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A Transformative Time for Refractory Depression Treatment

March 08, 2019
Michael E. Thase, MD, speaks at the 2019 Elevate by Psych Congress in Boston, Massachusetts.

BOSTON, Mass.—The recognition of the antidepressant effects of ketamine represents a transformative moment in the treatment of refractory depression, Michael E. Thase, MD, said at the opening session of the third annual Elevate by Psych Congress. Esketamine, a nasal spray derived from ketamine, was approved by the US Food and Drug Administration (FDA) 3 days earlier.

“I do think this is transformative because it’s gotten us to rapid treatments through a mechanism unrelated to monoamines and that’s a cool and exciting thing,” said Dr. Thase, a researcher on many mood disorder treatments and Professor of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

The emergence of ketamine, an antagonist the N-methyl-D-aspartate (NMDA) receptor, sets the stage for the development of related treatments that have similar but more selective mechanisms of action and do not have the abuse potential of ketamine,  Dr. Thase said.

“Just as fluoxetine or escitalopram represented substantial safety improvements over say (tricyclic antidepressants) imipramine or amitriptyline … by the year 2030, you may be seeing much more highly selective drugs that don’t have abuse liability, that you don’t have to worry about people not being able to drive for 6 hours after they take a dose and so forth,” he explained.

A New Generation of Depression Treatment Approaches

Between 2000 and 2010, experts realized that the effectiveness of existing antidepressants had been exaggerated, and that they actually only offer a 10% to 20% advantage over placebo, the speaker said.

After reviewing the complex set of factors that contribute to depression, Dr. Thase remarked “of course we should have never expected serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors to treat everybody.”

“The long dominant view that the monoamines were the pathway to the treatment of depression really leaves about 30% to 40% of our patients not properly treated. The brain is too complex to think about single selective agents delivering those kinds of antidepressant effects,” he said. “It’s nice, in retrospect, that so many people do get better with these safe, first-line agents.”

In the 1990s and 2000s, researchers began to develop the methodologies to examine other central nervous system response systems, he explained, noting 4 of them have survived the last decade and have promising findings in the works right now: glutamate and glycine, GABA, endogenous opioids, and inflammatory cytokines.

Over Time, Untreated Depression Changes the Brain

Esketamine will be available to prescribers within a few months and insurers will be under heavy pressure to include it on drug formulary lists, Dr. Thase said. Providers will need to register and agree to take steps to minimize risks, and patients will need to belong to a registry, he explained.

He predicted that another depression treatment will also be approved by the FDA by the end of 2019—allopregnanolone, also known as brexanolone and SAGE-547. Administered through a 48-to-60 hour infusion, the drug has shown efficacy for severe postpartum depression and exhibited a rapid response time.

An oral version of the drug, SAGE-217, has demonstrated effect not only for postpartum depression, but also for depression in women who aren’t pregnant and a small number of men, he said. Large-scale studies of the drug are now underway for the treatment of major depressive disorder and bipolar disorder, he added.

Dr. Thase also reviewed other drugs which have been studied recently but failed to show efficacy or gain approval. He said even more new drugs and mechanisms of action are being researching—but none of them are within 4 years of becoming something for clinicians to prescribe.

Psych Congress cochair Charles Raison, MD, who also researches potential antidepressant treatments, described Dr. Thase’s talk as “hopeful and sobering.”

“The fact that we have these 2 new agents that look very promising—the ketamine-based things and the allopregnanolone—is really quite remarkable and the fact that they both work quickly is also an amazing thing,” he said. “But it ain’t easy. It’s going to be interesting over the next few years to see whether we can capitalize on this as a field and keep finding things.”

—Terri Airov


“An update on MDD treatment: beyond the monoaminergic hypothesis.” Presented at Elevate by Psych Congress: Boston, MA; March 8, 2019.

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