Vitamin D supplementation in bipolar depression: A double blind placebo controlled trial

doi:10.1016/j.jpsychires.2017.07.021

Journal of Psychiatric Research

Volume 95, December 2017, Pages 48-53

Previous Presentation: Poster at the SOBP annual meeting, Atlanta GA, 5.12.16

https://doi.org/10.1016/j.jpsychires.2017.07.021 Get rights and content

Abstract

Objective

Bipolar depression is difficult to treat. Vitamin D supplementation is well tolerated and may improve mood via its neurotransmitter synthesis regulation, nerve growth factor enhancement and antioxidant properties. Vitamin D adjunct reduces unipolar depression, but has not been tried in bipolar depression.

Methods

18-70yos with DSM IV bipolar depression and Vitamin D deficiency (<30 ng/ml) were randomized in a controlled double blind trial of 5000IU Vitamin D₃ po qday supplementation versus placebo for twelve weeks. Change in Montgomery-Åsberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), Young Mania Rating Scale (YMRS), medication, and tolerance were assessed q2weeks.

Results

16 VitD vs 17 placebo subjects did not differ in baseline characteristics (mean = 44 yo, SD = 13), VitD level (19.2 ± 65.8 g/ml vs 19.3 ± 5.5 ng/ml respectively) or mood ratings (MADRS 21.3 ± 6.4 vs 22.8 ± 6.9 respectively). At 12wks, the placebo group VitD levels remained unchanged, while the VitD group levels increased to 28 ng/ml. MADRS score decreased significantly in both placebo (mean = 6.42 (95% CI [2.28 to 10.56]) and VitD groups (mean = 9.54 (95% CI[3.51 to 15.56]) (p = 0.031), but there were no differences between treatment groups (time by treatment interaction estimate: 0.29, t₍₂₃₎ = 0.14, p = 0.89); VitD and placebo groups had similar reductions in YMRS and HAM-A. Vitamin D₃ was well tolerated.

Conclusions

In this small study, despite a greater rise in Vitamin D levels in the VitD supplementation group, there was no significant difference reduction in depressive symptoms. However both groups’ VitD levels remained deficient. Vitamin D₃ supplementation vs placebo did not improve reduction in mood elevation or anxiety symptoms.

Introduction

Bipolar disorders are pervasive (Puchacz et al., 1996, Kessler et al., 2005) and bipolar depression, often the predominant mood pole, can be particularly difficult to treat. Mood disorders are a major public health problem and are associated with considerable burden of disease, suicides, physical comorbidities, high economic costs, and poor quality of life. (Qureshi and Al-Bedah, 2013, Mavranezouli and Lokkerbol, 2016). Medications either have significant adverse effects (antipsychotics or antiepileptics), lack rigorous evidence for effectiveness (antidepressants) or leave patients with lingering depressive symptoms.

Augmentation strategies for improving inadequate response to antidepressants has become of great interest in the feild. The adjunctive use of standardized pharmaceutical-grade nutrients, known as nutraceuticals, like Vitamin D, has the potential to modulate several neurochemical pathways implicated in depression (Sarris et al., 2016)New effective and tolerable treatment options for bipolar depression would lead to widespread improvement of care for persons with bipolar disorder.

Vitamin D holds potential. It is a fat-soluble vitamin naturally present in a few foods and synthesized endogenously through skin exposure to sunlight. Vitamin D is biologically inert and must undergo two hydroxylations in the body for activation. The first converts Vitamin D to 25-hydroxyVitamin D [25(OH)D], calcidiol. The second forms the neuroactive 1,25-dihydroxyVitamin D [1,25(OH)₂D], or calcitriol. Serum concentration of 25(OH)D are the best indicator of Vitamin D status (Medicine, 2010) given 25(OH)D is the main circulating form of vitamin D, and has a half-life of two to three weeks. In contrast, 1,25(OH) ₂D has a shorter half-life of about four hours, circulates in much lower concentrations, and is susceptible to fluctuations induced by parathyroid hormone (PTH) in response to subtle changes in calcium levels (Misra et al., 2014).

