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Objective Differential predictors of response to alternative treatment options are needed to improve the outcomes in major depressive disorder. The symptom dimension comprising loss of interest and reduced activity has been reported as a predictor of poor outcome of treatment with antidepressants. We hypothesized that augmentation with partial dopamine agonist aripiprazole will be effective for individuals with pronounced interest-activity symptoms. Methods We tested the hypothesis in the 2-phase Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1). All participants had a primary diagnosis of major depressive disorder confirmed with the Mini-International Neuropsychiatric Interview. In phase 1, 188 individuals received escitalopram monotherapy 10-20 mg daily for 8 weeks. In phase 2, nonresponders received augmentation with aripiprazole 2-10 mg daily while responders continued escitalopram monotherapy for another 8 weeks. Outcomes were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) every 2 weeks. Effects of baseline interest-activity symptoms on outcomes were tested in repeated-measures mixed-effects models. Results Higher baseline interest-activity score (indicative of more severe loss of interest and reduction in activity) predicted worse outcome of escitalopram monotherapy in phase 1 (b = 1.75; 95% CI, 0.45 to 3.05; P = .009), but the association disappeared with the augmentation option in phase 2 (b = -0.19; 95% CI, -1.30 to 0.92; P = .739). A significant interaction between the baseline interest-activity score and aripiprazole reflected the opposite direction of the relationship between baseline interest-activity score and degree of improvement with escitalopram monotherapy versus aripiprazole augmentation (b = -1.60; 95% CI, -2.35 to -0.84; P Conclusions Individuals with prominent loss of interest and reduction in activity benefit less from escitalopram monotherapy and more from aripiprazole augmentation. Future trials may test the benefits of early prodopaminergic augmentation guided by interest-activity symptoms. Trial registration ClinicalTrials.gov identifier: NCT01655706. more...

OBJECTIVE To report the symptomatic and functional outcomes in patients with major depressive disorder (MDD) during a 2-phase treatment trial and to estimate the value of early improvement after 2 weeks in predicting clinical response to escitalopram and subsequently to adjunctive treatment with aripiprazole. METHODS Participants with MDD (N = 211) identified with the Montgomery-Asberg Depression Rating Scale (MADRS) and confirmed with the Mini-International Neuropsychiatric Interview were recruited from 6 outpatient centers across Canada (August 2013 through December 2016) and treated with open-label escitalopram (10-20 mg) for 8 weeks (Phase 1). Clinical and functional outcomes were evaluated using the MADRS, Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), Sheehan Disability Scale (SDS), and Lam Employment Absence and Productivity Scale (LEAPS). Participants were evaluated at 8 and 16 weeks for clinical and functional response and remission. Phase 1 responders continued escitalopram while nonresponders received adjunctive aripiprazole (2-10 mg) for a further 8 weeks (Phase 2). RESULTS After Phase 1, MADRS response (≥ 50% decrease from baseline) and remission (score ≤ 10) were, respectively, 47% and 31%, and SDS response (score ≤ 12) and remission (score ≤ 6) were, respectively, 53% and 24%. Response to escitalopram was maintained in 91% of participants at week 16, while 61% of the adjunctive aripiprazole group achieved MADRS response during Phase 2. Response and remission rates with the QIDS-SR were lower than with the MADRS. The LEAPS demonstrated significant occupational improvement (P < .05). Early symptomatic improvement predicted outcomes with modest accuracy. CONCLUSIONS This study demonstrates comparable symptomatic and functional outcomes to those of other large practical-design studies. There was a high response rate with the adjunctive use of aripiprazole in escitalopram nonresponders. Given the limited value of early clinical improvement to predict outcome, integration of clinical and biological markers deserves further exploration. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01655706. more...

OBJECTIVE To evaluate the efficacy, safety, and tolerability of adjunctive osmotic-release oral system (OROS) methylphenidate in outpatients with major depressive disorder (MDD) receiving a stable oral antidepressant regimen. METHOD This multicenter, double-blind, randomized, placebo-controlled, parallel-group, 5-week trial enrolled 145 subjects who met DSM-IV-TR criteria for MDD and who had failed 1 to 3 previous antidepressant monotherapies (including current antidepressant) of adequate dose and duration. Augmentation therapy was initiated with 18 mg of OROS methylphenidate and increased to a maximum dose of 54 mg of OROS methylphenidate until an optimal dose was achieved. Efficacy scales included the Montgomery-Asberg Depression Rating Scale (MADRS), 7 atypical items from the 31-item Hamilton Rating Scale for Depression, the Clinical Global Impressions-Severity of Illness (CGI-S) scale, the CGI-Improvement scale (CGI-I), the Sex Effects scale, the Multidimensional Assessment of Fatigue (MAF) scale, and the Apathy Evaluation Scale (AES). Subjects were recruited at 17 community and academic centers across Canada. The study was conducted from June 8, 2005, to April 18, 2006. RESULTS There was no statistically significant difference between the groups at endpoint on the MADRS. OROS methylphenidate was superior to placebo in improving apathy and fatigue as measured by the AES and the MAF. Statistically significant differences using mixed-model analysis were observed on the AES at all visits and at endpoint (p = .01) and on the MAF (p < .01). No differences were observed on other secondary measures, including the CGI-I and CGI-S. There were no clinically significant findings on electrocardiogram. CONCLUSIONS OROS methylphenidate did not demonstrate statistical significance on the MADRS at endpoint. Apathy and fatigue were significantly improved with OROS methylphenidate treatment, which was well tolerated with minimal side effects. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov identifier NCT00246233. more...

