ClinicalTrials.gov identifiers: NCT00419003, NCT00548964, and NCT00768430.

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 IQ, current IQ, and tests from the MATRICS 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 hours following treatment had poorer baseline neurocognitive performance relative to non-responders, 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 hours; Fisher’s Exact Test 2-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.