Effect of Esketamine Nasal Spray on Cognition in Patients With Treatment-Resistant Depression: Results From Four Phase 3 Studies.
Randall L. Morrison, Jaskaran Singh, Ella Daly, Maggie Fedgchin, Rachel Ochs-Ross, Keith Karcher, Rosanne Lane, Kim Cooper, Gerard Sanacora, Paul Maruff, Wayne C. Drevets
The International Journal of Neuropsychopharmacology November 1, 2024 DOI: 10.1093/ijnp/pyae046 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pooled analysis of randomized controlled trials Double-blind Peer reviewed |
|---|---|
| Sample size | 884 |
| Population | Patients with treatment-resistant depression (aged 18–64 years and 65 years or older) |
| Interventions | Esketamine nasal spray oral antidepressant |
| Dose | 56/84 mg (for ages 18-64) or 28/56/84 mg (for ages 65+) |
| Duration | Short-term: 28 days; long-term maintenance: variable, with cognitive assessments at 12-week intervals |
| Topics | Depression Esketamine |
| Keywords | Cogstate battery test Randomized controlled trials Depression treatment Cognitive function cognition Mental performance Thinking skills Memory Ketamine derivative Rcts Treatment-resistant depression tr |
| Citations | 9 |
| Key findings | Short-term and long-term treatment with esketamine plus an oral antidepressant did not produce negative effects on cognition in patients with treatment-resistant depression. |
Abstract
While esketamine is effective in treatment-resistant depression (TRD), detailed information about the effect of esketamine on cognition is relatively scarce. This analysis assessed the effect of short-term (3 double-blind [DB] studies: DB1, DB2, and DB4) or long-term maintenance treatment (DB3) with esketamine nasal spray (ESK) compared with a placebo (PBO) combined with active-comparator, on cognition in patients with TRD. Patients (DB1/DB2/DB3: [18-64 years, n = 747]; DB4: [65 years or older, n = 137]) with TRD received ESK (DB1/DB2/DB3: 56/84 mg; DB4: 28/56/84 mg) or PBO+newly initiated oral antidepressant (OAD) as per treatment schedules. Cognitive assessments-Cogstate battery and Hopkins Verbal Learning Test-Revised-were administered at baseline, Day 28/early withdrawal, and follow-up visits in DB1/DB2/DB4 and at 12-week intervals in the DB3 maintenance phase. Descriptive statistics were used to analyze ESK effects on cognition with effect sizes and 95% confidence intervals to express the nature and magnitude of treatment effects relative to active-comparator+PBO. Correlation between depression severity (Montgomery-Ǻsberg Depression Rating Scale scores [MADRS]) and cognition was assessed at baseline and endpoint(s). At baseline, mild-to-moderate impairment in psychomotor function, attention, and memory (working and episodic) were evident. For each DB1/DB2/DB4, group mean performance in Z-scores for ESK+OAD and OAD+PBO groups on all cognitive tests remained similar or slightly improved from baseline at endpoint (Day 28) and follow-up assessments. Similarly, in DB3 (maintenance phase), both groups generally showed improvement in cognitive performance at endpoint(s). Correlations between MADRS scores and performance on the cognitive test battery were small at baseline and endpoint(s). This analysis did not identify evidence of negative effects on cognition following short-term or long-term maintenance treatment with ESK+OAD in patients with TRD.
Comparable studies
Other randomized controlled trials on esketamine for depression, most cited first.
Citations in the library
Cited by 9
- Ketamine for Depression, but at What Cost? A Review of Ketamine’s Neurotoxic Effects From Preclinical and Human Studies American Journal of Psychiatry September 10, 2025
- Urological symptoms following ketamine treatment for psychiatric disorders: A systematic review. Journal of Psychopharmacology June 30, 2025
- Comparative Efficacy and Functional Outcomes of Psychedelic-Assisted Therapies in Treatment-Resistant Depression: A Systematic Review of Recent Clinical Trials. Cureus April 1, 2025
- Psychedelics in treatment-resistant depression: a comprehensive review of mechanisms, clinical evidence, and recommendations. Neuropsychiatrie June 30, 2026
- Cognitive Effects of Esketamine in Treatment-Resistant Depression: A Systematic Review. Journal of Clinical Psychopharmacology March 24, 2026
and 4 more in the library
Cites 8
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
and 3 more in the library