Brain functional and structural long-term effects of electroconvulsive therapy and its association with clinical response and cognitive side effects

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Major depressive disorder (MDD) is the leading cause of disability worldwide and a major contributor to the global burden of disease. Electroconvulsive therapy (ECT) is one of the most rapid-acting and effective treatments for patients suffering from severe treatment-refractory depression with response rates of up to 70%. Although the clinical efficacy of ECT is well-documented, its widespread use has been limited by (a) the lack of knowledge about its biological mechanism of action and (b) potential (long-term) cognitive side-effects. To date, available neuroimaging techniques have provided valuable insights into the neuronal mechanisms of ECT in humans, mainly focusing on direct short-term effects on brain structure and resting state connectivity and its relation to immediate symptom improvement and clinical response. However, its biological mechanism is poorly understood. The investigation of long-term brain functional and structural changes through ECT and their relation to clinical response and neurocognitive side-effects would add valuable knowledge about the mechanisms of ECT. The main objective of the proposed project is the long-term investigation of the brain structural and brain functional mechanisms of ECT, with a focus on its association with long-term treatment success (remission/relapse) and (neuro-) cognitive functioning. The principle design of this prospective, naturalistic case-control study comprises three samples and four time-points. A sample of patients with severe MDD treated with ECT, a control sample of patients with severe MDD treated only with medication, and a healthy control sample shall be assessed using structural and functional magnetic resonance imaging, neuropsychological assessments and clinical ratings at four time-points: At baseline, directly after an ECT course of about six weeks, at follow-up after six months, and at follow-up after 12 months. The proposed project aims to provide new insights into (long-term) neurobiological effects of ECT, which might help to understand the brain-structural and functional underpinnings of two clinically relevant and unresolved questions: (1) Why do some patients show clinical response, including a stable remission, months after a successful ECT while others do not respond to ECT or show a relapse at follow-up? (2) Why do some patients show (short-term and long-term) cognitive impairments while others show improvements? In addition, a subsequent objective is the application and evaluation of multivariate machine-learning to predict individual patients’ clinical response and cognitive functioning based on the neurobiological knowledge in the context of personalized medicine. In summary, the proposed project would not only enhance our knowledge of mechanisms of ECT, but also aims to expand our understanding of the neurobiological underpinnings of major depression itself. Finally, the knowledge gained would provide the potential for a translation into clinical practice.