Context Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects—for instance, within a few hours or days—would have an enormous impact on patient care and public health. Objective To determine whether an N-methyl-d-aspartate–receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. Design A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009. Setting Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant). Interventions Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion. Main Outcome Measures Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. Results Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d=0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d=0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point. Conclusion In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-d-aspartate antagonist. Trial Registration clinicaltrials.gov Identifier: NCT00088699

Background Currently, no pharmacological treatments for bipolar depression exist that exert rapid (within hours) antidepressant or antisuicidal effects. We previously reported that intravenous administration of the N-methyl-D-aspartate (NMDA) antagonist ketamine produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. The present study sought to replicate this finding in an independent sample. Methods In this double-blind, randomized, crossover, placebo-controlled study, 15 subjects with DSM-IV bipolar I or II depression maintained on therapeutic levels of lithium or valproate received a single intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on two test days two weeks apart. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS), which was used to rate overall depressive symptoms at baseline, at 40, 80, 110, and 230 minutes post-infusion, and on Days 1, 2, 3, 7, 10, and 14 post-infusion. Results Within 40 minutes, depressive symptoms as well as suicidal ideation significantly improved in subjects receiving ketamine compared to placebo (d=0.89, 95% C.I. = 0.61–1.16 and 0.98, 95% C.I. = 0.64–1.33, respectively); this improvement remained significant through Day 3. Seventy-nine percent of subjects responded to ketamine and 0% responded to placebo at some point during the trial. The most common side effect was dissociative symptoms, which occurred only at the 40-minute time-point. Conclusion This study replicated our previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response. In addition, we found that ketamine rapidly improved suicidal ideation in these patients.

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest GWAS to date of DSM-IV diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case/control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, N = 46,568; African; N = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; p = 9.8E-13) and African ancestries (rs2066702; p = 2.2E-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, ADHD, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and non-pathological drinking behaviors.