Low Vitamin D levels have been associated with bipolar disorder (Berk et al., 2007), and mechanistically, Vitamin D has promise. Vitamin D has several potential neuroendocrinological mechanisms to influence mood. In its active form, Vitamin D₃ can cross the blood-brain barrier and bind to Vitamin D Receptors found in brain areas involved with depression, such as the prefrontal cortex, hypothalamus, and substantia nigra (Kalueff and Tuohimaa, 2007, Bertone-Johnson, 2009). Vitamin D is involved in neurotransmitter synthesis regulation, nerve growth factor enhancement and antioxidant properties (Humble, 2010). Vitamin D₃, as a neuroactive steroid (Panzica and Melcangi, 2008), may act on the gamma-aminobutyric acid (GABAergic) system and play a role in mood regulation. For example, alterations in neuroactive steroid levels may modify GABA_A receptor subunits (Maguire et al., 2009), influencing mood (Carta et al., 2012) and GABA deficit as an explanatory hypothetical model of major depression has found increasing support (Mohler, 2012, Mann et al., 2014). Vitamin D can increase the expression of genes encoding for tyrosine hydroxylase (Puchacz et al., 1996) in the limiting step of synthesizing mood influencing neurotransmitters dopamine and norepinephrine (Bertone-Johnson, 2009). Beyond neurotransmitter regulation, Vitamin D₃ is also a potent enhancer of nerve growth factor (NGF) and glial derived neurotrophic factor (GDNF) (Humble, 2010) where GDNF may also be involved in depression (Zhang et al., 2009).

Finally, Vitamin D₃ exhibits a neuroprotective effect through several mechanisms, including lowering Ca²⁺ concentration in the brain and promoting antioxidant defense (Eyles et al., 2013; Kalueff and Tuohimaa, 2007, Humble, 2010).

Section snippets

Design

This randomized double blind placebo controlled trial of Vitamin D₃ supplementation occurred between 6/2013 and 4/2015. Participants were recruited from central Massachusetts, USA through electronic and print newspapers, Craig's list and psychiatric practices including academic and community. A telephone prescreening was conducted to inquire about bipolar disorder mood symptoms, knowledge of Vitamin D states, and potential exclusion criteria (below). Potentially eligible participants were

Participants

Screening and randomization results are presented in Fig. 1. The mean age of participants was 44.2 (SD 13.1) years, 48.5% were women. Participants’ demographic characteristics were comparable at baseline between the two groups (Table 1). Five (29%) of 17 participants withdrew from the Vitamin D group and 3 (19%) of 16 participants withdrew from the placebo group; 25 completed the trial.

There was no significant difference in the proportion of participants taking a mood stabilizing (lithium,

Discussion

In this first study to examine Vitamin D supplementation in adults with bipolar depression and insufficient Vitamin D levels, significant increase in Vitamin D levels did not result in a reduction of depression symptoms compared to the placebo group or those with no change in Vitamin D levels. There was no significant difference in the proportion who responded or remitted between the two groups. Possible contributors to the high placebo response rate include increased attention given to the pt,

Acknowledgements

None.

Funding

Brain and Behavior (NARSAD) Young Investigator Award to Wendy Marsh.

Role of the sponsors

The supporters had no role in the design, analysis, interpretation, or publication of this study.

Conflict of interest statement

Marsh: No Conflicts of Interest.

Penny: No Conflicts of Interest.

Rothschild: has received grant or research support from Allergan, Alkermes, Janssen, the National Institute of Mental Health (UO1 MH062624-06A2), and Takeda, and is a consultant to Eli Lilly and Company, GlaxoSmithKline, and Pfizer Inc.

