Neurocognitive effects of repeated ketamine infusions in comorbid posttraumatic stress disorder and major depressive disorder

Albott and colleagues situate the study within growing clinical interest in ketamine, an NMDA receptor antagonist that produces rapid antidepressant effects and is being explored for comorbid conditions such as PTSD. While acute ketamine administration produces transient dissociative and cognitive effects, the long-term neurocognitive consequences—particularly following repeated therapeutic dosing—remain uncertain. Observational data from recreational users suggest dose-related cognitive deficits, whereas emerging clinical trials in depressed samples report mixed findings, with some studies showing improvements in specific cognitive domains after repeated infusions. The study aimed to address two gaps: first, to characterise neurocognitive changes following a course of six ketamine infusions in individuals with comorbid PTSD and major depressive disorder (MDD); second, to evaluate whether baseline neurocognitive functioning predicts subsequent change in PTSD and depression symptoms. The investigators focused on a trauma-exposed veteran cohort because PTSD commonly co-occurs with MDD and is associated with cognitive dysfunction, creating a clinically relevant population for assessing both safety and potential cognitive predictors of treatment response.

This was an open-label clinical study conducted at the Minneapolis VA Health Care System (registered NCT02577250) in which veterans with chronic PTSD and treatment‑resistant MDD received six intravenous ketamine infusions. Eligibility required clinician-determined PTSD (CAPS-5) and MDD (SCID for DSM-IV), failure to recover after at least two antidepressant trials, stable psychotropic medication dosing during the study, and absence of unstable medical/CNS conditions, recent substance use disorder, psychosis, bipolar disorder, or imminent suicidal risk. Women of childbearing potential required a negative pregnancy test and contraception use. Baseline assessments occurred within 1 week before dosing. Participants received six IV infusions of ketamine hydrochloride 0.5 mg/kg administered over 40 minutes on a Monday–Wednesday–Friday schedule across 12 days, with standard monitoring and side-effect checks during and up to at least 2 hours post-infusion. Primary clinical outcomes were change in PTSD symptoms (PCL-5) and change in depression severity (MADRS). Secondary outcomes included CAPS-5 change, remission and response rates for PTSD and depression, domain-level PTSD symptoms, and relapse during follow-up. The PCL-5 and MADRS were collected 1 hour before and 24 hours after each infusion; CAPS-5 and MADRS were also collected within 1 week pre- and post-series and weekly for up to 8 weeks post-final infusion. Neurocognitive testing used a 2-hour CogState battery at baseline and within one week after infusion-series completion to assess attention, working/visual/verbal memory, processing speed, and set shifting. For each CogState task a single outcome metric was chosen to maximise sensitivity to change; measures were normally distributed or transformed to normality. Statistical analyses included paired-samples t-tests for within-subject cognitive change, Pearson correlations between baseline cognition and change in CAPS-5 and MADRS at 1 week post-series, ANOVAs to examine potential confounders (gender, education, medication classes), and hierarchical linear regressions to adjust significant associations for identified covariates. Significance was set at alpha = 0.05.

Of 24 consented individuals, 19 met eligibility and 16 received all six infusions; data for one early participant were excluded because of a PTSD measure change, yielding an analysis sample of n = 15. Paired comparisons of neurocognitive performance before and within 1 week after the infusion series found no significant worsening in any cognitive domain. Rather, spatial working memory improved: total errors on the Groton Maze Learning task decreased by a mean of 14.4 errors (95% CI: 2.329 to 26.471; t(14) = 2.559, p = .023), a medium effect size. All other CogState tasks showed non-significant changes with small effect sizes. Baseline neurocognitive performance correlated with clinical change from baseline to 1 week post-series. Greater improvement in PTSD symptoms (CAPS-5) was associated with poorer baseline working memory (one-back ONB: r = -0.545, p = .036; Groton maze GML: r = 0.609, p = .016), slower processing speed (detection DET: r = 0.586, p = .028), and better baseline set shifting (SETS: r = -0.545, p = .036). For depression (MADRS), larger symptom reductions correlated with worse baseline working memory (ONB: r = -0.564, p = .029; two-back TWOB: r = -0.566, p = .028), poorer verbal learning (International Shopping List ISL: r = -0.528, p = .043), slower processing speed (Groton-maze chase GMCT: r = -0.591, p = .020), and better set shifting (SETS: r = -0.565, p = .028). Figures in the paper present these domain-level correlations. Analyses of potential confounders showed no significant effects of gender, marital status, or education on clinical or cognitive outcomes. Concomitant antidepressant use was linked to better attention and faster processing speed, while benzodiazepine use was associated with worse working memory. After adjusting for antidepressant use, the association between processing speed and PTSD improvement remained significant. The relationship between baseline working memory (2-back) and depression change lost significance after adjustment for benzodiazepine use.

Albott and colleagues interpret the findings as indicating that a six-infusion ketamine regimen did not produce short-term neurocognitive impairments in veterans with comorbid PTSD and MDD; instead, spatial working memory improved with a medium effect size. This outcome aligns with several prior studies in depressed samples that reported either no cognitive decline or improvements in specific cognitive domains following repeated ketamine dosing. The authors highlight that baseline neurocognitive profiles were associated with clinical response: individuals with poorer working memory and slower processing speed but intact or better set shifting tended to show greater reductions in PTSD and depression symptoms. They position this pattern as a potential predictive profile for ketamine response in comorbid PTSD and treatment-resistant depression, noting that the broader literature on cognitive predictors of ketamine response is mixed. The paper suggests two non‑mutually exclusive mechanisms: symptom reduction freeing cognitive resources for prefrontal engagement, or a direct pro-cognitive action of ketamine that helps reallocate cognitive resources to adaptive coping. Key limitations acknowledged by the investigators include the open-label design without a placebo control, small sample size, and potential confounding by concomitant medications (notably antidepressants and benzodiazepines). These constraints limit causal inference and generalisability. The authors recommend larger placebo-controlled trials powered to examine mediator and moderator effects, and further exploration of how concomitant medications influence both cognitive function and clinical response to ketamine.

The study concluded that serial ketamine infusions were not associated with adverse neurocognitive effects when assessed within 7 days of completing a six‑infusion series in veterans with comorbid PTSD and MDD. Greater improvements in depression were associated with poorer baseline working and verbal memory, slower processing speed, and better set shifting; a similar pattern—decreased baseline working memory and better set shifting—was associated with greater PTSD improvement.