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Novel Therapeutics for Major Depression

September 23, 2015

SAN DIEGO— In the 40 years since antidepressants first became available, most pharmacologic advances have come in the form of reducing the burden of adverse events and increasing safety in overdose. However, researchers have not been able to improve the efficacy of antidepressant medications. 

“There really is not any evidence that newer agents in groups of depressed people work better than older agents,” said Charles Raison, MD. 

Despite the seeming stagnation in development of therapies for major depression, novel interventions are on the horizon. Dr. Raison identified and explained these upcoming therapies in his pre-conference presentation at the 28th Annual U.S. Psychiatric and Mental Health Congress. 

Considering Ketamine 

Several of the promising treatments in development for depression likely share a common N-methyl-D-aspartate receptor (NMDA) receptor antagonism. The most well-known of these treatments is ketamine, which has been used for years as an anesthetic and has only recently been studied for its antidepressant properties. In contrast to traditional medications that may take weeks to work, ketamine can quickly produce an antidepressant response, though the response may not be sustained. 

One study involved patients with treatment-resistant depression who were randomly assigned under double-blind conditions to receive a single infusion of ketamine or midazolam, a benzodiazepine used as a control.  The antidepressive effects of ketamine were significantly greater than those of midazolam, but the effects did not last for more than 7 days, though there were signs that some patients who received ketamine still had a response weeks later. 

The brain appears to change in response to ketamine. An animal model of stressed rats showed that the stripped down, bare synapses of the stressed animals blossomed after exposure to ketamine. They look “like a Christmas tree,” said Dr. Raison. “Massive neurogenesis, massive synaptogenesis.” 

Researchers have also studied whether one dose or several doses of ketamine is best. In a study of 24 patients with treatment resistant depression, 70.8% had a response (defined as a 50% reduction in symptoms) to ketamine if given multiple doses, which was higher than responses to a single dose. 

“The people who did well were the ones who had a full response at 4 hours,” said Dr. Raison. “If they have that immediate response, they’re much more likely to have a subsequent response.” 

However, he cautioned that when treatment was stopped, patients had a median relapse time of 18 days. Thus, ketamine is not a one-time treatment for most people. 

Scopolamine and Nitrous Oxide 

Other promising new pharmacologic treatments include scopolamine, an anticholinergic medication originally used to prevent nausea, and nitrous oxide, the “laughing gas” associated with dental work. 

“For many people, the longer-term effects of scopolamine might be more promising than ketamine, and the side effect profile is not very burdensome,” he said. “The data for this treatment are small, but they’ve been replicated once and the effect sizes are large.” 

Nitrous oxide is another NMDA antagonist. A recent study exposed 20 adults with treatment-resistant depression to 1 hour of nitrous oxide or oxygen. After exposure, participants exposed to nitrous oxide experienced a rapid antidepressant effect that lasted 2 hours, 1 day, and 1 week after the intervention. 

“I’ve now described 3 modalities that appear to work by similar mechanisms, that work very rapidly, but that don’t have long carrying capacity. However, there are lots of circumstances in psychiatry where that can make all the difference in the world,” said Dr. Raison. 

Other Promising Interventions 

Patients may also benefit from blue light therapy for depression, even when patients don’t have a seasonal pattern to their symptoms. To assess light therapy’s influence on depression, researchers administered 3 weeks of hourly blue light session to 89 patients with depression. Those receiving the blue light therapy not only were less depressed and slept better, but they also had reduced levels of the stress hormone cortisol 3 weeks later. 

“This is a low-tech intervention. It’s not going to benefit everybody, but that bright blue light is good for more people than those who have the winter blues,” said Dr. Raison. 

Bright light therapy ties into an idea that Dr. Raison has studied throughout his career. “I think that sensory pathways, some more than others, hold promise as deep brain stimulators,” he said. “Nature has evolved unbelievable precision in how the senses tell your brain what to feel. It’s constantly telling your brain where you stand as an individual—whether you’re a winner and going to leave grandchildren, or whether you’re at risk of dying young and childless.” 

Research suggests the ability to make facial expressions impacts our capacity to feel emotion. Injections of botulinum toxin, which have been used to therapeutically paralyze certain groups of facial muscles for cosmetic purposes, are now being investigated for possible antidepressive properties. 

Two double-blind, randomized, placebo-controlled trials of botulinum toxin have shown promise. In the larger trial, 85 participants with major depression received either botulinum toxin or saline injections into the corrugator and procerus frown muscles. Six weeks after the injection, 52% of the participants in the botulinum toxin responded compared with 15% of those in the placebo groups.

The Far Horizon 

Dr. Raison explained that an examination of human evolution leads researchers to another avenue of antidepressant development that is far from prime time. Our ancestors coevolved with microbes and parasites that are collectively termed “Old Friends.” 

These Old Friends teach our immune system tolerance, a crucial function in preventing inflammation and the depression often associated with it. One Old Friend, Mycobacterium vaccae, has shown promise in animal models in increasing proactive behavior and in reducing anxiety and colitis following chronic stress, said Dr. Raison. 

We’ve lost many of our Old Friends as a result of advances in sanitation, hygiene, and medicine, none of which we’d want to undo. In the long-term, researchers may be able to develop novel therapies that target the microbiota and selectively put us back in touch with Old Friends who might help to ease mental illness. 

Dr. Raison concluded his presentation by noting how all the interventions he discussed are surprising when viewed through the more narrow lens of traditional antidepressant medications, highlighting the fact that advances in the treatment of depression may be more likely to come from creative science than from continual pursuit of what is already “tried and true.” 

—Lauren LeBano 


1. Raison C. Emerging treatment strategies and novel therapeutics for major depression. Session presented at the U.S. Psychiatric and Mental Health Congress pre-conference; September 9, 2015; San Diego, CA.

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