Introduction

This meta-analysis examined the effect of vitamin D supplementation on primary depression, with a particular focus on how baseline 25-hydroxyvitamin D [25(OH)D] levels influence treatment outcomes. The study aimed to clarify conflicting results from previous meta-analyses by conducting more precise subgroup analyses based on baseline vitamin D status.

Background and Rationale

Depression as a Global Health Challenge

Depression is one of the top ten causes of disability worldwide, with incident cases increasing from 172 million in 1990 to 258 million in 2017—a 49.86% increase. The high prevalence affects quality of life and places significant burden on social economies, making effective treatment strategies crucial.

Vitamin D and Depression Connection

Biological Mechanisms:

• Vitamin D receptors (VDR) are abundant in brain areas including cingulate cortex and hippocampus
• All major enzymes involved in 1,25(OH)₂D₃ production and metabolism are highly expressed in embryonic and adult brain
• Vitamin D may regulate neurotransmitter synthesis and brain development
• Potential link to pathophysiology of depression, schizophrenia, and Alzheimer’s disease

Observational Evidence:

• Serum 25(OH)D levels show inverse relationship with mental health and life stress
• Low serum 25(OH)D levels found in patients with depression
• Folate deficiency associated with depression, severe symptoms, and increased relapse risk

Methods

Search Strategy and Selection

Registration: PROSPERO (CRD42022291388) Guidelines: PRISMA Statement compliance

Databases Searched:

• PubMed
• Embase
• Cochrane Library
• Web of Science
• American clinical trial registries (for unpublished data)

Search Period: Database inception to July 2021 (updated to May 2022)

Inclusion Criteria

Population: Adults over 18 years old Condition: Depression diagnosed by recognized criteria or published depression measures, or volunteers without depression Intervention: Vitamin D supplementation at any dosage Comparator: Placebo Outcome: Quantitative change in depressive symptoms using standard scales/questionnaires Study Design: Randomized controlled trials

Exclusion Criteria

• Participants under 18 years old
• Pregnant women
• Vitamin D administered with other interventions (except calcium)
• Participants with diagnosed diseases other than depression
• Non-standard measurement scales
• Non-English publications
• Non-randomized studies

Results

Study Characteristics

Total Studies: 18 randomized controlled trials Total Participants: 23,686 Publication Period: 2006-2021 Geographic Distribution:

• Norway: 3 studies
• United States: 3 studies
• Australia: 3 studies
• Iran: 4 studies
• Denmark: 2 studies
• Other countries: 3 studies

Participant Demographics:

• Age range: 20-80 years
• Sample sizes: 33 to 18,353 participants
• Baseline 25(OH)D levels: 53% of subjects had levels <50 nmol/L
• Depression status: 9 studies included patients with depression, remainder were adults without depression

Intervention Details:

• Vitamin D doses: 800 IU daily to 500,000 IU annually
• Duration: 6 weeks to 15 months
• Assessment scales: BDI, SF-12, SIGH-SAD, MADRS, HAM-D 17, and others

Primary Meta-Analysis Results

Overall Effect:

• SMD = -0.15 (95% CI: -0.26 to -0.04, p < 0.05)
• I² = 78% (substantial heterogeneity)
• Interpretation: Small but statistically significant effect favoring vitamin D supplementation

Key Subgroup Analyses

Depression Status Analysis

Subjects WITH Depression:

• SMD = -0.53 (95% CI: -1.03 to -0.04, p < 0.05)
• I² = 88%
• Interpretation: Moderate to large effect in patients with depression

Subjects WITHOUT Depression:

• SMD = 0.00 (95% CI: -0.06 to 0.06, p > 0.05)
• I² = 0%
• Interpretation: No effect in healthy individuals (floor effect)

Baseline 25(OH)D Level Analysis

25(OH)D Levels >50 nmol/L (Sufficient):

• SMD = -0.38 (95% CI: -0.68 to -0.08, p < 0.05)
• I² = 86%
• Interpretation: Significant improvement in those with sufficient baseline levels

25(OH)D Levels ≤50 nmol/L (Deficient):

• SMD = -0.22 (95% CI: -0.54 to 0.11, p > 0.05)
• I² = 77%
• Interpretation: No significant improvement in vitamin D deficient individuals

Combined Analysis: Depression Status + Baseline Levels

Depression Patients with 25(OH)D >50 nmol/L:

• SMD = -0.92 (95% CI: -1.58 to -0.25, p < 0.05)
• I² = 78%
• Interpretation: Large effect size in depressed patients with sufficient baseline vitamin D

Depression Patients with 25(OH)D ≤50 nmol/L:

• No significant effect observed
• Interpretation: Vitamin D supplementation ineffective in deficient patients

Additional Subgroup Analyses

Age-Related Effects

Ages 18-60 years:

• SMD = -0.19 (95% CI: -0.36 to -0.02, p < 0.05)
• I² = 61%

Ages >60 years:

• SMD = -0.11 (95% CI: -0.27 to 0.06, p > 0.05)
• I² = 92%

Supplementation Frequency

Weekly Supplementation:

