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Vitamin D Carries Minimal Association with Treatment-Resistant or Atypical Depression

Vitamin D showed weak association with treatment-resistant depression (TRD) and atypical depression (AD), researchers found in a study published in Translational Psychiatry.

Researchers utilized phenotype and genotype data from the UK Biobank prospective cohort study. They conducted a follow-up with 157,366 individuals of the cohort. Those individuals completed the online Mental Health Questionnaire (MHQ).

The researchers included sex, age, smoking status, the Townsend deprivation index (TDI), body mass index (BMI), ethnicity (white/nonwhite), alcohol consumption frequency, and season of blood draw as covariates in their analyses.

They utilized logistic regression to determine whether vitamin D and subtypes of depression were linked and completed case analysis in observational analysis of each depression subtype, excluding individuals with missing data. Logistic regression enabled polygenic risk score analysis (PRS). Control individuals included in the study did not satisfy criteria for TRD (at least 2 diagnostic codes for unipolar depressive disorder and at least 2 switches between antidepressant drugs that had been prescribed for at least 6 weeks). Those control individuals included patients with major depressive disorder (MDD).

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In observational analysis, higher vitamin D levels were associated with a slight decrease in risk of AD compared with individuals who likely had MDD (AOR 0.93). Vitamin D slightly decreased risk of AD in the base model after adjustment for covariates (AOR 0.92). Observational analysis did not show this connection for serum vitamin D and risk of TRD compared with patients with probable MDD.

Vitamin D PRS was not linked with prevalent TRD (n=1891 OR 1.01) or AD (n=2101 OR 1.04), according to PRS genetic analysis and 2-sample Mendelian randomization analysis (MR).

The study listed various limitations including that estimates of statistical power in the MR may be inflated due to overfitting and winner’s curse since the variance explained by the vitamin D SNPs was calculated from the same population used for the discovery analysis (GWAS) and may therefore be higher than if calculated in an external sample.

“Our comprehensive investigations indicated some evidence of an association between vitamin D and TRD/AD observationally, but little evidence of association when using PRS and MR, mirroring findings of genetic studies of vitamin D on broad depression phenotypes,” the researchers said.

“Results do not support further clinical trials of vitamin D in these MDD subtypes but do not rule out that small effects may exist that require larger samples to detect.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Arathimos R, Ronaldson A, Howe LJ, et al. Vitamin D and the risk of treatment-resistant and atypical depression: a Mendelian randomization. Transl Psychiatry. Published online November 4, 2021. doi:10.1038/s41398-021-01674-3

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Source: Psychiatry Advisor