The Effects of Ketamine on Cognition in Unipolar and Bipolar Depression: A Systematic Review

To determine the objective neurocognitive effects of (1) single-dose ketamine, (2) repeated-dose ketamine, (3) ketamine adjunct to electroconvulsive therapy (ECT), and (4) ketamine as the anesthetic for ECT in major depressive disorder (MDD) and depression in bipolar disorder (BD).

Cochrane, MEDLINE, Embase, and PsycINFO databases were searched on March 19, 2020 (updated July 2, 2020), using the terms terms major depressive disorder bipolar disorder and ketamine and their synonyms. Clinical trial registries (search date May 4, 2020) and reference sections of included articles were also searched. There was no restriction on language or year of publication.

Of 4,035 identified articles, 17 met inclusion criteria. Controlled and open-label studies of adults who received at least 1 ketamine treatment for a current major depressive episode, as part of MDD or BD, were included. Only studies measuring cognition using at least 1 validated, objective neurocognitive assessment were eligible.

Results are presented using a narrative review format. Data regarding change in cognitive performance from baseline to end-of-treatment and/or differences in cognition between ketamine and control groups were extracted.

There were no negative effects of single- or repeated-dose intravenous ketamine up to 2 weeks post-treatment in MDD. Limited data were available for BD populations, as well as on other routes of ketamine administration.

Data to definitively answer the question of whether ketamine has substantive or persistent cognitive effects are insufficient; thus, larger controlled trials measuring cognition as the primary outcome are needed. Future research should focus on different routes of ketamine administration, ketamine enantiomers, and BD populations.