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The role of adipokines in the rapid antidepressant effects of ketamine

Abstract

We previously found that body mass index (BMI) strongly predicted response to ketamine. Adipokines have a key role in metabolism (including BMI). They directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders. Here, we sought to examine the role of three key adipokines—adiponectin, resistin and leptin—as potential predictors of response to ketamine or as possible transducers of its therapeutic effects. Eighty treatment-resistant subjects who met DSM-IV criteria for either major depressive disorder (MDD) or bipolar disorder I/II and who were currently experiencing a major depressive episode received a single ketamine infusion (0.5 mg kg−1 for 40 min). Plasma adipokine levels were measured at three time points (pre-infusion baseline, 230 min post infusion and day 1 post infusion). Overall improvement and response were assessed using percent change from baseline on the Montgomery–Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. Lower baseline levels of adiponectin significantly predicted ketamine’s antidepressant efficacy, suggesting an adverse metabolic state. Because adiponectin significantly improves insulin sensitivity and has potent anti-inflammatory effects, this finding suggests that specific systemic abnormalities might predict positive response to ketamine. A ketamine-induced decrease in resistin was also observed; because resistin is a potent pro-inflammatory compound, this decrease suggests that ketamine’s anti-inflammatory effects may be transduced, in part, by its impact on resistin. Overall, the findings suggest that adipokines may either predict response to ketamine or have a role in its possible therapeutic effects.

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Acknowledgements

Funding for this work (NCT00088699) was provided by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIA MH002857), by a NARSAD Independent Investigator to CAZ and by a Brain and Behavior Mood Disorders Research Award to CAZ. We thank the 7SE research unit and staff for their support.

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Correspondence to R Machado-Vieira.

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CAZ is listed as a co-inventor on a patent application for the use of ketamine and its metabolites in major depression. He has assigned his rights in the patent to the US government but will share a percentage of any royalties that may be received by the government. The remaining authors declare no conflict of interest.

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Machado-Vieira, R., Gold, P., Luckenbaugh, D. et al. The role of adipokines in the rapid antidepressant effects of ketamine. Mol Psychiatry 22, 127–133 (2017). https://doi.org/10.1038/mp.2016.36

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