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The aim of this clinical trial is to compare the effect of antidepressants in combination with different dietary supplements in patients with depression. Our main objective is to compare the efficacy of antidepressants in combination with either L-methyl folate, Vit B12, or magnesium) in patients with depressive disorders. The levels of depressive symptoms as measured by the Patient Health Questionnaire (PHQ-9) at base level and during follow-up.
This is an open-label study assessing the comparative efficacy of antidepressants in combination therapy of either L-methylfolate, mecobalamin, or magnesium in patients with Depressive Disorder. The plan is to enroll 84 patients with depression based on Patient Health Questionnaire (PHQ-9) score of 9 and above, which is a valid and reliable Structured Clinical Interview. The investigators will collect data from the enrolled patient populations. The participants will be able to receive their results, on request, upon completion of the study. The investigators hypothesize that depressive symptoms can be improved by the addition of above mentioned nutritional supplementations with antidepressant medication.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Antidepressant | No Intervention | Participants receive either escitalopram 10-20mg, sertraline 50-100mg, fluoxetine 20-40mg, duloxetine 30-60mg, mirtazapine 15-30mg, venlafaxine 75-150mg, trazodone 50-100mg, amitriptyline 25-75mg, or clomipramine 25-75mg orally daily for 4 weeks. | |
| Antidepressant and L-methylfolate | Experimental | Participants receive a combination of antidepressant and L-methylfolate 400µg twice daily orally for 4 weeks |
|
| Antidepressant and injectable mecobalamin | Experimental | Participants receive a combination of antidepressant and mecobalamin 500µg intramuscularly stat on alternate days (6 total injections) |
|
| Antidepressant and Magnesium | Experimental | Participants receive a combination of antidepressant and magnesium glycinate 400mg (Elemental: ≈120mg) twice daily orally for 4 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| L-methylfolate | Dietary Supplement | Participants receive L-methylfolate 400µg orally twice daily for 4 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Patient Health Questionnaire (PHQ-9) | The change in the total PHQ-9 score between baseline and 4-weeks follow-up is the primary outcome measure. This measure is a patient-rated inventory of depressive symptoms. All items are scored on scales ranging from 0-3 and the sum of the scores provides the total score for the measure. On this scale, higher scores indicate poorer outcomes. Scores 9-19 and 20-27 are considered moderate and severe depression respectively. | Baseline and 4 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Patient Health Questionnaire (PHQ-9) | The change in the total PHQ-9 score between baseline, and the intermediate 2-weeks, and 4-weeks follow-up is the secondary outcome measures. This measure is a patient-rated inventory of depressive symptoms. All items are scored on scales ranging from 0-3 and the sum of the scores provides the total score for the measure. On this scale, higher scores indicate poorer outcomes. Scores 9-19 and 20-27 are considered moderate and severe depression respectively. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Afifa Siddique, MBBS | IIMC-T, Riphah International University, Rawalpindi | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pakistan Railway Hospital, IIMC-T, Riphah International University | Rawalpindi | Punjab Province | Pakistan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27910808 | Background | Serefko A, Szopa A, Poleszak E. Magnesium and depression. Magnes Res. 2016 Mar 1;29(3):112-119. doi: 10.1684/mrh.2016.0407. | |
| 28654669 | Background | Tarleton EK, Littenberg B, MacLean CD, Kennedy AG, Daley C. Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PLoS One. 2017 Jun 27;12(6):e0180067. doi: 10.1371/journal.pone.0180067. eCollection 2017. |
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| ID | Term |
|---|---|
| D003863 | Depression |
| ID | Term |
|---|---|
| D001526 | Behavioral Symptoms |
| D001519 | Behavior |
