Depression and Anxiety treatment with Vitamin D - probable molecular pathways - June 2022

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Molecular Basis Underlying the Therapeutic Potential of Vitamin D for the Treatment of Depression and Anxiety

Int. J. Mol. Sci. 2022, 23, 7077. https://doi.org/10.3390/ijms23137077
Bruna R. Kouba 1, Anderson Camargo 1 , Joana Gil-Mohapel 2,3,* and Ana Lucia S. Rodrigues h*
Citation: Kouba, B.R.; Camargo, A.; Gil-Mohapel, J.; Rodrigues, A.L.S. .
Center of Biological Sciences, Department of Biochemistry, Federal University of Santa Catarina, Florianopolis 88040-900, SC, Brazil; rkba.bruna@gmail.com (B.R.K.); camargo.andersonc@gmail.com (A.C.)
Island Medical Program, Faculty of Medicine, University of British Columbia, Victoria, BC V8P 5C2, Canada
Division of Medical Sciences, University of Victoria, Victoria, BC V8P 5C2, Canada
Correspondence: jgil@uvic.ca (J.G.-M.); ana.l.rodrigues@ufsc.br (A.L.S.R.); Tel.: +1-250-721-6586 (J.G.-M.); +55-(48)-3721-5043 (A.L.S.R.)

Major depressive disorder and anxiety disorders are common and disabling conditions that affect millions of people worldwide. Despite being different disorders, symptoms of depression and anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately. Therefore, compounds capable of exerting beneficial effects against both disorders are of special interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many functions that go beyond its effects on calcium-phosphorus metabolism. Particularly, antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its antidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the management of these disorders.
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From PDF: Clinical Studies: Effects of Vitamin D in Depression and Anxiety

Several studies have reported that vitamin D supplementation improves symptoms of depression and anxiety associated with various medical conditions, including type II diabetes, Crohn's disease, ulcerative colitis, and obesity [101-105].
However, the potential therapeutic effects of vitamin D in individuals primarily diagnosed with depression or anxiety remain controversial.
For example, vitamin D supplementation (1600IU for 6 months) was shown to significantly improve anxiety symptoms, but not depressive symptoms, in patients with vitamin D deficiency [106].
Likewise, supplementation with 2800 IU of vitamin D in patients with depression did not promote a significant reduction in Hamilton D-17 scores [107].
On the other hand, supplementation with 50,000 IU of vitamin D for 2 weeks was able to improve depression severity, as assessed with the Beck Depression Inventory-II (BDI-II), although no changes in serotonin levels were detected [108].
However, in another study, cholecalciferol treatment (50,000 IU for 3 months) significantly increased serum serotonin levels, while decreasing BDI scores in women with moderate, severe, and extreme depression.
Interestingly, among men, an improvement in the severity of depressive symptoms with vitamin D supplementation was only observed in those diagnosed with severe depression [83].
Beneficial effects of vitamin D (50,000 IU for 8 weeks) supplementation have also been observed in older adults (over 60 years of age) with depression [109]. However, lower doses of vitamin D (400 IU daily for 2 years) were not able to improve depressive symptoms [110].
Finally, a single dose of vitamin D (300,000 IU) was reported as an effective and safe intervention in MDD with concurrent vitamin D deficiency [111,112]. In patients with depression, the daily administration of 1500 IU vitamin D3 plus 20 mg fluoxetine for 8 weeks was superior to fluoxetine alone [113].
Another study reported that vitamin D supplementation (50,000 IU once/week for 3 months) in combination with standard of care improved the severity of anxiety in individuals diagnosed with Generalized Anxiety Disorder by increasing serotonin concentrations and decreasing the levels of the inflammatory biomarker neopterin [114].
Overall, although there is compelling clinical evidence pointing to the benefits of vitamin D for the management of depression and anxiety, it is important to note that divergent results have also been obtained [46].
Multiple factors may contribute to these discrepant results, including

• differences in the doses of vitamin D used,
• treatment time,
• serum 25-hydroxyvitamin D levels at baseline,
• nutritional condition at the onset of the treatment,
• age and sex of the individuals,
• as well as the presence of comorbidities that may influence the efficacy of vitamin D supplementation. Additionally, the heterogeneity observed in clinical studies may also be associated with genetic polymorphisms that may affect vitamin D efficacy [115-117].