• SMD = -0.34 (95% CI: -0.58 to -0.10, p < 0.05)
• I² = 90%
• Note: Results showed high heterogeneity, requiring cautious interpretation

Daily Supplementation:

• SMD = 0.02 (95% CI: -0.01 to 0.04, p > 0.05)
• I² = 0%

Less Frequent Supplementation:

• SMD = -0.03 (95% CI: -0.15 to 0.09, p > 0.05)
• I² = 11%

Geographic Analysis

South-west Asia:

• SMD = -0.94 (95% CI: -1.43 to -0.45, p < 0.05)
• I² = 73%
• Interpretation: Most significant improvement, though with increased heterogeneity

Risk of Bias Assessment

Overall Quality:

• 45% of studies (n=8) had unclear overall risk of bias
• Main concerns: inadequate allocation concealment and blinding
• Funding sources and conflicts of interest not always provided
• Risk levels often unknown due to insufficient reporting

Key Findings and Clinical Implications

Paradoxical Baseline Vitamin D Effect

Unexpected Finding: Vitamin D supplementation was effective only in patients with baseline 25(OH)D levels >50 nmol/L, not in those with deficiency (≤50 nmol/L).

Possible Explanations:

1. Threshold Effect: Relatively high 25(OH)D levels may be required for alleviating depression
2. Metabolic Capacity: Subjects with higher baseline levels may be better able to reach therapeutic CNS concentrations
3. Underlying Health Status: Higher baseline levels may indicate better overall health status

Comparison with D-Health Trial

The D-Health trial (January 2023) showed opposite results:

• Reduced antidepressant use in participants with predicted 25(OH)D <50 nmol/L
• Increased antidepressant use in participants with predicted 25(OH)D ≥50 nmol/L

Differences Explaining Discrepancy:

• D-Health: <24.2% had 25(OH)D <50 nmol/L
• Present meta-analysis: 53.1% had 25(OH)D <50 nmol/L
• Different baseline prevalence of vitamin D deficiency may affect outcomes

Clinical Recommendations

Target Population:

• Patients with primary depression
• Baseline 25(OH)D levels >50 nmol/L
• Ages 18-60 years

Treatment Approach:

• Weekly supplementation may be more effective than daily
• Monitor baseline 25(OH)D levels before treatment
• Consider geographic and demographic factors

Limitations

Study-Level Limitations

Heterogeneity Issues:

• Small sample sizes (66% had <100 participants)
• Varied study designs and depression scales
• Different vitamin D doses and durations
• Assay standardization challenges across countries and time periods

Methodological Concerns:

• Studies conducted at different times and locations
• Serum 25(OH)D assay variations difficult to standardize
• Not all heterogeneity could be reduced through subgroup analysis

Confounding Factors:

• Skin color, sun exposure, seasonality, dietary patterns not always adjusted
• Potential confounding factors affecting vitamin D levels and efficacy

Meta-Analysis Limitations

Exclusions:

• D-Health trial excluded due to different methodology (no baseline questionnaires, ongoing antidepressant use)
• Some trials lacked baseline 25(OH)D data, limiting subgroup analysis

Sample Size:

• Relatively small overall sample for some subgroups
• Need for larger, well-designed RCTs to confirm findings

Future Research Directions

Priority Areas

Mechanistic Studies:

• Investigate optimal 25(OH)D levels for depression treatment
• Explore why higher baseline levels predict better response
• Study individual variation in vitamin D receptor sensitivity

Clinical Trials:

• Larger sample sizes with adequate power
• Standardized 25(OH)D assays across sites
• Longer follow-up periods
• Focus on patients with sufficient baseline vitamin D levels

Population Studies:

• Investigate effectiveness across different ethnic groups
• Study impact of geographic location and sun exposure
• Examine dose-response relationships in sufficient vs. deficient populations

Conclusion

This meta-analysis provides important insights into vitamin D supplementation for primary depression, revealing a paradoxical finding that challenges conventional assumptions about vitamin D deficiency and depression treatment.

Key Clinical Takeaways:

Efficacy Findings:

• Small overall effect (SMD = -0.15) in general population
• Moderate to large effect (SMD = -0.53) in patients with depression
• No effect in healthy individuals without depression

Baseline Vitamin D Paradox:

• Supplementation effective only in patients with baseline 25(OH)D >50 nmol/L
• No benefit in vitamin D deficient patients (≤50 nmol/L)
• Largest effect (SMD = -0.92) in depressed patients with sufficient baseline levels

Clinical Implications:

• Measure baseline 25(OH)D levels before treatment
• Consider vitamin D supplementation primarily for depressed patients with sufficient baseline levels
• Weekly supplementation may be more effective than daily dosing
• Results may not generalize to populations with low vitamin D deficiency prevalence

Research Needs: The unexpected finding that vitamin D supplementation works best in those with adequate baseline levels requires further investigation. Future studies should focus on understanding the mechanisms behind this paradox and determining optimal treatment strategies based on individual vitamin D status.

This research suggests that the relationship between vitamin D and depression is more complex than previously understood, emphasizing the need for personalized approaches based on baseline vitamin D status rather than universal supplementation strategies.