Benefits of vitamin D treatment for major depressive disorder and seasonal affective disorder: an
overview of the efficacy and suitability of Vitamin D as a treatment option versus conventional treatment
Michiel Waalboer s2243962
Supervisor: dr. ing. J.D.A. (Jocelien) Olivier Mentor: prof. dr. E.A. (Eddy) van der Zee
Benefits of vitamin D treatment for major depressive disorder and seasonal affective disorder: an overview of
the efficacy and suitability of Vitamin D as a treatment option versus conventional treatment
Author Michiel Waalboer
Supervisor
dr. ing. J.D.A. (Jocelien) Olivier
June 19th 2018, Rijksuniversiteit Groningen
PREFACE
This thesis serves as one of the final undertakings of me as a master-student at the
University of Groningen. It was written as part of the graduation requirements for the Biology (neuroscience) master’s program.
I came up with the research topic in early October (2017) and contacted dr. ing. Jocelien Olivier because of her expertise on the subject matter. Jocelien agreed to be my supervisor and advised me on structure and planning.
At the time, I was still contemplating the idea of doing my second research project at the University of Leiden, where I was to start in December. A decision I’ve since then made and have not regretted.
Because I was fully engaged in the process of moving to another city (and finalizing my first research project), Jocelien allowed me to start the project in late November.
We both agreed that given the circumstances it was very unlikely that I would finish my thesis within such a short time-period.
I would therefore like to express my sincere gratitude towards dr. ing. Jocelien Olivier, for allowing me to complete the assignment in a manner that is less than usual.
This has resulted in me writing a report that I feel comfortable with releasing.
As for the thesis itself, it goes without saying that it was difficult at times to retrieve only the applicable information amongst a sea of literature.
Regarding vitamin D, a vitamin that is known to influence the expression of ~1000 genes. It can be hard to select only that which is of value. However, once the wheat was separated from the chaff, the outline of my thesis became more clear.
As soon as the structure was set and a handful of articles had been selected it became easier to write and I especially enjoyed the challenging aspects of presenting the relevant information.
It is therefore that I often chose to visually present the facts and figures in a style that is hopefully more easy to understand than a purely written version.
Vitamin D is a complex molecule that is involved in many biological processes, and instead of overwhelming the reader with a long cascade of molecular interactions, I often chose for a simple yet relevant representation of its actions inside the body with regard to the topic at hand.
I have learned a lot from writing this thesis and I hope that this aspect makes for an interesting read. I hope you will enjoy reading this thesis.
Michiel Waalboer
Den Haag 2018 - 06 - 19
SUMMARY
Depression is a mental health condition that affects all aspects of human life. It is
characterised by negative emotions, anhedonia or even physical discomfort. This obstructive state of well-being can result in a disability to perform yet mundane daily tasks or even ensue in complete social withdrawal. Depression also contributes heavily to the global disease burden and the subsequent healthcare costs that are associated with the disease are very high.
The precise mechanisms that underlie this disease remain elusive. Nevertheless, there exist several treatment options that help alleviate some of the symptoms that are affiliated with depression. These treatments however, vary in both their therapeutic efficacy and adverse secondary effects. Pharmacological treatments that target the dopaminergic and
serotonergic pathways inside brain are often used to treat various forms of depression and can be effective in some cases. However this type of treatment is also associated with many unwanted side effects. Because to this day no ideal treatment method has been found, it is pivotal to explore alternative methods of treatment.
The idea that vitamin D deficiency could play a part in some cases of depression has been established a long time ago. Studies have shown that bio-metabolic pathways associated with depression appear to be (sometimes directly) affected by vitamin D. Both the
dopaminergic and serotonergic metabolic pathways are thought to be involved in the
regulation of mood and subsequent behavioral patterns, and are main targets for the present antidepressant treatment. Vitamin D is believed to play a key role for the synthesis of
dopamine, serotonin and melatonin and might therefore be an interesting key player in depression.
