The potential pro-cognitive effects with intravenous subanesthetic ketamine in adults with treatment-resistant major depressive or bipolar disorders and suicidality

Background: Ketamine has rapid and robust antidepressant effects in depression, while its effects on cognitive measures are less clearly understood. This aim of the study herein is to determine whether ketamine has direct pro-cognitive effects in real-world treatment depression and/or suicidality. Methods: Subjects with unipolar (n = 84) and bipolar (n = 27) depression suffering treatment resistance or suicidality received six infusions of ketamine (0.5 mg/kg) during a 12-day period. Depression symptoms were assessed using the Montgomery-Asberg Depression Rating Scale at baseline, day 13 and day 26. Cognitive domains, including processing speed, working memory, visual learning and verbal learning were also measured using the MATRICS Consensus Cognitive Battery at the same time-points. Results: Significant improvement was observed in processing speed at day 13 (effect size [ES] = 0.501) and day 26 (ES = 0.654), and verbal learning at day 13 (ES = 0.362). Path analysis showed significant direct (beta = 2.444, P = 0.017) and indirect (beta = 1.220, P = 0.048) effect of ketamine on processing speed, indicating its improvement was partly independent of improvement in depressive symptoms. The direct effect (beta = 1.963, P = 0.052) of ketamine on verbal learning was not significant, whereas the indirect effect (beta = 1.386, P = 0.024) was significant, indicating treatment with ketamine indirectly improved verbal learning performance, via changes in depressive symptom. Conclusion: Six infusions of ketamine have a potential mood independent pro-cognitive effect on processing speed in adults with treatment depression and/or suicidality. The potential pro-cognitive effects of ketamine provide the basis for hypothesizing that other clinical outcomes (e.g., suicidality, functional impairment) reported with ketamine treatment may be in part mediated by improvement in cognition.