Discontinuing Esketamine Nasal Spray Not Linked to Withdrawal Syndrome in Treatment-Resistant Depression

Discontinuing short- or long-term use of esketamine nasal spray may not be associated with withdrawal symptoms, according to research presented at Psych Congress 2019, held October 3 to 6 in San Diego, California.

Esketamine, an N-methyl-D-aspartate receptor antagonist, was approved by the United States Food and Drug Administration for the management of treatment-resistant depression in adults.

It is thought that esketamine discontinuation may not result in a withdrawal syndrome, as the drug is quickly cleared from the plasma and administered intermittently (every 3 to 14 days), thus preventing its accumulation.

In this post hoc analysis of data from the Physicians Withdrawal Checklist (PWC) obtained during the SUSTAIN-2 open-label phase 3 trial (Clinicaltrials.gov Identifier: NCT02497287), in which the long-term safety and efficacy of esketamine were studied, investigators examined the occurrence of severe adverse events after treatment discontinuation. In the SUSTAIN-2 study, participants ≥18 years of age with treatment-resistant depression, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria, exhibited single-episode or recurrent major depressive disorder in the absence of psychotic features.

Patients were initiated on an oral antidepressant plus esketamine nasal spray for up to 1 year. Patients were eligible if their depressive episode at time of enrollment had not responded to ≥2 antidepressants and if they had not had substance use disorder in the 6 months preceding the trial.

There were multiple phases in the trial: the induction phase in which esketamine was administered twice a week for 4 weeks, in addition to an antidepressant (duloxetine, sertraline, escitalopram, or venlafaxine extended release); an optimization/maintenance phase in which the antidepressant was continued and esketamine was dosed weekly or biweekly for up to 48 weeks; and a follow-up phase consisting of a 4-week period after esketamine discontinuation, during which treatment with the antidepressant was encouraged and the use of concurrent medication allowed.

The use of a set of medications, including anticonvulsants, lithium, and psychostimulants was prohibited during the treatment phase.

Data were analyzed from patients who had received esketamine for a minimum of 4 weeks and had at least 1 follow-up visit during which they were assessed with the 20-item PWC. Outcomes of this post hoc analysis were PWC-20 conducted at weeks 1, 2, and/or 4 of the follow-up phase (0-3 scale; range of total scores, 0-60), the PWC-Depression Symptoms subscale (PWC-DS; 12 items, including anxiety, irritability, insomnia, and fatigue; range, 0-36), and the PWC-Withdrawal Symptoms subscale (PWC-WS; 8 items, including nausea, diarrhea, dizziness, and paresthesia; range, 0-36).

Of 307 patients from 19 countries who had a follow-up phase, 216 and 91 were classified as responders and nonresponders to esketamine treatment, respectively (exhibiting a reduction ≥50% and <50% in Montgomery-Asberg Depression Rating Scale scores from baseline to the end of the induction phase, respectively). Individuals categorized as nonresponders were discontinued from the study.

The mean Montgomery-Asberg Depression Rating Scale scores at baseline were 31.0±4.98 in responders and 31.1±5.59 in nonresponders. Serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitors were initiated by 52.3% and 47.7% of responders, respectively, and by 41.8% and 58.2% of nonresponders, respectively, at baseline.

The mean percentage of patients who reported symptoms was found to be stable from one visit to the next and to depend on the item examined. In addition, the mean incidence of PWC-DS (50% of patients; eg, depression, anxiety, and fatigue) was higher compared with that of PWC-WS (<20%) at all time points examined. In addition, the mean PWC-20 total score was found to be stable at all time points (week 1, 7.5±6.96; week 2, 7.4±7.1, week 4, 7.2±6.93; end of treatment, 7.2±6.8).

Nonresponders had a higher PWC-DS incidence compared with responders, and the incidence of PWC-WS was comparably low in both groups. The mean PWC-20 scores were found to be much higher in nonresponders vs responders, and nonresponders had higher PWC-DS and PWC-WS than responders.

Severe PWC-WS symptoms were reported by 4 responders (6 symptoms, 5 of which were reported at the last visit; diaphoresis, diarrhea, increased acuity, nausea, paresthesias), and by 9 nonresponders (16 symptoms; diaphoresis, diarrhea, dizziness, nausea, paresthesias), with diaphoresis most commonly reported.

“The totality of evidence suggests stopping after short- or long-term use of [esketamine] nasal spray is highly unlikely to be associated with withdrawal syndrome,” concluded the study investigators.

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Reference

Yieh L, Aluisio L, Wajs E, et al. Withdrawal symptom assessment – esketamine nasal spray: open-label safety study in treatment-resistant depression. Presented at: Psych Congress 2019; October 3-6, 2019; San Diego, CA. Poster 242.