Treatment-resistant depression (TRD) is a severely disabling disorder with limited treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Current research suggests that depression may result from abnormal function within neural networks involved in mood regulation. Neuroimaging studies further identify the subgenual cingulate (Cg25) as a critical member of this network, with additional evidence demonstrating sustained Cg25 overactivity in TRD patients.
Studies in the surgical treatment of Parkinson's disease have shown that chronic stimulation of specific brain regions can alter activity with the neural networks involved in motor activity and lead to significant improvements in the symptoms of the disease. Based on this line of reasoning, our group in Toronto piloted Deep Brain Stimulation (DBS) of the white matter immediately adjacent to Cg25 as a means for therapeutically altering function of putative depression networks in patients with TRD. Based on the encouraging first findings demonstrating sustained clinical benefit of chronic DBS of this region, this new study will further test the safety, efficacy, and mechanisms of action of this approach as a treatment strategy in a new group of TRD patients.
Twenty TRD patients will be enrolled and implanted with bilateral electrodes in the subgenual cingulate white matter using MRI guidance. Following randomized and blinded determination of the sites of stimulation within each hemisphere producing the most robust acute mood effects, a placebo-controlled trial of chronic stimulation of the identified optimal targets will be initiated for 1 month. The blinded control period will be followed by open chronic stimulation at the selected contacts for a period of 6 months. Pre-operative medications will be continued without changes to evaluate specific effects of chronic DBS. The 6 month chronic stimulation period will be followed by a blinded discontinuation period to further characterize persistent DBS effects and their time course. Stimulation will be resumed at pre-discontinuation parameters if patients show a depressive relapse without stimulation. Patients will be followed closely throughout the study to monitor the effects of acute and chronic DBS on their mood, cognition, and overall well-being using standardized neurological and psychiatric rating scales. DBS electrodes will remain implanted and chronic stimulation continued indefinitely unless there are complications requiring discontinuation and/or explantation. Potential mechanisms mediating DBS effects will also be assessed using a variety of measurements including sleep, neuroendocrine, neuropsychological, EEG, and neuroimaging studies (fMRI, blood flow PET, diffusion tensor tractography), Such studies will also be used to further define potential responder-nonresponder differences that might impact future patient selection.