The relationship between vitamin D status and mood disorders has emerged as a subject of considerable interest within the psychiatric and nutritional sciences, prompting extensive investigation into both the observational links and interventional potential of this fat-soluble vitamin. Depression and anxiety constitute mood disorders that substantially affect health status, quality of life, and the global burden of disease, with the World Health Organization estimating that approximately 280 million individuals worldwide experience depression (Akpinar & Gezmen Karadag, 2022). One of the putative mechanisms implicated in the pathophysiology of these mood disorders involves oxidative stress and inflammation, thereupon directing attention toward antioxidant and immunomodulatory nutrients such as vitamin D. There are notable points of intersection between the brain regions involved in the pathophysiology of depression and anxiety and those regions where vitamin D metabolism occurs, including the limbic system, cortex, and cerebellum (Akpinar & Gezmen Karadag, 2022).

Vitamin D is a secosteroid hormone that can traverse the blood-brain barrier, with receptors located throughout various brain regions associated in mood regulation (Khan et al., 2022). Approximately one-fifth of vitamin D is obtained through dietary intake, while the remaining 80% is synthesized from 7-dehydrocholesterol in the skin upon exposure to ultraviolet radiation (Akpinar & Gezmen Karadag, 2022). The active form of the vitamin, 1,25-dihydroxyvitamin D (calcitriol), binds to vitamin D receptors located on cell membranes throughout the central nervous system to mediate gene transcription and non-genomic reactions that influence neurotransmitter synthesis, neurotrophin release, and neuroplasticity. These biological substrates provide a plausible mechanistic framework for the hypothesis that vitamin D status may influence mood regulation and psychiatric symptomatology.

Despite this biological plausibility, the clinical significance of the vitamin D-mood relationship remains a subject of ongoing debate. This narrative review examines the current evidence regarding the observational correlation between vitamin D and mood disorders, evaluates the efficacy of supplementation interventions, and delineates the circumscribed yet pragmatic role of vitamin D assessment and correction within contemporary psychiatric practice. The synthesis presented herein draws upon systematic reviews, meta-analyses, and randomized controlled trials to provide clinicians with an empirically supported framework for integrating vitamin D considerations into comprehensive psychiatric care.

Neurobiological Mechanisms

Several neurobiological pathways have been proposed to explain the potential influence of vitamin D on mood regulation, providing mechanistic context for interpreting the observational and interventional literature. These mechanisms encompass serotonergic neurotransmission, neuroinflammatory processes, and neuroplasticity mediated by neurotrophic factors. Understanding these pathways may help elucidate why clinical trial results have been variable and may inform the identification of patient subgroups most likely to benefit from supplementation.

The Serotonergic Pathway

A compelling mechanistic model involves the differential regulation of serotonin synthesis by vitamin D in central versus peripheral tissues. Vitamin D influences the expression of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis, through distinct isoforms in different anatomical compartments (Huiberts & Smolders, 2021). In the brain, sufficient serum 25(OH)D levels promote expression of tryptophan hydroxylase 2 (TPH2), thereby facilitating serotonin production within the central nervous system. Conversely, in peripheral tissues outside the blood-brain barrier, adequate vitamin D status inhibits tryptophan hydroxylase 1 (TPH1), reducing peripheral serotonin synthesis (Huiberts & Smolders, 2021). This differential regulation has important implications: sufficient central serotonin availability supports mood regulation, cognitive function, and impulse control, while reduced peripheral serotonin may facilitate appropriate melatonin synthesis in the pineal gland during evening hours.

Notably, serum 25(OH)D and its active metabolite 1,25(OH)2D exhibit circadian variation, with higher levels during midday and lower levels in the evening and night (Huiberts & Smolders, 2021). This diurnal pattern may be functionally significant: relatively higher daytime vitamin D levels could promote central serotonin synthesis via TPH2 activation, while the evening decline permits TPH1 expression in the pineal gland, enabling conversion of serotonin to melatonin to facilitate sleep. Disruption of this circadian pattern through ill-timed supplementation or chronically low vitamin D status could theoretically impair both mood regulation and sleep quality. This temporal dimension of vitamin D physiology may partly explain the inconsistent outcomes observed in clinical trials, where timing of supplementation is rarely standardized or reported.

