title: Ketamine safety and tolerability in clinical trials for treatment-resistant depression.
abstract: OBJECTIVE
  Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD.
  
  
  METHODS
  Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation.
  
  
  RESULTS
  The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P < .05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information.
  
  
  CONCLUSIONS
  In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted.
  
  
  BACKGROUND
  ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.
authors.affiliation: Department of Psychiatry, Mood and Anxiety Disorders Program.
authors.forename: Le-Ben
authors.initials: LB
authors.lastname: Wan
authors.forename: Cara F
authors.initials: CF
authors.lastname: Levitch
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Perez
authors.forename: Jess W
authors.initials: JW
authors.lastname: Brallier
authors.forename: Dan V
authors.initials: DV
authors.lastname: Iosifescu
authors.forename: Lee C
authors.initials: LC
authors.lastname: Chang
authors.forename: Alexandra
authors.initials: A
authors.lastname: Foulkes
authors.forename: Sanjay J
authors.initials: SJ
authors.lastname: Mathew
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Charney
authors.forename: James W
authors.initials: JW
authors.lastname: Murrough
mesh_terms: D000328:Adult; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine