Good News for a Promising New Depression Drug

On October 15th, Sage Therapeutics announced positive interim results from its SHORELINE study of zuranolone, one of a new class of antidepressant medications called neurosteroids. Zuranolone is a close cousin of Sage’s brexanolone (marketed as Zulresso), which received FDA approval for the treatment of post-partum depression a year earlier. Neurosteroids join a group of breakthrough treatments for depression that offer sufferers relief from their symptoms within hours or just a few days—a marked contrast to the antidepressants available to be prescribed by psychiatrists up to now. Like the anesthetic drug ketamine, neurosteroids promise to be breakthrough treatments for serious depression, with a mechanism of action that is totally unlike that of previous antidepressants.

Current antidepressants all work by increasing or modulating the effects of brain chemicals called neuroamines, nitrogen-containing signaling molecules (neurotransmitters) like serotonin, noradrenaline, and dopamine. The first of these drugs was discovered completely by accident in the 1950s when imipramine, a molecule originally synthesized as a possible antihistamine, was found to help with depression symptoms. Once it was determined that imipramine increased levels of neuroamines in the brain, other drugs that had this same effect were developed, eventually resulting in the several dozen agents on the market today. But whether it’s imipramine, fluoxetine (FDA-approved in 1989 and marketed as Prozac) or vortioxetine (approved in 2013 and marketed as Trintellix), they all have the same basic mechanism of action: neuroamine signal modulation. Unfortunately, built into this mechanism is a frustrating weeks-long delay in onset of efficacy, antidepressant side-effects like weight gain and sexual dysfunction, as well as a lack of efficacy in up to 20% of depression sufferers who take them.

In the early 1990s however, developments in the neurobiology of depression started to cast doubt on the “neuroamine” hypothesis of depression. The very newest models of depression now suggest that the amine neurotransmitters are no more than bit players in the depression story. Animal studies and neuroimaging have revealed that the real action is taking place instead in brain circuits that use the non-amine neurotransmitters glutamate and gamma-amino butyric acid (GABA) to communicate. To quote a 2019 review article that appeared in the neuroscience journal Neuron, current “studies of the neurophysiological basis of [depression] have focused both on the principle excitatory glutamate neurons, as well as inhibitory GABA interneurons. [These studies] demonstrate structural, functional and neurochemical deficits in both major neuronal types that could lead to degradation of signal integrity in cortical and hippocampal regions.” In mood disorder circles, “chemical imbalance” is definitely out, “altered connectivity” is in when it comes to discussing the cause of mood disorders.

The new rapid-acting antidepressants target these glutamate and GABA circuits directly. This is in contrast to the older antidepressants, which appear to work by triggering brain stem cells to develop into new neurons in the hippocampus, a process that takes weeks to unfold. This explains the long delay before the onset of improvement in symptoms. Neurosteroids, on the other hand, boost sluggish GABA circuits in the depressed brain directly, bringing about relief in a matter of hours. And there’s even more good news: the volunteers in the SHORELINE study took zuranolone for only two weeks and although some needed another 14-day course of the drug a few weeks later, nearly half stayed well through the rest of the one-year study period.

Best case scenario: Zuranolone offers the possibility of the seriously depressed patient taking the first pill at bedtime and waking up the next morning already feeling significantly better, then continuing to improve while taking the drug for another two weeks and staying well for up to a year. What’s not to love?

Although SHORELINE was an open observational study (i.e., not placebo-controlled) these interim results appear to validate Sage’s persistence and commitment to zuranolone. The drug’s future looked bleak in November 2019, when Sage reported disappointing results from zuranolone’s placebo-controlled MOUNTAIN study. That study found no significant difference in the HAMD-17 depression scores between the depressed volunteers who took the drug and those who took a placebo. However, a secondary analysis of data revealed that nearly 10% of the subjects who were supposed to be taking zuranolone during the study had undetectable drug levels in their bloodstreams, strongly suggesting that they hadn’t been taking it at all. Throwing out the data from those subjects, the difference in depression scores reached statistical significance but the study still received an official “fail.” That’s because this kind of data tweaking is strictly verboten when results of clinical trials are reported. Primary outcome analysis must include every subject who was randomized, the so-called “intent-to-treat” group.

After announcing the failure of the MOUNTAIN study, Sage saw its stock price fall by 50%. But these new results suggest that Wall Street may have thrown the baby out with the bathwater last fall. Results from a previous smaller Phase II study, reported in the prestigious New England Journal of Medicine, were unequivocally positive. That finding together with these new data suggest that zuranolone may well find its way to market, something that will cheer investors for sure, but much more importantly, may represent a giant leap forward in the treatment of depression and new hope for millions of sufferers.