Neuroinflammatory Mechanisms

Vitamin D exerts anti-inflammatory effects through multiple cellular and molecular pathways with relevance to neuropsychiatric conditions. Vitamin D deficiency is associated with elevated inflammatory markers, including C-reactive protein and interleukin-6, both of which have been implicated in the pathophysiology of depression (Raza et al., 2025). At the cellular level, vitamin D modulates the TLR4-MyD88-NF-kB signaling pathway, a central mediator of innate immune responses and neuroinflammation. Additionally, vitamin D influences microglial polarization, promoting the M2 phenotype associated with anti-inflammatory and neuroprotective functions rather than the pro-inflammatory M1 phenotype (Raza et al., 2025). These immunomodulatory actions may be particularly relevant for patients with comorbid inflammatory conditions, potentially explaining why some studies have observed mood benefits in populations with diabetes, autoimmune disorders, or other inflammatory states.

Neuroplasticity and Neurotrophic Factors

Vitamin D contributes to neuroplasticity through regulation of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF). Vitamin D influences long-term potentiation (LTP), a cellular mechanism fundamental to learning and memory, by regulating calcium signaling and BDNF expression (Raza et al., 2025). BDNF is essential for neuronal survival, growth, and differentiation, and dysregulation of BDNF signaling has been consistently implicated in the pathophysiology of depression. Furthermore, vitamin D affects perineuronal nets, specialized extracellular matrix structures surrounding certain neurons; deficiency-induced dysregulation of these structures may contribute to cognitive deficits observed in some individuals with mood disorders (Raza et al., 2025). Collectively, these neuroplasticity-related mechanisms provide additional biological rationale for the hypothesis that adequate vitamin D status may support optimal brain function and mood regulation, while deficiency may compromise neural adaptation and resilience.

Observational Evidence Regarding Vitamin D and Major Depressive Disorder

While these neurobiological pathways offer a compelling theoretical framework for the vitamin D-mood relationship, their clinical relevance depends upon whether the proposed mechanisms translate into observable patterns in human populations. The following sections evaluate the epidemiological associations and interventional evidence to assess the degree to which theoretical rationale is supported by empirical outcomes.

Prevalence and Epidemiological Associations

Across the psychiatric and nutrition literature, lower circulating 25-hydroxyvitamin D (25[OH]D) concentrations are frequently associated with greater depressive symptom burden, and this association is commonly reported in observational datasets spanning diverse populations and geographic regions. A cross-sectional study of adults in Peshawar, Pakistan found a higher frequency of vitamin D deficiency among individuals endorsing depressive symptoms, with the investigators concluding that depression was common among those with vitamin D deficiency (Khan et al., 2022). In this study, vitamin D levels were within normal range among healthy subjects while below normal ranges were observed in depressed subjects, with 50% of depressed participants demonstrating severe depression on the Beck Depression Inventory and exhibiting concomitant vitamin D deficiency.

Prospective data from large population cohorts have similarly demonstrated associations between vitamin D deficiency and subsequent depression risk. The VITAL-DEP trial investigators noted that observational data have shown associations between low levels of serum 25-hydroxyvitamin D and higher late-life depression risk (Okereke et al., 2020). Research has documented that patients with severe vitamin D deficiency who were over 70 years of age were more likely to present with mood disorders, and longitudinal studies have demonstrated that vitamin D deficiency may constitute a risk factor for depressive disorder in population-based cohorts (Khan et al., 2022).

