**9. Mood disorders**

Vitamin D receptor mutant gene leads to the translation of mutant mRNA into defective vitamin D receptor proteins. Normal VDR is responsible for the regulation of glucocorticoid signalling, which, in this case, gets dysfunctional due to vitamin D deficiency. Dysfunctional glucocorticoid signalling is majorly implicated in several mood disorders like major depressive disorders, seasonal affective disorders, etc. Glucocorticoid, a type of cortisol, is seen to be increased in MDD and decreased in bone disorders. According to the recent diagnostic and statistical manual of mental disorders (DSM-IV), a major depressive disorder is diagnosed or said to be present when a person exhibits at least five of the following symptoms during 2 weeks, most of the day or nearly every day:


**115**

*Association of Vitamin D Deficiency and Mood Disorders: A Systematic Review*

Genes are encoding for vitamin D3, 25-hydroxylase, and 1α-hydroxylase (CYP27B1), where CYP27B1 are the enzymes that metabolize vitamin D3 into calciferol hormones, which is further involved in brain functions. These are expressed in neurons and glial cells presenting VDR. Calciferol hormone, being a neuroactive compound, regulates the behavioral functions such as anxiety, hyperactivity, and depression. Hypovitaminosis is a deficient condition that is found to be associated with an increased risk of multiple sclerosis, seasonal affective disorder, schizophrenia, Parkinson's disease, and Alzheimer's disease. Vitamin D deficiency could also be associated with autism, explained by a piece of indirectly related evidence. Furthermore, mood and cognitive performance appear to be dependent on plasma

Prevalence of seasonal affective disorder is seen when the vitamin D stored in the body are low with prominent seasonal changes. The disorder occurs during a particular time of a year where the sun exposure to the skin decreases leading to vitamin D deficiency, and the symptoms of the disorder can be resumed spontaneously on sun exposure. The individuals suffering from seasonal affective disorder have typically reported depression-like symptoms mostly in the winter months, where the levels of intensity of sunlight and photoperiod were predominately reduced [19–21]. Studies in the United Kingdom estimated the prevalence of SAD between 2.4 and 3.5%. The etiology of this disorder has not been fully elucidated, but the mechanisms leading to SAD are understood and linked to reduced sunlight exposure and daylight length. SAD is led via an eye-brain-endocrine system pathway or a skin-vitamin D causal pathway. In the mammalian population, the first stage of in vivo vitamin D synthesis necessitates the irradiation of skin by UVB light, dependently showing the lower vitamin D serum levels in the winter months than that in summer months. It has been also postulated that at cellular or subcellular levels, vitamin D can directly influence the endocrine system of our body via ligand binding on vitamin D receptors present in the entire central nervous system of a human body [21]. A prospective, randomized controlled trial was conducted in a group of 15 subjects with SAD to postulate the hypothesis of the association of vitamin D deficiency and seasonal affective disorder in which eight subjects received 100,000 IU of vitamin D and seven subjects received phototherapy. The Hamilton Depression Scale, Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Depression version (SIGH-SAD), and the SAD-8 depression scale were administered for the evaluation at two stages of treatment, i.e., first at onset of treatment and second after one month of the therapy. Also, intervention therapy was used to measure serum levels of 25-hydroxyvitamin D (25-OH D) planned in a gap of 1 week before and after the intervention. Improvement in all subjects was seen with the one's receiving vitamin D. Depression scale measure had no significant results for the phototherapy [1, 22].

Major improvement was seen in both the abovementioned groups, and this improvement in 25(OH)D was intertwiningly associated with the improvement in depression scale score. Hence, it is evident that vitamin D supplementation has an

In order to understand the seasonality of mood change, it is integral to understand

the seasonal changes in photoperiod to hypothesize the most vitamin D-deficient mood disorders. Many biological techniques are utilized for detecting photoperiod.

important role in the treatment of SAD [10, 13, 14].

*DOI: http://dx.doi.org/10.5772/intechopen.90617*

vitamin D level to some extent [19].

