Magnesium Bisglycinate in Major Depressive Disorder

The DREAM-BiG (Depression REsponse to Adjunctive Magnesium-BisGlycinate) study is a single-centre, randomized, double-blind, placebo-controlled, parallel-arm academic clinical trial designed to evaluate the efficacy and safety of adjunctive magnesium bisglycinate in adults with Major Depressive Disorder (MDD) receiving stable standard-of-care antidepressant therapy. The study will be conducted in the Departments of Pharmacology and Psychiatry at AIIMS Bhubaneswar. Eligible participants will be men and women aged 18-65 years with a DSM-5 diagnosis of MDD and mild-to-severe depressive symptoms, defined by a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of ≥7, who are receiving a stable dose of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Following written informed consent, participants will undergo detailed clinical evaluation, anthropometric assessment, and baseline measurement of clinical and biochemical parameters. A total of 84 participants will be randomization using computer-generated block randomization with a block size of six and a 2:1 allocation ratio favoring the intervention arm. Allocation concealment will be ensured through sequentially numbered, identical-appearing capsule containers, and participants, treating psychiatrists, outcome assessors, and investigators will remain blinded to treatment allocation throughout the study. Participants in the intervention group will receive magnesium bisglycinate capsules providing 220 mg elemental magnesium daily, while those in the control group will receive matching placebo capsules containing microcrystalline cellulose; both interventions will be administered as add-on therapy for 8 weeks alongside ongoing antidepressant treatment. Clinical assessments will be conducted at baseline and Week 8 using validated rating scales, including MADRS for depressive symptoms, Hamilton Anxiety Rating Scale (HAM-A) for anxiety, Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) for sleep-related outcomes, and Clinical Global Impression scales (CGI-S and CGI-I) for overall clinical status. Blood samples will be collected at baseline and follow-up for estimation of serum magnesium, glycine, and brain-derived neurotrophic factor (BDNF). Treatment-emergent adverse events will be actively monitored throughout the study, with severity and causality assessed using standardized pharmacovigilance tools. Statistical analyses will compare changes from baseline to Week 8 between study groups, with change in MADRS score serving as the primary efficacy endpoint.

Inclusion criteria

• Patients with a diagnosis of Major Depressive Disorder (MDD) as per DSM-5 criteria.
• Patients of either sex within the age group of 18-65 years.
• Mild to severe depression, defined as a baseline MADRS score ≥7.
• Currently receiving a stable dose of antidepressant monotherapy (SSRI or SNRI) in equivalent doses.
• Willing and able to provide written informed consent.

Exclusion criteria

• Known hypersensitivity or allergy to magnesium supplements or glycine.
• History of renal impairment (previous history of AKI, CKD, currently on dialysis).
• Diagnosis of bipolar affective disorder, schizoaffective disorder, schizophrenia, or any other psychotic disorder.
• Active suicidal ideation with intent or a recent suicide attempt (within the past 6 months), as assessed by the treating psychiatrist.
• Current substance use disorder (except nicotine, alcohol and caffeine), as per DSM-5 criteria.
• Pregnancy, lactation, or women of childbearing potential not using adequate contraception.
• Concurrent use of magnesium-containing supplements, antacids, or laxatives.
• History of significant severe medical comorbidity, including uncontrolled hypothyroidism, Cushing's syndrome, active malignancy, myasthenia gravis, or severe hepatic impairment.
• Use of medications with significant pharmacokinetic interactions with magnesium (e.g., tetracyclines, fluoroquinolones, bisphosphonates, diuretics) that cannot be temporally separated by ≥2 hours.
• Electroconvulsive therapy (ECT) received within the past 3 months.