Interpretive Constraints — Confounding and Reverse Causality

The central interpretive constraint confronting the observational literature is that associations are highly susceptible to confounding and reverse causality, particularly because depression can reduce outdoor activity, impair nutritional intake, increase systemic inflammation, and co-occur with medical illnesses that themselves correlate with low vitamin D status. Review-level syntheses of the field therefore characterize the vitamin D-mood relationship as biologically plausible but empirically inconsistent, especially when moving from correlation to causal inference. A narrative review focused on anxiety and depression concluded that findings across studies are contradictory, attributing this inconsistency to variable cutoffs for vitamin D sufficiency, differences in sampled populations and comorbidities, and variability in symptom measurement instruments (Akpinar & Gezmen Karadag, 2022).

A structured narrative review that integrated brain-derived neurotrophic factor (BDNF) with mood and cognition similarly indicated that vitamin D status is associated with mood and neurocognitive outcomes in some datasets, but it emphasized that stronger conclusions require adequately powered, longer-term studies with objective measures (Skoczek-Rubinska et al., 2025). Taken together, the most defensible interpretation is that a correlation is commonly observed, but it does not establish that low vitamin D is a primary etiologic driver of mood disorders, nor that supplementation will reliably improve mood across patient populations. There is no international consensus on the cutoff points of serum 25(OH)D for proficiency or deficiency, which further complicates cross-study comparisons and clinical interpretation (Akpinar & Gezmen Karadag, 2022).

Interventional Evidence Pertaining to Randomized Controlled Trials of Vitamin D Supplementation

Meta-Analytic Evidence on Depressive Symptoms

The interventional evidence indicates that vitamin D supplementation is not a consistently effective antidepressant intervention across broad populations, although subgroup benefit remains plausible, particularly among individuals who are vitamin D insufficient at baseline or who have co-occurring inflammatory or medical conditions. A comprehensive dose-response meta-analysis published in Psychological Medicine included 31 randomized controlled trials with 24,189 participants and found that each 1000 IU/day of vitamin D3 supplementation slightly reduced depressive symptoms in individuals with and without depression (SMD: -0.32, 95% CI -0.43 to -0.22; GRADE = moderate) (Ghaemi et al., 2024). The effect was more pronounced in those with depressive symptoms at baseline (SMD: -0.57, 95% CI -0.69 to -0.44; n = 15 studies).

Critically, this meta-analysis revealed a temporal pattern wherein effects diminished substantially with longer follow-up durations. Trials with follow-up of eight weeks or less demonstrated stronger effects (SMD: -0.45, 95% CI -0.70 to -0.20; n = 8) compared to those lasting 24 to 52 weeks (SMD: -0.13, 95% CI -0.28 to 0.02; n = 5) or longer than 52 weeks (SMD: 0.14, 95% CI -0.16 to 0.44; n = 3), with a statistically significant group difference (p < 0.001) (Ghaemi et al., 2024). These findings suggest that vitamin D3 supplementation may effectively reduce depressive symptoms in the short term, but the durability of this effect is questionable. The greatest reduction occurred at 8000 IU/day (SMD: -2.04, 95% CI -3.77 to -0.31), though such high doses warrant careful consideration of safety parameters.

Another systematic review and meta-analysis examining vitamin D supplements specifically for depressed patients reported an overall standardized mean difference of -0.49 (95% CI -0.75 to -0.23), indicating a moderate effect favoring supplementation in clinical populations (Srifuengfung et al., 2023). Forest plot analyses demonstrated variability across age groups, with adult populations showing the largest pooled effect (SMD: -0.70, 95% CI -1.09 to -0.31) while elderly populations demonstrated more modest effects (SMD: -0.41, 95% CI -1.18 to 0.35). Notably, vitamin D3 supplementation had no significant effects on anxiety symptoms across the analyzed trials (Ghaemi et al., 2024); however, one small randomized controlled trial (Eid et al., 2019; n = 30) did report improvements in GAD-7 scores with 50,000 IU weekly vitamin D supplementation in patients with generalized anxiety disorder and vitamin D deficiency, though this single study does not alter the overall meta-analytic conclusion.

