Melatonin as a Neuroprotective Adjunct in Bipolar Patients Undergoing Electroconvulsive Therapy: A Double-blind Randomized Controlled Trial.

Introduction: Bipolar disorder (BD) is frequently treated with electroconvulsive therapy (ECT), which, despite its efficacy in severe mood episodes, is often complicated by cognitive impairment. To our knowledge, no standard prophylactic therapy currently exists to prevent these adverse effects. Melatonin, with established antioxidant and neuroprotective properties, may attenuate ECT-related cognitive dysfunction. Methods: In this randomized, double-blind, placebo-controlled trial, 46 inpatients with BD undergoing ECT were allocated 1:1 to receive either melatonin (3 mg nightly) or identical placebo capsules. Study medication was administered from 24 h before the first ECT session until 24 h after the final session. Cognitive outcomes were assessed using the mini-mental state examination (MMSE) and its subdomains at baseline and after each ECT session. Secondary outcomes included systolic and diastolic blood pressure. Adverse events were recorded throughout the trial. Results: Compared with placebo, melatonin significantly improved global cognition across the ECT course (group × time interaction, P=0.021). At the final session, patients receiving melatonin demonstrated higher MMSE scores (27.9±1.8 vs 26.5±2.0), with the strongest improvements in recall (+0.6 points, P=0.012) and attention/calculation (+0.5 points, P=0.018). Blood pressure (BP) values remained stable (Δ systolic BP: -1.2±3.1 mm Hg melatonin vs -0.8±2.9 mm Hg placebo, P=0.64), and melatonin was also well tolerated. Conclusion: Adjunctive melatonin reduced ECT-related cognitive impairment in BD patients, with pronounced benefits in memory and attention, while maintaining an excellent safety profile. These findings support melatonin as a simple, inexpensive, and widely accessible therapeutic option to support cognition in this vulnerable population. Highlights: Melatonin improved overall cognition in bipolar patients receiving ECT.The greatest cognitive gains were observed in the recall and attention/calculation domains.Melatonin was well tolerated with no significant adverse effects observed.No hemodynamic instability occurred during ECT sessions with melatonin use.Melatonin is a safe adjunctive option for reducing ECT-related cognitive decline. Plain Language Summary: Electroconvulsive therapy (ECT) is a powerful and often life-saving treatment for people with severe bipolar disorder, especially when other treatments do not work. However, one of the biggest problems with ECT is that it can cause memory problems and difficulties with thinking, which makes many patients and families worried about choosing this treatment. Melatonin is a natural hormone produced by the body, best known for regulating sleep. But research has also shown that melatonin has protective effects on the brain, including reducing stress from harmful molecules (oxidative stress) and helping nerve cells work better. Because of these properties, we wanted to test whether melatonin could help protect patients from memory and thinking problems caused by ECT. In our study, 46 patients with bipolar disorder who were scheduled to receive ECT took part. Half of them received melatonin, and the other half received a placebo (an inactive pill) during their treatment course. We measured their thinking and memory using a standard test before and after ECT. Patients who took melatonin showed better performance, especially in remembering words and focusing on tasks, compared with those who took a placebo. Importantly, melatonin was safe and caused no serious side effects. These findings suggest that melatonin, which is inexpensive and widely available, could be a simple way to make ECT safer and easier for patients by protecting their memory. If confirmed in larger studies, this approach could encourage more patients to accept ECT when needed, thereby improving treatment outcomes and quality of life.