Effect of Esketamine Nasal Spray on Cognition in Patients With Treatment-Resistant Depression: Results From Four Phase 3 Studies.

Abstract

<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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).<h4>Conclusions</h4>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.

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