From PDF Conclusions and Future Directions

In this review, we discussed the main evidence underlining the therapeutic potential of vitamin D in the management of depression and anxiety disorders. Of particular relevance, compelling evidence suggests that vitamin D possesses

• antioxidant,
• anti-inflammatory,
• pro-neurogenic, and
• neuromodulatory properties,

and, thus, may act in a similar manner to classic antidepressants. In support, several preclinical studies have shown the beneficial effects of vitamin D supplementation in animal models of these mood disorders. Given this, some studies have investigated the possible synergistic or additive beneficial effects of vitamin D and current pharmacotherapy for the management of anxiety and depression. However, the clinical studies that assess the efficacy of vitamin D supplementation in the treatment of depression and anxiety are still scarce and their results are, at times, controversial. The discrepant results from clinical trials call for the need to conduct future studies, so as to establish a protocol for vitamin D supplementation that is effective in preventing or attenuating depressive and anxiety symptoms. Therefore, appropriately randomized clinical trials assessing the potential of vitamin D as co-adjuvant for the treatment of these mood disorders are warranted, so as to ascertain the true therapeutic value of this vitamin in the context of depression and anxiety.

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85. Jiang, P.; Zhang, L.H.; Cai, H.L.; Li, H.D.; Liu, Y.P.; Tang, M.M.; Dang, R.L.; Zhu, W.Y.; Xue, Y.; He, X. Neurochemical Effects of Chronic Administration of Calcitriol in Rats. Nutrients 2014, 6, 6048-6059. [CrossRef] [PubMed]
86. Pertile, R.A.N.; Cui, X.; Eyles, D.W. Vitamin D Signaling and the Differentiation of Developing Dopamine Systems. Neuroscience 2016, 333, 193-203. [CrossRef]
87. Sabir, M.S.; Haussier, M.R.; Mallick, S.; Kaneko, I.; Lucas, D.A.; Haussier, C.A.; Whitfield, G.K.; Jurutka, P.W. Optimal Vitamin D Spurs Serotonin: 1,25-Dihydroxyvitamin D Represses Serotonin Reuptake Transport (SERT) and Degradation (MAO-A) Gene Expression in Cultured Rat Serotonergic Neuronal Cell Lines. Genes Nutr. 2018,13,19. [CrossRef]
88. Luthold, R.V.; Fernandes, G.R.; Franco-de-Moraes, A.C.; Folchetti, L.G.D.; Ferreira, S.R.G. Gut Microbiota Interactions with the Immunomodulatory Role of Vitamin D in Normal Individuals. Metabolism 2017, 69, 76-86. [CrossRef]
89. Assa, A.; Vong, L.; Pinnell, L.J.; Avitzur, N.; Johnson-Henry, K.C.; Sherman, P.M. Vitamin D Deficiency Promotes Epithelial Barrier Dysfunction and Intestinal Inflammation. J. Infect. Dis. 2014, 210,1296-1305. [CrossRef]
90. Ooi, J.H.; Li, Y.; Rogers, C.J.; Cantorna, M.T. Vitamin D Regulates the Gut Microbiome and Protects Mice from Dextran Sodium Sulfate-Induced Colitis. J. Nutr. 2013,143,1679-1686. [CrossRef]
91. Wu, S.; Liao, A.P.; Xia, Y.; Chun Li, Y.; Li, J.D.; Sartor, R.B.; Sun, J. Vitamin D Receptor Negatively Regulates Bacterial-Stimulated NF-KB Activity in Intestine. Am. J. Pathol. 2010,177, 686-697. [CrossRef] [PubMed]
92. Fedotova, J.; Dudnichenko, T.; Kruzliak, P.; Puchavskaya, Z. Different Effects of Vitamin D Hormone Treatment on Depression-like Behavior in the Adult Ovariectomized Female Rats. Biomed. Pharmacother. 2016, 84,1865-1872. [CrossRef] [PubMed]
