American Psychiatric Association Annual Meeting
American Psychiatric Association Annual Meeting
Perspective from Jeffrey P. Kahn, MD
May 19, 2019
3 min read

Next-generation antidepressants show promise for treatment-resistant disease

Perspective from Jeffrey P. Kahn, MD
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James Murrough

SAN FRANCISCO — In a session here, experts discussed advances in the understanding and treatment of treatment-resistant depression.

Next-gen antidepressants

James Murrough, MD , associate professor of psychiatry and neuroscience and director of the Depression and Anxiety Center for Discovery and Treatment, Icahn School of Medicine at Mount Sinai, talked about the novel mechanisms and rapid efficacy of the next generation of antidepressants.

The global burden of depression continues to rise, prompting questions about what clinicians can do, he said.

“By and large, conventional pharmacotherapies for this disorder all pretty much work the same way to the extent that a proportion of our patients are not doing well on one antidepressant or the next or the next,” he said. “We think this is one reason that when you give a second agent that’s essentially pharmocogenetically or pharmacomechanistically the same, then maybe we shouldn’t expect a different result. As we think about what’s our next generation of antidepressants, maybe we can move outside of the autoimmune system.”

Ketamine, the first drug to show rapid depressant effects, modulates the glutamate system, Murrough said. Some glutamate targets of novel drug discovery for depression include the enhancement of presynaptic release, EAAT function and protein translation. He went on to discuss the growing evidence supporting ketamine for treatment-resistant depression, including research in repeated dosing studies and intranasal esketamine.

However, Murrough said, not all glutamate modulators are antidepressants, though it’s unclear why. Some of these include memantine, riluzole and lanicemine.

He also discussed the rapid antidepressant effect observed in the novel GABA-A modulator brexanolone (Zulresso, Sage Therapeutics), which was recently approved by the FDA for the treatment of postpartum depression. The GABA-A modulator and glutamate modulator are very tightly linked, but there’s still a lot to learn from these mechanisms, Murrough said.

Moving beyond monoamines, Murrough presented some potential directions for the future treatment of depression, including the glutamate modulators NMDAR antagonists, mGluR2/3 antagonists, mGluR5 antagonists, AMPAR potentiators, EAAT2 potentiators and GlyT1 inhibitors.

“I think there’s a lot of hope and excitement about not just some of the targets I emphasized, but also other targets that we can start making a difference in terms of identifying novel treatments for our patients,” he concluded.

Inflammation may play a role

In his talk, Andrew Miller, MD, professor of psychiatry and behavioral sciences, Emory University, discussed the mechanisms and treatment implications of inflammation and treatment-resistance in depression.

Data suggest there’s a link between inflammation and depression. Miller said that depressed patients show all the “carbon features” of a chronic inflammatory response with increases of inflammatory cytokines (like interleukin 6 [IL-6]) and acute phase reactants (C-reactive protein [CRP]).

“There seems to be a special relationship between inflammation and treatment resistance,” Miller said.

Research also indicated a stepwise change in increasing inflammation is associated with increased treatment resistance. Clinical predictors of antidepressant nonresponse include obesity, early life stress, medical illness and personality disorders/anxiety.

Other than targeting inflammation directly, Miller discussed targeting downstream effects of inflammation on dopamine or glutamate as another important therapeutic option for treatment-resistance.

Miller focused on administering a variety of inflammatory stimuli, which decrease neural activity in the dopamine-rich ventral striatum in association with decreased motivation and administering inflammatory cytokines (IFN-alpha or IL-6), which decrease the dopamine in the ventral striatum.

“As inflammation goes up, the connectivity between this ventral striatum region and the ventral pre-frontal cortex goes down,” Miller said. “Your reward circuitry is tanking as a function of increased inflammation.”

Dopaminergic medication that may help patients with high inflammation and treatment-resistance includes bupropion, stimulants and monoamine oxidase inhibitors.

“We can identify patients with high inflammation rather than biomarkers like C-reactive proteins,” Miller said. “I think this really opens the door to precision medicine.” – by Savannah Demko


Murrough J, et al. Advances in the Understanding and Treatment of Treatment-Resistant Depression. Presented at: APA Annual Meeting; May 18-22, 2019; San Francisco.

Disclosures: Murrough reports ties to industry related to ketamine. Miler reports no relevant financial disclosures. Photo credit to Mount Sinai Health System.