Antidepressant effects of ketamine in depressed patients

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 +/- SD 10 points vs. 0 +/- 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.

[1]  P. Eide,et al.  Reply to S.T. Meller: Ketamine: relief from chronic pain through actions at the NMDA receptor. , 1997, Pain.

[2]  P. Santosh,et al.  Loading dose imipramine--new approach to pharmacotherapy of melancholic depression. , 1996, Journal of psychiatric research.

[3]  D. Kupfer,et al.  Acute antidepressant effect following pulse loading with intravenous and oral clomipramine. , 1989, Archives of general psychiatry.

[4]  P. Skolnick,et al.  Antidepressant-like actions of the polyamine site NMDA antagonist, eliprodil (SL-82.0715) , 1995, Pharmacology Biochemistry and Behavior.

[5]  S. Vale,et al.  Amantadine in depression. , 1971, Lancet.

[6]  R. Porsolt,et al.  MK-801 and enantiomers: Potential antidepressants or false positives in classical screening models? , 1993, Pharmacology Biochemistry and Behavior.

[7]  K. Elliott,et al.  N-Methyl-D-Aspartate (NMDA) Receptors, Mu and Kappa Opioid Tolerance, and Perspectives on New Analgesic Drug Development , 1995, Neuropsychopharmacology.

[8]  S. Ho,et al.  Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors. , 1996, European journal of pharmacology.

[9]  F. Richards.  LUNG BLOOD-FLOW IN MITRAL STENOSIS. , 1965, Lancet.

[10]  E. Domino,et al.  Pharmacologic effects of CI‐581, a new dissociative anesthetic, in man , 1965, Clinical pharmacology and therapeutics.

[11]  N. Mjellem,et al.  Reduction of NMDA-induced behaviour after acute and chronic administration of desipramine in mice , 1993, Neuropharmacology.

[12]  W. Danysz,et al.  Potential antidepressive properties of amantadine, memantine and bifemelane. , 1993, Pharmacology & toxicology.

[13]  C. Gambarana,et al.  Dizocilpine antagonizes the effect of chronic imipramine on learned helplessness in rats , 1993, Pharmacology Biochemistry and Behavior.

[14]  G. Sethuraman,et al.  Pulse intravenous clomipramine for depressed adolescents: double-blind, controlled trial. , 1997, The American journal of psychiatry.

[15]  P. Skolnick,et al.  Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. , 1996, Pharmacopsychiatry.

[16]  G. Crane.  Cyloserine as an antidepressant agent. , 1959, The American journal of psychiatry.

[17]  M. Papp,et al.  Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. , 1994, European journal of pharmacology.

[18]  Meller St.  Ketamine: relief from chronic pain through actions at the NMDA receptor? , 1996 .

[19]  P. Skolnick,et al.  Adaptation of the N-methyl-D-aspartate receptor complex following chronic antidepressant treatments. , 1994, The Journal of pharmacology and experimental therapeutics.

[20]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.

[21]  P. Skolnick,et al.  Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. , 1990, European journal of pharmacology.

[22]  E. Przegaliński,et al.  Antidepressant-like Effects of a Partial Agonist at Strychnine-insensitive Glycine Receptors and a Competitive NMDA Receptor Antagonist , 1997, Neuropharmacology.

[23]  N. Lindefors,et al.  Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex , 1997, Brain Research.

[24]  M. Papp,et al.  Antidepressant-like effects of 1-aminocyclopropanecarboxylic acid and D-cycloserine in an animal model of depression. , 1996, European journal of pharmacology.

[25]  G. Crane.  The psychotropic effects of cycloserine: A new use for an antibiotic , 1961 .

[26]  S. T. Meller.  Ketamine: relief from chronic pain through actions at the NMDA receptor? , 1996, Pain.