Indeed, low serum levels of vitamin D appear to be positively correlated with the occurrence of depressive like symptoms. However, not all people who are depressed also suffer from low levels of vitamin D. Although it can be difficult to establish a cause and effect
relationship, most studies conclude that low levels of vitamin D are associated with depression. In conjunction with more traditional approaches, vitamin D treatment can therefore be worth considering as a viable treatment option.
In conclusion, hard evidence that vitamin D could be used to actually prevent or cure
depression altogether is at this point unsubstantiated. Low levels of vitamin D are associated with depression but a causal link has not been proven to exist. Therefore recommending vitamin D as the sole treatment for depression is not founded in research. Future research is necessary to conclude on whether or not vitamin D should be advised to use for patients who are suffering from depression.
Table of Contents
1. Introduction ... 1
2. 1 Vitamin D ... 4
2. 2 Physiological effects of vitamin D ... 5
3. Vitamin D, the brain, depression and mood ... 6
4. 1 Vitamin D and the dopaminergic pathway(s) ... 8
4. 2 Vitamin D and the serotonergic pathway(s) ... 9
5. Vitamin D supplementation in clinical trials ... 12
6. Conclusion ... 15
7. References ……… 17
1 1. Introduction
Depression or Major depressive disorder (MDD) is a frequently occurring mental health condition that affects mood and the overall state of well-being (Sidney, 2008. IHO, 2017).
MDD affects people from all ages and it is estimated that more than 800 million people worldwide are affected. The disease is associated with a high mortality rate and
subsequently high healthcare costs. Depression is also the leading cause of disability and contributes heavily to the global disease burden (WHO, 2017).
Currently the physiological mechanisms that underlie this disease remain mostly obscured.
Whilst there are a variety of treatment options available, the effectiveness of these can be situational and largely varies between those who receive the treatment (Khan, 2012. IHO, 2017).
Patients that suffer from MDD are often prescribed what are commonly referred to as antidepressants. Most antidepressants fall under the category of either the tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) or Selective serotonin noradrenaline reuptake inhibitors (SSNRIs) (IHO, 2017). The most commonly prescribed antidepressants are SSRIs (Cherney, 2017). These drugs act by constraining the reuptake of the serotonin neurotransmitter (a chemical that has long been associated with depression), effectively increasing the availability of serotonin at the synaptic cleft (Figure 1).
Figure 1. Adopted from: Elsevier Inc. items and derived items © 2010 by Saunders, an imprint of Elsevier Inc. Antidepressants.
Mechanistic action of the selective serotonin reuptake inhibitor (SSRIs) class of drugs. LEFT: Serotonin is released by the pre- synaptic neuron and traverses the synaptic cleft. Serotonin then binds to a membrane receptor that is present at the post- synaptic neuron. Serotonin is subsequently released and actively reabsorbed by the pre-synaptic neuron. This process is aided by the actions of the serotonin transporter (SERT) reuptake pump. RIGHT: SSRIs inhibit Serotonin from binding to the reuptake pump. The result of this blockage is that serotonin accumulates within the synaptic cleft. The high availability of unbound serotonin results in an increased transmission and firing of action potentials at the post-synaptic neuron.
2 Depending on the severity of the depression (moderate, severe, chronic- but probably not mild depression), SSRI’s can indeed be used as a form of treatment (IHO, 2017). However SSRIs are also known for their many side effects. These include among others: sexual dysfunction, weight gain, sleep disturbance, nausea and nervousness (Cherney, 2017, Ferguson, 2001). Furthermore, opinions on the efficacy of antidepressants are controversial and while many believe that the use of SSRIs can be an effective treatment, others believe these drugs help patients no better than placebo treatment (Kirsch, 2014).
Alternative conventional treatment methods such as electroconvulsive therapy or cognitive interventions face similar problems in that there is either minimal difference from placebo, highly individual adaptation or fragile evidence of the supposed benefits (Bracken, 2012).
