Original Article

Effect of Vitamin A Supplementation on Fatigue and Depression in Multiple Sclerosis Patients: A Double-blind Placebo-controlled Clinical Trial


Decreasing the population and activation of inflammatory T helper cells in multiple sclerosis (MS) patients using vitamin A derivatives (retinoic acids) has been well documented. The present study determined the effect of vitamin A supplementation on psychiatric signs in MS patients. The subjects were 101 relapsing-remitting MS patients enrolled in a placebo-controlled randomized clinical trial. The treatment group was administered 25000 IU/d retinyl palmitate (RP) for 6 months followed by 10000 IU/d RP for another 6 months. The results for baseline characteristics, modified fatigue impact scale and Beck Depression Inventory-II were recorded at the beginning and end of the one-year study. The non-normal distribution data was compared between groups using a nonparametric test and normal distribution data was analyzed using a parametric test. (ClinicalTrials.gov Identifiers: NCT01417273). The results showed significant improvement in the treatment group for fatigue (p=0.004) and depression (p=0.01). Vitamin A supplementation helped during interferon therapy in the treatment process and improved psychiatric outcomes for anti-inflammatory mechanisms.

1. Aranami T, Yamamura T. Th17 Cells and autoimmune encephalomyelitis (EAE/MS). Allergol Int 2008;57(2):115-20.

2. Lovett-Racke AE, Racke MK. Retinoic acid promotes the development of Th2-like human myelin basic protein- reactive T cells. Cell immunol 2002; 215(1):54-60.

3. Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y, Shevach EM et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 2008;111(3):1013-20.

4. Racke MK, Burnett D, Pak SH, Albert PS, Cannella B, Raine CS et al. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol 1995;154(1):450-8.

5. Qu ZX1, Pliskin N, Jensen MW, White D, Arnason BG.Etretinate augments interferon beta-1b effects on suppressor cells in multiple sclerosis. Arch Neurol 2001;58(1):87-90.

6. Soprano DR, Soprano KJ. Pharmacological doses of some synthetic retinoids can modulate both the aryl hydrocarbon receptor and retinoid receptor pathways. J Nutr 2003; 133(1):277S-281S.

7. Sedjo RL, Ranger-Moore J, Foote J, Craft NE, Alberts DS, Xu MJ, et al. Circulating endogenous retinoic acid concentrations among participants enrolled in a randomized placebo-controlled clinical trial of retinyl palmitate. Cancer Epidemiol Biomarkers Prev 2004;13(11 pt 1):1687-92.

8. Bitarafan S, Harirchian MH, Sahraian MA, Keramatipour M, Beladi Moghadam N, Togha M, et al., Impact of vitamin A supplementation on RAR gene expression in multiple sclerosis patients. J Mol Neurosci 2013;51(2):478-84.

9. Mohammadzadeh Honarvar N, Harirchian MH, Koohdani F, Siassi F, Abdolahi M, Bitarafan S, et al. The effect of vitamin a supplementation on retinoic acid-related orphan receptor γt (RORγt) and interleukin-17 (IL-17) gene expression in avonex-treated multiple sclerotic patients. J Mol Neurosci 2013; 51(3):749-53.

10. Maden M. Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci 2007; 8(10):755-65.

11. Mey J, Mccaffery P. Retinoic acid signaling in the nervous system of adult vertebrates. The Neuroscientist 2004; 10(5):409-21.

12. Bakshi R, Shaikh ZA, Miletich RS, Czarnecki D, Dmochowski J, Henschel K, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler J 2000; 6(3):181-5.

13. Jafarirad S, Siassi F, Harirchian MH, Sahraian MA, Eshraghian MR, Shokri F, et al. The effect of vitamin A supplementation on stimulated T-cell proliferation with myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. J Neurosci Rural Pract 2012; 3(3):294-8.

14. Harrirchian MH, Mohammadzadeh Honarvar N, Koohdani F, Bitarafan S, Siassi F, Jafarirad S, et al. The Effect of Vitamin A Supplementation on Disease Progression, Cytokine Levels and Gene Expression in Multiple Sclerotic Patients: Study Protocol for a Randomized Controlled Trial. Acta Med Iran 2014;52(2):94-100.

