AN OPEN-LABEL, TWO-ARM STUDY OF KETAMINE’S EFFECTS ON FLUID COGNITION IN MOOD DISORDERS WITH AND WITHOUT PSYCHOSIS

Background

Individuals with mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), frequently exhibit neurocognitive deficits; however, no pharmacological treatments effectively target cognition. Cognitive dysfunction is especially prominent in individuals with prior psychotic symptoms. Ketamine, an N-methyl-D-aspartate receptor antagonist, has rapid antidepressant and anti-suicidal ideation effects in unipolar and bipolar depression and may improve cognition through glutamate-mediated synaptic plasticity. Emerging evidence suggests that ketamine can enhance fluid cognition (ability to reason, learn and solve novel problems without relying on prior knowledge) within hours to days, sometimes independently of mood improvement. This study evaluates baseline fluid cognition by psychosis history, ketamine-related cognitive improvement, differential response by psychosis status, and safety in individuals with prior psychotic experiences.

Methods

Twenty subjects (age = 41.05 ± 13.85; 11 female; 13 with MDD, 7 with BD) were included by convenience sampling. Prior psychotic experience was assessed at baseline using the Questionnaire for Psychotic Experiences or a clinical interview. Ten subjects received up to five open-label ketamine infusions (0.5 mg/kg over 40 minutes) over three weeks; the remaining subjects comprised a no-intervention group for comparison purposes. Participants who received ketamine had a lifetime history of suicidal ideation but were not in an active suicide crisis. The NIH Toolbox Fluid Cognition Composite and the Montgomery–Åsberg Depression Rating Scale (MADRS) were assessed at baseline, after the first infusion (or a comparable time point for the no-intervention group), and after the final infusion. Adverse events were recorded using MedDRA on the days following the first and last infusions. Independent-samples t-tests assessed baseline Fluid Cognition differences by psychosis history. Linear mixed-effects models examined changes in MADRS and Fluid Cognition across condition (baseline, no-intervention, post-infusion 1, and post-infusion 5) and by psychosis status, controlling for diagnosis and including random intercepts for subjects. Adverse events were summarized descriptively.

Results

No subjects had a primary psychotic disorder or psychotic symptoms within two weeks prior to study inclusion. Six participants had prior psychotic experiences. Baseline Fluid Cognition did not differ by psychosis history (98.5 ± 11.6 vs. 98.8 ± 13.7; t = 0.04, p = 0.96). Ketamine reduced MADRS scores across conditions [F(3, 23.27) = 4.68, p = 0.011], with no effect of psychosis history [F(1, 16.67) = 0.07, p = 0.79]. Ketamine was also associated with improvement in cognition across conditions [F(3, 18.45) = 16.73, p < 0.001], again with no effect of psychosis history [F(1, 16.89) = 0.04, p = 0.85]. Participants with prior psychotic experiences reported only mild, transient adverse events (e.g., gastrointestinal symptoms, muscle pain), with no hallucinations or psychotic symptoms observed.

Conclusion

Ketamine was well tolerated and was associated with improvements in depressive symptoms and fluid cognition in individuals with mood disorders, regardless of prior psychotic experiences. No psychotic symptoms persisted on the days following the infusions. These findings suggest that repeated ketamine infusions may be a safe and effective intervention to enhance mood and cognition in mood disorders, including in individuals with a history of psychosis. Further studies with larger samples are needed to confirm these findings and to evaluate long-term safety and efficacy.