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A Systematic Review of Neurocognitive Effects of Subanesthetic Doses of Intravenous Ketamine in Major Depressive Disorder, Post-Traumatic Stress Disorder, and Healthy Population

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Abstract

Background and Objective

Ketamine, a noncompetitive, high-affinity antagonist of the N-methyl-d-aspartate type glutamate receptor, has been investigated for its high efficacy and rapid antidepressant effect and, more recently, for its potential utility in post-traumatic stress disorder (PTSD). The proposal that ketamine’s antidepressant and anti-suicidal mechanism may be in part due to its procognitive effect contrasts with the well-established decreased performance on spatial working memory and pattern recognition memory among long-term frequent users. We aimed to review the neurocognitive effects of subanesthetic doses of intravenous ketamine in pharmacological studies among healthy subjects and patients with PTSD or depression.

Methods

We included studies in English, among healthy adults, or with PTSD or unipolar or bipolar depression where the primary or secondary cognitive outcomes were measured by means of validated neuropsychological test. We excluded studies that reported the use of ketamine only in combination with other drugs or psychotherapy, or studies investigating emotion-laden cognitive functions.

Results

Ketamine administration among patients with depression and possibly with PTSD does not show significant impairment of cognitive functions in the short-term, in contrast with the immediate altered cognitive dysfunction found in healthy subjects. The potential procognitive effects of ketamine seem more pronounced in cognitive domains of executive function, which is in line with the putative molecular, cellular, and synaptic mechanisms of ketamine’s therapeutic action.

Conclusions

The potential procognitive effect of ketamine deserves further exploration. Whether ketamine has transient or sustained neurocognitive benefits beyond its antidepressant effects is unknown. Improved cognition by ketamine might be used to facilitate psychotherapy interventions for PTSD and depression.

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Authors and Affiliations

  1. Mental Health Service Line, Minneapolis VA Medical Center, One Veterans Drive 116-A, Minneapolis, MN, 55417, USA

    Paulo R. Shiroma & Yelena Vorobyov

  2. Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, USA

    Paulo R. Shiroma

  3. Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

    Mario Renato Velit-Salazar

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This work was supported by U.S. Department of Veterans Affairs Clinical Sciences Research and Development Merit Review Award (grant I01 CX001803 to Dr Shiroma). The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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PRS and MRV-S contributed to conception and design of the review and writing of the manuscript. PRS, MRV-S, and YV provided critical review of the work and final approval of manuscript.

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Shiroma, P.R., Velit-Salazar, M.R. & Vorobyov, Y. A Systematic Review of Neurocognitive Effects of Subanesthetic Doses of Intravenous Ketamine in Major Depressive Disorder, Post-Traumatic Stress Disorder, and Healthy Population. Clin Drug Investig 42, 549–566 (2022). https://doi.org/10.1007/s40261-022-01169-z

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