From The Quarterly, Winter 2014

Depression is a major public health concern worldwide. According to the World Health Organization, it is the leading cause of disability worldwide. While there are current treatments available for depression, including psychotherapy, medications and brain stimulation techniques, many patients do not get relief from symptoms with the current options. The medications that are currently available can take weeks––sometimes months––to take effect, and only about half of patients respond to them.

“One of the biggest problems in the treatment of depression to day is a delay in onset of therapeutic effects, ”says Stephanie Dulawa, Ph.D. “There has been a great need to discover faster-acting drugs.”

In a paper published on October 29th in the journal Molecular Psychiatry, Dr. Dulawa and her team report on such a potential development. In a study supported by a 2012 NARSAD Young Investigator Grant, they found that when serotonin 2C receptors were selectively blocked in mouse models of depression, reduction in the animals’ depression-like behaviors occurred within five days. While the most commonly used antidepressant medications affect signaling by serotonin, a neurotransmitter known to play a role in mood, the researchers here studied serotonin pathways previously shown to generate antidepressant effects but that had never been studied for how quickly symptoms were alleviated. Among the serotonin receptor subtypes the researchers studied, serotonin 2C receptors stood out in that regard.

In recent years, there have been intensive efforts to develop new medications that act with alternative mechanisms to those in the current antidepressant medications, and that act more quickly to alleviate symptoms. Among the pharmacological approaches developed to date, only ketamine and scopolamine have been shown to lift depression symptoms quickly. Ketamine is believed to work through the glutamate system in the brain and scopolamine interacts with cell receptors for the neurotransmitter acetylcholine. Both of these medications can have serious side effects and Dr. Dulawa believes that her team’s discovery may offer a safer alternative.

Seroton in 2C receptors normally inhibit the release of dopamine from certain neurons. Dopamine is another neurotransmitter commonly associated with mood. Dr. Dulawa thinks what is happening when 2C is blocked is that more dopamine is released into the medial prefrontal cortex of the brain. The researchers also observed that blocking serotonin 2C receptors induced classical markers of antidepressant action, none of which were induced by five days of treatment with the antidepressant citalopram (Celexa®), a selective serotonin reuptake inhibitor (SSRI) . SSRIs are the most commonly prescribed class of antidepressants available.

Dr. Dulawa’s team is now investigating ways to block 2C receptors in clinical trials. The research team hopes this work will lead to the development o f a new class of fast-acting antidepressant medications.