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In this phase 3 open-label study of 802 patients with treatment-resistant depression, long-term esketamine nasal spray plus an oral antidepressant had a manageable safety profile over up to 1 year. Treatment-emergent adverse events were reported in 723/802 patients (90.1%), most commonly dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine because of adverse events, 55 patients (6.9%) had serious treatment-emergent adverse events, and 2 deaths occurred, neither considered related to esketamine by investigators.

Most esketamine-related adverse events were mild or moderate, occurred on dosing days shortly after administration, and resolved the same day. The study also reported no case of interstitial or ulcerative cystitis and no occurrence of respiratory depression.

Dissociation was reported in 27.6% of patients and was generally transient. Changes in Clinician Administered Dissociative States Scale scores peaked at 40 minutes after dosing and generally resolved within 1.5 hours on the same dosing day.

The study also found that mean maximum postdose dissociation scores declined over time in a post hoc longitudinal analysis. Dissociative symptoms were described in different ways, including perceptual changes and feeling disconnected from oneself, thoughts, feelings, space, or time.

Blood pressure increases were typically transient, peaking around 40 minutes after dosing and returning close to predose values by 1.5 hours. The greatest mean (SD) postdose increase was 9.6 (11.99) mm Hg systolic and 5.6 (8.32) mm Hg diastolic in induction, and 9.2 (11.30) mm Hg systolic and 5.9 (7.28) mm Hg diastolic in optimization/maintenance.

Treatment-emergent acute hypertension, defined as systolic blood pressure at least 180 mm Hg or diastolic blood pressure at least 110 mm Hg, occurred in 33/802 patients (4.1%). Four patients met discontinuation criteria because of elevated blood pressure and were withdrawn from the study.

No case of interstitial or ulcerative cystitis was reported during the study. Overall bladder symptom scores remained low over time, suggesting no or minimal bladder symptoms.

Urinary tract infection was reported in 65 patients (8.1%), and 136 patients (17.0%) reported treatment-emergent adverse events related to renal and urinary disorders. There were 5 adverse events of cystitis, all of which resolved while esketamine treatment continued, and the serious renal or urinary events reported were not considered related to esketamine.

Cognitive performance generally improved or remained stable during long-term treatment. Across the overall study population, group mean performance on tests of reaction time, visual and verbal learning and memory, working memory, and executive function either improved from baseline or remained stable through week 44.

In patients younger than 65 years, all cognitive test performance remained stable or slightly improved. In patients 65 years or older, higher cognitive functions also improved or remained stable, but simple and choice reaction time showed slowing beginning at week 20 of optimization/maintenance; the authors noted that interpretation was limited by high intraindividual variability, small sample size, lack of a control group, and the absence of impaired reaction times at endpoints and follow-up.

Clinically relevant sedation was uncommon and usually brief. Sedation defined as a Modified Observer's Assessment of Alertness/Sedation score of 3 or lower occurred in 8.4% of patients during induction and 7.0% during optimization/maintenance.

At the dosing-session level, MOAA/S scores of 3 or lower occurred in 1.8% of induction sessions and 0.5% of optimization/maintenance sessions. The longest reported sedation episode lasted 1 hour 30 minutes starting 45 minutes postdose, and patients with deep sedation recovered spontaneously without ventilation or resuscitation.

Depressive symptoms improved during the 4-week induction phase and the improvement appeared to be sustained during ongoing treatment in responders. Mean (SD) Montgomery-Asberg Depression Rating Scale total score change from induction baseline to endpoint was -16.4 (8.76) in 756 patients.

Among patients who entered optimization/maintenance, mean (SD) change from optimization/maintenance baseline to endpoint was 0.3 (8.12), indicating that symptom improvement was largely maintained. Response and remission rates were 78.4% and 47.2% at induction endpoint and 76.5% and 58.2% at optimization/maintenance endpoint, respectively, using remission defined as a MADRS score of 12 or lower.

Every-other-week dosing was feasible for a substantial proportion of patients during maintenance. During the optimization/maintenance phase, 24.0% of patients received weekly dosing, 38.1% were maintained on every-other-week dosing, and 37.8% switched more than once between weekly and every-other-week schedules.

Dosing frequency was determined by an algorithm based on symptoms: patients were treated weekly if the Montgomery-Asberg Depression Rating Scale total score was greater than 12 and every other week if the score was 12 or lower, with reassessment every 4 weeks.

The study found no indication of abuse, and withdrawal symptoms appeared infrequent and generally mild. There were no reports of drug seeking, overdose, or abuse of esketamine or ketamine, and no patient requests to increase dosing frequency beyond protocol or to exceed 84 mg.

Mean (SD) Physician Withdrawal Checklist total scores were 8.0 (7.61) at end of treatment, 7.9 (6.91) at week 1, 8.0 (7.42) at week 2, and 7.7 (7.07) at week 4 of follow-up. The authors concluded that discontinuation-related symptoms were infrequent, mild, and generally difficult to distinguish from early return of major depressive disorder symptoms.

The main limitations were the open-label design, the absence of a control group, and the fact that a new oral antidepressant was started at the same time as esketamine for direct-entry patients. These features limit how confidently the findings can be attributed to esketamine alone and make efficacy and some safety interpretations less certain than in a blinded controlled trial.

The authors also noted that exclusion of patients with clinically relevant psychiatric or medical comorbidities or substance dependence may limit generalizability. For cognition, interpretation in older adults was additionally limited by small sample size, lack of a control group, and possible practice effects from repeated testing.