Discovery Of New Drugs For Depression:

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Mouse Studies Advance Search for New Class of Antidepressants

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In this social defeat test, the black mouse is submissive to the aggressive white mouse. Credit: Xiaolei Zhu

February 7, 2019

Drug developed at Johns Hopkins targets brain chemical distinct from other antidepressants on the market

In experiments with mice, researchers at Johns Hopkins Medicine report a promising advance in the search for a new class of drugs to treat major depression. A compound developed by the Johns Hopkins Drug Discovery team targets a chemical in specific cells of the mammalian brain, and eases signs of social avoidance and depression in rodents, without some of the toxic side effects that have bedeviled its parent compound.

Most of the antidepressant drugs on the market target serotonin or norepinephrine neurotransmitters—chemical messengers in the brain—but these medications don’t work for some people with depression. They also can take four weeks or more to fully take effect. The new experimental compound, dubbed JHU-083, targets the neurotransmitter glutamate, and in a report published in the March issue of the journal Neuropsychopharmacology, the researchers say its effects appear in mice much quicker.

“From a therapeutic perspective, the drug’s action is against very specific brain immune cells, namely microglia involved in many types of neuro-inflammation and linked to neurodegeneration,” says Atsushi Kamiya, M.D., Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “We hope that this means it will have a wide range of therapeutic possibilities in many brain diseases associated with neuro-inflammation.”

Recently, experiments in animals and humans have shown that too many glutamate messages in the brain, in addition to other well-known factors, likely play a role in major depression too. As a result, the search for chemical compounds that reduce glutamate has heated up. Ketamine, an anesthetic and illicit “date rape drug” or “party drug,” is believed to act on glutamate and has been heavily touted as a treatment for depression, which led to the opening of ketamine clinics to treat resistant depression. But, ketamine also produces abrupt and lengthy “highs,” bad hallucinations, nausea, addiction and high blood pressure.

As a result, the Johns Hopkins researchers and others have sought drugs that have similar antidepressant properties without the unwanted side effects.