When ketamine was found to exert a rapid antidepressant effect by researchers at the National Institute of Mental Health (NIMH) more than a decade ago, it sparked hope for a new generation of treatments for depressive disorders. Now, new drug candidates are finally edging toward the finish line.
Esketamine nasal spray, an isomer of ketamine and antagonist to the N-methyl-D-aspartate (NMDA) receptor, may be the closest to reaching clinics. Just last month, Janssen Pharmaceutical Companies of Johnson & Johnson announced the company had submitted a new drug application (NDA) to the Food and Drug Administration (FDA) seeking approval of esketamine nasal spray for treatment-resistant depression in adults.
According to the press release by Janssen, the NDA is based on five pivotal phase 3 studies of esketamine nasal spray in patients with treatment-resistant depression: three short-term studies, one withdrawal maintenance-of-effect study, and one long-term safety study up to a year.
The results of two phase 3 trials of esketamine were presented at the APA Annual Meeting in May. In one trial, patients who failed to respond to at least two antidepressants during the current episode of depression were randomized to two treatments: esketamine nasal spray (56 mg or 84 mg) plus a new antidepressant or placebo nasal spray plus a new antidepressant. Patients who received esketamine experienced a statistically significantly greater drop on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28 compared with placebo. In patients 65 years and older with treatment-resistant depression, esketamine missed the primary efficacy endpoint in a phase 3 trial.
In the clinical trials, esketamine treatment was linked to side effects such as dizziness, nausea, increased blood pressure, and dissociation, which are similar to the side effects of ketamine.
Other NMDA receptor antagonists are also making their way through clinical development, including rapastinel (previously known as GLYX-13) and AGN-241741. Both molecules were developed by Naurex Inc. and recently acquired by Allergan. Rapastinel is purported to exert a rapid antidepressant effect, like ketamine, without the dissociative side effects. Several phase 3 trials of rapastinel as an adjunctive treatment and as monotherapy in major depressive disorder are currently ongoing. AGN241741 is being tested in phase 2 trials.
Another NMDA receptor antagonist, dextromethorphan, is combined with bupropion in a product known as AXS-05. In addition to its known effectiveness as an antidepressant, bupropion inhibits the metabolism of dextromethorphan by liver enzymes, so that dextromethorphan may accumulate in the body and reach therapeutic levels. AXS-05 is currently in phase 3 trials for treatment-resistant depression and for agitation associated with Alzheimer disease.
Read the rest of the article here: https://doi.org/10.1176/appi.pn.2018.pp9a1
Author: Jun Yan