93. Fedotova, J.O. Vitamin D3 Treatment Differentially Affects Anxiety-like Behavior in the Old Ovariectomized Female Rats and Old Ovariectomized Female Rats Treated with Low Dose of 17ß-Estradiol. BMC Med. Genet. 2019, 20, 49. [CrossRef] [PubMed]
94. Camargo, A.; Dalmagro, A.P.; Rikel, L.; da Silva, E.B.; Simäo da Silva, K.A.B.; Zeni, A.L.B. Cholecalciferol Counteracts Depressive- like Behavior and Oxidative Stress Induced by Repeated Corticosterone Treatment in Mice. Eur. J. Pharmacol. 2018, 833,451-461. [CrossRef]
95. Da Silva Souza, S.V.; da Rosa, P.B.; Neis, V.B.; Moreira, J.D.; Rodrigues, A.L.S.; Moretti, M. Effects of Cholecalciferol on Behavior and Production of Reactive Oxygen Species in Female Mice Subjected to Corticosterone-Induced Model of Depression. Naunyn. Schmiedebergs Arch. Pharmacol. 2020, 393,111-120. [CrossRef]
96. Neis, V.B.; Werle, I.; Moretti, M.; Rosa, P.B.; Camargo, A.; Dalsenter, Y.D.O.; Platt, N.; Rosado, A.F.; Engel, W.D.; de Almeida, GR.L.; et al. Involvement of Serotonergic Neurotransmission in the Antidepressant-like Effect Elicited by Cholecalciferol in the Chronic Unpredictable Stress Model in Mice. Metab. Brain Dis. 2022, 37,1597-1608. [CrossRef]
97. Zhang, W.; Guo, Y.; Wang, K.; Chen, L.; Jiang, P. Neuroprotective Effects of Vitamin D and 17ß-Estradiol against Ovariectomy- Induced Neuroinflammation and Depressive-like State: Role of the AMPK/NF-KB Pathway. Int. Immunopharmacol. 2020, 86, 106734. [CrossRef]
98. Bakhtiari-Dovvombaygi, H.; Izadi, S.; Zare Moghaddam, M.; Hashemzehi, M.; Hosseini, M.; Azhdari-Zarmehri, H.; Dinpanah, H; Beheshti, F. Beneficial Effects of Vitamin D on Anxiety and Depression-like Behaviors Induced by Unpredictable Chronic Mild Stress by Suppression of Brain Oxidative Stress and Neuroinflammation in Rats. Naunyn. Schmiedebergs Arch. Pharmacol. 2021, 394, 655-667. [CrossRef]
99. Jiang, P.; Zhang, W.Y.; Li, H.D.; Cai, H.L.; Liu, Y.P.; Chen, L.Y. Stress and Vitamin D: Altered Vitamin D Metabolism in Both the Hippocampus and Myocardium of Chronic Unpredictable Mild Stress Exposed Rats. Psychoneuroendocrinology 2013, 38, 2091-2098. [CrossRef]
100. Groves, N.J.; Bradford, D.; Sullivan, R.K.P.; Conn, K.A.; Aljelaify, R.F.; McGrath, J.J.; Burne, T.H.J. Behavioural Effects of Adult Vitamin D Deficiency in BALB/c Mice Are Not Associated with Proliferation or Survival of Neurons in the Adult Hippocampus. PLoS ONE 2016,11, e0152328. [CrossRef]
101. Jorde, R.; Sneve, M.; Figenschau, Y.; Svartberg, J.; Waterloo, K. Effects of Vitamin D Supplementation on Symptoms of Depression in Overweight and Obese Subjects: Randomized Double-Blind Trial. J. Intern. Med. 2008,264, 599-609. [CrossRef] [PubMed]
102. Narula, N.; Cooray, M.; Anglin, R.; Muqtadir, Z.; Narula, A.; Marshall, J.K. Impact of High-Dose Vitamin D3 Supplementation in Patients with Crohn's Disease in Remission: A Pilot Randomized Double-Blind Controlled Study. Dig. Dis. Sci. 2017, 62, 448-455. [CrossRef] [PubMed]
103. Penckofer, S.; Byrn, M.; Adams, W.; Emanuele, M.A.; Mumby, P.; Kouba, J.; Wallis, D.E. Vitamin D Supplementation Improves Mood in Women with Type 2 Diabetes. J. Diabetes Res. 2017,2017, 8232863. [CrossRef]
104. Sharifi, A.; Vahedi, H.; Nedjat, S.; Mohamadkhani, A.; Hosseinzadeh Attar, M.J. Vitamin D Decreases Beck Depression Inventory Score in Patients with Mild to Moderate Ulcerative Colitis: A Double-Blind Randomized Placebo-Controlled Trial. J. Diet. Suppl. 2019,16, 541-549. [CrossRef] [PubMed]
