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Background: Although antipsychotic agents have a long history of use in depression, their effectiveness in treating core symptoms of depression such as loss of interest has been questioned. Adjunctive aripiprazole is beneficial for the treatment of patients with major depressive disorder but its effects on specific symptoms have not been reported. The objective of this study was to examine the effects of aripiprazole on core symptoms of depression., Methods: This is a post-hoc, pooled analysis of two trials of aripiprazole augmentation of standard antidepressants (ADT) in patients with major depression. Patients with an inadequate response to ADT received adjunctive aripiprazole (n=373) or placebo (n=368) for 6 weeks. Change on four subscales of the 17-item Hamilton Depression Rating Scale (HAM-D17) that capture core depression symptoms was determined and change on individual HAM-D items also was assessed. The magnitude of within-group change for the subscales and individual items was expressed as effect size (ES) and between-group significance tested with ANCOVA. The magnitude of change was also examined comparing the response rates for aripiprazole and placebo on HAM-D17 and the four subscales. Change on three composite subscales - anxiety, insomnia and drive was also examined., Results: Within-group change on the four core subscales was substantial (ES=1.1-1.2) and similar to that for the 17-item HAM-D total score. Between-group comparisons indicated mean change and response rates were significantly greater with adjunctive aripiprazole than placebo for each core subscale (all p<0.01). Individual HAM-D17 items showing the greatest change from baseline with adjunctive aripiprazole: depressed mood (within-group ES=1.03) work and activities (ES=0.86), guilt (ES=0.77) and psychic anxiety (ES=0.67) are the same symptoms identified by each of the core subscales and each of these items differed significantly from change on that item with placebo (p<0.01). On three composite scales, adjunctive aripiprazole was significantly more effective than placebo with respect to mean change for anxiety, insomnia and drive (all p<0.001)., Conclusions: Aripiprazole augmentation of standard ADT results in significant, clinically meaningful changes in the core symptoms of depression. It is also associated with significant change in anxiety, insomnia, and drive components of the 17-item HAM-D.

Objective: The authors sought to determine by meta-analysis the efficacy and tolerability of adjunctive atypical antipsychotic agents in major depressive disorder., Method: Searches were conducted of MEDLINE/PubMed (1966 to January 2009), the Cochrane database, abstracts of major psychiatric meetings since 2000, and online trial registries. Manufacturers of atypical antipsychotic agents without online registries were contacted. Trials selected were acute-phase, parallel-group, double-blind controlled trials with random assignment to adjunctive atypical antipsychotic or placebo. Patients had nonpsychotic unipolar major depressive disorder that was resistant to prior antidepressant treatment. Response, remission, and discontinuation rates were either reported or obtained. Data were extracted by one author and checked by the second. Data included study design, number of patients, patient characteristics, methods of establishing treatment resistance, drug doses, duration of the adjunctive trial, depression scale used, response and remission rates, and discontinuation rates for any reason or for adverse events., Results: Sixteen trials with 3,480 patients were pooled using a fixed-effects meta-analysis. Adjunctive atypical antipsychotics were significantly more effective than placebo (response: odds ratio=1.69, 95% CI=1.46-1.95, z=7.00, N=16, p<0.00001; remission: odds ratio=2.00, 95% CI=1.69-2.37, z=8.03, N=16, p<0.00001). Mean odds ratios did not differ among the atypical agents and were not affected by trial duration or method of establishing treatment resistance. Discontinuation rates for adverse events were higher for atypical agents than for placebo (odds ratio=3.91, 95% CI=2.68-5.72, z=7.05, N=15, p<0.00001)., Conclusions: Atypical antipsychotics are effective augmentation agents in major depressive disorder but are associated with an increased risk of discontinuation due to adverse events.

Major depressive disorder (MDD) is a disabling psychiatric condition for which effective treatment remains an outstanding need. Antidepressants are currently the mainstay of treatment for depression; however, almost two-thirds of patients will fail to achieve remission with initial treatment. As a result, a range of augmentation and combination strategies have been used in order to improve outcomes for patients. Despite the popularity of these approaches, limited data from double-blind, randomized, placebo-controlled studies are available to allow clinicians to determine which are the most effective augmentation options or which patients are most likely to respond to which options. Recently, evidence has shown that adjunctive therapy with atypical antipsychotics has the potential for beneficial antidepressant effects in the absence of psychotic symptoms. In particular, aripiprazole has shown efficacy as an augmentation option with standard antidepressant therapy in two, large, randomized, double-blind studies. Based on these efficacy and safety data, aripiprazole was recently approved by the FDA as adjunctive therapy for MDD. The availability of this new treatment option should allow more patients with MDD to achieve remission and, ultimately, long-term, successful outcomes.

