Elsevier

Journal of Affective Disorders

Volume 156, 1 March 2014, Pages 24-35
Journal of Affective Disorders

Review
A review of ketamine in affective disorders: Current evidence of clinical efficacy, limitations of use and pre-clinical evidence on proposed mechanisms of action

https://doi.org/10.1016/j.jad.2013.11.014Get rights and content

Abstract

Introduction

Recent research has seen low-dose ketamine emerge as a novel, rapid-acting antidepressant. Ketamine, an N-methy-d-aspartate (NMDA) receptor antagonist, leads to effects on the glutamatergic system and abnormalities in this neurotransmittor system are present in depression. This article aims to (1) review the clinical literature on low-dose ketamine as a rapid-acting antidepressant in affective disorders, (2) provide a critical overview of the limitations of ketamine and research attempts to overcome these (3) discuss the proposed mechanisms of action of ketamine and (4) point towards future research directions.

Method

The electronic database Pubmed, Web of Science and sciencedirect were searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, electroconvulsive therapy, mechanism of action.

Result

The literature demonstrates evidence supporting a rapid-acting antidepressant effect of low-dose intravenous ketamine in major depressive disorder, in bipolar depression and in depression with suicidal ideation. There are mixed results as to whether ketamine leads to a reduction in time to remission in patients undergoing electroconvulsive therapy (ECT). Efforts to unravel ketamine′s therapeutic mechanism of action have implicated the mammalian target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen synthase kinase (GSK-3). Ketamine′s limiting factors are the transient nature of its antidepressant effect and concerns regarding abuse, and research efforts to overcome these are reviewed.

Conclusion

Current and future research studies are using ketamine as a promising tool to evaluate the glutamatergic neurotransmittor system to learn more about the pathophysiology of depression and develop more specific rapid-acting antidepressant treatments.

Section snippets

Background

Major depressive disorder (MDD) is a debilitating mental illness that affects millions of people worldwide leading to severe health and socioeconomic consequences (Kessler et al., 2003). Despite antidepressant treatment patients continue to experience low remission rates, residual subsyndromal symptoms, relapses and persistent functional impairment. It is widely accepted that all current antidepressants require a lag period of several weeks before improvements in mood and wellbeing are felt.

Aims

The overall objective of this article is to review the evidence to date on the use of ketamine as a rapid-acting antidepressant. The specific aims are to:

  • Review the clinical literature to date on low-dose intravenous ketamine as a rapid-acting antidepressant in affective disorders,

  • Provide a critical overview of the limitations of ketamine use in affective disorders and research attempts to overcome these,

  • Discuss the proposed mechanisms of action of ketamine, derived mainly from preclinical

Method

The search was performed using Pubmed, Web of science and sciencedirect for papers published up to June 2013 using the following search terms (MeSH/All fields): ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, electroconvulsive therapy, mechanism of action. All relevant clinical reports involving the assessment of ketamine′s antidepressant potential were considered. In addition, we

Results

Ketamine and treatment-resistant depression as search terms yielded a total of 70 articles of which 60 were relevant. Ketamine and rapid-acting antidepressant yielded 17 papers (15 relevant) and N-methyl-d-aspartate receptor antagonist and rapid-acting antidepressant yielded 10 papers (7 relevant). Ketamine and bipolar depression revealed 43 articles of which 29 were relevant. Ketamine and suicidal ideation revealed 10 articles of which 8 were relevant. Ketamine, Electroconvulsive therapy, and

Conclusion

Subanaesthetic doses of intravenous ketamine offers a unique opportunity to learn more about the psychopharmacological dysregulation of the glutamatergic system in depression and there have been significant developments in this field in the last decade. Perhaps the greatest opportunity that emerges from this exciting research, however, is to conduct further studies that elucidate the mechanism of action of ketamine's rapid response to determine if NMDA receptor antagonists such as ketamine,

Role of funding source

The Alimentary Pharmabiotic Centre is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan. This publication is supported in part by a research grant from SFI under Grant Number SFI/12/RC/2273 and by the Health Research Board (HRB) through a Health Research Award (grant no. HRA_POR/2011/23; T.G.D., J.F.C. and G.C.). The Centre was previously funded by GlaxoSmithKline. J.F.C. is also funded by the European Community's Seventh

Conflict of interest

None.

Acknowledgements

The authors would like to acknowledge the significant contribution of Berneniece Riedewald in the drawing of Fig. 1.

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