title: Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories.
abstract: BACKGROUND
  Ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear.
  
  
  METHODS
  We searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges' g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects.
  
  
  RESULTS
  A total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = -1.00, 95% CI -1.28 to -0.73, p < 0.001), and loosing superiority by days 10-12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5-8 (Hedges' g = -0.37, 95% CI -0.66 to -0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3-5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3-5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant.
  
  
  CONCLUSIONS
  A single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.
authors: Keio University School of Medicine,Tokyo,Japan.
authors: T
authors: T
authors: Kishimoto
authors: The Zucker Hillside Hospital,Psychiatry Research,Northwell Health System,Glen Oaks,NY,USA.
authors: J M
authors: JM
authors: Chawla
authors: The Zucker Hillside Hospital,Psychiatry Research,Northwell Health System,Glen Oaks,NY,USA.
authors: K
authors: K
authors: Hagi
authors: National Institute of Mental Health,Bethesda,Northwell Health System,MD,USA.
authors: C A
authors: CA
authors: Zarate
authors: The Zucker Hillside Hospital,Psychiatry Research,Northwell Health System,Glen Oaks,NY,USA.
authors: J M
authors: JM
authors: Kane
authors: Klinik und Poliklinik für Psychiatrie und Psychotherapie,Universitätsklinikum Carl Gustav Carus,Technische Universität,Dresden,Germany.
authors: M
authors: M
authors: Bauer
authors: The Zucker Hillside Hospital,Psychiatry Research,Northwell Health System,Glen Oaks,NY,USA.
authors: C U
authors: CU
authors: Correll
mesh_terms: D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: Bipolar depression; N-methyl-d-aspartate receptor antagonists; depression; ketamine; meta-analyses; trajectories