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| ID | Term |
|---|---|
| C005984 | 5-methyltetrahydrofolate |
| D014805 | Vitamin B 12 |
| C019476 | mecobalamin |
| D008274 | Magnesium |
| ID | Term |
|---|---|
| D045728 | Corrinoids |
| D045725 | Tetrapyrroles |
| D011758 | Pyrroles |
| D001393 | Azoles |
| D006573 |
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| Vitamin B12 | Dietary Supplement | Participants receive mecobalamin 500µg intramuscularly stat on alternate days (6 total injections) |
|
|
| magnesium | Dietary Supplement | Participants receive magnesium glycinate 400mg twice daily orally for 4 weeks (elemental 120mg approx.) |
|
|
| Baseline, 2-weeks and 4-weeks |
| Side-effects | A self-assessment questionnaire for undesirable effects in psychopharmacological treatment, developed by the Department of Psychiatry, Riphah International University, Pakistan. This is to investigate the presence or absence of 4 symptoms (diarrhea, drowsiness, insomnia, and rash), and their relationship with the treatment. | Baseline, 2-weeks, and 4-weeks follow up |
| Depressive symptoms remission | Remission rate of Major Depression in the two groups over the course of treatment, defining remission as a score ≤ 4 on the PHQ-9 scale. | Baseline, 2 weeks, 4 weeks |
| 30611059 | Background | Sun C, Wang R, Li Z, Zhang D. Dietary magnesium intake and risk of depression. J Affect Disord. 2019 Mar 1;246:627-632. doi: 10.1016/j.jad.2018.12.114. Epub 2018 Dec 27. |
| 33864354 | Background | Noah L, Dye L, Bois De Fer B, Mazur A, Pickering G, Pouteau E. Effect of magnesium and vitamin B6 supplementation on mental health and quality of life in stressed healthy adults: Post-hoc analysis of a randomised controlled trial. Stress Health. 2021 Dec;37(5):1000-1009. doi: 10.1002/smi.3051. Epub 2021 May 6. |
| 36883502 | Background | Chaban capital O, CyrillicS, Khaustova OO, Assonov DO, Sak LV. SAFETY AND EFFICACY OF THE COMPLEX DEPRILIUM(R) IN REDUCING SUBCLINICAL SYMPTOMS OF DEPRESSION IN PATIENTS WITH CHRONIC NON-COMMUNICABLE DISEASES: DOUBLE-BLIND RANDOMIZED CONTROLLED STUDY. Wiad Lek. 2023;76(1):136-144. doi: 10.36740/WLek202301119. |
| 34794190 | Background | Maruf AA, Poweleit EA, Brown LC, Strawn JR, Bousman CA. Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders. Pharmacopsychiatry. 2022 May;55(3):139-147. doi: 10.1055/a-1681-2047. Epub 2021 Nov 18. |
| 33132780 | Background | Hardin A, Baldwin-Sayre C. L-Methylfolate as a Monotherapy for Treatment-Resistant Depression: A Case Study. Integr Med (Encinitas). 2020 Aug;19(4):14-18. |
| 31058543 | Background | Dartois LL, Stutzman DL, Morrow M. L-methylfolate Augmentation to Antidepressants for Adolescents with Treatment-Resistant Depression: A Case Series. J Child Adolesc Psychopharmacol. 2019 Jun;29(5):386-391. doi: 10.1089/cap.2019.0006. Epub 2019 May 6. |
| 33809274 | Background | Markun S, Gravestock I, Jager L, Rosemann T, Pichierri G, Burgstaller JM. Effects of Vitamin B12 Supplementation on Cognitive Function, Depressive Symptoms, and Fatigue: A Systematic Review, Meta-Analysis, and Meta-Regression. Nutrients. 2021 Mar 12;13(3):923. doi: 10.3390/nu13030923. |
| 34510193 | Background | Carter B, Zenasni Z, Moat SJ, Hudson PR, Russell IT, McCaddon A; FolATED group consists of the following authors. Plasma Methylmalonic Acid Concentration in Folic Acid-Supplemented Depressed Patients with Low or Marginal Vitamin B-12: A Randomized Trial. J Nutr. 2021 Dec 3;151(12):3738-3745. doi: 10.1093/jn/nxab280. |
| 42283837 | Derived | Siddique A, Naeem U, Khokhar MM, Irshad M, Farooq T, Kanwal S. Clinical evaluation of adjunctive magnesium therapy in patients receiving antidepressants for depression-open label, nonrandomized clinical trial. Naunyn Schmiedebergs Arch Pharmacol. 2026 Jun 12. doi: 10.1007/s00210-026-05540-1. Online ahead of print. |
| 39844190 | Derived | Siddique A, Khokhar MM, Waheed A, Naeem U, Aziz SA. Effect of combination therapy of methylfolate with antidepressants in patients with depressive disorder. BMC Pharmacol Toxicol. 2025 Jan 22;26(1):14. doi: 10.1186/s40360-025-00846-x. |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D008673 | Metals, Alkaline Earth |
| D004602 | Elements |
| D007287 | Inorganic Chemicals |
| D019565 | Metals, Light |
| D008670 | Metals |