Objective: Second-generation antidepressants are commonly used to treat major depression in late-life. This systematic review and meta-analysis was undertaken to assess the evidence for efficacy of second-generation antidepressants in late-life major depression., Methods: The Cochrane Library (2006 [3]), MEDLINE (1966 to August 2006), and meeting presentations were searched for trials of second-generation antidepressants (nontricyclics) marketed in the United States. Published and unpublished placebo-controlled randomized clinical trials in outpatients 60 years and older, with nonpsychotic, unipolar major depression were selected. Clinical characteristics and outcomes were extracted. Outcomes were expressed as odds ratios (OR), risk differences, and weighted mean differences., Results: Ten unique trials (four unpublished) with 13 contrasts met selection criteria. Trials were 6-12 weeks duration, and included 2,377 patients who received active drug and 1,788 received placebo. The ORs by meta-analysis for response and remission were 1.40 (95% confidence interval [CI] 1.24-1.57, z = 5.45, N = 13, p <0.001) and 1.27 (CI 1.12-1.44, z = 3.67, N = 13, p <0.001), respectively, with significant heterogeneity for response and remission among the trials. Mean pooled response rates for antidepressant and placebo were 44.4% and 34.7%, respectively. The OR for response was significantly higher in the 10-12 week trials (OR = 1.73, CI 1.42-2.09, z = 5.51, N = 5, p <0.001) than the 6-8 week trials (OR = 1.22, CI 1.05-1.42, z = 2.60, N = 8, p = 0.01). ORs for discontinuation for any reason and for adverse events were significantly higher with drugs than with placebo., Conclusions: Antidepressants are more effective than placebo in elderly depressed subjects although effects are modest and vary. Identification of the characteristics of responders and nonresponders will be crucial to improving treatment outcomes.

The goal of the present work was to conduct a meta-analysis comparing reboxetine and the selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder (MDD). Medline/Pubmed was searched for double-blind, randomized trials comparing these two agents for MDD. The makers of reboxetine (Pfizer Inc.) were also contacted to provide missing data and/or unpublished studies. 9 trials (n=2641) were combined using a random effects model. Response rates were comparable between the SSRI (63.9%) and reboxetine (59.2%)-treated groups (p=0.118). There was no significant difference in the degree of improvement in psychosocial functioning, as measured by the social adaptation self-evaluation scale, between the two groups. Overall discontinuation rates (25.1% versus 32.0%; p=0.015), and the rate of discontinuation due to intolerance (8.5% versus 12.6%; p=0.007) favored SSRI treatment. The rate of discontinuation due to lack of efficacy did not differ significantly between the two groups. SSRI-treated patients were more likely to experience nausea, hypersomnia, and fatigue. Reboxetine-treated patients were more likely to experience constipation, difficulty urinating, and insomnia. These results suggest that the NRI reboxetine and the SSRIs differ with respect to their side-effect profile and overall tolerability but not their efficacy in treating MDD.

Objective: To determine effects of sertraline on suicidal thinking and behavior in patients with late-life major depression., Methods: This was a secondary analysis of an eight-week, placebo-controlled, double-blind randomized trial of a multicenter trial at 66 clinical sites. Outpatients >/=60 years of age with major depression and a Hamilton Depression Rating (HAMD) score >/=18 were included. Intervention was sertraline 50-100 mg/day or placebo for eight weeks. Measurements were 17-item HAMD administered at baseline and two-week intervals. HAMD Item 3 used to assess suicidal ideation (SI) and behavior. Reports of serious adverse events (SAEs), adverse events (AEs) leading to discontinuation, and spontaneously reported adverse events reviewed., Results: A total of 747 patients received at least one dose of medication, and 728 had at least one posttreatment assessment. Mean age (+/-SD) was 69.8 +/- 6.7 years (range: 59-97 years) and 56% were female. There were no completed suicides or suicide attempts during the double-blind trial. One SAE, hospitalization, was associated with SI in a patient on sertraline. No other AEs were associated with SI or behavior. HAMD Item 3 ratings progressively declined during the trial with significantly lower values for sertraline than placebo (Z = 2.41, p <0.02). In 248 patients with HAMD Item 3 of zero at baseline, the percentage of patients whose Item 3 ratings increased during treatment did not differ in the two groups (22.4% versus 25.8% for sertraline and placebo, respectively.), Conclusion: Sertraline was associated with significantly lower HAMD Item 3 scores than placebo during treatment. There was no evidence of greater emergent suicidal thinking or behavior with sertraline than placebo.

Valid and reliable methods of assessing outcome in depression are crucial to antidepressant efficacy studies but are also important for all studies that relate response to other variables. In this paper we review basic issues of reliability and validity associated with outcome measurement. We distinguish between scales or inventories designed for screening or diagnosis and those intended for outcome assessment. We note historical changes in patient selection (e.g. outpatients instead of inpatients, differentiating psychotic and non-psychotic) and how these changes affect commonly used scales such as the Hamilton Depression Rating Scale. We examine whether antidepressants with different mechanisms of action are best assessed with similar or different symptoms. And we review studies that have identified 'core' symptoms of depression and compare these findings to the magnitude of individual symptom change we found in five studies of selective serotonergic or nonadrenergic antidepressants.

