en Clinical Neuroscience Clinical Neuroscience Original Original <div style="text-align: justify;"><strong>Introduction</strong>: 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.<br> <strong>Methods</strong>: 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.<br> <strong>Results</strong>: Compared with placebo, melatonin significantly improved global cognition across the ECT course (group &times; time interaction, P=0.021). At the final session, patients receiving melatonin demonstrated higher MMSE scores (27.9&plusmn;1.8 vs 26.5&plusmn;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 (&Delta; systolic BP: &ndash;1.2&plusmn;3.1 mm Hg melatonin vs &ndash;0.8&plusmn;2.9 mm Hg placebo, P=0.64), and melatonin was also well tolerated.<br> <strong>Conclusion</strong>: 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.</div> Bipolar disorder (BD), Electroconvulsive therapy (ECT), Cognitive impairment, Melatonin, Adjunctive therapy 97 112 http://bcn.iums.ac.ir/browse.php?a_code=A-10-8317-1&slc_lang=en&sid=1 Maryam Shahrokhi shahrokhi.mail85@gmail.com 13700319475328460057341 13700319475328460057341 No Bio Environmental Health Hazards Research Center, Jiroft University of Medical Sciences, Jiroft, Iran. Robabeh Soleimani soleimani.dr@gmail.com 13700319475328460057342 13700319475328460057342 No Department of Psychiatry, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran. Mahdi Ahmadinia M.ahmadiniam@gmail.com 13700319475328460057343 13700319475328460057343 No Lung Transplantation Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. AmirMahdi Rezapour amir.rezapoor1998@gmail.com 13700319475328460057344 13700319475328460057344 No Student Research Committee, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran. Saeed Taatirad saeedtaatirad@gmail.com 13700319475328460057345 13700319475328460057345 No Department of Psychiatry, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran. Faezeh Jamali faezeh.jamalii@gmail.com 13700319475328460057346 13700319475328460057346 No Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Hamed Jafari Mohamadabadi hamedjafarimohamadabadi@gmail.com 13700319475328460057347 13700319475328460057347 No Department of Psychiatry, Psychosis Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. Roja Qobadighadikolaei roja.ghobadi@gmail.com 13700319475328460057348 13700319475328460057348 Yes Department of Clinical Pharmacy, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.