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

Abstract

Background: 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 (three double-blind [DB] studies; DB1, DB2, and DB4) or long-term maintenance treatment (DB3) with esketamine nasal spray (ESK) compared to an active-comparator+placebo (PBO), on cognition in patients with TRD.

Methods: Patients (DB1/DB2/DB3: [18-64years, n=747]; DB4: [≥65years, n=137]) with TRD received ESK (DB1/DB2/DB3:56/84mg; DB4:28/56/84mg) 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 DB3 maintenance phase. Descriptive statistics were used to analyze ESK effects on cognition with effect sizes and 95% confidence intervals (CIs) used to express the nature/magnitude of treatment effects relative to active-comparator+PBO. Correlation between depression severity (MADRS scores) and cognition was assessed at baseline and endpoint(s).

Results: At baseline, mild-to-moderate impairment in psychomotor function, attention, and memory (working/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/slightly improved from, baseline at endpoint (Day-28) and follow-up assessments. Similarly, in DB3(limited to participants ≥65years), 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).

Conclusion: 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.