: Paroxetine CR and paroxetine IR are effective and well tolerated treatments for major depressive disorder in elderly patients, including those with chronic depression.