Vitamin D₃ supplementation in multiple sclerosis: Symptoms and biomarkers of depression

Highlights

• The effect of vitamin D supplements on depressive symptoms and immunological biomarkers was explored in an RRMS population.

• 48 weeks of high-dose vitamin D₃ supplementation did not reduce depression scores compared to placebo.

• Vitamin D₃ supplements did not skew cytokine balances towards a more anti-inflammatory profile compared to placebo.

• Additional studies need to further elucidate whether vitamin D supplements ameliorate manifest depression in MS.

Abstract

Depressive symptoms are common in multiple sclerosis (MS), and both depression and MS have been associated with a poor vitamin D status. As cytokine-mediated inflammatory processes play a role in the pathogenesis of both disorders, we hypothesized that vitamin D₃ supplementation reduces depressive symptoms in MS via its immunomodulatory properties. In this randomized pilot study relapsing remitting (RR) MS patients received either vitamin D₃ supplementation (n = 20; 14.000 IU/day) or placebo (n = 20) during 48 weeks. Pre- and post-supplementation depression scores, measured using the Hospital Anxiety Depression Scale (HADS) depression subscale (HADS-D), showed a significant decrease within the vitamin D₃ group (median HADS-D 4.0 to 3.0, p = 0.02), a trend towards a decrease within the placebo group (median HADS-D 3.0 to 2.0, p = 0.06), but no significantly different reductions between groups (p = 0.78). Furthermore, no reductions in pro- and anti-inflammatory cytokine balances, secreted by stimulated leukocytes and CD8⁺ T cells, were found in the vitamin D₃ compared to the placebo arm. Therefore, we found no evidence for a reduction of depressive symptoms or related biomarkers upon vitamin D₃ supplementation in RRMS patients in this exploratory study. Whether vitamin D₃ supplementation is of benefit in manifest depression in MS needs to be assessed by additional studies.

Introduction

Multiple sclerosis (MS) can have a major impact on quality of life. Local inflammation in the central nervous system (CNS) causes disturbed signaling of affected neurons, leading to a large variety of symptoms, such as motoric or sensory dysfunction or visual disturbances. Other MS symptoms cannot be explained by local inflammation alone, including fatigue and depression. With up to 90% of the patients with MS complaining of fatigue, it is the most reported symptom of MS. [1] Fatigue is a complex symptom with a multifocal etiology. Also, depressive disorder is frequent in MS, with lifetime prevalence rates going up to 50% [2], whereas in the general population a prevalence of up to 20% is reported [3]. Depressive disorder in MS needs to be considered as a major concern, since it negatively affects quality of life and may cause or perpetuate fatigue [2]. Also, it may lead to medication nonadherence [4], which could influence long-term disease outcomes.

The underlying mechanisms for depression (in MS) are not completely understood, and several (combinations of) theories have been proposed in order to explain the complex pathogenesis. These theories include the monoamine hypothesis [5], based on the deficiency of particularly serotonin and noradrenalin, the neurogenesis or neurodegeneration hypothesis [6], particularly involving atrophy of the hippocampus [7], the hypothalamic-pituitary-adrenal (HPA)-axis dysfunction theory [8], and the inflammatory theory [9]. The latter describes the importance of cytokines in the development of depression. Both in MS and in depressive disorder increased pro-inflammatory cytokine levels (i.e. the monocyte/macrophage derived cytokines tumor necrosis factor alpha (TNFα), interleukin (IL)-1 and IL-6) have been observed in the circulation and in the cerebrospinal fluid (CSF) [10], [11], [12]. These cytokines were positively associated with depression severity, [10] and were reduced upon antidepressant therapies [10], [13]. Also, the proportion of CD8⁺ (but not CD4⁺) T cells producing TNFα and interferon-gamma (IFNγ) was shown to be increased in patients with MS with a depressive disorder compared to the ones without a depressive disorder [14]. Anti-inflammatory therapy such as anti-TNF therapy markedly improved mood in treatment-resistant depressive disorder, [15] and pro-inflammatory cytokines are shown to induce sickness behaviour (i.a. fatigue, depression, loss of appetite) [10]. Furthermore, in each theory previously mentioned a role for pro-inflammatory cytokines has been suggested: they may cause serotonergic depletion [10], induce imbalance in the kynurenine pathway with neurotoxicity as a result, [6] and induce HPA-axis activity [16]. Although some studies report decreased anti-inflammatory IL-10 levels in depressed people [17], and antidepressant therapies have shown to increase IL-10 [13], it is not clear whether also a decrease in anti-inflammatory cytokines contributes to depression [18]. However, an imbalance in pro- and anti-inflammatory cytokines may play a central role in the development of depression (in MS) and well-balanced pro- and anti-inflammatory cytokines may prevent and/or ameliorate depression [13].

Insufficiency of vitamin D has been associated with MS risk and MS disease activity, [19], [20] as well as with the presence and severity of depressive disorder (in MS) [21], [22]. Vitamin D is a steroid hormone with immunomodulatory properties, causing a decrease in the production of pro-inflammatory cytokines and an increase in the production of anti-inflammatory cytokines [23]. Therefore, particularly in the context of the chronic inflammation in MS, vitamin D supplementation might prevent or ameliorate depressive disorder. However, data appear conflicting with respect to the role of vitamin D in depressive disorder in patients with MS [22], [24], and with respect to the benefit of vitamin D supplementation in depression in general [25]. Therefore we used a randomized placebo-controlled trial (RCT) to explore the effect of high dose vitamin D₃ supplementation on depressive symptoms in MS. Fatigue was assessed as a potential confounder [2], [14]. We also assessed the TNFα/IL-10 balance before and after supplementation, and the proportion of CD8⁺ T cells producing pro- and anti-inflammatory cytokines, since the mode of action by which vitamin D could ameliorate depression may reflect a normalization of the pro-inflammatory/anti-inflammatory cytokine ratio.