As a categorical condition, MDD can be difficult to describe. MDD features a broad range of symptoms that also vary between each patient. The overall connecting factor appears to be a general feeling of unwavering negative emotions. However manifestations of the disease can be directly opposing. Whereas some patients sleep more and eat less, others react by doing the opposite. Moreover, MDD is a persistent condition that can span many months / years or even decades. An ideal treatment would therefore not only include short-term relief but should also be sustainable (Pies, 2012). Because to this day no ideal treatment has been found, it is pivotal to explore all possibilities that might help those who are burdened by MDD.
Figure 2. Graphs retrieved from: John W. Ayers, PhD. Seasonality in Seeking Mental Health Information on Google. American Journal of Preventive Medicine. 2013. Seasonality and most likely the influence of light appears to influence the occurrence of several mood disorders, including depression. Google search results for various mental health conditions spikes during the winter season and drops off during summer time. Multiple wavelet plots for each disorder indicate the variability over several years. Numbers at the bottom of each graph represent the calculated intensity of the seasonal effect (95% CI). Y axis:
Difference from mean, annual component. X axis: week number on calendar.
3 A long standing proposition that dates back even to ancient Greece is that exposure to sunlight could be used to treat a variety of ailments (Reevy, 2010). The same basic principle has for long been applied via a treatment called light therapy, or phototherapy. Light therapy consist of frequent exposure to a light source set to a specific wavelength and / or intensity (Virk, 2009). Around the turn of the 19th century this technique was often used to treat several mood disorders, including MDD (Reevy, 2010). Light therapy is also frequently associated as a treatment for seasonal affective disorder (SAD) (Lam, 1998).
SAD is a remitting form of depression that is thought to be influenced by the change of seasons and coincidentally the length of days (Roecklein, 2005). Symptoms usually reoccur around the same time each year (~fall through winter) and follow a predictable pattern (Ayers, 2013) (Figure 2). The exact mechanisms trough which SAD propagates are not fully understood, however it is believed that people who suffer from SAD experience a difficulty in regulating the serotonin neurotransmitter (Gupta, 2013. Melrose, 2015).
Serotonin is transported by the SERT protein, which is found at higher levels during the winter months in patients whom are diagnosed with SAD. SERT is responsible for transporting serotonin away from the synaptic cleft and back to the presynaptic neuron.
Higher levels of SERT can thus lead to an overall lower serotonin activity (Montañez, 2003).
In fact genotypical variation in the promotor region of the SERT allele has been associated with the occurrence of several psychiatric disorders and an altered response to
antidepressants in both humans and rodents (Andre, 2015. Mitchell, 2015)
SAD patients may also suffer from high levels of melatonin which is a subsequent molecule in the serotonin synthesis pathway. This compound is thought to be involved in the regulation of the sleep -wake cycle (Claustrat, 2015). Melatonin production follows both a circannual and circadian rhythm (high before sleep onset and low after waking) and increases when the days become shorter (less light hours during the day). High levels of melatonin are generally associated with feelings of tiredness and decreased physical activity, both of which are common in patients with SAD and MDD (Madsen, 2017).
As days become darker, people are also more likely to develop a vitamin D deficiency, as vitamin D production is largely dependent on the exposure of sunlight to the skin (Wacker, 2013). Subsequently, low levels of vitamin D are often observed in people who suffer from depression in both SAD and MDD patients (Parker, 2017). Vitamin D is vital for several key functions in the body and in the brain. Notably, vitamin D acts as a necessary precursor to both serotonin as well as melatonin and functions as a pro-hormone that influences
countless of pathways inside the body (Nair, 2012). Although vitamin D can be synthesised through direct sunlight exposure, dietary supplementation is also possible. This dualistic uptake mechanism makes for perhaps a promising treatment regimen that is both non- invasive and easy to adhere to. In fact many studies have investigated the effects of vitamin D as a nutritional supplement for patients suffering from depression. However vitamin D treatment has not been massively adopted as a clinical practice as a treatment for MDD and SAD (Parker, 2017).
