Intranasal esketamine shows promise in treatment-resistant depression

According to a small phase 2 clinical trial published in JAMA Psychiatry (doi: 10.1001/jamapsychiatry.2017.3739), intranasal esketamine has the potential to be an effective treatment for patients with treatment-resistant depression.

The parent drug ketamine is an NMDA-receptor antagonist licensed for use as an anaesthetic for diagnostic and surgical procedures. It has been shown in previous studies to have an antidepressant effect, but one limitation of its therapeutic use is that it requires intravenous or intramuscular administration; it is also a well-known drug of abuse. Esketamine, the S-enantiomer of ketamine, has a higher affinity for the NMDA receptor than the R-enantiomer and is now being developed in an intranasal formulation for the treatment of major depressive disorder.

The study authors randomised 67 patients with treatment-resistant depression to treatment with intranasal esketamine 28mg, 56mg or 84mg twice weekly, or placebo, in addition to their existing antidepressant treatment.

After just one week of treatment, there was a significant and clinically meaningful improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total score in all three esketamine groups compared with placebo, with a significant ascending dose-response relationship (least squares mean difference vs placebo: -4.2 with 28mg, -6.3 with 56mg, and -9.0 with 84mg esketamine; p<0.001). The improvement was sustained in the two-month open-label phase, when the dosing frequency was reduced to fortnightly, and persisted for up to two months after cessation of treatment.

Five per cent of patients treated with esketamine had adverse events leading to discontinuation, compared with none receiving placebo. These included syncope and headache. The authors also noted that perceptual changes and/or dissociative symptoms began shortly after the start of intranasal dosing in up to a quarter of patients, but these resolved within two hours and were diminished with repeated dosing. No participant manifested symptoms suggestive of psychosis, although patients with a history of psychotic symptoms or substance use disorders were excluded from the study.

The authors conclude that intranasal esketamine appears to be effective for patients with treatment-resistant depression with a rapid onset and is generally well tolerated. They add that the results support the need for larger clinical trials, and a phase 3 study to determine optimal dosing frequency is already underway.

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