Acute cognitive effects of single-dose intravenous ketamine in major depressive and posttraumatic stress disorder

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant and anti‑suicidal effects when given intravenously (IV) at subanesthetic doses. Its growing off‑label clinical use in major depressive disorder (MDD) and posttraumatic stress disorder (PTSD), and the approval of intranasal esketamine for treatment‑resistant depression, have raised concerns about central nervous system risks, particularly cognitive dysfunction. Prior experimental and clinical literature indicates that high doses and chronic abuse of ketamine can impair attention, memory and psychomotor function, but evidence is limited regarding the cognitive effects of therapeutic, subanesthetic IV ketamine in people with MDD or PTSD; notably, no prior study had examined PTSD specifically, and existing MDD studies report inconsistent results that may reflect methodological differences. Davis and colleagues set out to characterise the acute cognitive effects of a single therapeutic (subanesthetic) IV ketamine dose in adults with MDD and/or PTSD compared with matched healthy controls (HC). The investigators assessed attention, working memory, executive function and verbal memory at baseline, 2 hours and 1 day after ketamine administration, and tested three main questions: whether ketamine produces rapid mood improvement in the clinical group, whether it causes an acute cognitive decline at 2 hours that resolves by 1 day, and whether baseline symptom level influences cognitive responses. Tests were chosen for sensitivity to ketamine effects and for low practice effects at short retest intervals.

Participants were community‑recruited adults aged 18–60 years, English speaking and without recent regular psychiatric medication use. The clinical group comprised people meeting DSM‑IV‑TR criteria for MDD (n = 14) and/or PTSD (n = 15) on the SCID, required to be in a current major depressive episode if diagnosed with MDD, free of other psychiatric disorders except anxiety disorders, and off psychotropic medication for at least 2 months. The healthy control group (n = 29) had no current or lifetime psychiatric diagnoses and no first‑degree relatives with psychiatric illness. Groups were matched on age, sex and smoking status; years of education differed between groups. Ketamine was administered intravenously in a neuroimaging context under medical supervision with monitoring of vital signs before and during the 3 h post‑injection period. Two closely similar dosing regimens were used across participants because of parallel imaging protocols: half the subjects received an initial bolus of 0.23 mg/kg over 1 min followed by 0.58 mg/kg per hour for 1 h, and the other half received a constant infusion of 0.5 mg/kg over 40 min. The investigators report no substantive differences in demographics, clinical variables or cognition as a function of dosing regimen. Mood was assessed using the Structured Clinical Interview for DSM (SCID) at screening, and symptom measures included the Hamilton Depression Rating Scale, Beck Depression Inventory‑II (BDI‑II) and Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline, 2 h and 1 day post‑ketamine. Treatment response was defined using the minimum clinically important difference (MCID) on the BDI‑II (three points). Premorbid IQ was estimated with the Wechsler Test of Adult Reading. Cognition was measured with Cogstate tests selected for sensitivity to ketamine effects and minimal practice effects: Detection (DET) for psychomotor speed, Identification (IDN) for visual attention, One Back (ONB) for working memory speed, One Card Learning (OCL) for visual learning accuracy, Groton Maze Learning Test (GMLT) for executive function (errors), and International Shopping List Test (ISLT) for verbal memory. Main measures were standardised to age‑stratified normative data, signs were adjusted so that negative z‑scores indicated poorer performance, and outcomes were combined into an attention composite (DET+IDN), a working memory composite (OCL+ONB) and two individual domain scores (GMLT for executive function, ISLT for verbal memory). Statistical analysis proceeded in stages. Group matching was tested with chi‑squared tests and ANOVAs. Repeated‑measures ANOVA examined mood change across time and diagnostic group. For cognitive outcomes, change scores from baseline to each post‑ketamine timepoint were analysed using ANCOVA models with baseline score and years of education as covariates (one model per cognitive outcome). The clinical group was combined (MDD+PTSD) for primary analyses to preserve power and because prior literature suggested similar effects; exploratory analyses compared MDD and PTSD subgroups. Multivariate ANCOVA was used to examine relationships between baseline cognition, diagnosis and treatment response. Cohen's d was reported for effect sizes and the Benjamini–Hochberg procedure controlled for multiple comparisons.