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2024, Journal of Affective Disorders
Previous meta-analyses reported inconsistent results on the effect of vitamin D on depression because of different baseline concentrations of 25-hydroxyvitamin D [25(OH)D], highlighting the need for a more accurate subgroup analysis of previously published findings. The goal of the present study was to evaluate the effect of vitamin D supplementation on depression in adults.
A systematic search in numerous databases including PubMed, Embase, and Web of Science was performed. Randomized-controlled trials comparing the effect of vitamin D on depression in adults were selected.
Eighteen studies met the inclusion criteria in the retrieved citations. The meta-analysis showed that vitamin D supplementation had a significant effect on overall reduction in depression symptom scores (SMD = −0.15, 95 % CI [−0.26, −0.04]). Sub-group analysis showed that vitamin D supplementation significantly reduced depressive symptom scores in patients with serum 25(OH)D levels higher than 50 nmol/L (SMD = −0.38, 95 % CI [−0.68, −0.08]).
Vitamin D supplementation has a benefit on improving depressive symptoms in adults with primary depression and 25(OH)D levels higher than 50 nmol/L but has no effect on improving depressive symptoms in adults with primary depression and 25(OH)D levels lower than 50 nmol/L. Relatively high levels of 25(OH)D maybe required for alleviating depression.
The randomized studies included in this study were designed and completed at different times and countries, the variability in duration and dose of vitamin D supplementation may have introduced significant heterogeneity and have militated against observation of the effects of vitamin D supplementation on depression.
Alternations of vitamin D and cognitive function in first-diagnosed and drug-naïve BD patients: Physical activity as a moderator
2023, Journal of Affective Disorders
The pathophysiological mechanism of cognitive impairments of bipolar disorder (BD) has not yet been completely revealed. It is well known that Vitamin D and physical activity (PA) are associated with BD. However, specific links between Vitamin D and cognitive deficits in BD are still unclear.
The serum levels of vitamin D were measured. The cognitive performances of 102 first-diagnosed and drug-naïve BD patients were evaluated for analysis. The repeatable battery for the assessment of neuropsychological status (RBANS) and the Stroop Color-Word test was used in this study. PA was collected by international physical activity questionnaire.
Patients with BD had high levels of serum vitamin D. Furthermore, immediate and delayed memory was negatively associated with vitamin D levels in patients' group. The serum levels of vitamin D in patients with low PA were positively associated with memory. However, increased PA attenuated the protective effect of vitamin D on executive cognition.
It is concluded that the increased levels of vitamin D were observed in the serum of patients with BD. Thus, it is found that more PA is less beneficial to cognition of patients with BD than longer resting.
A preliminary investigation of the clinical and cognitive correlates of circulating vitamin D in bipolar disorder
2023, Psychiatry Research
The role that vitamin D plays in the cognitive and clinical characteristics of bipolar disorder (BD) is unclear. We examined differences in the levels and deficiency status of vitamin D in an Australian sample of BD patients compared to healthy controls; and determined the extent to which vitamin D is associated with clinical variables and cognitive function in the sample. 22 healthy controls and 55 stable outpatients with a diagnosis of BD and low-grade mood symptomatology provided a sample of blood and completed cognitive tests and clinical measures. Plasma concentrations of 25-hydroxyvitamin D (vitamin D) were assayed and used to segregate participants into subgroups with sufficient or deficient levels of vitamin D. Subgroups were then compared in terms of global cognition and a range of sociodemographic and clinical factors (number of past mood episodes, illness duration, seasonal mood pattern, mood symptom severity), while mean levels of vitamin D were compared between patients and controls. Although almost 27% of the current sample were vitamin D deficient, no significant differences in mean vitamin D levels or the prevalence of vitamin D deficiency were evident between BD patients and controls. Vitamin D was not associated with global cognition in either patients or controls, nor any of the clinical measures assessed in the study.
In conclusion, we observed no difference in the vitamin D levels and deficiency status of an Australian sample of healthy individuals and BD patients with low grade mood symptomatology compared to controls. Clinical symptoms and global cognition also appear to be independent of vitamin D levels in BD.
Adverse health outcomes in vitamin D supplementation trials for depression: A systematic review
2021, Ageing Research Reviews
