Potential for Yet Another Totally Different Antidepressant

Current pharmacologic treatments for depression may be relegated to second-tier treatments within the next decade. Why? Several classes of medications with mechanisms that are different from current drugs are showing promise and could be approved as antidepressants over the next several years. We have discussed some of these drugs in previous posts, including ketamine-like drugs and neurosteroid-based medications. In addition, the possibility that psychedelic-assisted therapy has antidepressant effects is under active study.

In an article published in Molecular Psychiatry, Aaron Tan and colleagues report that ezogabine, a new anticonvulsant recently approved by the FDA, may have antidepressant properties. Although the data in this article are preliminary and based on a small open-label study, the logic underlying the hypothesis is interesting.

Previous studies using a mouse model of depression involving chronic social defeat discovered that some mice were susceptible to this type of stress and others were resilient. Using molecular techniques, investigators found that resilience was related to expression of a specific membrane channel called the KCNQ potassium channel, which helps regulate excitability of nerve cells. By augmenting this channel, they were able to enhance resiliency in mice.

Ezogabine (also known as retigabine) acts by opening KCNQ channels. It has been shown to have antidepressant effects in mouse models of depression and enhance response to rewards. Depressed humans have diminished response to reward.

Because ezogabine is already FDA-approved, Tan and colleagues were able to perform a small clinical study involving 18 individuals suffering from major depressive disorder. None of the individuals was taking other psychotropic medications during the course of the study.

This was an open-label study, which means that there was no placebo control and all participants in the study were given ezogabine. Therefore, observed responses to treatment may have been a result of drug-related and/or non-drug-related mechanisms. However, in addition to examining antidepressant effects, Tan’s group also examined the effects of ezogabine on reward responses as well as connectivity of brain regions involved in reward processing.

After treatment with ezogabine for ten weeks, participants in the study experienced a significant reduction in depressive symptoms as measured by self-report and clinician-administered rating scales. The antidepressant effects were correlated with enhancement of the response to rewarding stimuli and with changes in brain connectivity in regions of the brain associated with reward processing as measured by functional magnetic resonance imaging (fMRI).

A larger, placebo-controlled study of ezogabine for depression is the logical next step and, in fact, is underway. Should this study be successful, it is likely that further work would seek to support approval of this drug for the treatment of depression. This would be a good example of repurposing a drug that has already been approved for a different indication. Use of ezogabine for treatment of depression would also be consistent with the use of other anticonvulsant treatments in psychiatry and support the hypothesis that altering the balance of excitation and inhibition in brain circuits may be a viable strategy for treating certain psychiatric illnesses.

It is likely that several new generation antidepressants will become available within the next few years with more likely to come over the next decade. Advances in basic neuroscience research are responsible for these discoveries. These may be only the beginning of discoveries of revolutionary new approaches to the treatment of depressive and anxiety disorders, the most disabling of medical illnesses.