Grant: Project Grant

Major depression affects 1 in 6 people and is more common in women. In Canada, it is the second main cause of disability. People with depression are more likely to have anxiety, thoughts of suicide, and memory problems. Low serotonin levels are often linked to depression, so first-choice antidepressants like SSRIs are used to increase serotonin in the brain. However, these medicines take weeks to work, and only about 30% of patients find long-term relief. Our research aims to understand why some patients do not respond to SSRIs and to find better treatment options for them. We are looking closely at the serotonin-1A autoreceptor, which helps control serotonin levels. Many patients who don't respond to SSRIs have too many serotonin-1A autoreceptors. To study this issue, we created mice that lack a key gene that controls the receptor. These mice have more serotonin-1A autoreceptors and less serotonin. Like depressed people, these mice are less active in brain areas related to depression, show more anxiety and depression traits, and do not respond to SSRIs. We will compare male and female knockout mice to see how we can overcome the resistance to SSRIs with new types of antidepressant drugs. We found new drugs that can mimic serotonin action in the brain, leading to rapid changes in the wiring of the serotonin system. This discovery may help improve and speed up response to depression treatments and guide how to better treat patients who do not respond to SSRIs. Learning how to rewire the serotonin system could lead to new ways to help patients recover quickly from depression. These studies may lead to better treatment options for people with depression who do not get better with SSRIs.