Intranasal Esketamine Versus Quetiapine for Acute Bipolar Depression: A Randomized Controlled Trial

Background

Bipolar depression is a major contributor to disability and remains difficult to treat. Current pharmacological options, including quetiapine and lurasidone, often have slow onset of action and limited efficacy. Esketamine, an NMDA receptor antagonist with rapid antidepressant properties approved for treatment-resistant unipolar depression, has not been rigorously evaluated in bipolar depression. This trial assessed the efficacy and safety of intranasal esketamine compared with quetiapine as adjunctive therapy for acute bipolar depression.

Methods

In this multicenter, randomized, active-controlled, double-blind, double-dummy trial, 398 adults with bipolar I or II disorder experiencing a major depressive episode (MADRS score of 25 or greater) while receiving a mood stabilizer (lithium or valproate) were randomized 1:1 to intranasal esketamine 56-84 mg twice weekly plus oral placebo, or intranasal placebo plus quetiapine 300 mg daily, for 8 weeks. The primary endpoint was change in MADRS total score from baseline to week 8. Key secondary endpoints included MADRS response and remission rates, and Clinical Global Impression-Severity (CGI-S) score change.

Results

At week 8, the esketamine group showed a mean MADRS reduction of 18.7 points versus 13.9 points for quetiapine (least-squares mean difference, -4.8; 95% CI, -7.1 to -2.5; P<0.001). Response rates were 58.2% versus 41.7% (P=0.001), and remission rates were 39.8% versus 24.6% (P=0.002). The antidepressant effect of esketamine was evident within 24 hours of the first dose, with significant separation from quetiapine maintained at all subsequent time points. Treatment-emergent mania occurred in 2.5% of esketamine-treated patients versus 3.0% with quetiapine (P=0.78). The most common adverse events with esketamine were dissociation (31%), dizziness (24%), and nausea (18%), which were transient and diminished with repeated dosing.

Conclusions

Intranasal esketamine adjunctive to a mood stabilizer provides rapid and sustained antidepressant effects in acute bipolar depression, with efficacy superior to quetiapine and no increased risk of manic switch.