105. Yosaee, S.; Soltani, S.; Esteghamati, A.; Motevalian, S.A.; Tehrani-Doost, M.; Clark, C.C.T.; Jazayeri, S. Effects of Zinc, Vitamin D, and Their Co-Supplementation on Mood, Serum Cortisol, and Brain-Derived Neurotrophic Factor in Patients with Obesity and Mild to Moderate Depressive Symptoms: A Phase II, 12-Wk, 2 x 2 Factorial Design, Double-Blind, Randomized, PlaceboControlled Trial. Nutrition 2020, 71,110601. [CrossRef]
106. Zhu, C.; Zhang, Y.; Wang, T.; Lin, Y.; Yu, J.; Xia, Q.; Zhu, P.; Zhu, D. Vitamin D Supplementation Improves Anxiety but Not Depression Symptoms in Patients with Vitamin D Deficiency. Brain Behav. 2020,10, e01760. [CrossRef] [PubMed]
107. Hansen, J.P.; Pareek, M.; Hvolby, A.; Schmedes, A.; Toft, T.; Dahl, E.; Nielsen, C.T. Vitamin D3 Supplementation and Treatment Outcomes in Patients with Depression (D3-Vit-Dep). BMC Res. Notes 2019,12, 203. [CrossRef]
108. Kaviani, M.; Nikooyeh, B.; Zand, H.; Yaghmaei, P.; Neyestani, T.R. Effects of Vitamin D Supplementation on Depression and Some Involved Neurotransmitters. J. Affect. Disord. 2020,269, 28-35. [CrossRef]
109. Alavi, N.M.; Khademalhoseini, S.; Vakili, Z.; Assarian, F. Effect of Vitamin D Supplementation on Depression in Elderly Patients: A Randomized Clinical Trial. Clin. Nutr. 2019, 38, 2065-2070. [CrossRef]
110. Bertone-Johnson, E.R.; Powers, S.I.; Spangler, L.; Larson, J.; Michael, Y.L.; Millen, A.E.; Bueche, M.N.; Salmoirago-Blotcher, E.; Wassertheil-Smoller, S.; Brunner, R.L.; et al. Vitamin D Supplementation and Depression in the Women's Health Initiative Calcium and Vitamin D Trial. Am. J. Epidemiol. 2012,176,1-13. [CrossRef]
111. Mozaffari-Khosravi, H.; Nabizade, L.; Yassini-Ardakani, S.M.; Hadinedoushan, H.; Barzegar, K. The Effect of 2 Different Single Injections of High Dose of Vitamin D on Improving the Depression in Depressed Patients With Vitamin D Deficiency: A Randomized Clinical Trial. J. Clin. Psychopharmacol. 2013, 33, 378-385. [CrossRef] [PubMed]
112. Vellekkatt, F.; Menon, V.; Rajappa, M.; Sahoo, J. Effect of Adjunctive Single Dose Parenteral Vitamin D Supplementation in Major Depressive Disorder with Concurrent Vitamin D Deficiency: A Double-Blind Randomized Placebo-Controlled Trial. J. Psychiatr. Res. 2020,129, 250-256. [CrossRef] [PubMed]
113. Khoraminya, N.; Tehrani-Doost, M.; Jazayeri, S.; Hosseini, A.; Djazayery, A. Therapeutic Effects of Vitamin D as Adjunctive Therapy to Fluoxetine in Patients with Major Depressive Disorder. Aust. N. Z. J. Psychiatry 2013,47, 271-275. [CrossRef] [PubMed]
114. Eid, A.; Khoja, S.; AlGhamdi, S.; Alsufiani, H.; Alzeben, F.; Alhejaili, N.; Tayeb, H.O.; Tarazi, F.I. Vitamin D Supplementation Ameliorates Severity of Generalized Anxiety Disorder (GAD). Metab. Brain Dis. 2019, 34,1781-1786. [CrossRef] [PubMed]
115. Valdivielso, J.M.; Fernandez, E. Vitamin D receptor polymorphisms and diseases. Clin. Chim. Acta 2006, 371,1-12. [CrossRef]
116. Lye, M.S.; Tor, Y.S.; Tey, Y.Y.; Shahabudin, A.; Loh, S.P.; Ibrahim, N.; Stanslas, J.; Rosli, R.; Ling, K.H. BsmI-ApaI-TaqI TAC (BAt) Haplotype of Vitamin D Receptor Gene Is Associated with Increased Risk of Major Depressive Disorder. J. Mol. Neurosci. 2020, 71, 981-990. [CrossRef]
117. Usategui-Martín, R.; De Luis-Román, D.A.; Fernández-Gómez, J.M.; Ruiz-Mambrilla, M.; Pérez-Castrillón, J.L. Vitamin D Receptor (VDR) Gene Polymorphisms Modify the Response to Vitamin D Supplementation: A Systematic Review and Meta-Analysis. Nutrients 2022,14, 360. [CrossRef]

