Cardiac Safety of Esketamine Nasal Spray in Treatment-Resistant Depression: Results From the Clinical Development Program

Aim: To evaluate the cardiac safety of esketamine nasal spray administered to patients with treatment-resistant depression (TRD).

Methods: Cardiovascular (CV) effects of esketamine nasal spray (28-84 mg twice weekly, once weekly, or every other week), in combination with an oral antidepressant (AD), were evaluated in 1,708 esketamine-treated adults with TRD enrolled in 5 double-blind (DB), placebo-controlled and 1 open-label trial.

Results: Adverse events (AEs) of increased blood pressure (BP) occurred in 12.8% of all esketamine-treated patients (in DB trials: esketamine+AD 11.6% vs. AD+placebo 3.9%; OR 3.2 [1.9, 5.8]). AEs related to abnormal heart rate (e.g., palpitations, tachycardia) were reported in 3.0% of all esketamine-treated patients (in DB trials: 1.6% vs. 0.8%; OR 1.9 [0.5, 8.6]), of which 96% of CV events were mild/moderate and 88% resolved. The largest mean maximum SBP/DBP increases across intranasal dosing days were 13.3/8.7 mmHg for esketamine+AD and 6.1/4.9 mmHg for AD+placebo in 2 studies (4-week; age 18-64 years) and 16.0/9.5 mmHg and 11.1/6.8 mmHg, respectively, in an elderly study (age ≥65). The percentage of patients (age 18-64) with markedly abnormal BP elevation (SBP ≥180 and/or DBP ≥110) ranged from 2.0–4.9% in esketamine+AD vs. 0¬–0.9% in AD+placebo treatment groups across studies/phases and was higher in patients with (5.5–7.6%) vs. without (2.9–4.3%) histories of hypertension; in elderly, BP elevations were higher (esketamine+AD 11.1% vs. AD+placebo 6.2%).

Conclusions: BP elevations following intranasal dosing of esketamine are generally transient, asymptomatic, self-limiting without rescue medications, and not associated with serious CV safety sequelae in TRD patients.

This poster was presented at the 32nd annual Psych Congress, held Oct. 3-6, 2019, in San Diego, California.