OBJECTIVE: Intravenous N-methyl-d-aspartate (NMDA) antagonists have shown promising results in rapidly ameliorating depression symptoms, but placebo-controlled trials of oral NMDA antagonists as monotherapy have not observed efficacy. We conducted a randomized, double-blind, placebo-controlled trial of the NMDA antagonist memantine as an augmentation treatment for patients with DSM-IV major depressive disorder. METHOD: Adult outpatients with major depressive disorder and partial response or nonresponse to their current antidepressant (as indicated by a 17-item Hamilton Depression Rating Scale score of >/= 16 at baseline) were randomized (from July 2006-December 2011) to add memantine (flexible dose 5-20 mg/d, with all memantine group participants reaching the dose of 20 mg/d) (n = 15) or placebo (n = 16) to their existing treatment for 8 weeks. The primary outcome, change in Montgomery-Asberg Depression Rating Score (MADRS), was evaluated with repeated-measures mixed effects models using last-observation-carried-forward methods. Secondary outcomes included other depression and anxiety rating scales, suicidal and delusional ideation, and other adverse effects. RESULTS: 84% of participants completed the trial, including 93% of participants receiving memantine. Participants receiving memantine did not show a statistically or clinically significant change in MADRS scores compared to placebo, either over the entire study (beta = 0.133, favoring placebo, P = .74) or at study completion (week 8 mean [SD] MADRS score change = -7.13 [6.61] [memantine]; -7.25 [11.14] [placebo]; P = .97). A minimal to small effect size (comparing change to baseline variability) favoring placebo was observed (Cohen d = 0.19). Similarly, no substantial effect sizes favoring memantine nor statistically significant between-group differences were observed on secondary efficacy outcomes. CONCLUSIONS: This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment for major depressive disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00344682.

OBJECTIVE: To further define the metabolic profiles of second-generation antipsychotics during the treatment of young patients with early psychosis, with a view to better inform prescribing clinicians. METHOD: Weight, body mass index (BMI), glucose, and serum lipids were measured in the 52-week Comparison of Atypicals for First Episode (CAFE) study, in which olanzapine, quetiapine, and risperidone were evaluated, and whose primary outcomes have been reported elsewhere. These metabolic data were analyzed using a mixed random coefficients model for continuous longitudinal measures and a logistic regression model for categorical responses. RESULTS: Of the 400 patients recruited, 31% were overweight and 18% were obese at baseline, and 17 (4.3%) patients met criteria for metabolic syndrome. After 12 and 52 weeks of treatment, weight gain >or=7% from baseline was reported in 29.2% and 50.0% of quetiapine-treated patients, 59.8% and 80.0% of olanzapine-treated patients, and 32.5% and 57.6% of risperidone-treated patients, respectively. Weight gain after 12 and 52 weeks of treatment was estimated as [Least Squares Mean (SE)] 15.6 (+/-1.1) and 24.2 (+/-1.9) lb for olanzapine, 8.6 (+/-1.1) and 14.0 (+/-1.9) lb with risperidone and 7.9 (+/-1.1) and 12.1 (+/-1.8) lb for quetiapine respectively. In women, greater weight gain occurred during risperidone treatment compared with quetiapine treatment. By week 52, increases in BMI >or=1 unit occurred with significantly higher frequency in olanzapine-treated patients compared with quetiapine- or risperidone-treated patients. By 52 weeks, treatment-emergent metabolic syndrome was reported in 51 individuals (13.4% of the total population), of whom 22 were receiving olanzapine, 18 quetiapine, and 11 risperidone. Risperidone was associated with the smallest elevations in triglyceride and total cholesterol levels. CONCLUSION: Weight gain and metabolic syndrome occur commonly even in young patients receiving antipsychotic treatment for early psychosis. Targeted interventions are therefore warranted from the onset of antipsychotic therapy.