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VitaminDWiki - Depression category contains

• Low vitamin D is associated with most types of depression, Including: Seasonal Affective Disorder. manic depression, bipolar disorder, dysthymia, Depression during/after pregnancy, Seniors, Suicide
• Depression substantially reduced by Vitamin D, Omega-3, Magnesium, etc – many studies
• Depression 1.6 X more likely if low Vitamin D, taking Vitamin D reduces depression – umbrella of meta-analyses – Jan 2023
• Depression: Low vitamin D in the strongest of 11 risk factors – Jan 2023
• Yet another study confirms Depression is treated by weekly Vitamin D (50,000 IU)– RCT Dec 2019
• Depression treated by Omega-3 (again) – meta-analysis Aug 2019
• Supplementing with Vitamin D (or getting more sun) decreases most types of depression as well as drugs
• Omega-3, Magnesium, and St. Johns' Wort also decrease depression
  • Speculate that some combination (Vit D, Omega-3, Mg, St John's) will decrease depression even more
  • Note: Both Omega-3 and Magnesium increase the amount of vitamin D which gets to tissues
• Antidepressants reduce cellular Vitamin D, increasing fractures, CVD, etc. - Oct 2022
• There are 269 items in the Depression category in VitaminDWiki

Some recent publications

• Depression in seniors greatly reduced by Vitamin D (50,000 IU weekly) – meta-analysis June 2023
• Depression reduced if take more than 5,000 IU of vitamin D daily – umbrella meta-analysis – Jan 2023
• Post-partum depression and low Vitamin D - many studies
• Depression: Low vitamin D in the strongest of 11 risk factors – Jan 2023

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14+ VitaminDWiki pages have ANXIETY in the title

This list is automatically updated