This study was conducted in accordance with the PRISMA 2020 guidelines [10]. A research protocol was established prior to data collection. This systematic review protocol was not prospectively registered in PROSPERO (International Prospective Register of Systematic Reviews) or other public registry. The review was initiated as a time-sensitive project aimed at providing updated evidence on a rapidly evolving clinical question, and the additional time required for PROSPERO registration and approval would have delayed the project substantially. At the time of project initiation, protocol registration was encouraged but not universally required by all journals in the field. A detailed internal protocol was developed before data extraction and followed throughout the review process, and no substantial deviations from the planned methods occurred. Nevertheless, the absence of public protocol registration represents a limitation because it reduces transparency regarding potential protocol deviations. Future systematic reviews should prioritize prospective protocol registration in PROSPERO or similar registries to enhance transparency and reduce the risk of selective reporting or post-hoc methodological changes.

A comprehensive literature search was conducted in PubMed/MEDLINE, Web of Science, PsycINFO, and CINAHL databases to identify relevant studies published between January 1, 2020, and November 30, 2025. Search terms were developed using the Population, Intervention, Comparison, and Outcome (PICO) framework and included Medical Subject Headings (MeSH) and free-text keywords. The search strategy incorporated terms related to the population (“adult women,” “female”), intervention (“vitamin D,” “cholecalciferol,” “ergocalciferol,” “vitamin D supplementation”), outcome (“depression,” “depressive symptoms,” “major depressive disorder”), and study design (“randomized controlled trial,” “RCT,” “clinical trial”).

The selected databases provided broad coverage of medical, psychological, and nursing literature relevant to the research question. The Cochrane Central Register of Controlled Trials (CENTRAL) was not searched because preliminary scoping indicated substantial overlap with the selected databases, particularly for recent vitamin D and depression trials, and resource constraints required prioritization. No formal hand searching or gray literature searches were conducted to focus on peer-reviewed, indexed studies. These decisions may have resulted in missed studies and are acknowledged as limitations. Search syntax was tailored to each database, and filters were applied to include RCTs within the specified timeframe. Title and abstract screening was performed independently by two reviewers, followed by full-text assessment for eligibility. Disagreements were resolved by consensus. Duplicate and irrelevant articles were removed. The study selection process was summarized using a PRISMA flow diagram (Figure 1).

Studies were included if they met the following PICOS criteria: (1) Population: women aged ≥ 18 years; (2) Intervention: vitamin D supplementation (cholecalciferol or ergocalciferol) as the primary intervention; (3) Comparison: placebo or no-treatment control group; (4) Outcome: depressive symptoms assessed using validated instruments, such as Beck Depression Inventory (BDI), Patient Health Questionnaire (PHQ), Hamilton Depression Rating Scale (HDRS), or Center for Epidemiologic Studies Depression Scale (CES-D); and (5) Study design: RCTs published in English or Korean. Studies were excluded if they: (1) were review articles, meta-analyses, or systematic reviews; (2) were non-RCTs or observational studies; (3) included only male participants or pediatric populations; (4) involved multi-nutrient interventions without vitamin D as the primary intervention; (5) failed to report depression-related outcomes; or (6) were unpublished or non-peer-reviewed materials (e.g., conference abstracts or study protocols).

Two reviewers independently extracted data using a standardized form. Extracted information included: (1) study characteristics (first author, publication year, country); (2) study design and sample size; (3) participant demographics (age, baseline health status, baseline vitamin D levels, baseline depression severity); (4) intervention characteristics (vitamin D form, dosage, frequency, duration); (5) comparator type (placebo or no-treatment); (6) outcome measurement tools and time points; (7) depression outcomes (baseline and post-intervention scores, mean differences, standard deviations, effect sizes); (8) adverse events; (9) attrition rates; (10) trial registration; and (11) funding sources. When data were missing or unclear, authors were contacted for clarification.

The methodological quality of included studies was assessed using the Cochrane risk of bias 2.0 (RoB 2.0) tool [11], which evaluates five domains: (1) randomization process; (2) deviations from intended interventions; (3) missing outcome data; (4) measurement of the outcome; and (5) selection of the reported result. Each domain was evaluated as “low risk,” “some concerns,” or “high risk” of bias. Two reviewers independently performed the assessment, and disagreements were resolved through reviewer consensus. Overall risk of bias for each study was determined based on the highest risk level across all domains. Publication bias was examined when at least ten studies were available using funnel plot visualization and Egger’s regression test to detect asymmetry. However, due to the limited number of included studies, formal publication bias assessment could not be performed

