Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression
This open-label study (n=66) finds that four ketamine infusions (35mg/70kg) led to improvements in cognition both immediately (measured after the first and fourth infusion) and up to five weeks later. As seen in other studies, antidepressant effects reverted to baseline at five weeks.
Authors
- Zavaliangos-Petropulu, A.
- Mcclintock, S. M.
- Khalil, J.
Published
Abstract
Introduction
Ketamine treatment prompts a rapid antidepressant response in treatment-resistant depression (TRD). We performed an exploratory investigation of how ketamine treatment in TRD affects different cognitive domains and relates to antidepressant response.
Methods
Patients with TRD (N = 66; 30 M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg). Neurocognitive function and depressive symptoms were assessed at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks following end of treatment. Mixed effect models tested for changes in seven neurocognitive domains and antidepressant response, with post-hoc pairwise comparisons between timepoints, including follow-up. Relationships between change in neurocognitive function and antidepressant response over the course of treatment were tested with Pearson's correlation and mediation analyses. Associations between baseline neurocognitive performance and antidepressant response were tested with Pearson's correlation.
Results
Significant improvements in inhibition, working memory, processing speed, and overall fluid cognition were observed after the first and fourth ketamine infusion. Improvements in processing speed and overall fluid cognition persisted through follow-up. Significant improvements in depressive symptoms reverted towards baseline at follow-up. Baseline working memory and change in inhibition were moderately correlated with antidepressant response, however, improvements in neurocognitive performance were statistically independent from antidepressant response.
Conclusion
Antidepressant ketamine leads to improved neurocognitive function, which persist for at least 5 weeks. Neurocognitive improvements observed appear independent of antidepressant response, suggesting ketamine may target overlapping but distinct functional brain systems.
Limitations
Research investigating repeated serial ketamine treatments is important to determine cognitive safety. This study is a naturalistic design and does not include placebo.
Research Summary of 'Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression'
Introduction
Major depressive disorder affects a large global population and around 30% of patients do not remit after two or more adequate antidepressant trials, meeting criteria for treatment-resistant depression (TRD). Subanesthetic ketamine produces rapid antidepressant effects in many patients, but those effects are typically short-lived and the cognitive consequences of repeated, clinically administered ketamine remain incompletely characterised. Prior clinical work has reported mixed findings: some studies identify transient cognitive deficits immediately after ketamine, whereas others report improvements in specific domains (for example, processing speed, visual memory) within days to weeks. It is also unresolved whether any cognitive changes following ketamine are secondary to mood improvement or reflect effects on partly distinct brain systems. Zavaliangos-Petropulu and colleagues conducted an exploratory, naturalistic investigation to clarify how four subanesthetic ketamine infusions affect multiple neurocognitive domains in people with TRD, and how cognitive change relates to antidepressant response. Using the NIHToolbox Cognition Battery, assessments were made at baseline, 24 hours after the first and fourth infusion, and at 5 weeks post-treatment; the study tested whether serial ketamine would produce no cognitive harm, would improve fluid cognitive abilities (for example, working memory) with durable effects at 5 weeks, and whether cognitive gains would be mediated by improvement in depressive symptoms. Healthy controls were included in supplementary analyses to help interpret practice effects and longitudinal change.
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Study Details
- Study Typeindividual
- Journal
- Compound
- Topics
- APA Citation
Zavaliangos-Petropulu, A., McClintock, S. M., Khalil, J., Joshi, S. H., Taraku, B., Al-Sharif, N. B., Espinoza, R. T., & Narr, K. L. (2023). Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression. Journal of Affective Disorders, 333, 161-171. https://doi.org/10.1016/j.jad.2023.04.015
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