The VITAL-DEP Trial and Definitive Long-Term Evidence

The largest and most methodologically rigorous trial addressing this question is the Vitamin D and Omega-3 Trial-Depression Endpoint Prevention (VITAL-DEP), an ancillary study to the VITAL trial that randomized 18,353 adults aged 50 years or older in the United States. Participants were randomized in a 2 x 2 factorial design to vitamin D3 (2000 IU/day of cholecalciferol) and fish oil or placebo, with a median treatment duration of 5.3 years and 90.5% trial completion rate (Okereke et al., 2020). The primary outcomes were the risk of depression or clinically relevant depressive symptoms and the mean difference in mood scores on the 8-item Patient Health Questionnaire depression scale (PHQ-8).

The results were uniformly null across all prespecified outcomes and subgroups. Risk of depression or clinically relevant depressive symptoms was not significantly different between the vitamin D3 group (609 events; 12.9/1000 person-years) and the placebo group (625 events; 13.3/1000 person-years), yielding a hazard ratio of 0.97 (95% CI 0.87 to 1.09; p = .62) (Okereke et al., 2020). Cumulative incidence curves showed lack of separation between treatment groups over the entire follow-up period. The mean difference for change between treatment groups in PHQ-8 scores was not significantly different from zero over the entire follow-up (0.01 points; 95% CI -0.04 to 0.05 points) or at any time point during follow-up.

Importantly, there were no significant differences in the effects of vitamin D3 on risk of depression or clinically relevant depressive symptoms among subgroups, including those with low baseline vitamin D levels, older age, history of depression, or elevated baseline depressive symptoms. Tests of interaction were not significant for any subgroup examined. These findings from a large, well-conducted, long-term trial provide compelling evidence that vitamin D3 supplementation does not prevent depression in the general adult population, even among those with putative risk factors for vitamin D-responsive mood symptoms.

Findings in Healthy Adult Populations

A systematic review specifically examining mental health outcomes in healthy adults similarly concluded that vitamin D supplementation did not confirm a consistent positive influence on mental health outcomes, with any supportive findings largely limited to depression outcomes in a subset of studies (Guzek et al., 2021). Among 14 included studies, seven were associated with low risk of bias, and of these high-quality studies, some reported protective effects of vitamin D while others found no beneficial effects. None of the high-quality studies that assessed outcomes other than depression (mental well-being, quality of life, anxiety, mood) supported positive effects of vitamin D supplementation.

This pattern suggests that, in generally healthy and often non-deficient samples, supplementation does not produce robust, generalizable mood improvement. The review further noted that supplementation may need to be combined with physical activity to provide effective results, and that supplementation appears less effective than vitamin D supply from food sources (Guzek et al., 2021). The included studies were conducted in diverse populations and followed various doses and intervals of administration, and the inconsistent observations align with general controversies associated with the therapeutic use of vitamin D supplementation across multiple health domains.

Clinical Utility of Vitamin D in Psychiatric Practice

Positioning Vitamin D Within Psychiatric Care

The most evidence-aligned conclusion is that vitamin D has limited application as a primary psychiatric intervention, but meaningful application as a medical comorbidity screen and correction strategy that can be integrated into comprehensive psychiatric practice. Multiple reviews emphasize inconsistency in psychiatric outcomes and the absence of vitamin D supplementation as a core intervention in mood disorder guidelines, while simultaneously recommending screening for deficiency and monitoring levels when supplementation is employed (Akpinar & Gezmen Karadag, 2022). From a psychiatric workflow perspective, this positions vitamin D similarly to other general medical contributors to symptom burden: correction is clinically appropriate when abnormal, yet correction does not equate to an antidepressant treatment model.

A systematic review spanning multiple mental and neurologic disorders reported an overall pattern consistent with therapeutic potential for vitamin D in certain conditions, while simultaneously noting that magnitude of benefit varied considerably by disorder (AlGhamdi, 2024). The findings strongly indicate that vitamin D supplementation may benefit a range of mental health and neurological disorders, but the specific magnitude of beneficial impact varies by condition. This heterogeneity supports a clinical approach wherein vitamin D assessment is incorporated into the medical evaluation of psychiatric patients, with supplementation recommended when deficiency is documented, rather than as an empirical mood intervention.