**10.1 Seasonal affective disorder**

**10. Types of vitamin D-deficient mood disorders**

• Recurrent suicidal thoughts with or without a plan [1]

*Association of Vitamin D Deficiency and Mood Disorders: A Systematic Review DOI: http://dx.doi.org/10.5772/intechopen.90617*

Genes are encoding for vitamin D3, 25-hydroxylase, and 1α-hydroxylase (CYP27B1), where CYP27B1 are the enzymes that metabolize vitamin D3 into calciferol hormones, which is further involved in brain functions. These are expressed in neurons and glial cells presenting VDR. Calciferol hormone, being a neuroactive compound, regulates the behavioral functions such as anxiety, hyperactivity, and depression. Hypovitaminosis is a deficient condition that is found to be associated with an increased risk of multiple sclerosis, seasonal affective disorder, schizophrenia, Parkinson's disease, and Alzheimer's disease. Vitamin D deficiency could also be associated with autism, explained by a piece of indirectly related evidence. Furthermore, mood and cognitive performance appear to be dependent on plasma vitamin D level to some extent [19].

### **10. Types of vitamin D-deficient mood disorders**

#### **10.1 Seasonal affective disorder**

*Vitamin D Deficiency*

origin [14, 15].

**9. Mood disorders**

of the day or nearly every day:

• Significant weight loss or gain

• Psychomotor agitation or retardation

• Insomnia or hypersomnia

• Fatigue or loss of energy

and cognition

• Loss of interest or pleasure in daily activities

• Feelings of worthlessness or inappropriate guilt

• Recurrent suicidal thoughts with or without a plan [1]

• Depressed mood

the presence of the VDR and 1α- hydroxylase in the human brain and confirmed the cell expression for either the receptor or the activating enzyme in neuronal or glial

Vitamin D receptors and the 1α-hydroxylase enzyme have been isolated and found in the regions of the cerebral cortex and cerebellum, suggesting the conversion of calcifediol into an active form of vitamin D, i.e., calcitriol in the brain for a local cellular response [3, 18]. Several studies discuss the deficiency of vitamin D in the body at its targeted ligand binding sites due to less sunlight exposure or sun blockage, vitamin D receptor mutation causing phenotypic-conformational changes at the ligand binding site, and insufficient vitamin D-fortified diet, all causing major or minor mood disorders and illustrate the effectiveness of vitamin D or sunlight therapy (phototherapy), gene therapy, or supplemented vitamin D diet therapy for the treatment of depression and other mood disorders, demonstrating the associations between 25(OH) vitamin D concentrations and mood alone or mood and cognition in adults of all ages, including pregnant women, older adults,

Vitamin D receptor mutant gene leads to the translation of mutant mRNA into defective vitamin D receptor proteins. Normal VDR is responsible for the regulation of glucocorticoid signalling, which, in this case, gets dysfunctional due to vitamin D deficiency. Dysfunctional glucocorticoid signalling is majorly implicated in several mood disorders like major depressive disorders, seasonal affective disorders, etc. Glucocorticoid, a type of cortisol, is seen to be increased in MDD and decreased in bone disorders. According to the recent diagnostic and statistical manual of mental disorders (DSM-IV), a major depressive disorder is diagnosed or said to be present when a person exhibits at least five of the following symptoms during 2 weeks, most

• Diminished ability to concentrate or make decisions, problem with attention

**8. Effect of vitamin D on mood and cognition**

and targeted vitamin D-deficient population globally [3, 10].

