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Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response

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Abstract

Rationale

The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD). Despite the promise of a novel and urgently needed treatment for refractory depression, concerns regarding potential adverse neurocognitive effects of ketamine remain.

Objectives

Although extensive research has been conducted in healthy volunteers, there is a paucity of studies examining the neurocognitive effects of ketamine in depressed patients. Therefore, the aims of the current study were to characterize the relationship between baseline neurocognition and antidepressant response to ketamine, measure the acute impact of ketamine on neurocognition, and investigate the relationship between acute neurocognitive effects of ketamine and antidepressant response.

Methods

Neurocognitive functioning was assessed in 25 patients with TRD using a comprehensive battery: estimated premorbid intelligence quotient (IQ), current IQ, and tests from the MATRICS Consensus Cognitive Battery (MCCB). A subset of the MCCB was repeated immediately following a 40-min intravenous infusion of ketamine (0.5 mg/kg).

Results

Patients who responded to ketamine 24 h following treatment had poorer baseline neurocognitive performance relative to nonresponders and, in particular, slower processing speed (F = 8.42; df = 23; p = 0.008). Ketamine was associated with selective impairments in memory recall, and the degree of cognitive change carried negative prognostic significance (e.g., negative cognitive effects immediately after ketamine predicted lower response rate at 24 h; Fisher's exact test two-sided p = 0.027).

Conclusions

Taken together, our findings suggest a potential baseline neurocognitive predictor of ketamine response and an inverse relationship between the cognitive effects of ketamine and antidepressant efficacy.

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Acknowledgments

This work was supported by National Institutes of Health (NIH) grant number UL1TR000067 (Mount Sinai Clinical and Translational Science Award) and by a NARSAD award from the Brain and Behavior Research Foundation (S.J. Mathew). Dr. Murrough is supported by a Career Development Award from NIH/NIMH (K23MH094707).

Conflict of interest

In the past 2 years, Dr. Murrough has received research support from Evotec, Janssen Pharmaceuticals, and Avanir. Dr. Iosifescu has consulted for CNS Response, Inc. and has received grant/research support through Mount Sinai School of Medicine from Brainsway, Euthymics Bioscience Inc., Neosync, and Shire. In the next 2 years, it is likely he will receive grants from Hoffmann-La Roche Inc. and Astrazeneca LP. Dr. Charney has been named as an inventor on a pending use-patent of ketamine for the treatment of depression. If ketamine was shown to be effective in the treatment of depression and received approval from the Food and Drug Administration for this indication, Dr. Charney and Mount Sinai School of Medicine could benefit financially. Dr. Mathew has received consulting fees or research support from Allergan, AstraZeneca, Bristol-Myers Squibb, Cephalon, Inc., Corcept, Johnson & Johnson, Noven, Roche, and Takeda. All other authors declare no conflict of interest.

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Murrough, J.W., Wan, LB., Iacoviello, B. et al. Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response. Psychopharmacology 231, 481–488 (2014). https://doi.org/10.1007/s00213-013-3255-x

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  • DOI: https://doi.org/10.1007/s00213-013-3255-x

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