From rigidity to flexibility: ketamine-induced changes in cognitive flexibility in major depressive disorder

Background

Major depressive disorder (MDD) is associated with impairments in cognitive flexibility, a key executive function underlying adaptive behaviour and goal-directed decision-making [4]. These deficits are linked to dysfunction in prefrontal–striatal circuits and altered glutamatergic neurotransmission, contributing to poor functional outcomes, impaired psychosocial functioning, and increased relapse risk [2]. Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, produces rapid antidepressant effects, likely mediated by enhanced synaptic plasticity, increased glutamatergic throughput, and downstream activation of neurotrophic signalling pathways [1,2]. Preclinical studies demonstrate that ketamine restores synaptic connectivity, increases dendritic spine density, and enhances long-term potentiation in the prefrontal cortex [2]. Emerging clinical evidence suggests potential benefits on executive functions, including reduced perseveration and improved set-shifting, which may translate into better real-world functioning [3]. However, data on sustained cognitive effects, their clinical relevance, and their independence from mood improvement remain limited. This study aimed to investigate ketamine’s effects on cognitive flexibility in MDD and explore predictors of cognitive response.

Methods

A randomised, double-blind, placebo-controlled trial was conducted in n = 30 patients with moderate-to-severe MDD. Participants received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) or placebo (saline) [1,3]. Cognitive flexibility was assessed using the Intra-Extra Dimensional Set Shift (IED) task, measuring rule acquisition, attentional set formation, and set-shifting performance, at baseline, 24 hours, and 7 days post-infusion. Depressive symptoms were measured with the Hamilton Depression Rating Scale (HDRS, 17 items). Data were analysed using mixed-effects models with time × treatment interactions, and effect sizes were calculated using Cohen’s d. Sensitivity analyses were conducted to control for potential confounders, including baseline symptom severity.

Results

Ketamine produced a significant improvement in cognitive flexibility compared with placebo. Patients in the ketamine group showed faster intra-dimensional and extra-dimensional set-shifting, improved task efficiency, and reduced perseverative errors at 24 hours (p < 0.01, Cohen’s d = 0.82) [3]. These effects persisted at day 7 (p < 0.05), suggesting sustained cognitive benefits beyond the acute phase. Importantly, improvements remained significant after controlling for HDRS score reductions, indicating a direct effect on executive function independent of mood improvement. Exploratory analyses revealed that baseline executive performance predicted the magnitude of cognitive gains (r = 0.45, p = 0.02), highlighting potential inter-individual variability and the relevance of stratification approaches [4]. No serious adverse events were observed, and treatment was well tolerated [1,3].

Conclusions

Ketamine enhances cognitive flexibility in MDD, supporting a shift from cognitive rigidity to adaptive processing, potentially via glutamatergic modulation of prefrontal circuits and synaptic plasticity mechanisms [2]. These findings highlight a dissociable cognitive effect beyond antidepressant response and suggest that ketamine may improve functional and behavioural outcomes through executive enhancement [3,4]. Future studies should integrate multimodal neuroimaging, longitudinal designs, and precision medicine approaches to identify biomarkers, optimise patient selection, and clarify the durability of effects following repeated administration. Understanding the relationship between cognitive improvement and real-world functioning will be critical for clinical translation.

References

1. Berman RM et al. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry.
2. Duman RS et al. (2012). Synaptic plasticity and depression: new insights from ketamine. Nature Medicine.
3. Murrough JW et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant depression. American Journal of Psychiatry.
4. Diamond A. (2013). Executive functions. Annual Review of Psychology.