Sample characteristics showed the MDD/PTSD and HC groups were similar in age, sex, IQ and BMI, although years of education differed (t = 8.78, p = 0.004). Baseline mood ratings indicated moderate depression in the clinical group (MADRS mean 22.7 ± 4.7; BDI‑II mean 22.0 ± 8.7). No cognitive scores or change scores met the pre‑specified outlier criterion, so no data were excluded. Mood outcomes: Repeated‑measures ANOVA revealed a significant interaction of diagnostic status and depressive symptom severity across timepoints (F = 11.39, p < .001, d = 0.86). Mean symptom severity in the MDD/PTSD group decreased from moderate at baseline to mild at both 2 h and 1 day post‑ketamine. Using the BDI‑II MCID, 9/14 (64.3%) MDD participants were classified as responders, improving on average 11.6 points (52.5%) at 2 h and 8 points (36.4%) at 1 day; 11/15 (73.3%) PTSD participants were responders, improving on average 11.8 points (53.3%) at 2 h and 9.3 points (42.2%) at 1 day. On the clinician MADRS at 2 h, PTSD participants had significantly lower scores than MDD participants (mean difference 7.1 points, p < .001, d = 0.99). Cognitive outcomes: At 2 h post‑ketamine, both groups showed declines in executive function (EF) and verbal memory (VM); healthy controls also evidenced declines in attention (ATTN), VM and EF at 2 h, but the pattern differed between groups. In the combined MDD/PTSD group, attention, EF and VM performance declined at 2 h and returned to baseline by 1 day. Working memory (WM) performance was not affected by ketamine in either group at either timepoint. When comparing groups, the magnitude of decline in attention was significantly larger in the MDD/PTSD group than in HC (F = 6.99, p = .012, d = 0.56); EF and VM declines did not differ significantly between groups. All ketamine‑related cognitive declines resolved by 1 day after dosing. Exploratory analyses: Direct comparisons between MDD and PTSD subgroups showed no significant differences on attention or verbal memory. Individuals with MDD performed worse than those with PTSD on executive function at 2 h and on working memory at 1 day (WM: F = 4.56, p = .031). No significant relationships were found between baseline cognitive functioning and treatment responder status, nor between change in cognitive functioning and responder status.

Davis and colleagues interpret the findings as showing robust, rapid antidepressant effects of a single subanesthetic IV ketamine dose in both MDD and PTSD, accompanied by transient, domain‑specific cognitive effects. Specifically, ketamine produced acute declines in attention, executive function and verbal memory at 2 h post‑administration in the combined clinical sample, with the attentional decrement larger in the MDD/PTSD group than in healthy controls; all observed cognitive impairments resolved by 1 day. Working memory was unaffected. The authors note that, from a neuropsychopharmacological standpoint, therapeutic IV ketamine induces short‑lived impairments in higher cognitive functions, and in their mixed clinical sample this effect extends to attention. The discussion situates these results within prior literature showing that NMDA antagonists can disrupt motor coordination and attention, and that higher ketamine doses impair psychomotor performance relevant to driving safety. The transient nature of the deficits observed here—restricted to the acute period and resolving after drug clearance—is consistent with human experimental models and with recovery seen after abstinence in chronic users. By including a PTSD subgroup, the study contributes new data suggesting generally comparable acute cognitive effects across MDD and PTSD, with a few domain‑specific differences in exploratory analyses. The investigators acknowledge several limitations that temper interpretation. The study lacked a randomised, placebo‑controlled design, so practice effects, fatigue or stress cannot be ruled out as contributors to cognitive changes. Sample size was modest, limiting representativeness and statistical power. Only short‑term effects (2 h and 1 day) were assessed, so longer‑term cognitive consequences and the exact timecourse of recovery remain unknown. The cognitive battery, while sensitive to ketamine effects, is not exhaustive and differences from other studies may reflect measure selection. Procedural variability in dosing regimens (two similar infusion protocols) was present, though the authors report no effect of dosing on outcomes. Finally, the clinical sample excluded participants taking psychiatric medication, limiting generalisability to broader patient populations. Given the potential impact of cognitive deficits on functional recovery in MDD and PTSD, the authors recommend longitudinal studies with larger, more representative samples, inclusion of cognitive batteries in clinical trials of ketamine, and careful attention to study design when evaluating ketamine's cognitive risks and benefits.