This article explores the role of vitamin D in relation to depression. From its efficacy as a treatment to its role involving mood/behaviour and as a precursor to serotonin. An attempt is made to answer the question if and when vitamin D could potentially be used to treat MDD and SAD.
4 2. Vitamin D
Figure 3. The term vitamin D refers to a group of molecular compounds that contains Vitamin D1, D2, D3, D4 and D5. Most commonly however, vitamin D refers to either vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol) or both (calciferol) (Alexander, 1994). Vitamin D2 and vitamin D3 exhibit only one slight difference in their side-chain structure and function identically inside the body (Ross, 2011).
Vitamin D (Figure 3) refers to a group of fat-soluble chemical compounds that serve a variety of different functions inside the human body, hence membrane receptors for vitamin D are present throughout various cell types and major organs, including the brain and intestines (Khanal, 2007). Physiological functions of vitamin D are numerous and include (among other) the regulation and re-absorption of calcium, phosphate and magnesium ions as well as its utilization as a pro-hormone (DeLuca, 1986). Vitamin D is as well believed to play an
important role in the immune system and can also affect muscle contractibility (Prietl, 2013).
Furthermore, vitamin D plays a vital role in bone maintenance as it is necessary for mineral metabolism (Bikle, 2012). Overall, vitamin D is thus important for homeostasis as well as the regulation of other bodily functions (DeLuca, 1986). This section will provide an in depth focus on several of vitamin D’s most important functions, as well as its possible relationship to depression and mood.
Vitamin D refers to a group of similar steroidal structures, rather than one specific molecule.
Vitamin D2 or ergocalciferol is produced by some plants, fungi and yeast in a process that requires UV radiation (Jäpelt, 2013). It is abundantly present in mushrooms and can be added to various food sources in an attempt to boost nutritional content. Vitamin D3, also referred to as cholecalciferol is the form of vitamin D that is found mostly in animal species, including humans. Both Vitamin D2 and D3 can be ingested directly from a food source that contains the molecule.
A unique aspect of vitamin D is that it can also be synthesised in the skin by (sun)light exposure (Baggerly, 2015). Vitamin D3 characteristically is synthesised in the skin from a compound called 7-dehydrocholesterol. Ultraviolet B (UVB) radiation with a wavelength of 290 to 320 nm helps to reorganise the 7-dehydrocholesterol into an intermediate called previtamin D3 which spontaneously converts into vitamin D3 by a process called thermal isomerization (Meana-Pañeda, 2012). Vitamin D3 production thus relies on both the
availability of 7-dehydrocholesterol as well as a sufficient amount of UVB radiation reaching the dermis layer of the skin. Highly pigmented skin, as is found in individuals with African descent contains large quantities of melanin that is known to protect against harmful UVB radiation. As a result however, these people require a relatively higher amount of radiation in order to produce sufficient quantities of vitamin D. This effect becomes further magnified if these individuals reside in places with relatively low levels of sunlight exposure (latitude, seasonal effects) (Shoenfeld, 2009).
5 Indeed vitamin D insufficiency appears to be more prevalent among dark skinned individuals that reside at higher latitudes which possibly increases their risk of developing a depression (Harris, 2006. Nair, 2012). Vitamin D levels have also been reported to decline with an increase in age. This is believed to be at least partially caused by the fact that 7-
dehydrocholesterol is less available in elderly people as opposed to younger individuals (Gallagher, 2013).
While vitamin D supplementation can be toxic if taken in excessive amounts, toxic levels of vitamin D cannot be reached through prolonged sunlight exposure (Alshahrani, 2013).
2. 2 Physiological effects of vitamin D
It is important to note that both Vitamin D2 and vitamin D3 are not considered biologically active and thus exert no direct physiological effect. In order to become active, Vitamin D first has to be converted into a compound called 1,25-hydroxyvitamin D. This process is aided by enzymes that are naturally present within the liver (Nair, 2010). The 1,25-hydroxyvitamin D is then transported via the blood stream with the help of carrier proteins (vitamin D-binding protein in particular). Finally, it arrives in the kidneys, where it is once again converted trough enzymatic activity. This final step in the process yields 1,25-dihydroxycholecalciferol which has a half-life of only several hours and can be transported across the blood-brain barrier (BBB) (Kumar, 1984).
