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Ketamine for Treatment-Resistant Unipolar Depression

Current Evidence

CNS Drugs volume 26, pages 189–204 (2012)Cite this article

Abstract

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action andsignificant 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 rapid-onset 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.

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Acknowledgements

This work was generously supported by the Department of Veterans Affairs (via salary support for Drs Mathew and Clark), the National Institute of Mental Health (5R01MH81870 to Dr Mathew, 1K23MH094707-01 to Dr Murrough), NARSAD (awards to Drs Mathew, Lapidus and Murrough) and the Mount Sinai Clinical and Translational Sciences Award (UL1RR029887). The sponsors did not have a role in the preparation of this article.

Dr Mathew and Dr Charney (Dean of Mount Sinai School of Medicine) and the Mount Sinai School of Medicine have been named on a use patent application of ketamine for the treatment of depression. If ketamine were shown to be effective in the treatment of depression and received approval from the FDA for this indication, Dr Charney and the Mount Sinai School of Medicine could benefit financially. Dr Mathew has relinquished his claim to any royalties and will not benefit financially if ketamine is approved for this use.

Dr Mathew has received grant/research support from Evotec, GlaxoSmithKline, NARSAD, NIMH, Novartis and Roche Pharmaceuticals during the last 5 years. Medication for a National Institutes of Health funded study has been provided by Sanofi. In 2010–11, Dr Mathew received consulting or lecture fees from AstraZeneca, Cephalon, Inc. and Roche.

Dr Shah has received grant/research support from PPD, Inc., Johnson & Johnson and Roche Pharmaceuticals.

Within the last 2 years, Dr Murrough has received salary support through a Mount Sinai School of Medicine research fellowship funded with an educational grant from AstraZeneca.

Drs Shah, Clark, Jarun, Lapidus, Ostermeyer and Murrough have no conflicts of interest that are directly relevant to the content of this review.

The authors wish to thank the following individuals for their significant contributions to this work: Mount Sinai School of Medicine: Dennis Charney, M.D., Dan Iosifescu, M.D., David Reich, M.D. and Andrew Perez, M.D.; Baylor College of Medicine: Rayan Al Jurdi, M.D., Lee Chang, M.D., Thomas Newton, M.D. and Richard de la Garza II, Ph.D.

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  1. Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, One Baylor Plaza MS: BCM350, Houston, TX, 77030, USA

    Sanjay J. Mathew MD, Asim Shah, Crystal Clark, Noor Jarun & Britta Ostermeyer

  2. Michael E. Debakey VA Medical Center, Houston, TX, USA

    Sanjay J. Mathew MD & Crystal Clark

  3. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

    Sanjay J. Mathew MD, Kyle Lapidus & James W. Murrough

  4. Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA

    James W. Murrough

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  1. Sanjay J. Mathew MD
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  2. Asim Shah
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Correspondence to Sanjay J. Mathew MD.

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Mathew, S.J., Shah, A., Lapidus, K. et al. Ketamine for Treatment-Resistant Unipolar Depression. CNS Drugs 26, 189–204 (2012). https://doi.org/10.2165/11599770-000000000-00000

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Keywords

  • Ketamine
  • NMDA Receptor
  • Major Depressive Disorder
  • Complex Regional Pain Syndrome
  • Riluzole