Safety Considerations and Monitoring

Supplementation should be operationalized with attention to safety parameters and realistic expectations regarding therapeutic outcomes. Some evidence suggests that vitamin D levels substantially above physiological norms may be associated with adverse effects, supporting the clinical rationale for monitoring when supplementing rather than empirically escalating dose (Akpinar & Gezmen Karadag, 2022). Definitions of adequate serum 25(OH)D levels vary by organization: the National Academy of Medicine considers levels of 20 ng/mL (50 nmol/L) or higher to be adequate for most individuals and identifies levels exceeding 50 ng/mL (125 nmol/L) as potentially concerning, while the Endocrine Society recommends levels of 30 ng/mL (75 nmol/L) or higher as adequate (Michos et al., 2021; Cesareo et al., 2018). Vitamin D intoxication, though rare in clinical practice, has been reported at serum levels exceeding 150 ng/mL and may produce hypercalcemia and associated complications.

Clinicians should distinguish among dosing categories when counseling patients. Physiologic replacement dosing, typically 800 to 2000 IU daily, is appropriate for maintenance of adequate levels in most adults. Short-term repletion protocols using higher doses (e.g., 50,000 IU weekly for 8 to 12 weeks) may be employed under medical supervision when documented deficiency requires more rapid correction. Supraphysiologic dosing, such as the 8000 IU/day associated with the largest effect size in some meta-analyses, should be considered experimental and reserved for research contexts with appropriate monitoring. This framework protects against lay extrapolation from meta-analytic signals that may not translate safely into clinical practice.

Furthermore, vitamin D should not be treated as the only dietary intervention for mental health outcomes; broader lifestyle and dietary factors may be necessary for measurable effects (Guzek et al., 2021). The structured narrative review focusing on BDNF and mood-cognitive outcomes similarly supports a defined yet limited clinical role: vitamin D supplementation may support mood and cognition through BDNF modulation especially in those with insufficient vitamin D levels, but definitive conclusions require stronger long-term trials (Skoczek-Rubinska et al., 2025). Therefore, the empirical data support the proposition that vitamin D has limited direct clinical application as a psychiatric treatment, yet it retains pragmatic clinical relevance as part of comprehensive medical assessment and deficiency correction that may, in certain patients, contribute to symptomatic improvement.

Moderators of Treatment Response

Reviews that focus specifically on mood and anxiety emphasize inconsistency as a core limitation and highlight moderators that likely determine whether a therapeutic effect emerges. These moderators include baseline 25(OH)D level, depressive severity, comorbid inflammatory disease, dose and formulation, and duration of supplementation (Akpinar & Gezmen Karadag, 2022; Skoczek-Rubinska et al., 2025). Evidence regarding the optimal baseline vitamin D status for treatment response remains conflicting. One meta-analysis of 25 studies (n = 7,534) reported that vitamin D was effective in individuals with major depressive disorder and plasma 25(OH)D levels of 50 nmol/L or below, with supplements less than 4000 IU for eight weeks or longer (Akpinar & Gezmen Karadag, 2022). However, a more recent meta-analysis by Wang et al. (2023) found the opposite pattern, with significant reductions in depressive symptoms only among patients with baseline 25(OH)D levels higher than 50 nmol/L (SMD -0.38), not in those with levels below this threshold; this finding is counterintuitive and conflicts with the mechanistic expectation that deficient individuals would benefit most from supplementation. Adding further complexity, Srifuengfung et al. (2023) found no moderating effect of baseline serum 25(OH)D levels on treatment response in their systematic review of 16 RCTs involving depressed patients. This three-way discrepancy reflects substantial ongoing variability in the literature and underscores the need for further research to identify which patient characteristics reliably predict treatment response.

