Spravato Safety Holds Up Long-Term for Treatment-Resistant Depression

NASHVILLE, Tenn. -- Esketamine nasal spray (Spravato) showed consistent long-term safety outcomes for patients with treatment-resistant depression (TRD), according to follow-up data from the SUSTAIN-3 trial.

In the open-label, phase III study, intermittent dosing of esketamine for up to 6.5 years had a similar safety profile as dosing for up to 1 year, according to Reina Benabou, MD, PhD, vice president and head of medical affairs at Janssen Neuroscience in New York City, at a Psych Congress 2023 poster presentation.

The most common adverse events (AEs) among 1,110 patients were headache (36.9%), dizziness (33.9%), nausea (33.6%), dissociation (25.5%), nasopharyngitis (23.8%), somnolence (23.1%) and dysgeusia (20.2%). Benabou noted that AEs tended to be transient, lasting for an hour or two, and dissipated while the patients were being monitored after receiving their dose of esketamine.

"The major side effects of Spravato are somnolence, dissociation and high blood pressure, and what we see is that those side effects don't happen in everybody -- it's about 50% -- and they tend to dissipate after the second treatment or third treatment," Benabou told MedPage Today. There were no new safety signals, according to the poster.

While serious AEs were reported in 18.8% of patients, events related to depression that required hospitalization occurred in 2.1% of patients. The researchers said they considered 98.5% of serious AEs unlikely to be related to esketamine.

There were nine deaths (0.8%) during the study period and, of those, three were associated with COVID-19 while two patients had pneumonia. There was one death related to completed suicide, according to the study. The overall rate of completed suicide in the study was 0.026 per 100 patients-years (95% CI 0-0.15), which compared favorably to a corresponding rate found in a meta-analysis of TRD patients who received other treatments (0.47 per 100 patients-years, 95% CI 0.22-1.00).

Benabou said that improvement of depression was sustained with long-term, intermittent doses of the treatment when paired with daily antidepressant use in patients with TRD. The study showed that 50% were in remission at the end of the study period, which was defined as having a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≤12.

"Our data is very consistent in terms of efficacy and in terms of safety," Benabou said.

For SUSTAIN-3, patients were recruited from one of six phase III "parent" trials of esketamine, including TRANSFORM-1, -2 and -3 and SUSTAIN-1 and -2. Patients had an mean age 49.6, while 66.6% were female, 86.8% were white, 42.3% were from Europe, and 29.9% were from North America.

The mean length of exposure to esketamine was 42.9 months, with 51% receiving the treatment for longer than 42 months; 0.04% received the treatment for ≥72 months.

In a separate Psych Congress poster, Janssen researchers presented a 46-month analysis of Risk Evaluation and Mitigation Strategy (REMS) data for esketamine post-marketing. They looked at 34,110 patients who received at least one dose of the agent, and reported that ≤0.05% patients with TRD in the U.S. experienced serious AEs during the first 12 treatments with intermittent dosing.