Pharmacodynamic Interactions Between Ketamine and Psychiatric Medications Used in the Treatment of Depression: A Systematic Review

Int J Neuropsychopharmacol. 2021 Oct 23;24(10):808-831. doi: 10.1093/ijnp/pyab039.


Background: The use of ketamine for depression has increased rapidly in the past decades. Ketamine is often prescribed as an add-on to other drugs used in psychiatric patients, but clear information on drug-drug interactions is lacking. With this review, we aim to provide an overview of the pharmacodynamic interactions between ketamine and mood stabilizers, benzodiazepines, monoamine oxidase-inhibitors, antipsychotics, and psychostimulants.

Methods: MEDLINE and Web of Science were searched.

Results: Twenty-four studies were included. For lithium, no significant interactions with ketamine were reported. Two out of 5 studies on lamotrigine indicated that the effects of ketamine were attenuated. Benzodiazepines were repeatedly shown to reduce the duration of ketamine's antidepressant effect. For the monoamine oxidase-inhibitor tranylcypromine, case reports showed no relevant changes in vital signs during concurrent S-ketamine use. One paper indicated an interaction between ketamine and haloperidol, 2 other studies did not. Four papers investigated risperidone, including 3 neuroimaging studies showing an attenuating effect of risperidone on ketamine-induced brain perfusion changes. Clozapine significantly blunted ketamine-induced positive symptoms in patients with schizophrenia but not in healthy participants. One paper reported no effect of olanzapine on ketamine's acute psychotomimetic effects.

Conclusion: Current literature shows that benzodiazepines and probably lamotrigine reduce ketamine's treatment outcome, which should be taken into account when considering ketamine treatment. There is evidence for an interaction between ketamine and clozapine, haloperidol, and risperidone. Due to small sample sizes, different subject groups and various outcome parameters, the evidence is of low quality. More studies are needed to provide insight into pharmacodynamic interactions with ketamine.

Keywords: Depression; ketamine; pharmacodynamic interactions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Antidepressive Agents / therapeutic use
  • Antipsychotic Agents / therapeutic use
  • Benzodiazepines / therapeutic use
  • Bipolar Disorder / drug therapy
  • Clozapine / therapeutic use
  • Depression / drug therapy*
  • Drug Interactions
  • Female
  • Haloperidol / therapeutic use
  • Humans
  • Ketamine / therapeutic use*
  • Lithium / therapeutic use
  • Male
  • Olanzapine / therapeutic use
  • Psychotropic Drugs / therapeutic use*
  • Risperidone / therapeutic use
  • Schizophrenia / drug therapy
  • Treatment Outcome


  • Antidepressive Agents
  • Antipsychotic Agents
  • Psychotropic Drugs
  • Benzodiazepines
  • Ketamine
  • Lithium
  • Clozapine
  • Haloperidol
  • Risperidone
  • Olanzapine