Repeated or high-dose subanesthetic ketamine causes excitotoxic neuronal damage and lasting cognitive deficits in animals, especially perinates. Infrequent low-to-moderate doses (<1 mg/kg human intravenous equivalent) do not produce overt brain damage in rats and nonhuman primates. In humans, frequent high-dose (>1 g/day) recreational users show memory and executive function impairments. However, a large clinical trial found that intranasal esketamine at up to 84 mg weekly or every other week for several years is associated with maintained or slightly improved cognition in adults with major depression, though some elderly patients showed potential worsening in attention and processing speed. Direct comparisons of esketamine and off-label racemic ketamine at higher doses are lacking.
Adding cognitive behavioral therapy to esketamine treatment reduces suicidal ideation more than esketamine alone in people with major depression and suicidal thoughts. In a randomized trial of 93 patients, 72% completed the study, meeting feasibility goals. Those who received 16 weeks of CBT plus esketamine showed greater improvement on three measures of suicidal ideation than those receiving esketamine with usual care: a mean difference of -1.91 on the Beck Scale for Suicidal Ideation, -0.33 on the Clinician Global Improvement Scale for Suicide Severity, and -3.77 on the depression rating scale. No difference was found on the Columbia-Suicide Severity Rating Scale or in suicide-related events.
In a multisite randomized trial comparing cognitive effects of intravenous ketamine and electroconvulsive therapy (ECT) in patients with treatment-resistant depression, those receiving six ketamine treatments showed superior cognitive functioning after a three-week treatment course compared with those receiving nine ECT sessions. No significant differences in cognitive task performance were associated with response to either treatment. Among responders followed for up to six months, no group differences emerged. Subjective memory measures were mixed: both groups improved on the Squire Memory Complaint Questionnaire, with ketamine recipients reporting greater functional gains, while ketamine-treated patients reported improvements on a global self-evaluation of memory but ECT-treated patients reported a decline. Within the ketamine group, improvements in executive functioning and cognitive flexibility survived adjustment for changes in depression, suggesting partial independence of cognitive and mood effects.