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

An intranasal formulation of esketamine, combined with an oral antidepressant, is approved in the USA and the European Union for adults with treatment-resistant depression (TRD). Transient cardiovascular stimulatory effects have been reported with ketamine. Cardiovascular effects of esketamine nasal spray, combined with an oral antidepressant, were evaluated in 1708 esketamine-treated adults with TRD in six trials (five double-blind, placebo-controlled (486 placebo-treated patients); one open-label) of 4–52 weeks’ duration. Patients with established cardiovascular disease, including uncontrolled hypertension (> 140/> 90 mmHg), history of hypertensive crisis, or clinically significant electrocardiogram (ECG) abnormalities, were excluded from enrollment. Effects on cardiac repolarization were assessed in a phase I randomized, positive- and active-controlled thorough corrected QT (QTc) interval study. For adverse events, odds ratio (OR) [95% confidence interval] for esketamine/antidepressant versus antidepressant/placebo was calculated. Adverse events related to increased BP were reported in 12.8% of all esketamine-treated patients (in double-blind trials: esketamine/antidepressant 11.6% vs. antidepressant/placebo 3.9%; OR 3.2 [1.9–5.8]). Among the patients without a history of hypertension, new antihypertensive medication was initiated by 2.1% (6/280) of patients in the esketamine/antidepressant group versus 1.2% (2/171) of patients in the antidepressant/placebo group, in the double-blinded studies. Adverse events related to abnormal heart rate were reported in 3.0% of all esketamine-treated patients (in double-blind trials: 1.6% vs. 0.8%; OR 1.9 [0.5–8.6]). Overall, three cardiovascular adverse events related to BP increase were reported as serious and severe, and there was one fatal event considered unrelated (acute cardiac failure). BP increases reached the maximum postdose value within ~ 40 min of esketamine dosing and returned to the predose range by ~ 1.5 h postdose. In two studies (4-week duration, age 18–64 years), the largest mean maximum systolic/diastolic postdose BP increases were 13.3/8.7 mmHg for esketamine/antidepressant and 6.1/4.9 mmHg for antidepressant/placebo, and in a short-term elderly study (age ≥ 65 years) were 16.0/9.5 and 11.1/6.8 mmHg, respectively. Across studies/study phases, < 2% of patients discontinued esketamine due to adverse events of increased BP and tachycardia. No clinically relevant effect on ECG parameters was observed. Therapeutic and supratherapeutic doses of esketamine did not prolong the QTcF (QT corrected by Fridericia’s equation) interval (baseline-corrected values of − 2.02 to 2.16 ms, and − 3.51 to 4.89 ms, respectively). BP elevations following esketamine dosing are generally transient, asymptomatic, and not associated with serious cardiovascular safety sequalae. Further evaluation of long-term cardiovascular outcomes is warranted.