Title : The efficacy of amantadine as an adjunctive therapy in treating depression and cognitive impairment in patients with bipolar depression at Imam Hossein, Shariati, andImam Ali hospitals in Karaj a randomized double-blind placebo-controlled clinical trial

The aim of this study is to determine the efficacy of amantadine as an adjunctive therapy in improving depression and cognitive impairment in patients with bipolar depression.

Double-blind, randomized, placebo-controlled, parallel-group clinical trial, phase 3, with 64 patients (32 per group), block randomization with block size of four, and allocation concealment by sealed envelopes.

The study will be conducted at psychiatry outpatient clinics of Imam Hossein, Shariati and Imam Ali hospitals in Karaj, Iran. Eligible patients will be randomized to amantadine or placebo. Participants, caregivers, investigators, outcome assessors and data analyst will be blinded. Identical capsules will be prepared by the hospital pharmacy.

Inclusion criteria: age 30 to 60 years; bipolar disorder type I or II in active depressive episode based on DSM-5-TR; literacy; Beck Depression Inventory-II score of 20 or higher; informed consent. Exclusion criteria: age outside 30 to 60 years; illiteracy; Beck score below 20; inappropriate serum lithium level; recent electroconvulsive therapy or substance use; amantadine hypersensitivity; active post-traumatic stress disorder, cluster B personality disorder or psychosis; active neurological, severe liver, renal or cardiovascular disease; pregnancy or breastfeeding; monoamine oxidase inhibitor or strong anticholinergic use; seizure history.

Intervention group: lithium (serum level 0.8 to 1.2 milliequivalent per liter) plus amantadine 100 milligrams daily for 12 weeks. Control group: lithium plus placebo for 12 weeks.

Depression severity by Beck Depression Inventory-II; cognitive function by Neuropsychiatry Unit Cognitive Assessment Tool, Trail Making Test parts A and B, and Wisconsin Card Sorting Test; assessed at baseline, weeks 4, 8 and 12.

Randomization will be performed using a block randomization method with fixed block sizes of four (1:1 allocation ratio). The unit of randomization is the individual patient. The randomization sequence will be generated by a statistician independent of the research team using computer-generated random numbers (e.g., Random Allocation Software). Allocation concealment will be ensured using sequentially numbered, opaque, sealed envelopes (SNOSE) prepared by the same independent person. Each envelope will contain the allocation code (amantadine or placebo) and will be opened by the clinical investigator only after the participant has been enrolled, completed baseline assessments, and signed the informed consent form. No stratification will be applied.

This study is a double-blind trial. Participants, clinical caregivers (psychiatrists and nurses responsible for patient care), the principal investigator and research team, outcome assessors, and the data analyst will all be blinded to treatment allocation. Amantadine and placebo will be provided as identical capsules in terms of appearance, size, color, and packaging, prepared by the hospital pharmacy under a code. Neither the participants nor any member of the research team will know which treatment a participant is receiving. The randomization codes will be kept by an independent person outside the research team and will be revealed only after the statistical analysis is complete, or in case of a medical emergency requiring unblinding. The data analyst will receive coded group labels (A/B) and will perform the analysis without knowledge of the actual treatment.

De-identified individual participant data (IPD) underlying the primary and secondary outcomes, study protocol, statistical analysis plan, informed consent form, analysis codes, and data dictionary.

Access will begin 6 months after publication of the main results and will remain available for 5 years.

Researchers affiliated with academic or scientific institutions.

Data will be shared for non-commercial research purposes, including re-analysis and verification of published results. Requesters must sign a data access agreement and agree not to attempt re-identification of participants.

Requests should be sent to the principal investigator, Dr. Rahim Badrfam, at the Clinical Research Development Unit of Imam Hossein Hospital, Alborz University of Medical Sciences, Karaj, Iran. Email:rbadrfam@gmail.com

The request will be reviewed by the principal investigator and the Clinical Research Development Unit within 2 weeks. If approved, a data access agreement will be sent to the requester. Upon signing the agreement, the de-identified data will be transferred securely within 4 weeks.