Single Ketamine Infusion and Neurocognitive Performance in Bipolar Depression

Earlier research has shown that a single subanaesthetic infusion of ketamine (0.5 mg/kg) can produce a rapid antidepressant effect in treatment-resistant unipolar depression and, when added to mood-stabilising drugs, in bipolar depression. Cognitive deficits are a prominent feature of depressive episodes and of bipolar disorder more generally; previous studies have reported mixed effects of ketamine on cognition, with some transient impairments after a single infusion and improvements reported after serial infusions in treatment-resistant major depression. Permoda-Osip and colleagues set out to examine whether a single ketamine infusion would alter neurocognitive performance in patients with bipolar depression who were maintained on mood-stabilising medication. Specifically, the study measured cognitive performance before and on the third day after infusion and tested whether any cognitive changes related to baseline depression severity or to the antidepressant response to ketamine.

This was an open clinical study of 18 in‑patients (4 male, 14 female), aged 27–67 years (mean 50 ± 11), carrying DSM‑IV diagnoses of bipolar disorder with current depressive episodes; diagnoses were established by consensus of at least two psychiatrists using SCID. The mean illness duration was 16 ± 7 years and the current depressive episode averaged 4.8 ± 2.4 months. All participants were receiving one or more mood‑stabilising agents (examples reported: lithium, quetiapine, lamotrigine, valproate, aripiprazole, carbamazepine, olanzapine). Antidepressant drugs were discontinued at least 7 days before infusion. A single intravenous infusion of ketamine at 0.5 mg/kg was administered between 08:00 and 08:45. Patients were closely monitored during the infusion and for 6 consecutive hours afterwards. Depressive symptoms were assessed with the 17‑item Hamilton Depression Rating Scale (HDRS) at baseline, and at 6, 12, 24 hours, and on days 3, 7, 10 and 14 after infusion. Inclusion required a baseline HDRS score of at least 18. The investigators defined response as a 50% or greater reduction in HDRS relative to baseline measured on day 7. Neurocognitive assessment comprised the Trail Making Test (TMT) and the Stroop colour‑word interference test. TMT Part A was used to assess psychomotor speed; Part B assessed set‑shifting and aspects of executive function and visuospatial working memory. The Stroop test included a black‑ink word‑reading condition (RNCb) to capture verbal abilities and attention, and a colour‑naming, mismatched condition (NCWd) to probe verbal working memory and executive control. Ethics approval and informed consent were obtained. The extracted text does not clearly report whether assessors were blinded to clinical response or other procedural blinding.

Baseline mean HDRS score for the 18 patients was 24 ± 5. Mean HDRS fell to 13 ± 6 on day 3 and to 12 ± 7 on day 7 after the ketamine infusion. By the day‑7 definition of response, 8 patients (44%) met the criterion of at least 50% reduction in HDRS. Performance on all neurocognitive tests was reported to be significantly better on day 3 compared with baseline. The degree of cognitive improvement correlated positively with baseline impairment on the respective tests, meaning patients with worse performance at baseline tended to show larger gains by day 3. No significant correlations were found between the magnitude of cognitive improvement and either baseline HDRS score or reduction of depressive symptoms at day 3 or day 7. The extracted text does not present detailed test‑by‑test numerical scores or statistical values (for example, means, standard deviations or p‑values for each cognitive measure) in the prose; it refers to a performance table that is not included in the provided extraction. Adverse events or tolerability data beyond the 6‑hour monitoring period are not described in the extracted text.

Permoda-Osip and colleagues interpret the findings as suggesting that a single subanaesthetic ketamine infusion may produce measurable improvement in neuropsychological performance by day 3 in bipolar depressed patients who remain on mood‑stabilising medication. Reported gains encompassed psychomotor speed, verbal abilities and executive functions such as set‑shifting. Because cognitive improvement did not correlate with baseline depression severity or with symptomatic reduction at days 3 or 7, the investigators propose that the cognitive effects observed may be at least partly independent of the antidepressant response. The authors acknowledge several key limitations. Practice effects on repeated cognitive testing could account for some improvement, antidepressant discontinuation 7 days before infusion might have influenced cognition, and the absence of a control group limits causal inference. They also note differences between their findings and prior studies in major depression that linked cognitive change to mood improvement; such discrepancies might reflect diagnostic differences (major vs bipolar depression) and the continuous use of mood‑stabilising drugs in their sample, which could modulate both antidepressant and cognitive responses to ketamine. Finally, the investigators situate their results alongside other reports of cognitive improvement following serial ketamine infusions in treatment‑resistant depression, while emphasising that differences in patient populations and treatment background temper direct comparison. The extracted text does not report the authors proposing specific mechanistic explanations beyond these comparative observations, nor does it state explicit recommendations for clinical practice or future trial design within the provided sections.