Background: We examined two previously published studies comparing a norepinephrine (NE) selective agent, reboxetine, and a serotonin (5-HT) selective agent, fluoxetine, to determine if these agents have different effects on individual depressive symptoms., Methods: Both studies were 8-week, double-blind, comparison studies of men and women with DSM III-R major depression. Within-group effect sizes for individual symptom change on the Hamilton Depression Rating Scale (HAMD) were determined in the observed case samples and in patients for whom the symptom was relatively severe at baseline. We required that any significant differences in one sample be cross-validated in the second., Results: Two hundred fifty-three subjects in study I and 168 subjects in study II were randomized to reboxetine or fluoxetine. In both samples, depressed mood, decreased interest, and psychic anxiety had the greatest change. Effect sizes for all HAMD symptoms were similar for the two drugs. No difference between groups in one sample was replicated in the second. Among subjects with severe symptoms, no significant differences were cross-validated., Conclusions: Reboxetine and fluoxetine appear to have similar effects on depressive symptoms. These data suggest that NE and 5-HT selective antidepressant drugs act through the same final common pathway and challenge the belief that symptom differences are useful for antidepressant selection.

Objective: The authors determined the symptoms frequently present in older patients with major depression that showed the greatest change during treatment and that best correlated with an independent measure of improvement (the Clinical Global Impression scale [CGI])., Methods: Subjects included 728 patients over the age of 60 years with major depression who were selected for entry into a clinical trial. Authors determined the frequency of symptoms on the 17-item Hamilton Rating Scale for Depression (Ham-D) and the effect size of symptom change during treatment., Results: Nine symptoms were identified that were frequent, showed the greatest change during treatment, and best correlated with CGI. The items included depressed mood; loss of interest in work and activities; psychic anxiety; somatic symptoms, general (decreased energy); somatic anxiety; guilt; middle insomnia; late insomnia; and suicidal ideation. These nine items accounted for 92% of the variance in the 17-item Ham-D score, correlated with the CGI at a level similar to the 17-item Ham-D, and were at least as sensitive as the 17-item Ham-D for detecting drug-placebo differences. A comparison with five other similar approaches in non-geriatric samples suggested that the symptoms identified were relatively similar in both age-groups., Conclusions: Symptoms frequent in patients with late-life depression are similar to those in mixed-aged samples. Nine of the Ham-D items appear most useful for assessment of change during treatment.

Objective: The efficacy and safety of duloxetine, a dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), were evaluated in the treatment of major depressive disorder (MDD) and associated pain symptoms in patients age 55 and older., Methods: Efficacy data were obtained from patients age > or =55 who participated in two identical, multicenter, double-blind studies in which patients with MDD were randomized to receive placebo (N=43) or duloxetine (60 mg/day; N=47) for 9 weeks. The primary efficacy measure was the mean change in Ham-D-17 total score. Pain symptoms were assessed with visual-analog scales. Safety data for patients age > or =55 were pooled from six randomized, 8- or 9-week, double-blind studies of duloxetine in which patients with MDD were randomized to receive placebo (N=90) or duloxetine (40 mg/day-120 mg/day; N=119)., Results: The combined results of these two investigations found that duloxetine was significantly superior to placebo for mean change in Ham-D-17 total score. The estimated probability of remission for duloxetine-treated patients (44.1%) was also significantly higher than that for placebo (16.1%). Reductions in overall pain, back pain, and pain while awake were also significantly greater for duloxetine than placebo. The rate of discontinuation due to adverse events was significantly higher for duloxetine-treated patients (21.0%) than placebo (6.7%). Abnormal elevations in vital signs at endpoint were not significantly different from placebo., Conclusions: In these two investigations, duloxetine 60 mg/day was an efficacious treatment for MDD and also alleviated pain symptoms in depression patients age 55 and older.

A sizable proportion of patients suffering from nonpsychotic unipolar depression experience only partial or no clinical response to antidepressant treatment. Switching, augmenting, and combining various pharmaceutical agents can be effective strategies for patients with treatment-resistant depression. The empirical evidence supporting these approaches is inconsistent, however, and there is a paucity of controlled studies to support their efficacy. Additionally, it has been difficult to demonstrate the advantages of these strategies over increasing the dose or duration of the initial drug treatment. This article will review available evidence and clinical considerations regarding switching, augmenting, and combining various agents in the treatment of patients suffering from nonpsychotic unipolar depression who have failed adequate courses of antidepressant treatment. More research is needed that controls for continued time on the initial agent, that compares different strategies, and that determines which patients are the best candidates for which treatment.