Abstract
A decade has now passed since research into the antidepressant effects of ketamine began in earnest, after the clinical trial reported by Zarate et al. in 2006 ( 1 Zarate Jr, C.A. Singh J.B. Carlson P.J. Brutsche N.E. Ameli R. Luckenbaugh D.A. et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63: 856-864 Crossref PubMed Scopus (2608) Google Scholar ). In that proof-of-concept study, 18 medication-free patients with treatment-resistant major depressive disorder (TRD) showed a large reduction in core depressive symptoms within hours of receiving a single low-dose 0.5 mg/kg intravenous infusion of ketamine as measured by the 21-item Hamilton Depression Rating Scale compared with saline placebo. Perhaps most strikingly, the antidepressant effects persisted without additional dosing of ketamine for days or up to several weeks in some cases. While these unexpected findings have been met with justifiable skepticism, replication from independent research programs is now fostering a degree of consensus in the field that ketamine is in fact associated with a true rapid-onset and persistent antidepressant effect, even in patients with TRD ( 2 Murrough J.W. Iosifescu D.V. Chang L.C. Al Jurdi R.K. Green C.E. Perez A.M. et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. Am J Psychiatry. 2013; 170: 1134-1142 Crossref PubMed Scopus (808) Google Scholar , 3 Newport D.J. Carpenter L.L. McDonald W.M. Potash J.B. Tohen M. Nemeroff C.B. et al. Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015; 172: 950-966 Crossref PubMed Scopus (401) Google Scholar ). If the observed effect is true, what are the implications and what are the critical research questions to now be asked? Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated RatsBiological PsychiatryVol. 80Issue 6PreviewThe mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. Full-Text PDF Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine TreatmentBiological PsychiatryVol. 80Issue 6PreviewMajor depressive disorder is increasingly recognized to involve functional deficits in both gamma-aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes, we used GABAA receptor γ2 subunit heterozygous (γ2+/−) mice, which we previously characterized as a model animal with construct, face, and predictive validity for major depressive disorder. Full-Text PDF Open AccessIntravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled StudyBiological PsychiatryVol. 80Issue 6PreviewThe purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant depression (TRD). Full-Text PDF Open Access
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