Experimental Compounds Rapidly Reduce Depression Signs in Mice

Since antidepressants currently on the market usually take two to four weeks to start working, there is an urgent need to find an antidepressant that can work faster than that.

Several studies suggest that the anesthetic ketamine can greatly reduce depression within hours, but it can also produce serious side effects, keeping it from being approved by the Food and Drug Administration for antidepressant use (Psychiatric News, September 17).

Now two experimental compounds are showing promise as fast-acting antidepressants, at least in animal models. Whereas ketamine inhibits glutamate receptors, these compounds antagonize a class of serotonin receptors known as 2c receptors.

The findings were reported online on October 29 in Molecular Psychiatry by Stephanie Dulawa, Ph.D., an associate professor of psychiatry and behavioral neuroscience at the University of Chicago, and colleagues.

Since several antidepressants on the market antagonize serotonin 2c receptors as part of their mode of action, Dulawa and colleagues decided to evaluate whether two experimental compounds designed expressly to antagonize these receptors—both commercially available for use in animals—might possess rapid antidepressant action in mice exhibiting depression-like behaviors. The compounds are known as SB242084 and RS102221.

They found that these compounds did show antidepressant efficacy in the mice, and they did so in only five days, whereas a conventional antidepressant they used for comparison (the SSRI citalopram) took at least two weeks to reduce depression-like symptoms.

She was not surprised by these findings, Dulawa said in an interview with Psychiatric News. “We thought that the compounds would have similar properties, she noted. “If they did not, then the effects might be due to some other property one of them has. Actually using two compounds was a good way to make sure that the effects were really mediated by blocking the serotonin 2c receptors.”

The researchers also attempted to learn why the two compounds were able to exert antidepressant effects in the mice within only five days. The answer appeared to be by increasing the action of the neurotransmitter dopamine within the medial prefrontal cortex of the mice’s brains, which in turn led to the activation of BDNF within that brain region. “Also, when we blocked dopamine receptors, the antidepressant effect disappeared,” Dulawa noted. “So activating dopamine receptors appears to be essential.”

The challenge now will be to see whether similar compounds might be able to rapidly, and safely, counter depression in human subjects. “We are screening for compounds to use in humans,” Dulawa said.

The research was funded by the National Institutes of Health, the Brain and Behavior Research Foundation, and the Geraldi Norton Foundation.