Grant: Project Grant

Major depression strikes 1 in 6 people and is twice as prevalent in women. In Canada, it is the second leading cause of disability. Depressed people have a greater risk of anxiety, suicide and cardiovascular diseases. Since reduced serotonin often leads to depression, first-line antidepressant drugs like selective serotonin reuptake inhibitors (SSRIs) work to increase serotonin in the brain. However, these drugs take many weeks to work and produce long-term recovery from depression in only 30% of patients. Our goal is to understand why some patients do not respond to SSRIs and find the best way to treat these patients. We focused on an important receptor for serotonin, the serotonin-1A autoreceptor. It is a strong inhibitor of the serotonin system. Human depressed patients who do not respond to SSRI treatment often have too many serotonin-1A autoreceptors. To model this genetic problem in mice, we knocked out a key genetic inhibitor of the receptor. These knockout mice have increased serotonin-1A autoreceptors and reduced serotonin. They have increased anxiety and depression traits and do not respond to SSRI treatment. Our research will compare male and female knockout mice to test how we can overcome this SSRI resistance using brain stimulation or other kinds of antidepressant drugs. In particular, we will overcome inhibition of the serotonin system using new therapies, including optogenetics to directly stimulate serotonin remodeling. Like depressed patients, our knockout mice show changes in activity in specific brain areas. Using optogenetics, we can to stimulate serotonin in specific brain areas whose activity is abnormal. These studies will guide brain stimulation approaches for treating depression. We will also test antidepressants that target different systems than serotonin in our SSRI-resistant mice. These studies could inform better treatment options in depressed patients who do not recovery when treated with SSRIs.