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The Question of Ketamine in Treatment-Resistant Depression

Summary and Comment |
September 26, 2013

The Question of Ketamine in Treatment-Resistant Depression

  1. Joel Yager, MD

Although these short-term results are encouraging, high adverse event rates and unresolved questions impede adopting this treatment.

  1. Joel Yager, MD

Ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, might prove useful for treatment-resistant depression (NEJM JW Psychiatry Dec 28 2012). In this first-ever multisite study, 73 patients with treatment-resistant depression (melancholic features in 65%) stopped all antidepressant medications for at least 1 week and were randomized in a 2:1 ratio to infusion with ketamine or midazolam as a psychoactive placebo.

At 24 hours, depressive symptoms decreased significantly more with ketamine than with midazolam (response rates, 64% vs. 28%). At 7 days, 21 of 47 ketamine patients and 4 of 25 midazolam patients continued to meet response criteria (at 4 weeks, 9 ketamine patients and no midazolam patients). More ketamine patients experienced transient psychoactive effects (significant dissociation in 8 [17%]) and hemodynamic effects (severe hypertensive reactions in 2).

Comment

These preliminary results are encouraging; yet, as an editorialist notes, great caution is needed: Even after exclusions for psychoses, recent alcohol or substance abuse, and various medical problems, ketamine-treated patients experienced a high rate of dissociation (which may be particularly troublesome for patients with comorbid post-traumatic stress or borderline personality disorders), and hypertensive responses were common. Because of potential adverse drug interactions, discontinuing medications 1 week (4 weeks for fluoxetine) before ketamine treatment is necessary, but might generate other difficulties. How long do the initial treatment effects ultimately persist, and how should the clinician proceed after they wear off? Will repeat ketamine infusions prove as effective as the initial one? Or would it be useful to return patients to their original treatments? Will individual genomic or other profiles allow us to better select patients likely to respond as well as those who are more likely to experience adverse effects? The number of questions suggests that ketamine is not yet ready for prime time.

  • Disclosures for Joel Yager, MD at time of publication Editorial boards Bulletin of the Menninger Clinic; Eating Disorders: Journal of Treatment and Research; Eating Disorders Review (Editor-in-Chief); Harvard Review of Psychiatry; International Journal of Eating Disorders; UpToDate Leadership positions in professional societies American Psychiatric Association (Chair, Steering Committee and Executive Committee on Practice Guidelines; Co-Chair, DSM5 Clinical and Public Health Committee; Chair, Council on Research and Quality Care)

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