15. Harirchian MH, Nasergivechi S, Maddah M, Meysamie A, Amini H, Shandiz EE, et al. Evaluation of the Persian version of Modified Fatigue Impact Scale in Iranian patients with multiple sclerosis. Iran J Neurol 2013;12(1):32-4.

16. Téllez N, Río J, Tintoré M, Nos C, Galán I, Montalban X.Does the Modified Fatigue Impact Scale offer a more comprehensive assessment of fatigue in MS? Mult Scler J 2005; 11(2):198-202.

17. Ghassemzadeh H, Mojtabai R, Karamghadiri N, Ebrahimkhani N. Psychometric properties of a Persian‐ language version of the Beck Depression Inventory‐ Second edition: BDI‐ II‐ PERSIAN. Depress Anxiety 2005; 21(4):185-92.

18. Krupp, L.B., et al., Fatigue in multiple sclerosis. Arch Neurol 1988; 45(4):435-7.

19. Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C.

Treatments for fatigue in multiple sclerosis: a rapid and systematic review. Health Technol Assess 2000; 4(27):1-61.

20. Comi G, Leocani L, Rossi P, Colombo B.Physiopathology and treatment of fatigue in multiple sclerosis. J Neurol 2001; 248(3):174-9.

21. Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieckmann P. Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult Scler J 2004; 10(2):165-9.

22. Whitlock FA, Siskind MM. Depression as a major symptom of multiple sclerosis. J Neurol Neurosurg Psychiatry 1980; 43(10):861-5.

23. Vattakatuchery JJ, Rickards H, Cavanna AE. Pathogenic mechanisms of depression in multiple sclerosis. J Neuropsychiatry Clin Neurosci 2011; 23(3):261-76.

24. Galeazzi GM, Ferrari S, Giaroli G, Mackinnon A, Merelli E, Motti L, et al. Psychiatric disorders and depression in multiple sclerosis outpatients: impact of disability and interferon beta therapy. Neurol Sci 2005; 26(4):255-62.

25. Rossi S, Studer V, Motta C, De Chiara V, Barbieri F, Bernardi G, et al. Inflammation inhibits GABA transmission in multiple sclerosis. Mult Scler J 2012;18(11):1633-5.

26. Dunham RM, Thapa M, Velazquez VM, Elrod EJ, Denning TL, Pulendran B, et al. Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. J Immunol 2013;190(5):2009-16.

27. Leo MA, Lasker JM, Raucy JL, Kim CI, Black M, Lieber CS. Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8. Arch Biochem Biophys 1989; 269(1):305-12.

28. Honarvar NM, Harrirchian MH, Koohdani F, Siassi F, Jafari Rad S, Abdolahi M et al. In Vitro Effect of Human Serum and Fetal Calf Serum on CD4+ T Cells Proliferation in Response to Myelin Oligodendrocyte Glycoprotein (MOG) in Correlation with RBP/TTR Ratio in Multiple Sclerotic Patients. J Mol Neurosci 2013;50(3):571-6.

29. Racke MK, Bonomo A, Scott DE, Cannella B, Levine A, Raine CS, et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 1994; 180(5):1961-6.

30. Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B, et al.Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-β- driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008; 181(4):2277-84.

31. Jafarirad S, Siassi F, Harirchian MH, Amani R, Bitarafan S, Saboor-Yaraghi A. The Effect of Vitamin A Supplementation on Biochemical Parameters in Multiple Sclerosis Patients. Iran Red Crescent Med J 2013;15(3):194–8.

32. Alberts D, Ranger-Moore J, Einspahr J, Saboda K, Bozzo P, Liu Y, et al. Safety and efficacy of dose-intensive oral vitamin A in subjects with sun-damaged skin. Clin Cancer Res 2004; 10(6):1875-80.

IssueVol 15, No 1 (2016) QRcode
SectionOriginal Article(s)
Depression Fatigue Multiple sclerosis Vitamin A

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Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Bitarafan S, Saboor-Yaraghi A, Sahraian M-A, Soltani D, Nafissi S, Togha M, Beladi Moghadam N, Roostaei T, Mohammadzadeh Honarvar N, Harirchian M-H. Effect of Vitamin A Supplementation on Fatigue and Depression in Multiple Sclerosis Patients: A Double-blind Placebo-controlled Clinical Trial. Iran J Allergy Asthma Immunol. 2016;15(1):13-19.