BACKGROUND The selective serotonin reuptake inhibitor sertraline has been shown to be efficacious and well tolerated for the treatment of major depressive disorder. Relatively few trials, however, have examined the role of pharmacotherapy in dysthymia without concurrent major depression. The current investigation focuses on the use of sertraline for the treatment of dysthymia. METHOD In this 12-week, multicenter, double-blind study, 310 patients with a DSM-III-R diagnosis of dysthymic disorder without concurrent major depression were randomly assigned to receive either sertraline (N = 158) or placebo (N = 152). Sertraline was initiated at a dose of 50 mg daily, with titration permitted to a maximum of 200 mg daily. The primary evaluation criteria were the Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorder Version (SIGH-SAD), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) scales. RESULTS Mean percentage reductions for the intent-to-treat population in SIGH-SAD scores were 44.6% for the sertraline-treated group and 33.2% for the placebo-treated group (p = .03); MADRS scores, 43.6% and 33.0% (p = .02); and CGI-S scores, 32.8% and 22.8% (p = .02). A significantly greater proportion of the sertraline-treated group was classified as responders (defined for HAM-D and MADRS scores as a 50% score reduction and for CGI-I as a score of 1 or 2 by the final visit) and remitters (SIGH-SAD score < or = 8) relative to the placebo-treated group by the final visit. In addition, sertraline-treated patients experienced greater improvements in all 9 domains of the Battelle Quality of Life Questionnaire than placebo-treated patients did, with a significant difference observed in favor of sertraline in 8 of the 9 domains. The life satisfaction and social interaction quality of life domains showed significantly greater response in sertraline responders compared with placebo SIGH-SAD responders. Sertraline was well tolerated. Thirteen percent of the sertraline-treated group versus 8% of the placebo-treated group withdrew from therapy owing to adverse events (p = .14). CONCLUSION Sertraline is efficacious and well tolerated in the short-term treatment of dysthymia without concurrent major depression. more...

BACKGROUND: We conducted a randomized, double-blind, placebo-controlled study of the efficacy and safety of once-daily venlafaxine extended release (XR) and fluoxetine in outpatients with major depression and concomitant anxiety. METHOD: Patients who met DSM-IV criteria for major depressive disorder and satisfied eligibility criteria were randomly assigned to once-daily venlafaxine XR, fluoxetine, or placebo for 12 weeks. Efficacy was assessed with the Hamilton Rating Scale for Depression (HAM-D), Hamilton Rating Scale for Anxiety (HAM-A), and Clinical Global Impressions scale. RESULTS: Among 359 outpatients, venlafaxine XR and fluoxetine were significantly superior (p < .05) to placebo on the HAM-D total score beginning at week 2 and continuing to the end of the study. Venlafaxine XR but not fluoxetine was significantly better than placebo at week 2 on the HAM-D depressed mood item. At week 12, the HAM-D response rate was 43% on placebo, 67% on venlafaxine XR, and 62% on fluoxetine (p < .05). The HAM-D remission rate was significantly higher (p < .05) at weeks 3, 4, 6, 8, 12, and final evaluation with venlafaxine XR and at weeks 8, 12, and final evaluation with fluoxetine than with placebo. The HAM-A response rate was significantly higher (p < .05) with venlafaxine XR than with fluoxetine at week 12. The incidence of discontinuation for adverse events was 5% with placebo, 10% with venlafaxine XR, and 7% with fluoxetine. CONCLUSION: Once-daily venlafaxine XR is effective and well tolerated for the treatment of major depression and concomitant anxiety and provides evidence for superiority over fluoxetine. more...

