New Mechanisms Emerging for the Treatment of Depression

SAN FRANCISCO—A number of innovative mechanisms of action for treating depression will likely debut over the next 3 years, following a decades-long drought in the availability of new approaches, Psych Congress co-chair Rakesh Jain, MD, MS, said at Elevate by Psych Congress 2017.

“There are 3 new mechanisms that very likely, and I mean very likely, will produce FDA-approved medications,” said Dr. Jain, a practicing psychiatrist and Clinical Professor, Department of Psychiatry, Texas Tech Health Sciences Center School of Medicine in Midland. “We have never seen this in psychiatry. This is a big deal.”

There has not been a new mechanism of action developed for treating depression since 1958, and many new approaches studied in recent years did not materialize, he said. In contrast, 4 new ways of treating Type 2 diabetes have arrived in the last 11 years.

Dr. Jain encouraged the attendees at Elevate, which is designed for early career clinicians, to start learning about the new approaches and treatments.

“This is big, because we will be able to deploy and employ receptors we have never really touched before, which means there are great opportunities, which also means we have to do some serious learning,” he said.

Glutamate and the NMDA Receptor

There are a massive number of drugs in development involving glutamate and the N-methyl-D-aspartate (NMDA) receptor, which responds to glutamate, Dr. Jain said. He predicted that today’s young clinicians will eventually see 5 to 10 such treatments approved for use.

“Glutamate is the Holy Grail when it comes to mood disorders,” he said. “There is not a part of the human cortex that does not have NMDA receptors.”

He noted that glutamate is 50% to 55% of the human neurotransmitter load. “It’s the single most prevalent neurotransmitter and we have left good money on the table by not going after it,” and continuing to target norepinephrine and serotonin, he said.

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He encouraged Elevate attendees to get to know 3 of the treatments: ketamine, esketamine, and rapastinel—and to get excited about them. “I think we’re going to help a bunch of people we haven’t helped before,” Dr. Jain said.

There is a large amount of data supporting the effectiveness of ketamine as a treatment for depression, and acceptance of it is increasing, Dr. Jain said. He does not expect it to be approved by the US Food and Drug Administration (FDA), however, since it is a generic drug and no companies are seeking the approval.

He feels ketamine should be considered by all clinicians as an option for treating refractory or severe acute depression. There is a 90% to 95% chance he would seek it out if he were severely depressed, Dr. Jain said.

“There’s too many patients who are sick,” he said. “To not at least know ketamine providers in your area would be amiss.”

He believes esketamine, a variation of ketamine, will receive approval from the FDA, and said it has some distinct benefits over ketamine. A proof-of-concept study published in 2016 showed dramatic effects on depressive symptoms within hours.

Esketamine also has benefits over rapastinel, which uses a different approach on the NMDA receptor. Phase 2 clinical trials of rapastinel were positive, one Phase 3 study is completed, and another is in progress, Dr. Jain said.

The therapies work without causing the same side effects that plague current treatments for depression, such as sedation, weight gain, and cognitive and sexual side effects, he noted.

“They simply have not had the problems you and I think are part and parcel of antidepressant therapy,” Dr. Jain said. “I actually think we’re going to avoid a bunch of side effects that have dogged us.”

An Anti-Inflammatory Approach

Another class of drugs involves the interleukin-6 (IL-6) anti-inflammatory pathway. IL-6 inhibitors are being developed for disorders ranging from rheumatoid arthritis to depression, Dr. Jain said.

“This is the riskiest of the 3 bets but it’s worth taking,” he said.

He presented a study published in Psychoneuroendocrinology in 2016 which suggested IL-6 may play a role in major depressive disorder (MDD). Participants with MDD, who were not on antidepressants, had higher levels of IL-6, on average, than the healthy controls at the start of the study. The treatment group took selective serotonin reuptake inhibitors (SSRIs) for 8 weeks. Those who responded to the medication showed a significant decrease in IL-6 levels over the study period, and nonresponders showed a nominal, but not statistically significant, increase in IL-6.

In addition, there have been a number of positive studies on combining a COX-2 inhibitor, a type of nonsteroidal anti-inflammatory drug (NSAID), with SSRIs for the treatment of treatment-refractory depression.

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Such studies suggest there may be an inflammatory basis for the reasons certain people don’t respond to antidepressants, and that has not been lost on researchers or the pharmaceutical industry, Dr. Jain said.

He highlighted one IL-6 inhibitor called sirukumab, which he said is actively being developed for the treatment for depression with or without inflammation. When the drug was studied as a treatment for rheumatoid arthritis, it “had really impressive, unintended, unexpected, benefits in the mood realm,” improving depressive symptoms and boosting wellness, according to Dr. Jain.

“I have high hopes for IL-6,” Dr. Jain said. “It’s time for psychiatry to get very interested in it.”

“Until this comes about, it makes perfectly great sense for you and I to adopt, universally, nonpharmacological means of attacking inflammation,” he added.

Opioid-Based Therapy

The third class of drugs under development involves the kappa opioid receptors (KORs). Dr. Jain  noted that drugs associated with the current opioid epidemic act on a different type of opioid receptor, the mu opioid receptors.

Activation of the KOR is associated with such symptoms as despair, sadness, and fatigue, and dampening down kappa could function as an antidepressant, he said. “This gives me great hope. Kappa receptor antagonism might offer our patients far more than we’ve been able to give to patients with SSRIs,” Dr. Jain said.

There have been multiple attempts to develop treatments targeting the KORs, but most have been shown to be problematic. One drug—ALKS 5461—is showing promise, said Dr. Jain, who expects it to be available in 12 to 16 months as an approved depression treatment.

ALKS 5461 combines samidorphan, which is a long-acting mu receptor antagonist, with buprenorphine, which is a partial mu receptor agonist and full kappa receptor antagonist. Putting the 2 together neutralizes the effect on the mu receptor, Dr. Jain said, noting the drug has not shown any indication of abuse or been associated with withdrawal symptoms.

“This concept is going to be one of our next antidepressants,” he said.

­—Terri Airov

Reference

“Emergence of opioid, glutamate, and immune modulators as the next wave of antidepressants.” Presented at Elevate by Psych Congress 2017; March 5, 2017; San Francisco, CA.