Data analysis was planned using Review Manager (RevMan), version 5.4 (The Cochrane Collaboration, London, UK). For continuous outcomes, standardized mean differences with 95% confidence intervals (CIs) were calculated. Statistical heterogeneity was assessed using Cochran’s Q test and Higgins’ I² statistic, with I² values of 25%, 50%, and 75% indicating low, moderate, and high heterogeneity, respectively. A fixed-effects model was used for I² < 50%, and a random-effects model for I² ≥ 50%. Subgroup analyses were performed to explore potential sources of heterogeneity, including: (1) baseline vitamin D status (deficient [< 20 ng/mL] vs. sufficient [≥ 30 ng/mL]); (2) supplementation dosage (< 4,000 vs. ≥ 4,000 IU/day); (3) intervention duration (< 12 vs. ≥ 12 weeks); (4) age group (reproductive age vs. postmenopausal); and (5) baseline depression severity (mild vs. moderate to severe). Sensitivity analyses were conducted by removing studies with high risk of bias to assess the robustness of findings. However, due to substantial clinical and methodological heterogeneity among the included studies (variation in participant characteristics, supplementation regimens, and outcome measures), quantitative meta-analysis was not performed. Instead, a qualitative narrative synthesis was conducted, summarizing study characteristics, intervention effects, and factors influencing outcomes.

This study involved analysis of previously published, publicly available data and did not include direct interaction with human participants. Therefore, this study was exempt from formal Institutional Review Board (IRB) review. All included studies reported appropriate ethics approval and informed consent from participants in their original publications. No additional ethical concerns were identified during the conduct of this systematic review.

The database search identified 239 records from PubMed/MEDLINE (n = 20), Web of Science (n = 100), PsycINFO (n = 50), and CINAHL (n = 69). No additional records were identified from other sources. After removing 140 duplicates, 99 unique records remained for title and abstract screening. Of these, 85 records were excluded as they were not RCTs (n = 32), did not include adult women (n = 18), did not assess depression outcome (n = 21), were review or meta-analysis (n = 8), or for other reasons, including conference abstracts and study protocols (n = 6), leaving 14 articles for full-text eligibility assessment. Following full-text review, 10 articles were further excluded as they involved multi-nutrient interventions (n = 3), lacked a placebo control (n = 2), were duplicate publications (n = 2), provided insufficient data (n = 2), or used inappropriate outcome measures (n = 1). Ultimately, four RCTs met all inclusion criteria and were included in the qualitative synthesis [6,7,9,12]. The study selection process is shown in the PRISMA flow diagram (Figure 1, Appendix 1).

Depressive symptoms were measured using validated standardized instruments, including the Beck Depression Inventory-II (BDI-II), Patient Health Questionnaire-9 (PHQ-9), Patient Health Questionnaire-8 (PHQ-8), and Center for Epidemiologic Studies Depression Scale (CES-D). Depression symptom severity was assessed at baseline and post-intervention, with some studies also reporting interim assessments. All four trials reported post-intervention vitamin D levels (Table 1).

The effects of vitamin D supplementation on depressive symptoms varied substantially across studies, influenced by baseline vitamin D status, supplementation dosage and duration, and baseline depression severity.

Substantial heterogeneity across studies precluded quantitative meta-analysis. Factors associated with treatment effects included.

Using the Cochrane RoB 2.0 tool, three studies [6,7,9] were rated as having low risk of bias across all domains. One study [12] raised some concerns, primarily related to deviations from intended interventions (open-label design without placebo control) and missing outcome data. No study was judged to have high risk of bias. Overall, the included studies demonstrated good methodological quality. Detailed risk of bias assessments are presented in Table 2. A funnel plot could not be produced due to the limited number of included studies; however, the presence of a large neutral trial [9] reduces concern for publication bias.

The observed findings are biologically plausible given the established role of vitamin D in central nervous system function. VDRs and vitamin D-activating enzyme 1α-hydroxylase are expressed in brain regions involved in mood regulation, including the hippocampus, prefrontal cortex, and hypothalamus [2]. Vitamin D influences neurotransmitter synthesis, particularly serotonin, through regulation of tryptophan hydroxylase, the rate-limiting enzyme in serotonin production [2]. Additionally, vitamin D is associated with increased BDNF levels, which supports neuroplasticity, neuronal survival, and synaptic function [3]. Furthermore, vitamin D exerts anti-inflammatory effects by reducing pro-inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-α, which have been implicated in depression pathophysiology. The consistency between these mechanistic pathways and the clinical improvements observed in deficient populations supports a causal role for vitamin D in mood regulation.