Studies in the literature include not only individuals with symptoms of major depression or anxiety but also individuals with chronic inflammatory diseases such as ulcerative colitis, Crohn's disease, and diabetes. Therefore, positive outcomes in individuals with these conditions may be associated with the effect of vitamin D as an immunomodulator on metabolic and inflammatory markers, rather than a direct neuropsychiatric mechanism. Vitamin D demonstrates potent immunosuppressant activity and may modulate pro-inflammatory cytokines, including IL-6, in the brain (Khan et al., 2022). This mechanistic complexity underscores the importance of identifying patient subgroups most likely to derive benefit from supplementation.

Clinical Synthesis

In psychiatric practice, the most defensible data-concordant position regarding vitamin D and mood disorders encompasses several key principles. First, low vitamin D is often associated with depressive symptom burden in observational studies, but this association does not establish causality, as the relationship is confounded by behavioral and medical factors that accompany both depression and vitamin D deficiency (Akpinar & Gezmen Karadag, 2022; Khan et al., 2022). Second, supplementation does not reliably improve mood across broadly defined or healthy adult populations in long-term trials, though subgroup effects remain plausible, particularly in deficiency or insufficiency states and in individuals with comorbid inflammatory conditions (Guzek et al., 2021; Okereke et al., 2020; Skoczek-Rubinska et al., 2025).

Third, vitamin D supplementation is best framed clinically as correction of a deficiency state and a component of holistic medical-psychiatric care, rather than a primary antidepressant intervention (Akpinar & Gezmen Karadag, 2022; Guzek et al., 2021). Vitamin D screening should be performed in the prevention and treatment planning of mood disorders, and serum levels must be followed when supplementation is initiated. Fourth, the short-term benefits observed in meta-analyses (8 weeks or less) do not persist over longer treatment durations, suggesting that any acute mood-related effects do not translate into sustained clinical improvement (Ghaemi et al., 2024). Fifth, evidence does not support vitamin D supplementation as monotherapy for depression, particularly in the absence of documented deficiency, and clinicians should prioritize evidence-based psychiatric treatments while addressing vitamin D status as a medical comorbidity.

Sixth, when supplementation is initiated, clinicians may consider advising patients to take vitamin D in the morning, a recommendation that has been proposed based on the serotonergic pathway mechanism. This rationale suggests that vitamin D promotes central serotonin synthesis (via TPH2) while inhibiting peripheral serotonin production (via TPH1) that serves as a precursor to melatonin in the pineal gland (Huiberts & Smolders, 2021). Morning administration may be physiologically congruent with the circadian peak of endogenous vitamin D and could theoretically avoid potential disruption of evening melatonin synthesis. While this timing recommendation lacks direct randomized trial evidence, it is consistent with known circadian physiology and carries no apparent risk.

Consequently, the empirical literature supports a clinically conservative stance: vitamin D supplementation may be reasonable as an adjunct when deficiency or insufficiency is present, but it should not be positioned as a stand-alone mood treatment with predictable antidepressant efficacy. Clinicians should incorporate vitamin D assessment into thorough psychiatric evaluations, recommend supplementation when deficiency is documented, monitor levels to ensure adequacy without toxicity, and maintain realistic expectations that deficiency correction may contribute to, but is unlikely to independently resolve, mood symptomatology. This approach honors both the biological plausibility of the vitamin D-mood relationship and the limitations of the interventional evidence base.

Concluding Thoughts

Screening for vitamin D deficiency is reasonable in patients with mood disorders, particularly those with limited sun exposure, older adults, individuals with inflammatory comorbidities (e.g., diabetes, autoimmune conditions), and patients with malabsorption syndromes. When deficiency is documented, treat for medical reasons using physiologic replacement dosing (800 to 2000 IU daily) or supervised repletion protocols as appropriate. Do not frame vitamin D supplementation as an antidepressant intervention; rather, position it as correction of a medical comorbidity that may contribute to overall wellness. Avoid megadosing without laboratory confirmation of deficiency and ongoing monitoring to prevent toxicity. Consider morning administration, which may be physiologically congruent with circadian vitamin D patterns and serotonergic regulation. Prioritize evidence-based psychiatric treatments while addressing vitamin D status as one component of comprehensive care.