Molecular And Neural Circuitry Mechanisms Underlying Antidepressant Treatment Resistance


Approximately 32-35 million adults in the US population (16%) experience an episode of majordepression in their lifetime, and commonly used treatments, such as selective serotonin reuptake inhibitors(SSRIs), are not ideal since only a subset of patients (~33%) achieves remission with initial treatment. Thereasons why some individuals remit to antidepressant treatments while others do not are unknown. Given thatantidepressants such as SSRIs are also commonly used to treat other psychiatric disorders, such asgeneralized anxiety disorder and obsessive-compulsive disorder, it is of critical importance to determine thedifferences between remitters and non-remitters to antidepressant treatment. Our overall research programaddresses this question by assessing antidepressant treatment resistance in mice. Preliminary data indicatethat both molecular and neural-circuit based approaches to modifying the dentate gyrus may be able to convertbehavioral non-responders to fluoxetine (a SSRI) into responders. Further preliminary data indicate that theseapproaches may also work as augmentation strategies for several other classes of antidepressants. TheSpecific Aims are: 1) Test the hypothesis that Activin signaling based modifications of dentate gyrus can alterthe behavioral response to fluoxetine through modulation of young adult-born granule cells; 2) To test thehypothesis that circuit-based approaches to silencing mature dentate gyrus granule cells can alter thebehavioral response to fluoxetine and to determine whether there are functional differences in DG inputsbetween responders and non-responders; and 3) Test the hypothesis that alterations in DG granule cells are acommon feature of behavioral non-response to different antidepressant treatments.
Effective start/end date2/16/171/31/22


  • National Institutes of Health (NIH)


Antidepressive Agents
Dentate Gyrus
Serotonin Uptake Inhibitors
Obsessive-Compulsive Disorder
Anxiety Disorders
Young Adult