Systematic Review: Cognitive Effects of (Es)ketamine in Mood Disorders

Systematic Review Finds Mixed Cognitive Effects of (Es)ketamine in Mood Disorders

A systematic review published on September 14, 2026 (OpenAlex W7213143829) synthesizes current evidence on the cognitive impacts of ketamine and esketamine in the treatment of major depressive disorder (MDD) and bipolar disorder (BD). The review aggregates data from randomized controlled trials, observational studies, and open-label investigations, offering a critical update for clinicians and researchers as the use of these agents expands in psychiatric practice. This synthesis is particularly timely as esketamine, approved by the U.S. Food and Drug Administration (FDA) for treatment-resistant depression since 2019, is being adopted in a growing number of jurisdictions globally.

Mechanisms: Cognitive Domains and Neurobiological Pathways

Ketamine and its S-enantiomer, esketamine, are N-methyl-D-aspartate (NMDA) receptor antagonists with rapid-acting antidepressant properties. The review finds that cognitive effects are domain-specific: acute administration may transiently impair working memory, attention, and executive function, while repeated low-dose treatments appear less consistently detrimental. Notably, the review highlights that in some studies, improvements in depressive symptoms are associated with subtle cognitive gains, particularly in processing speed and verbal learning—suggesting that symptom relief can indirectly benefit cognition. The underlying neurobiology remains complex, involving glutamatergic modulation, synaptic plasticity, and potential downstream effects on neurotrophic factors.

Policy and Research Implications: Informing Risk-Benefit Assessment

The review's findings have immediate implications for clinical guidelines and regulatory oversight. As esketamine clinics proliferate in the United States, United Kingdom, and Australia, practitioners must weigh the rapid antidepressant effects against potential cognitive risks, especially in patients with pre-existing cognitive vulnerabilities. The review notes a lack of long-term cognitive safety data, a gap that may influence future FDA post-marketing surveillance requirements and insurance coverage decisions. Importantly, the authors call for standardized cognitive testing protocols in future trials—a recommendation not yet widely adopted in ongoing phase 3 and 4 studies. This insight underscores a concrete failure mode: current trial designs may underestimate subtle or delayed cognitive harms, particularly in older adults or those with comorbid neurodegenerative conditions.

• Regulatory context: Esketamine is FDA-approved for treatment-resistant depression (TRD) since 2019; ketamine remains off-label for depression but is increasingly used in specialized clinics.
• Clinical uptake: The review may influence national guidelines, such as those from the American Psychiatric Association (APA) and National Institute for Health and Care Excellence (NICE), regarding cognitive monitoring during treatment.
• Research priorities: The review identifies a need for longer-term, adequately powered studies with harmonized cognitive endpoints.

Risks, Unknowns, and Real-World Considerations

Available evidence suggests that while most patients do not experience persistent cognitive decline with short-term (es)ketamine treatment, certain subgroups—such as older adults, those with baseline cognitive impairment, or those receiving high cumulative doses—may be at higher risk. The review also notes that some cognitive deficits, particularly in attention and memory, may be subtle and only detectable with sensitive neuropsychological tests. There is limited data on the effects of long-term, repeated dosing protocols now common in private practice, raising concerns about cumulative neurotoxicity. A non-obvious implication surfaced in the review is that improvements in mood may mask mild cognitive side effects in patient self-reports, complicating real-world risk assessment. This highlights the need for objective cognitive monitoring tools in clinical settings.

Looking Forward: Clinical and Regulatory Outlook

Future research will likely focus on stratifying cognitive risk by age, comorbidity, and genetic factors, as well as developing mitigation strategies for at-risk populations. Regulatory agencies may require more granular cognitive safety data as part of ongoing post-marketing commitments. For clinicians, the review reinforces the importance of baseline and follow-up cognitive assessments, especially as off-label and maintenance use of ketamine expands. As the field moves toward broader access, balancing rapid symptom relief with long-term cognitive safety remains a central challenge. The review’s call for harmonized cognitive outcome measures and real-world surveillance is likely to shape both trial design and clinical practice in the coming years.

How we research: This article was written and reviewed by Dr. Alex R. Mendel, MD, PhD, clinical psychiatrist and psychedelic research specialist, on 2026-09-16. Primary sources include the cited systematic review and FDA regulatory documents.