Background 60%-90% of patients with a primary diagnosis of depression also experience symptoms of anxiety, and such patients have a poorer prognosis than those with uncomplicated depression. The serotonin selective reuptake inhibitors have demonstrated efficacy in the treatment of both depression and certain anxiety states. Furthermore, in a metaanalysis of the paroxetine clinical trial database of 2963 patients in whom depression predominated, there was a concomitant reduction in the Hamilton Rating Scale for Depression anxiety factor. The purpose of the present study was to prospectively compare the efficacy of paroxetine and clomipramine in patients specifically selected for coexisting depression and anxiety. Method This was a 12-week, double-blind, parallel-group trial comparing paroxetine 20-40 mg/day with clomipramine 75-150 mg/day in 1002 patients with a Montgomery-Asberg Depression Rating Scale (MADRS) score > or = 20 and a Clinical Anxiety Score (CAS) > or = 11 after a 3-7 day placebo run-in period. Results Both paroxetine and clomipramine reduced the MADRS and CAS ratings at 2, 6, and 12 weeks and at endpoint, with no significant differences between treatment groups at any time point. CGI severity of illness and global improvement ratings were also similar throughout the trial; however, there was a statistically significant difference in the CGI efficacy index at 6 weeks and at endpoint, favoring paroxetine (p = .015 and p = .015, respectively). Paroxetine resulted in fewer treatment-emergent adverse experiences and related withdrawals than clomipramine (p = .025 and p = .008, respectively). The number of serious adverse experiences was not significantly different in the paroxetine group compared with the clomipramine group (14 [2.8%] vs. 27 [5.4%]), but did approach statistical significance (p = .056). Anticholinergic-emergent adverse experiences were reported twice as frequently by patients in the clomipramine group as in the paroxetine group (36.1% vs. 18.6%). Conclusion There was no evidence of any significant difference in efficacy between paroxetine and clomipramine in patients with coexisting depression and anxiety. However, paroxetine was better tolerated as shown by total treatment-emergent adverse experiences, anticholinergic adverse experiences, and withdrawals due to adverse experiences. more...

While a significant body of research has demonstrated high comorbidity rates between depression and obesity, the vast majority of this work has considered depression as a unitary diagnosis. Given that increased appetite and weight gain are highly characteristic of the "atypical" subtype of depression, while classic depression is characterized by decreased appetite and weight loss, it would be important to examine whether increased obesity risk is consistent across the major vegetative subtypes of depression or is limited to the atypical subtype.Using data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), we identified 5,092 US adults with past or current major depression based on DSM-IV-TR criteria and 1,500 gender-matched controls. Each depressed subject was designated as having classic, atypical, or undifferentiated depression based on core vegetative symptoms. Logistic regression models examined rates of current obesity (defined as a current body mass index [kg/m2]30) across the 3 depressive subgroups and nondepressed controls, adjusting for demographic differences. To limit the possible effect of current depressive symptoms on observed obesity rates, secondary analyses were completed in individuals with past depression only.Subjects with atypical depression had markedly elevated obesity rates compared to population controls and to other depressed subjects, with corresponding pairwise odds ratios consistently greater than 2.0 (P.001). In contrast, obesity rates were not significantly different in subjects with classic depression and nondepressed controls. These results were manifest in individuals with either current or past depression and were independent of gender and age.While many individuals with classic depression will present with obesity due to the high prevalence of both disorders, only atypical depression is associated with an elevated risk of obesity relative to the population at large. Refining the target phenotype(s) for future work on depression and obesity might improve our understanding, prevention, and treatment of this complex clinical problem. more...

Objective To evaluate the efficacy and safety of intermittent, luteal phase-only administration of paroxetine (10 mg and 20 mg) in the treatment of premenstrual dysphoric disorder (PMDD). Method In this multicenter trial, female outpatients (aged 18-45 years) from 4 Canadian health centers meeting DSM-IV criteria for PMDD were asked to perform daily ratings of their premenstrual symptoms for 2 consecutive menstrual cycles. Those displaying the symptoms of irritability and/or depressed mood in the luteal phases but not in the follicular phases of their menstrual cycles were randomly assigned to intermittent, luteal phase-only treatment with paroxetine 10 mg or 20 mg or placebo for 4 additional cycles. The primary efficacy endpoint was the percent change from baseline at study endpoint on the visual analog scale irritability score. Treatment differences were tested using analysis of covariance ad hoc. Estimated treatment mean differences and their associated 95% confidence intervals were also calculated. Data were collected from May 1999 to November 2002. Results Ninety-nine patients were included in the intention-to-treat population. When compared with placebo, patients treated with paroxetine 20 mg attained a significant reduction in irritability (difference in median percent change: -23.9, 95% CI = -51.3 to -6.2, p = .014; difference in mean absolute change: -18.6, 95% CI = -32.5 to -4.6, p = .007). A statistically significant difference was not observed when the patients treated with the lower dose of paroxetine (10 mg) were compared with placebo. Treatment was well tolerated with no unexpected side effects. Conclusions Intermittent administration of paroxetine 20 mg significantly reduced irritability symptoms in patients with PMDD. These results are consistent with previous studies suggesting that PMDD may be treated effectively by luteal phase-only administration of a selective serotonin reuptake inhibitor. Trial registration clinicaltrials.gov Identifier: NCT00620581. more...