Figure 4. Vitamin D2 and vitamin D3 are “activated” trough enzymatic activity in the liver and the kidneys before they can be transported across the BBB and elicit physiological effects inside the brain.
Vitamin D can be a potent activator / suppressor of several genetic pathways as there are many known genes that contain a so called vitamin D response element (VDRE). In fact it is estimated that vitamin D directly controls the expression of a very large portion of the
complete human genome (over 1000 genes) (Vukić, 2015). Therefore the amount of disorders and illnesses that are implicated to be associated with vitamin D deficiency are estimated to be quite numerous. These include but are not limited to certain types of cancer, heart / kidney disease, diabetes, MDD and SAD (Holick, 2008. Jhee, 2017. Roff, 2008).
Once activated, vitamin D is mostly known to function as a mediator that affects bone growth and mineral metabolism. It is believed that active vitamin D can act as a transcriptional
6 regulator that facilitates the availability of bone matrix proteins such as osteocalcin (Alissa, 2014). Vitamin D is also largely responsible for the uptake of calcium within the intestines.
Calcium is transported across epithelial cells with the help of transport-proteins of which the expression is influenced by vitamin D (DeLuca, 2004. Carlberg, 2014). Without the
availability of vitamin D this process is severely compromised and can result in shunted growth and bone fragility (Koo, 2013).
Vitamin D may also act as an important factor within the immune regulatory system. A large study of 19,000 participants concluded that individuals with <30 ng/ml vitamin D levels (considered clinically low) were more likely to report upper respiratory tract infection (Ginde, 2009). Many immune cells also express receptors that are specific for vitamin D and some are even capable of synthesising the active form of vitamin D themselves (Hewison, 2012).
Furthermore, low levels of vitamin D are associated with an increased susceptibility towards illness (Zhang, 2010). The immune system itself may be influenced by chronic stress which could lead to depression as it is believed that the rise of proinflammatory cytokines and glucocorticoids may in fact be linked to a decrease in the synthesis of brain serotonin (Leonard, 2010).
3. Vitamin D, the brain, depression and mood
Although the precise functioning of vitamin D inside the brain remains elusive, researchers have speculated on its role as a neuroprotective agent and as a mediator of the brain
development process (Kesby, 2011). It is currently believed that vitamin D may play a role in many, if not most CNS related processes, including the maintenance and survival of neurons as well as the release of neurotropic factors and as a contributing factor of brain affiliated functioning (Groves, 2017). Additionally, vitamin D is also linked to the release and synthesis of various neurotransmitters such as dopamine and serotonin (Lu, 2018. Berridge, 2017.
Kim, 2016. Fernandes de Abreu, 2009).
The active form of vitamin D is capable of crossing the BBB and has been demonstrated to act as a neurosteroid inside the central nervous system (CNS) , where it can influence neural excitability (Kesby, 2017). Vitamin D related enzymes are also abundantly present within the brain. The vitamin D receptor (VDR) itself exists even in the early stages of development and is found within most major brain structures, including the nucleus accumbens, hippocampus and the amygdala (Eserian, 2013). Especially the nucleus accumbens and amygdala which are both part of the “pleasure center” of the brain are of particular interest regarding MDD research (Berridge, 2015). It is speculated that certain affective disorders (including clinical depression) can induce the pathological absence of the normal pleasure response, or even promote excessive displeasure in the form of negative emotions, anxiety or fear (Pizzagalli, 2014).