Baseline vitamin D status emerged as a key determinant of treatment response. Three trials enrolling participants with vitamin D deficiency (< 20 ng/mL) or insufficiency (20~30 ng/mL) [6,7,12] consistently demonstrated improvements in depressive symptoms, whereas the study without baseline restriction [9] showed no effect. This pattern suggests that vitamin D supplementation is most effective as a corrective intervention for deficiency rather than as a universal preventive strategy. These findings align with the threshold hypothesis, which proposes that vitamin D-related neurobiological effects are optimized once serum levels reach sufficiency, with limited benefit beyond this threshold [13]. Identifying individuals with low baseline vitamin D levels may therefore be critical for maximizing clinical benefit and avoiding unnecessary supplementation.

Difference in dosing and duration of vitamin D supplementation for depression further explain the variability in outcomes across studies. High-dose regimens (25,000~50,000 IU weekly for 6~12 months) in women with vitamin D deficiency and comorbid conditions [6,7,12] were associated with therapeutic effects, with two trials demonstrating significant between-group differences [6,7]. In contrast, long-term, low-dose supplementation (2,000 IU daily) in the general population maintained vitamin D sufficiency but did not prevent depression onset or reduce symptom severity in individuals without baseline deficiency [9]. One trial comparing high-dose versus low-dose vitamin D found overall symptom improvement in both groups without significant between-group differences, suggesting that even lower doses (5,000 IU weekly) may be effective when baseline deficiency is corrected [12]. This distinction suggests that correction of vitamin D deficiency may be required to achieve therapeutic effects, whereas maintenance dosing alone may be insufficient to influence mood in individuals with adequate baseline status. However, the optimal dose and duration remain unclear and may vary depending on baseline vitamin D status, comorbid conditions, and individual patient characteristics. Future research should further evaluate dose-response relationships to refine optimal supplementation strategies.

The findings indicate that vitamin D supplementation may have therapeutic value for women with existing depressive symptoms and concurrent vitamin D deficiency but limited preventive benefit for the general population. The VITAL-DEP study [9], which enrolled participants without baseline depression diagnosis, found no reduction in depression incidence despite prolonged supplementation. In contrast, trials targeting individuals with baseline depressive symptoms reported improvements [6,7,12], suggesting that vitamin D may ameliorate existing symptoms but not prevent new-onset depression in individuals with adequate baseline vitamin D status. This distinction has important clinical implications, suggesting that vitamin D supplementation may be better positioned as an adjunctive treatment rather than a population-wide preventive intervention. Screening for vitamin D deficiency may therefore be most relevant in women presenting with depressive symptoms.

Focusing on women is clinically relevant given sex-specific differences in depression risk and vitamin D metabolism. Hormonal fluctuations across the reproductive lifespan—including pregnancy, postpartum period, and menopause—influence both vitamin D metabolism and mood regulation. Pregnancy and lactation increase vitamin D requirements, and postpartum depression affects up to 15% of women [14]. Women are also more likely to experience vitamin D deficiency because of factors such as reduced sun exposure (e.g., cultural practices, indoor occupations), higher adiposity, and dietary restrictions. The included studies enrolled women with specific characteristics: older women with prediabetes [6], adults with type 2 diabetes [7,12], and a general population including middle-aged and older adults [9]. However, none of the included trials specifically examined vitamin D supplementation effects across different reproductive stages (pregnancy, postpartum, perimenopause, postmenopause). This highlights a substantial gap in the literature and underscores the need for women-specific trials across different life stages to inform tailored clinical recommendations.

The findings of this review support several clinically relevant considerations for managing depression in adult women. Screening for vitamin D deficiency should be considered in women presenting with depressive symptoms, particularly those with risk factors such as chronic diseases (including type 2 diabetes and prediabetes), obesity, limited sun exposure, or dietary restrictions. Measurement of serum 25(OH)D levels can help identify women who may benefit from targeted supplementation.

For women with vitamin D deficiency (< 20 ng/mL) or insufficiency (20~30 ng/mL) and comorbid conditions such as diabetes or prediabetes, an individualized supplementation strategy is warranted. High-dose regimens (e.g., 25,000~50,000 IU weekly for 6~12 months) may be considered based on the evidence from included trials [6,7,12], followed by monitoring to achieve and maintain serum levels of at least 30 ng/mL. The evidence suggests that correction of vitamin D deficiency is important for symptom improvement, although the optimal dose may vary [12].

Vitamin D supplementation should be used as an adjunct to standard depression treatments rather than as a replacement. It may complement established interventions, including antidepressant medications and psychotherapy, particularly in women with documented vitamin D deficiency and comorbid metabolic conditions. Patients should be informed that vitamin D supplementation alone is not a treatment for depression and should not delay initiation of conventional therapies.

Current evidence does not support routine high-dose vitamin D supplementation for depression prevention in women without deficiency or baseline depressive symptoms. For the general population, maintaining adequate vitamin D status through a balanced diet, appropriate sun exposure, and standard daily supplementation (600~800 IU) is a reasonable approach and avoids unnecessary exposure to high doses.