**114**

Prevalence of seasonal affective disorder is seen when the vitamin D stored in the body are low with prominent seasonal changes. The disorder occurs during a particular time of a year where the sun exposure to the skin decreases leading to vitamin D deficiency, and the symptoms of the disorder can be resumed spontaneously on sun exposure. The individuals suffering from seasonal affective disorder have typically reported depression-like symptoms mostly in the winter months, where the levels of intensity of sunlight and photoperiod were predominately reduced [19–21]. Studies in the United Kingdom estimated the prevalence of SAD between 2.4 and 3.5%. The etiology of this disorder has not been fully elucidated, but the mechanisms leading to SAD are understood and linked to reduced sunlight exposure and daylight length. SAD is led via an eye-brain-endocrine system pathway or a skin-vitamin D causal pathway. In the mammalian population, the first stage of in vivo vitamin D synthesis necessitates the irradiation of skin by UVB light, dependently showing the lower vitamin D serum levels in the winter months than that in summer months. It has been also postulated that at cellular or subcellular levels, vitamin D can directly influence the endocrine system of our body via ligand binding on vitamin D receptors present in the entire central nervous system of a human body [21]. A prospective, randomized controlled trial was conducted in a group of 15 subjects with SAD to postulate the hypothesis of the association of vitamin D deficiency and seasonal affective disorder in which eight subjects received 100,000 IU of vitamin D and seven subjects received phototherapy. The Hamilton Depression Scale, Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Depression version (SIGH-SAD), and the SAD-8 depression scale were administered for the evaluation at two stages of treatment, i.e., first at onset of treatment and second after one month of the therapy. Also, intervention therapy was used to measure serum levels of 25-hydroxyvitamin D (25-OH D) planned in a gap of 1 week before and after the intervention. Improvement in all subjects was seen with the one's receiving vitamin D. Depression scale measure had no significant results for the phototherapy [1, 22]. Major improvement was seen in both the abovementioned groups, and this improvement in 25(OH)D was intertwiningly associated with the improvement in depression scale score. Hence, it is evident that vitamin D supplementation has an important role in the treatment of SAD [10, 13, 14].

In order to understand the seasonality of mood change, it is integral to understand the seasonal changes in photoperiod to hypothesize the most vitamin D-deficient mood disorders. Many biological techniques are utilized for detecting photoperiod.

For example, initiation of the behavioral changes such as migration patterns and breeding behavior is conserved in many species, primates, and humans which are evident with changes in season and intensity of sunrays. Further, the scientists pointed out that the regulation of circadian phase shift is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN has been shown to be involved in seasonal affective mood disorders. Further it was also presented that the SCN has an inhibitory action to the hypothalamic–pituitary–adrenal (HPA) axis and that this action can be altered by vitamin D dietary and supplementation restrictions [23].

#### **10.2 Major depressive disorders**

Major depressive disorder is a type of depressive disorder that is most likely to observe an association between vitamin D deficiency and anxio-depressive disorders. This association can be demonstrated with a parallel comparison between the motor and behavioral disorders observed in animal models of depression and VDR-KO mice [13]. Several theories are suggesting seasonal mood swings in humans. The binding of vitamin D on the ligand binding site of VDR present on the hypothalamic core (which plays a crucial role in mood regulation) can be witnessed to have a link between several seasonal changes in photoperiod and seasonal mood swings. Epidemiological data are coherent with such a cross-linking hypothesis. As an instance, the evidence is suggestive that the established low serum 25(OH) vitamin D2 concentrations are closely related to the active experience of mood disorders in 80 subjects aging 65 years and older. Many studies have demonstrated that significant lower serum 25(OH) vitamin D2 and 1,25(OH)2 vitamin D3 concentrations are observed in depressive sample subjects than healthy controlled subjects. Indirect confirmation was made by studying the association between depression and osteoporosis in around 4000 women aged 67 years [15]. Nevertheless, these results can also be mitigated and potentially related to functional impairment and physical inactivity, both of which reasons to increase with osteoporosis and have an independent correlative associated with depression [16].

Various clinical trials support the theory of the efficacy of vitamin D supplementation on mood disorders by varied sources like vitamin D-fortified diet, sunsoaking, etc. [17]. Improvement in depression scale experiments was noted, and the improvements were associated with vitamin D supplementation technique, while not much improvement was observed with the phototherapy technique. It is specifically prescribed to have at least 800 IU daily dose of vitamin D which plays a major decisive role in mood disorder case studies [4, 22, 24].

#### **10.3 Premenstrual syndrome**

Premenopausal women face one of the most common disorders known as premenstrual syndrome. Up to 20% of reproductive-aged women are affected in the range of moderate-to-severe premenstrual syndrome and is associated with significant levels of mood impairment. Irritability, mood swings, anxiety, depression, breast tenderness, bloating, and headaches are some of the most common symptoms included in PMS. Women are reported to have a depressed mood during the last week of the luteal phase which resides within for few days from the onset of menses [9]. Many studies have postulated that blood serum calcium levels and vitamin D levels are lower in women with PMS and that vitamin D supplementation and calcium supplementation may reduce the severity of the symptoms [25].

