A Systematic Review of Neurocognitive Effects of Subanesthetic Doses of Intravenous Ketamine in Major Depressive Disorder, Post-Traumatic Stress Disorder, and Healthy Population

Ketamine is a noncompetitive, high-affinity antagonist at the N-methyl-d-aspartate (NMDA) glutamate receptor that has attracted attention for its rapid antidepressant effects; its S-enantiomer, esketamine, is now FDA-approved for treatment-resistant depression. Shiroma and colleagues note ongoing safety concerns about cognitive effects at subanesthetic doses, set against evidence that longstanding, frequent recreational use is associated with impairments in spatial working memory and pattern recognition. Major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) themselves feature deficits across cognitive domains that can persist beyond mood symptom remission and may limit recovery and engagement with psychotherapies that require intact cognitive control and memory. This review therefore set out to summarise clinical trials that measured neurocognitive outcomes after subanesthetic intravenous (IV) ketamine in healthy subjects and in adults with PTSD or unipolar/bipolar depression. The investigators focused on ‘‘cold’’ cognitive domains (executive function, processing speed, learning and memory, attention/concentration) and excluded studies of emotion-laden or ‘‘hot’’ cognition, combination interventions, or non-validated cognitive measures.

The review followed the Preferred Reporting Items for Systematic Reviews (PRISMA) framework as a reporting guide. Eligibility criteria required English-language human studies of IV ketamine in adults (≥18 years), either randomized or open-label designs, with validated neuropsychological tests as primary or secondary cognitive outcomes. Exclusions included non-English reports, unavailable full texts, unvalidated psychometrics, lack of quantitative data, ketamine used only alongside other drugs or psychotherapy, studies of emotion-laden cognition, and case reports. Two investigators searched MEDLINE via PubMed up to April 2022 using MeSH and keyword combinations linking ketamine with PTSD or depressive disorders and with psychometrics or neuropsychological tests. Initial screening of search results was performed by one reviewer, with titles and abstracts checked for eligibility by two reviewers; full-text inclusion decisions and disagreements were resolved by consensus among the three authors. Data extraction used a predesigned Excel template capturing author, design, ketamine dose/regimen, neurocognitive and other outcomes, results, and comments, with the intent to produce a narrative synthesis. The extracted material does not clearly report use of a formal risk-of-bias or quality-assessment tool. The review collated studies across three populations (healthy subjects, depression, PTSD) and various experimental designs, doses and timing of cognitive assessments; where study-level methodological details appeared only in tables they were integrated into the narrative synthesis.

Neurocognitive effects in healthy subjects: Twelve eligible studies in healthy populations (published 1994–2016) used predominantly double-blind, randomized, saline-controlled designs with small samples (about 10–54 participants, young adults mostly in their late 20s to early 30s, roughly balanced by sex). The common administration was an IV bolus (0.12–0.26 mg/kg) followed by continuous infusion (0.1–0.8 mg/kg) for 40–80 minutes; one study used only continuous infusion. Cognitive testing was typically performed before, during and shortly after the infusion on the same day. Across studies, ketamine produced immediate impairments most consistently in delayed memory, working memory, executive function and attention, with additional deficits in abstraction, processing speed, episodic and semantic memory reported less frequently. Several studies found dose-dependent effects (for example, greater impairment at 0.5 mg/kg than at 0.1 mg/kg) and evidence that ketamine preferentially impaired encoding (learning and free recall/recognition) rather than retrieval. Some cognitive deficits correlated with dissociative or thought-disorder symptoms measured concurrently. Neurocognitive effects in major depressive disorder: Thirteen studies (2014–2022) enrolled middle-aged adults (sample sizes 13–84) with treatment-resistant depression (TRD) and related diagnostic mixes (MDD, bipolar disorder, some cohorts with suicidal ideation or comorbid PTSD). Most administered single (n = 5) or repeated (n = 8) IV infusions of 0.5 mg/kg over about 40 minutes; comparators included saline, low-dose ketamine (0.2 mg/kg), esketamine 0.25 mg/kg, and active placebo midazolam in several RCTs. Cognitive testing timepoints ranged from 40 minutes post-infusion to 26 weeks, with most assessments occurring within 2 weeks of the last infusion. Overall, the studies reported no consistent short-term (within 2 weeks) deleterious cognitive effects of single or repeated ketamine in depressed patients. Some trials found small improvements after treatment in visual memory/learning, processing speed and, to a lesser extent, episodic memory and attention; working memory improvements were more often reported after repeated infusions. Results were mixed regarding associations between cognition and antidepressant response: some studies found that poorer baseline processing speed or attention predicted better antidepressant response, others found no predictive relationship, and some reported that cognitive gains correlated with mood improvement while others did not. A few dose-specific findings were noted (for example, Chen and colleagues reported improved sustained attention and response inhibition at 0.5 mg/kg but not at 0.2 mg/kg). Neurocognitive effects in post-traumatic stress disorder: Only one eligible study examined PTSD specifically. Albott and colleagues conducted an open-label trial in 15 veterans with TRD and comorbid PTSD who received six IV infusions of 0.5 mg/kg over 12 days. Repeated infusions did not worsen cognitive measures; instead, working memory scores improved significantly after the infusion series. In this sample, lower baseline working memory, slower processing speed and faster set-shifting predicted greater symptomatic improvement in PTSD and depression, and lower baseline attention predicted greater improvement in depression.

