Trial PaperDepressive DisordersMajor Depressive Disorder (MDD)Ketamine

Antidepressant effects of ketamine in depressed patients

This double-blinded, randomised, placebo-controlled, within-subjects study (n=7) investigated the antidepressant efficacy of a single dose of ketamine (35mg/70kg) in patients with depression and found significant improvements in depressive symptoms within 72 hours after infusion.

Authors

  • John Krystal
  • Dennis Charney

Published

Biological Psychiatry
individual Study

Abstract

Background

A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression.

Methods

Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions.

Results

Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 6 SD 10 points vs. 0 6 12 points, respectively during active and sham treatment).

Conclusions

These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.

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Research Summary of 'Antidepressant effects of ketamine in depressed patients'

Introduction

A growing body of preclinical research implicates NMDA-class glutamate receptors in the pathophysiology of major depression and in the mechanism of action of antidepressant treatments. Animal studies have shown that NMDA receptor antagonists can produce antidepressant-like effects in many, but not all, paradigms, while chronic administration of conventional antidepressants produces changes in NMDA receptor function and subunit mRNA expression. Early clinical work with agents that modulate NMDA-related sites (for example, amantadine and D-cycloserine) provided some support for this hypothesis but was limited by design and drug-specific issues; overall clinical data on selective NMDA antagonists remain sparse. Berman and colleagues conducted the present study to test whether ketamine hydrochloride, a potent NMDA receptor antagonist, produces antidepressant effects in patients with major depressive episodes. The study aimed to compare a single low-dose intravenous ketamine infusion with saline in a randomised, double-blind, crossover design and to assess mood, depressive symptoms, perceptual effects and safety over the subsequent 72 hours.

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Study Details

Related Clinical Trial

Completed

Antidepressant Effects of Ketamine in Depressed Patients: A Randomized Double-Blind Placebo-Controlled Crossover Pilot

Randomized, double-blind, placebo-controlled crossover pilot (Department of Psychiatry, Yale University School of Medicine, New Haven CT; investigators: Ronald M. Berman, Angelo Cappiello, Amit Anand, David A. Oren, George R. Heninger, Dennis S. Charney, John H. Krystal) of a single 40-minute IV infusion of ketamine hydrochloride 0.5 mg/kg versus normal saline in 9 adults (4 men, 5 women; mean age 37 ± 10 years, range 23–56; 2 Hispanic, 7 Caucasian) meeting DSM-IV criteria for a major depressive episode (8 with recurrent unipolar MDD, 1 with bipolar disorder depressed phase), all medically healthy and unmedicated ≥2 weeks (confirmed by toxicology). Two treatment days separated by ≥1 week; 4 of 9 participants received ketamine first. Two participants withdrew before completing the second treatment day, leaving 7 who completed both conditions. Primary outcome: Hamilton Depression Rating Scale (HDRS-25) at baseline and 80 min, 230 min, 24h, 48h, and 72h post-infusion. Secondary outcomes: Beck Depression Inventory (BDI) at the same time points plus 10, 40, and 110 min; Brief Psychiatric Rating Scale (BPRS) at baseline and 10, 40, 80, 110, and 230 min; Visual Analogue Scale for "feeling high" (VAS-high) at baseline and 10, 40, 80, and 110 min. Analysed with repeated-measures ANOVA (Huynh–Feldt correction), condition × time interaction. IRB approved; no trial registry entry: the study pre-dates the ICMJE 2005 registration mandate by five years and the FDAAA 2007 requirement by seven years. This is the first reported randomized trial of ketamine as an antidepressant and is the foundational citation for the field.

Started
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
BERMAN-2000-BP-KETAMINE-MDD

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