Vitamin D deficiency is a universal risk factor for adverse health outcomes. Since depression is consistently associated with low vitamin D levels as well as several adverse health outcomes, vitamin D supplementation may be especially relevant for depressed persons. This review examines the potential benefits of vitamin D for (somatic) health outcomes in randomised controlled supplementation trials for depression.
Systematic literature search to assess whether adverse health outcomes, such as frailty, falls, or cognitive functioning, were included in vitamin D supplementation trials for depression, and whether these outcomes were affected by supplementation. The revised Cochrane tool for assessing risk of bias in randomised trials was used.
Thirty-one trials were included. Adverse health outcomes were considered in five studies. Two studies reported some beneficial effect on an adverse health outcome.
While depressed persons are at increased risk of vitamin D deficiency, supplementation trials hardly addressed the common negative health consequences of low vitamin D levels as secondary outcome measures. Well-designed trials of the effects of vitamin D supplementation in late-life depression should explore whether adverse health outcomes can be prevented or stabilised, and whether depression benefits from this improvement.
The role of vitamin D in bipolar disorder: Epidemiology and influence on disease activity
2021, Journal of Affective Disorders
Citation Excerpt :
Indeed, the correlation between levels of vitamin D and severity of depressive symptoms did not seem a unique feature of BD but a common characteristic shared with other psychiatric disorders, as shown by the cross-sectional study of Grønli et al. (2014) and by the RCT of Marsh et al. (2017). However, it should be noted that Marsh et al. (2017), together with Sikoglu et al. (2015), also reported that the administration of vitamin D is associated with a statistically significant reduction of depressive symptoms in BD patients, even if, as interesting as this data appears, the small size of the analysed samples should be taken into account. In contrast, evidence from studies exploring BD patients in manic phase seemed to be more consistent since they showed that BD patients have lower vitamin D levels than healthy controls (Sikoglu et al., 2015; Altunsoy et al., 2018) and also that vitamin D supplementation during a manic episode was associated with a reduction in YMRS scores (Sikoglu et al., 2015).
Although many studies found an association between psychiatric disorders, especially major depressive disorder, and vitamin D deficiency, little is still known about the association between vitamin D and bipolar disorder (BD). Therefore, the present review aims at providing an overview of the available literature exploring the role of vitamin D in BD patients in different phases of the disease.
From a bibliographic research in PubMed until April 2020, we collected ten original studies that fulfilled our inclusion criteria.
No significant differences in vitamin D levels between BD patients and other psychiatric disorders were found by most of the studies. In the majority of the studies, the average values of vitamin D in BD population were sub-threshold for vitamin D deficiency. Moreover, although an association between vitamin D levels and clinical symptomatology was observed in BD patients, it cannot be considered a specific marker of this disorder but a common characteristic shared with other psychiatric disorders, including schizophrenia and major depressive disorder. Finally, vitamin D supplementation was associated with a reduction in both depressive and manic symptoms.
Few studies with small and heterogeneous populations. Methodological heterogeneity in terms of vitamin D measurement and threshold.
The results showed that vitamin D status does not differ between BD and other psychiatric conditions. However, given the correlation between vitamin D levels and depressive or manic symptoms, we could hypothesize that an adequate vitamin D status could positively affect the mood balance thanks to its immunomodulatory activity.
The interactions between vitamin D and neurofilament light chain levels on cognitive domains in bipolar disorder
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View all citing articles on Scopus

View full text

Vitamin D supplementation in bipolar depression: A double blind placebo controlled trial

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Design

Participants

Discussion

Acknowledgements

Funding

Role of the sponsors

Conflict of interest statement

Schizophr. Res.

Med. Hypotheses

Am. J. Clin. Nutr.

Front. Neuroendocrinol.

Psychoneuroendocrinology

J. Photochem Photobiol. B

Psychiatry Res.

Neuropharmacology

Brain Res. Rev.

Brain Res. Mol. Brain Res.

Am. J. Geriatr. Psychiatry

Psychiatry Res.

Vitamin D deficiency and depression in adults: systematic review and meta-analysis

Br. J. Psychiatry

Vitamin D and the occurrence of depression: causal association or circumstantial evidence?

Nutr. Rev.

GABAergic neuroactive steroids: a new frontier in bipolar disorders?

Behav. Brain Funct.

Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder

J. Nutr. Health Aging

Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline

J. Clin. Endocrinol. Metab.

Neurosteroid hormone vitamin D and its utility in clinical nutrition

Curr. Opin. Clin. Nutr. Metab. Care