Shiroma and colleagues interpret their synthesis as showing a clear contrast between healthy-subject studies, which demonstrate immediate ketamine-associated cognitive impairment during or shortly after infusion, and clinical trials in depression and the single PTSD study, which generally show no short-term cognitive harm and in some cases modest improvements in executive and memory-related domains. They attribute these divergent findings to differences in study aims (experimental modelling of psychosis in healthy volunteers versus therapeutic use in clinical samples), dosing/regimen differences (bolus-plus-infusion versus standard 0.5 mg/kg over 40 minutes), and, importantly, timing of cognitive assessments (during infusion or at peak psychoactive effects versus 24 hours to weeks post-infusion). The authors discuss plausible biological mechanisms that could underlie transient cognitive improvement in clinical populations, noting preclinical and human evidence of rapid synaptogenesis in the prefrontal cortex within 30 minutes of a single ketamine administration (lasting up to about 72 hours), hippocampal neurogenesis after repeated dosing, upregulation of neurotrophic signalling pathways (BDNF, mTORC1) and modulation of dopamine systems. Imaging studies cited by the authors showed increased prefrontal connectivity after ketamine in responders, and a PTSD study reported greater ventromedial PFC–amygdala connectivity associated with symptom improvement after repeated treatment. From a clinical perspective, the authors propose a ‘‘therapeutic window’’ in which improved executive functioning and memory following ketamine could be used to enhance trauma-focused or cognitive behavioural psychotherapies; they describe small pilot efforts combining ketamine with cognitive behavioural therapy or prolonged exposure, reporting preliminary symptomatic and cognitive benefits and noting planned randomized trials. The review also highlights several limitations acknowledged by the investigators: cognitive outcomes were secondary in the clinical trials and not powered a priori; studies largely reported individual test scores rather than composite cognitive measures that may be more reliable; substantial heterogeneity existed across studies in design, placebo use, dosing frequency and timing of assessments; all depression studies involved TRD populations, limiting generalisability to other depressive subtypes; and the review excluded hot cognition measures, which may interact with cold cognition. The authors emphasise the need for longer-term follow-up studies (for example, 6 months) to assess cognitive effects of repeated ketamine exposure and for trials that carefully align timing of ketamine administration with psychotherapeutic processes.

The authors conclude that IV ketamine in patients with depression and possibly in PTSD is not associated with significant short-term cognitive impairment, in contrast to the immediate cognitive dysfunction observed in healthy subjects during or shortly after infusion. Improvements were most evident in executive function domains, which aligns with proposed molecular, synaptic and circuit-level effects of ketamine. Finally, the extent to which short-term cognitive gains contribute to clinical improvements in depressive or PTSD symptoms remains uncertain and warrants further investigation.