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

Abstract

Background 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. Methods 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 activecontrolled thorough corrected QT (QTc) interval study. For adverse events, odds ratio (OR) [95% confidence interval] for esketamine/antidepressant versus antidepressant/placebo was calculated. Results 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). Conclusions 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.

Practical recommendations for the management of treatment-resistant depression with esketamine nasal spray therapy: Basic science, evidence-based knowledge and expert guidance

“…dose (Doherty et al 2020); this time course is consistent with the pharmacokinetic profile of esketamine nasal spray (FDA 2019a).…”

“…Additionally, clinicians should check adherence and tolerability to current antihypertensive treatment. In esketamine nasal spray clinical studies, acute blood pressure elevation as an adverse event was more prevalent in patients with a history of hypertension (Doherty et al 2020). This reinforces the importance of managing pre-existing hypertension before initiating esketamine nasal spray treatment.…”

“…a Included 182 patients from ESKETINTRD3001 and ESKETINTRD3002. b Included 111 patients from ESKETINTRD3005 (55 patients in the esketamine nasal spray arm and 56 in the placebo arm; Doherty et al 2020).…”

“…The treating clinician and patient should be aware that most blood pressure adverse events appear shortly after dosing and are short-lived and self-resolving. In esketamine nasal spray clinical studies, blood pressure increases generally reached a maximum within 40 minutes of dosing and normalised within 1.5-2 h (Doherty et al 2020). Most cases of increased blood pressure were not associated with symptoms, did not result in serious cardiovascular safety sequelae and had no clinically relevant effect on electrocardiogram parameters, and fewer than 2% of patients discontinued due to cardiovascular adverse events (Doherty et al 2020).…”

“…In clinical studies of esketamine nasal spray, most cases of increased blood pressure were self-resolving without the need for medication (Popova et al 2019;Doherty et al 2020). However, in a short-term, doubleblind study, a small proportion of patients without a history of hypertension required an antihypertensive (2.1% in the esketamine arm vs 1.2% in the placebo arm; Doherty et al 2020). Antihypertensives prescribed in the esketamine arm included amlodipine, captopril, losartan, metoprolol and propranolol (Doherty et al 2020).…”