Research has shown that low levels of adult vitamin D (AVD) may predispose individuals to develop depression like symptoms and cognitive impairment (Okereke, 2016). A longevity cohort study in elderly people (China) reported that on a Mini-Mental State Examination (MMSE), participants (n= 1,202) that had low serum levels of vitamin D (<30 ng/ml) were at an increased risk of cognitive decline (Matchar, 2016). Cognitive impairment was defined by the authors as posting an MMSE score that was lower than 18 whilst cognitive decline was defined as having a ≥3 point decline from baseline test scores towards the end of the study.
Studies in AVD mice have also demonstrated that a vitamin D deficiency may lead to behavioural and neurochemical changes in the brain (Groves, 2013). According to the
7 authors this might be due to altered glutamatergic and GABAergic neurotransmission which is common in AVD mice and could lead to mild cognitive impairment (Groves, 2017). With regards to depression, vitamin D is believed to be important for the regulation and production of several key neurotransmitters including dopamine and serotonin (Kesby, 2009). Both the dopaminergic and the serotonergic pathway play a vital role in the regulation of mood and feelings of wellbeing (Nutt, 2008). Many antidepressants (as well as illicit drugs) specifically alter the production and / or release of these distinct molecules and lower levels of these neurotransmitters are associated with both depression and vitamin D deficiency (Cass, 2006.
IHO, 2017).
8 4. 1 Vitamin D and the dopaminergic pathway(s)
Dopamine or 3,4-dihydroxyphenethylamine (DA) is a monoamine and neurotransmitter that is synthesized from L-DOPA inside both the brain and kidneys. Dopamine belongs to a group of compounds that is generally referred to as the catecholamine’s. Besides dopamine this family also includes both epinephrine and norepinephrine. Dopamine is important as a neurotransmitter inside the brain as its functions include most notably, motor control and addictive - and reward motivated behavior (Arias-Carrión 2007, Jaber, 1996). Many illicit drugs specifically target the dopamine release system by either mimicking dopamine directly or by interfering with the re-uptake of dopamine (Arias-Carrión, 2010. Beaulieu, 2011).
Because dopamine is generally associated with feelings of happiness and pleasure it has long been hypothesized that dopamine deficiency could be associated with the onset of MDD (Dailly, 2004). This has resulted in an attempt by some to establish a direct causal
relationship between dopamine and depressive-like symptoms. However, due to the complex interplay between various neurotransmitters it is possible that such a direct link remains obscured (if it exists). In fact, while many studies focus exclusively on serotonin and its involvement in depressive symptoms, dopamine remains often overlooked. Nevertheless, low levels of dopamine have been associated with symptoms including reduced motivation, anhedonia (a decrease in pleasure from otherwise joyful activities) and even disturbed motor coordination. Most of which are also associated with MDD (Brookshire, 2012)
A noticeable element that further strengthens the possibility of a link between dopamine and depression is the fact that there appears to be seasonal variability of the central
dopaminergic system (Tsai, 2011). This seasonal variability has mostly been reported on in schizophrenic patients and is also observed in patients that suffer from SAD (Karson, 1984).
In fact, many of the reported symptoms correspond with those that are found in SAD patients, including tiredness, lack of motivation and anhedonia (Roecklein, 2005).
One study concluded that there appear to be significant differences between the striatal dopamine D2/D3 receptor availability of participants in low vs. high sunlight exposure (Tsai, 2011). Although it is not directly stated by the authors, these findings could indicate a possible link between dopamine, MDD (or SAD) and vitamin D. This is because
dopaminergic neurons targeting the striatum have also been observed to express the vitamin D3 receptor protein and it is believed that dopamine circuits are adjusted via vitamin D signaling pathways (Trinko, 2016).
