title: Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis.
abstract: 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 Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials.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 (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1-0.4 mg/kg i.v., and another assessed 0.1-0.5 mg/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 Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Maree
authors.initials: M
authors.lastname: Hackett
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Gregory
authors.initials: G
authors.lastname: Carter
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi). colleen.loo@unsw.edu.au.
authors.forename: Colleen
authors.initials: C
authors.lastname: Loo
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Verònica
authors.initials: V
authors.lastname: Gálvez
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Nick
authors.initials: N
authors.lastname: Glozier
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Paul
authors.initials: P
authors.lastname: Glue
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Kyle
authors.initials: K
authors.lastname: Lapidus
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Alexander
authors.initials: A
authors.lastname: McGirr
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Philip B
authors.initials: PB
authors.lastname: Mitchell
authors.affiliation: The George Institute for Global Health, The University of Sydney, Sydney, Australia (Drs Xu, Hackett, and Rodgers); Centre for Translational Neuroscience and Mental Health, University of Newcastle, Australia (Dr Carter); School of Psychiatry, University of New South Wales & Black Dog Institute, Sydney, Australia (Drs Loo, Gálvez, and Mitchell); Brain and Mind Research Institute, University of Sydney, Australia (Dr Glozier); Department of Psychiatry, University of Otago, New Zealand (Dr Glue); Departments of Psychiatry and Neurobiology, Stony Brook University, Stony Brook, NY (Dr Lapidus); Department of Psychiatry, University of British Colombia, Canada (Dr McGirr); Discipline of Pharmacology, Faculty of Health Sciences, The University of Adelaide, Adelaide, Australia (Dr Somogyi).
authors.forename: Anthony
authors.initials: A
authors.lastname: Rodgers
mesh_terms: D000928:Antidepressive Agents / Q000008:administration & dosage*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage*; D016032:Randomized Controlled Trials as Topic
chemical_list: D000928:Antidepressive Agents; D007649:Ketamine
keywords: Ketamine; major depression; meta-analysis