It is hypothesized that the dysregulation of calciotropic hormone is seen to be a major provocative factor in premenstrual syndrome. The severity of the symptoms of PMS is directly linked to calcium homeostasis, regulated directly by vitamin D

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*Association of Vitamin D Deficiency and Mood Disorders: A Systematic Review*

and parathyroid hormone as the key factors. However, low dietary vitamin D intake and inhibited induction of parathyroid hormone have been directly associated with

Vitamin D insufficiency is common in its most vulnerable pregnant population, and several studies have demonstrated the association of diminished levels of 25(OH) vitamin D with depressive symptoms [4]. Further, the diagnosis of low levels of 25(OH) vitamin D in maternal serum during pregnancy is associated with a higher incidental risk of postpartum depressive symptoms [26, 27]. Serum 25(OH) vitamin D levels for pregnant and postpartum women with major depressive episode, beginning within the first 4 weeks after childbirth, can be influenced by a multitude of factors like age, race/ethnicity, marital status, type of insurance, educational level, feeding type, and others. In addition, the season that accounts for the amount and strength of UVB exposure, i.e., photoperiod and vitamin D supplementation, also are found to be responsible for the episodes of major depression [28]. Vitamin D supplementation during pregnancy increases maternal serum 25(OH) vitamin D levels and thereby ensures higher availability for the offspring neuronal development. Vitamin D levels can also be inversely associated with infertility parameters, preeclampsia, blood glucose, bacterial vaginosis, primary caesarean section, and postpartum depression, but direct correlation is seen in

The core symptoms of PPD are similar to that of any major depressive disorder like depressed mood or loss of interest in normal activities, sleep and appetite disturbances, loss of energy, feelings of guilt, and suicidal thoughts. Hence, the diagnosis of PPD becomes challenging as the sleep pattern changes and weight changes are also often observed in the normal postpartum period. It is further also exhibited that the lower maternal 1,25(OH)2 vitamin D levels have been found to be associated with higher levels of postpartum depressive symptoms as per the Edinburgh Postpartum Depression Scale scores. The promising results were observed by only one randomized clinical trial wherein the assessment was done by administration of

Following birth in the first few days, the lower levels of 25(OH) vitamin D are reported for a greater risk of postnatal depressive symptoms and are also linked to serum vitamin D level in the second trimester of pregnancy. Further, the association of low 25(OH) vitamin D level was established with a continuous enhancing risk of reported level of symptoms that may indicate any one type of mood disturbance. Thus, it is confirmed that adequate intake of vitamin D is essential during pregnancy not only for the positive impact on the health and development of the offspring but also is a way to protect against postpartum mood disturbance in mothers [26]. Also, estrogen supplementation and vitamin D therapies have beneficiary effects on inflammatory response and related factors in women suffering from PPD [6, 29, 30]. When accounting the cortisol levels and hypothalamic–pituitary–adrenal axis reactivity in postpartum women, during the third trimester, maternal cortisol levels reach approximately three times that of nonpregnant levels. While the basal levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone, and cortisol are high, the HPA axis reactivity to stressful stimuli is dampened in late pregnancy. Furthermore, while the baseline cortisol levels return to normal within a couple of days after parturition, the hyporesponsiveness of HPA axis is found to be

The HPA axis hyperactivation or hypoactivation has always been associated with depressive states. It has also been hypothesized that depression during pregnancy

*DOI: http://dx.doi.org/10.5772/intechopen.90617*

**10.4 Postpartum depression (PPD)**

the development of premenstrual symptoms [8].

pregnancy associated with breast cancer [28, 29].

high-dose vitamin D therapy in depressed subjects [6, 7].

persistent in breastfeeding women [6].

and parathyroid hormone as the key factors. However, low dietary vitamin D intake and inhibited induction of parathyroid hormone have been directly associated with the development of premenstrual symptoms [8].
