Neurocognitive performance of repeated versus single intravenous subanesthetic ketamine in treatment resistant...

Ketamine demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine's neurocognitive effect in TRD is unclear. We aim to (1) characterize baseline neurocognitive performance as a predictor of the change in severity of depressive symptoms over time, and (2) investigate the association of six versus single intravenous (IV) ketamine and neurocognitive changes from baseline to the end of treatment.

Subjects with TRD were randomized to receive either five IV midazolam followed by a single IV ketamine or six IV ketamine during a 12-day period. Depression symptom assessments occurred prior and 24 h after infusion days using the Montgomery-Åsberg Depression Rating Scale. Neurocognitive tasks were designed to test attention, memory, speed of processing, and set shifting using the CogState battery at baseline and at the end of treatment.

Better complex working memory at baseline predicted improvement in MADRS scores of ketamine (vs midazolam) after 5 infusions. Most, but not all, neurocognitive functions remained stable or improved after repeated or single ketamine. There was a greater differential effect of treatment on speed of processing, set shifting, and spatial working memory that favors subjects in the six ketamine group. These cognitive improvements from baseline to the end of treatment were robust when controlling for age and changes in depression severity.

The study suggests that six IV ketamine compared to single IV ketamine has a mood independent procognitive effect among TRD patients. Large scale studies are needed to confirm whether ketamine enhances cognitive function in TRD.