Bilateral Prefrontal and Insular TMS for Depression in Schizophrenia

Project summary: Depression is a common symptom domain in people with schizophrenia spectrum disorders. Depression in schizophrenia can be difficult to treat, leading to further functional impairment, suffering, and even higher safety concerns in many patients. TMS to the dorsolateral prefrontal cortex is commonly used to treat depression in general, although evidence of its efficacy for depression in patients with schizophrenia is unclear, and indirect evidence may not support the efficacy, likely due to the more complex underlying brain circuitry mechanism associated with the comorbid depression and schizophrenia condition. The proposed study is to use an alternative approach to stimulate bilateral insula and lateral prefrontal cortex that is based on a strong neural network mechanism of depression in schizophrenia. The project will recruit patients with schizophrenia spectrum disorders and randomize them into active rTMS versus sham rTMS groups followed by three fMRI based target engagement outcome assessments at baseline and after 10, and 20 visits of daily rTMS. The proposal will use more intense theta burst stimulation, new and diffused stimulation sites and more stimulation sessions that are conceptualized to be more strongly modulating the neural circuitry mechanisms linked to this sometimes devastating comorbidity. The proposal will include two phases as two separate projects. The first proposed project is a R61 for two years. If the Go/Nogo milestones are not met, the study will end. If all Go/Nogo milestones are met, it will proceed to a R33 project for three more years. The trial will test the proposed mechanism of action at brain network level and determine whether the new stimulation strategy will indeed significantly engage the proposed network through modulating its functional connectivity in the direction for improving depression in people suffered from schizophrenia spectrum disorders.