Safety monitoring is recommended when high-dose vitamin D supplementation is prescribed. Serum calcium levels and renal function should be monitored during high-dose therapy to detect adverse effects. Long-term vitamin D intake exceeding 10,000 IU per day should be avoided to minimize toxicity risk, and patients should be advised against unsupervised dose escalation.

Several limitations should be considered when interpreting the findings of this review. Substantial heterogeneity across the included studies limited direct comparability and precluded quantitative meta-analysis. Differences in participant characteristics, including age ranges, baseline health status, and comorbidities, as well as supplementation regimens (dosage, frequency, and duration) and depression assessment tools, reduced the precision of effect estimates and generalizability of findings.

The small number of eligible studies (n = 4) represents a significant limitation. Three of the four included studies enrolled participants with specific comorbid conditions (type 2 diabetes or prediabetes) [6,7,12], which may limit generalizability to healthy women or those with other health conditions. The VITAL-DEP trial included both men and women (49% women) [9], and sex-specific analyses were not reported. The small number of eligible studies prevented formal assessment of publication bias using funnel plots or Egger’s regression. Although the inclusion of a large neutral trial [9] reduces concern for selective publication, the possibility that smaller null studies remain unpublished cannot be excluded.

Most included trials were relatively short in duration, with follow-up ranging from 6 months to 12 months [6,7,12], except for one large long-term study with median follow-up of 5.3 years [9]. Consequently, the persistence of beneficial effects following discontinuation of supplementation remains unclear, as does the optimal duration of maintenance therapy for women who initially respond to treatment. Questions about whether vitamin D supplementation provides lasting benefits or requires continuous administration to maintain symptom improvement cannot be adequately addressed with the current evidence base.

Mechanistic data were limited, as most trials focused on clinical outcomes such as depression symptom scores without consistently measuring biological markers such as BDNF, inflammatory cytokines, neurotransmitter activity, or neuroimaging correlates. This constrains understanding of the pathways through which vitamin D supplementation may influence depressive symptoms.

Our search strategy, while comprehensive, did not include all possible databases. Embase and the Cochrane Central Register of Controlled Trials were not searched, and no formal hand searching or gray literature review was conducted. These decisions may have resulted in missed studies, particularly those published in regional or non-indexed sources. Restricting the search to studies published between 2020 and 2025 may have excluded earlier relevant trials. However, this approach prioritized contemporary methodologies and populations and built upon prior reviews that synthesized pre-2020 evidence. Finally, the absence of prospective PROSPERO registration represents a limitation in transparency. Although a detailed internal protocol was established and followed without substantial deviation, public registration would have allowed independent verification of prespecified methods.

Future research should prioritize large, adequately powered RCTs designed specifically for women. Stratification by baseline vitamin D status (deficient, insufficient, and sufficient) and depression severity (mild, moderate, and severe) would allow identification of subgroups most likely to benefit from supplementation. Dose-response studies directly comparing supplementation regimens are needed to establish optimal dosing strategies. Head-to-head comparisons of daily versus intermittent dosing and varying dose levels should assess efficacy, safety, and adherence. Additionally, trials should include diverse populations, including healthy women without comorbid conditions, to enhance generalizability.

Life-course-focused research is warranted to examine vitamin D supplementation effects across reproductive stages, including pregnancy, postpartum period, perimenopause, and postmenopause, given stage-specific physiological and hormonal influences. Mechanistic studies incorporating biological markers, such as BDNF, inflammatory markers (e.g., interleukin-6, tumor necrosis factor-alpha, and C-reactive protein), neurotransmitter levels (e.g., serotonin and dopamine metabolites), and neuroimaging techniques would help clarify pathways through which vitamin D exerts its effects on mental health.

Standardization of depression assessment methodologies across studies would enhance the comparability and interpretability of findings. Future research should employ consistent, validated depression measurement tools and establish standardized time points for outcome assessment (e.g., baseline, 4 weeks, 8 weeks, 12 weeks, and 6 months). Additionally, studies should report both categorical outcomes (e.g., response and remission rates) and continuous measures (symptom severity scores) to provide a comprehensive picture of treatment effects [15,16]. Harmonization of outcome measures would facilitate future meta-analyses and enable more robust evidence synthesis.

Long-term follow-up studies are needed to evaluate the persistence of beneficial effects following discontinuation of supplementation, optimal duration of maintenance therapy, and long-term safety of various supplementation regimens. These studies should extend beyond the typical 6-month to 12-month timeframes to assess whether vitamin D supplementation provides lasting benefits or requires continuous administration. Additionally, long-term safety monitoring should include assessment of potential adverse effects, such as hypercalcemia, kidney stones, and cardiovascular events, particularly with higher supplementation doses.