Ketamine for Treatment-Resistant Unipolar Depression
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Ketamine for Treatment-Resistant Unipolar Depression Current Evidence Sanjay J. Mathew,1,2,3 Asim Shah,1 Kyle Lapidus,3 Crystal Clark,1,2 Noor Jarun,1 Britta Ostermeyer1 and James W. Murrough3,4 1 2 3 4
Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA Michael E. Debakey VA Medical Center, Houston, TX, USA Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA
Abstract
Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapidonset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD.
1. Introduction Unipolar major depressive disorder (MDD) is common, often chronic and ranks as a leading cause of disability worldwide. Antidepressant treatment
resistance remains a clinically significant problem despite 50 years of research aimed at discovering effective treatments.[1-5] This effort culminated in the National Institutes of Health funded STAR*D study, which underscored the high prevalence,
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chronicity and morbidity associated with treatment-resistant depression (TRD).[3] There is thus an undeniable public health imperative to develop new therapies for TRD to address persistent mood symptoms, promote sustained remission and improve quality of l
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