Grant: Operating Grant

In Canada, 5-6% of the population (~1.75 million people) have symptoms consistent with depression on a yearly basis. Though most patients respond to medications and/or psychotherapy, 10-15% are considered to be resistant to treatment. For this population, surgical therapy has been proposed, including a technique called deep brain stimulation or DBS. This consists of the implantation of wires into the brain for the delivery of electrical current. Overall, 50-60% of patients undergoing DBS have a substantial improvement after surgery. We have recently applied DBS to rats and observed a significant antidepressant effect in behavioral tests. We have also found that a molecule called serotonin was very important for the efficacy of this treatment. This is of interest as various therapies currently used in depression increase serotonin levels in the brain. In this proposal, we will address 1) how DBS given for a long period of time changes serotonin brain levels, 2) whether medications that increase serotonin levels potentiate the effects of DBS, and 3) whether mice with a specific mutation in a protein that regulates serotonin levels respond to DBS. Results from these studies may not only increase our knowledge on the mechanisms of DBS but also provide clinical insights. As an example, we may recognize that certain changes in the systems that produce or degrade serotonin are necessary before the full clinical effects of DBS are observed. Characterizing medications that potentiate the effects of DBS may pave the way for future clinical trials using these agents in patients receiving stimulation. In the clinical scenario, 40-70% of patients with depression bear specific genetic features that resemble to some extent those in the mice to be used in our study. These patients do not respond well to some of the most commonly used antidepressant medications and DBS could be an important treatment alternative for these individuals.