Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis

Background: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. Methods: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. Results: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50mg intra-nasal spray, another assessed 0.1–0.4mg/kg i.v., and another assessed 0.1–0.5mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6–7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2–5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7. Conclusion: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety.

[1]  M. Kuskowski,et al.  Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. , 2014, Journal of affective disorders.

[2]  H. Möller,et al.  Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: Report of two cases , 2009, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[3]  D. Charney,et al.  Effects of Intravenous Ketamine on Explicit and Implicit Measures of Suicidality in Treatment-Resistant Depression , 2009, Biological Psychiatry.

[4]  D. Charney,et al.  A Randomized Controlled Trial of Intranasal Ketamine in Major Depressive Disorder , 2014, Biological Psychiatry.

[5]  C. Lançon,et al.  [Ketamine in acute and severe major depressive disorder]. , 2014, Presse medicale.

[6]  V. Feigin,et al.  The Global Burden of Mental, Neurological and Substance Use Disorders: An Analysis from the Global Burden of Disease Study 2010 , 2015, PloS one.

[7]  J. Horáček,et al.  Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression. , 2013, Neuro endocrinology letters.

[8]  Michele Tarsilla.  Cochrane Handbook for Systematic Reviews of Interventions , 2010, Journal of MultiDisciplinary Evaluation.

[9]  Paul J Carlson,et al.  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. , 2006, Archives of general psychiatry.

[10]  R. Lam,et al.  A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes , 2014, Psychological Medicine.

[11]  Brian A Palmer,et al.  Serial infusions of low-dose ketamine for major depression , 2013, Journal of psychopharmacology.

[12]  S. Shergill,et al.  Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy , 2014, Therapeutic advances in psychopharmacology.

[13]  Stephen Senn,et al.  Cross-over trials in clinical research , 1993 .

[14]  D. Luckenbaugh,et al.  Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. , 2010, The Journal of clinical psychiatry.

[15]  M. Page-Sharp,et al.  Development of a Sublingual/Oral Formulation of Ketamine for Use in Neuropathic Pain , 2009, Clinical drug investigation.

[16]  P. Mitchell,et al.  Pilot dose–response trial of i.v. ketamine in treatment-resistant depression , 2014, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[17]  H. Manji,et al.  Rapid antidepressant effects: moving right along , 2013, Molecular Psychiatry.

[18]  Gregory Luke Larkin,et al.  A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency department. , 2011, The international journal of neuropsychopharmacology.

[19]  L. Boyer,et al.  La kétamine dans le traitement du trouble dépressif aigu sévère , 2014 .

[20]  S. Southwick,et al.  Measurement of Dissociative States with the Clinician-Administered Dissociative States Scale (CADSS) , 1998, Journal of traumatic stress.

[21]  R. Aitken.  Measurement of feelings using visual analogue scales. , 1969, Proceedings of the Royal Society of Medicine.

[22]  J. Overall,et al.  The Brief Psychiatric Rating Scale , 1962 .

[23]  L. Kegeles,et al.  Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept , 2013, Neuropsychopharmacology.

[24]  D. Charney,et al.  Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression , 2010, Biological Psychiatry.

[25]  R. C. Young,et al.  A Rating Scale for Mania: Reliability, Validity and Sensitivity , 1978, British Journal of Psychiatry.

[26]  A. Kudoh,et al.  Small-Dose Ketamine Improves the Postoperative State of Depressed Patients , 2002, Anesthesia and analgesia.

[27]  John H Krystal,et al.  Antidepressant effects of ketamine in depressed patients , 2000, Biological Psychiatry.

[28]  J. Krystal,et al.  The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS , 2011, Psychiatry Research: Neuroimaging.

[29]  Dennis S. Charney,et al.  Ketamine for Depression: Where Do We Go from Here? , 2012, Biological Psychiatry.

[30]  M. Hamilton.  A RATING SCALE FOR DEPRESSION , 1960, Journal of neurology, neurosurgery, and psychiatry.

[31]  D. Luckenbaugh,et al.  Replication of Ketamine's Antidepressant Efficacy in Bipolar Depression: A Randomized Controlled Add-On Trial , 2012, Biological Psychiatry.

[32]  E. Kochs,et al.  Improvement of Pain Treatment After Major Abdominal Surgery by Intravenous S(+)-Ketamine , 2004, Anesthesia and analgesia.

[33]  A. Takahashi.  Rating scale for depression , 1998 .

[34]  A. Rigby.  Cross‐over Trials in Clinical Research , 2003 .

[35]  J. Higgins.  Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration , 2011 .

[36]  W. Goodman,et al.  Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial , 2015, Psychological Medicine.

[37]  P. Mitchell,et al.  Ketamine as a new treatment for depression: A review of its efficacy and adverse effects , 2013, The Australian and New Zealand journal of psychiatry.

[38]  D. Luckenbaugh,et al.  A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. , 2010, Archives of general psychiatry.

[39]  G. Laje,et al.  Relationship of Ketamine's Plasma Metabolites with Response, Diagnosis, and Side Effects in Major Depression , 2012, Biological Psychiatry.

[40]  M. Ghasemi,et al.  Rapid antidepressant effects of repeated doses of ketamine compared with electroconvulsive therapy in hospitalized patients with major depressive disorder , 2014, Psychiatry Research.

[41]  M. Åsberg,et al.  A New Depression Scale Designed to be Sensitive to Change , 1979, British Journal of Psychiatry.

[42]  E. Kavalali,et al.  NMDA Receptor Blockade at Rest Triggers Rapid Behavioural Antidepressant Responses , 2011, Nature.

[43]  Dan V Iosifescu,et al.  Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. , 2013, The American journal of psychiatry.