Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

Seventy-three individuals were randomised and 72 received study medication (47 ketamine, 25 midazolam) in the parent trial. Due to missing or incomplete neurocognitive data (four ketamine, six midazolam), the neurocognitive sub-study included 62 patients: 43 randomised to ketamine and 19 to midazolam. One domain (visual learning) had additional missing data (n = 34 ketamine, n = 17 midazolam). Treatment groups were similar on age, sex distribution, baseline depression severity and degree of treatment resistance. At the 7-day assessment, repeated-measures ANOVA revealed a significant main effect of time across both treatment arms: participants improved from baseline on processing speed (F(1,59) = 6.58, p = 0.013), verbal learning (F(1,59) = 6.80, p = 0.012), and visual learning (F(1,48) = 6.48, p = 0.014) while controlling for change in depression severity. No significant changes were observed for working memory or reasoning/problem solving. There was no main effect of treatment condition (ketamine versus midazolam) on any neurocognitive domain, no effect of antidepressant responder status at either 24 hours or 7 days on cognitive performance, and no significant time-by-treatment or time-by-responder interaction effects. Baseline cognitive performance predicted antidepressant response to ketamine at 24 hours. In a backwards stepwise linear regression including age, baseline MADRS, and the five domain scores, the final model retained only processing speed (F(1,37) = 5.3, p = 0.027; beta = 0.43 ± 0.19; t = 2.3, p = 0.027), indicating that poorer processing speed at baseline was associated with greater improvement in MADRS score at 24 hours. A backwards stepwise logistic regression for categorical response yielded a model containing processing speed and visual learning (χ2 = 11.82, p = 0.003), but only processing speed was a significant predictor in that model (Exp(beta) = 0.823, Wald = 7.76, p = 0.005). On univariate comparisons, ketamine responders had lower baseline processing speed T-scores (43.37 ± 8.78) than ketamine non-responders (49.24 ± 10.1; F(1,45) = 4.36, p = 0.043). There was no association between baseline processing speed and baseline depression severity (r = −0.167, p = 0.164). No significant relationships between baseline cognitive measures and antidepressant response were observed for midazolam (data not shown).

Seven days after a single sub-anesthetic ketamine infusion in patients with TRD, the investigators found no evidence of deleterious effects on neurocognitive performance compared with an active midazolam control. Improvements observed over time in processing speed, verbal learning, and visual learning occurred across both treatment conditions and persisted after controlling for changes in depression severity, which the authors interpret as likely reflecting non-specific practice or learning effects from repeated testing. The study therefore replicates prior open-label findings suggesting absence of persistent cognitive impairment following single-dose ketamine in depressed patients. Murrough and colleagues also replicated their earlier observation that slower processing speed at baseline predicted a more robust rapid antidepressant response to ketamine at 24 hours. The authors note that this association was independent of baseline depression severity and was not observed for midazolam. They situate this finding within a mechanistic framework: processing speed and attention have been linked to dopaminergic functioning in prefrontal–subcortical circuits, and preclinical and some human data indicate that ketamine modulates dopamine signalling and rapidly enhances synaptic plasticity (BDNF-dependent) in cortical and subcortical regions. Nevertheless, the authors acknowledge that no study to date has directly established a causal relationship between dopamine signalling and ketamine’s antidepressant effects in humans, and they call for in vivo imaging and other mechanistic studies to clarify these pathways. Key limitations noted by the investigators include the single-dose design and the absence of immediate post-infusion cognitive testing in this trial (so acute cognitive effects at peak drug exposure were not assessed here), limited ability to generalise to repeated or long-term treatment regimens, and a sample size that—while comparatively large for this literature—may be insufficient to identify robust biological or cognitive biomarkers. They also highlight differences in neurocognitive assessment batteries across studies (this study used the MCCB and did not include a dedicated attention measure), which may complicate replication. The authors recommend that future trials employ standardised, multi-modal biomarker assessments (potentially combining neurocognitive testing, neuroimaging, qEEG and peripheral markers), explore dose and frequency parameters, and evaluate the cognitive effects of repeated ketamine administrations over longer time frames. In sum, the trial provides evidence that a single 0.5 mg/kg ketamine infusion is not associated with short-term adverse neurocognitive effects at 7 days in patients with TRD, and that reduced processing speed at baseline may be a candidate pre-treatment predictor of rapid antidepressant response; further, larger and more mechanistically oriented studies are required to confirm and extend these findings.