Amost half of all patients with major depression are inadequately treated by common antidepressants, so alternatives are very much required
Most common antidepressants act on the serotonin and related pathways in the brain. However, 45% of patients with major depression remain inadequately treated when prescribed these medicines, and alternatives are very much required. One potential option is rapastinel, which is being developed by US biotech Naurex, which was recently acquired by Allergan.1
It acts by a different mechanism, being an N-methyl-D-aspartate, or NMDA, receptor modulator. This is the same receptor that is blocked by compounds such as ketamine, which have been shown to have rapid antidepressant activity. However, these drugs are not ideal as they also have psychotomimetic effects that limit their clinical utility.
In contrast, the amidated tetrapeptide rapastinel readily crosses the blood–brain barrier and is a selective weak partial agonist of NMDA’s glycine site. This means it may have the antidepressant effects of ketamine without the negative psychotomimetic issues arising.2 Its antidepressant effects seem to result from NMDA receptor triggered synaptic plasticity in the frontal cortex.
In a Phase IIa trial, 48 male and 60 female patients with depression who had reported less than a 25% response to antidepressant treatment in their current episode were enrolled, and any antidepressant treatment withdrawn for at least two weeks before randomisation.3 Subjects were given a single intravenous dose of 1, 5, 10 or 30mg/kg of rapastinel or placebo. Their Hamilton depression rating scale 17 (HDRS-17) and brief psychiatric rating scale positive score (BPRS+) were assessed for at least 14 days after dosing.
Overall, the drug lowered depression scores with a U-shaped dose-response, analogous to that seen in animal studies. The 10mg/kg dose gave a statistically significant reduction in HDRS-17 both 24 hours and seven days after administration; by day 14, the differences from placebo were no longer significant. Importantly, there were no psychotomimetic side-effects at any dose level. No serious adverse events were observed, and all adverse events that emerged during treatment were mild or moderate, and included headache, dizziness, fatigue and gastrointestinal disturbances. Their incidence was similar across all treatment groups and those given placebo.
A Phase IIb study has also been reported4 involving 368 male and female subjects, who had suffered from major depressive disorder for an average of 18 years but had responded inadequately to another antidepressant, which they continued to take throughout the study. In the first part of a three-part study, subjects were given 5 or 10mg/kg rapastinel, with weekly follow-up injections and assessments, until they achieved a response. They were then given weekly placebo injections until they relapsed, and then dosed again to see if efficacy returned. The drug was more effective than placebo in alleviating depression, and the trial also showed it could alleviate symptoms after a forced relapse.
The company is planning Phase III trials, and the FDA has granted the drug fast track status as an adjunctive therapy in major depressive disorder. It is to be delivered via intravenous injection, with doses supplied in prefilled syringes.
1. J.R. Moskal et al. Neuropharmacol. 2005, 49, 1077
2. J. Burgdorf et al. Neuropsychopharmacol. 2013, 38, 729
3. S. Preskorn et al. Neuropsychopharmacol. 2012, 37 (Suppl. 1), Abst. W2
4. R. Burch et al. Neuropsychopharmacol. 2014, 39 (Suppl. 1), Abst. T68