Intranasal esketamine efficacious and safe as add-on therapy for treatment-resistant depression
A study has recently demonstrated that intranasal esketamine is efficacious and safe with sustainable responses for treatment-resistant depression (TRD).
In the phase II, double-blind, doubly randomized, placebo-controlled study in 67 patients conducted from January 2014 to September 2015, intranasal esketamine significantly reduced the Montgomery-Åsberg Depression Rating Scale (MADRS) total score compared with placebo. [JAMA Psychiatry 2017, doi: 10.1001/jamapsychiatry.2017.3739]
Significant reductions of the least square mean differences in MADRS total scores were found for all three doses of intranasal esketamine compared with placebo (28 mg, –4.2 [p=0.02]; 56 mg, –6.3 [p=0.001]; 84 mg, –9.0 [p<0.001]).
The study included a double-blind phase where patients (56 percent female; mean age, 44.7 years) were randomized to receive either placebo or eskatamine at 28 mg, 58 mg or 84 mg doses via a disposable nasal spray device.
This was followed by an open-label phase where esketamine 56 mg was administered on the first day with subsequent doses adjusted based on the investigator’s clinical judgment. The administration schedule was twice weekly for the first 2 weeks, weekly for the next 3 weeks, then every 2 weeks thereafter.
The open-label cohort showed sustained improvement in depressive symptoms despite administration of lower dosages of esketamine (mean MADRS total score change from open-label baseline to day 74, –7.2).
Improvement in mean MADRS ratings persisted over the 8-week follow-up phase without additional esketamine doses in participants who remained in the study.
“Results from the open-label phase suggest that improvement in depressive symptoms can be sustained with lower frequency [weekly or every 2 weeks] of esketamine administration,” the authors said.
The three most common treatment-emergent adverse events (TEAEs) observed among esketamine-treated participants during the double-blind phase were dizziness, headache and dissociative symptoms.
The type and frequency of adverse events reported in the open-label phase were similar to those in the double-blind phase.
A few patients (double blind cohort, 5 percent; open-label cohort, 2 percent) had to discontinue participation in the study because of adverse effects including syncope, headache, dissociative symptoms and ectopic pregnancy.
“Transient increases in systolic blood pressure support an increase in cardiac output as the underlying mechanism. This symptom was, however, dose dependent and attenuated with repeated administration,” the authors added.
Limitations of the study included a small sample size and exclusion of individuals with psychotic symptoms, substance/alcohol use disorders or significant medical comorbidities.
“The results of the study, however, support further investigation of the intranasal efficacy of esketamine for the treatment of TRD in larger trials. A phase III study evaluating the frequency of dosing and duration of effect is underway,” the authors concluded
About one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants.
Esketamine, an enantiomer of ketamine, has high affinity for the NMDA receptor and is being developed as an intranasal formulation for treatment of TRD. Rapid onset of antidepressant effect has previously been documented by its intravenous administration. [Biol Psychiatry 2016;80:424-431]