Besides influencing the dopaminergic pathway directly, vitamin D is also a prominent inducer of endogenous Glial cell-derived neurotrophic factor (GDNF) (Figure 5). GDNF in turn is especially important for the survival of many types of neurons, including dopaminergic neurons (Pertile, 2018). Evidence suggests that GDNF is closely involved in the development of several dopaminergic pathways and that cell apoptosis within the substantia nigra, at least in the early postnatal timeframe is regulated by GDNF (Burke, 1998). The substantia nigra is known as one of the primary centers of dopamine production and coincidentally also carries the highest density of the vitamin D receptor inside the brain (Eserian, 2013). Both GDNF and thus vitamin D also play a major role in the development of several important brain structures. A study preformed on developmentally deficient vitamin D (DVD) neonatal rats has shown that insufficient levels of vitamin D may result in lowered GDNF in the cerebrum (Cui, 2010). Other brain structures such as the ventral tegmental area (VTA) can also be influenced by reduced GDNF, which impacts dopamine release within the nucleus accumbens (Luan, 2018).
9
Figure 5. After synthesis, the active form of vitamin D is capable of traversing the blood brain barrier. Amongst various other activities, vitamin D is believed to up-regulate the expression of GDNF. GDNF actively supports the survival of dopaminergic neurons.
4. 2 Vitamin D and the serotonergic pathway(s)
Serotonin or 5-hydroxytryptamine (5-HT) is a hormone and (monoamine) neurotransmitter that is derived from amino acids. Serotonin is predominantly secreted by neuroendocrine cells within the gastrointestinal tract and only a small percentage is synthesized within the CNS. Nevertheless, serotonin is responsible for a wide range of brain related functions and subsequent behavioral patterns. These do not only include basic executive function and sensorimotor function but also complex social cognition and mood regulation (Cowen, 2015).
Many of the classified behavioral - and mood disorders have been reported to show signs of deficits that are thought to be closely related to the serotonergic pathway. These include attention deficit hyperactivity disorder, bipolar disorder, schizophrenia, Impulse -
control disorder, as well as MDD (Lin, 2014). Dysfunction of the serotonin transporter gene as a result of a genetic polymorphism has also been linked to aggression, fear,
psychopathology and unpleasant feelings of emotional well-being (Nomura, 2015). Like most neuropsychiatric disorders MDD is a condition that is affected by many constituents.
Therefore the interference between the genetic background and environmental factors remains key in the understanding of this convoluted disease.
Inside the brain, serotonin is synthesized from a compound called tryptophan (Figure 6).
Through the aid of tryptophan hydroxylase 2 (TPH2), tryptophan is biochemically converted into serotonin. Vitamin D acts by activating the transcription of the serotonin-synthesizing gene TPH2 which contains a vitamin D response element (VDRE). In cultured neuronal cells it has been demonstrated that the expression of TPH2 is indeed largely dependent on vitamin D bioavailability (Patrick, 2014). It is therefore postulated that insufficient
concentration-levels of active vitamin D could lead to a diminished serotonin synthesis.
10 In addition to vitamin D, the production of serotonin is also largely dependent on omega-3 fatty acids. Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) in particular work in conjunction with vitamin D and studies have demonstrated that high levels of these
molecules are correlated with an increase in serotonin (Patrick, 2015).
Figure 6. Tryptophan is transported across the BBB and is allocated to the pre-synaptic neuron. Only sufficient vitamin D levels allow for adequate expression of TPH2. This step is crucial for the conversion of tryptophan into 5-HTP (a necessary precursor to serotonin). EPA then, is a prerequisite for the release of serotonin by the pre-synaptic neuron. DHA facilitates the binding of serotonin to its receptor located on the post-synaptic neuron.
Besides serotonin as a neurotransmitter, the serotonergic pathway is also important for the endogenous production of melatonin inside the pineal gland. Melatonin, sometimes referred to as the “sleep hormone” is associated with feelings of tiredness and the onset of sleep in diurnal animal species (Melrose, 2015). However, recent evidence suggests that melatonin (perhaps as a consequence of it being an element in the serotonergic pathway) may be involved in SAD or even MDD in general. Nocturnal underproduction or daily overproduction of melatonin have both been observed in patients that suffer from depressive like symptoms (Káradóttir, 2001. Melrose, 2015).
Because serotonin acts as a precursor to melatonin, low serotonin levels are a likely cause of insufficient melatonin production. Therefore, the correlation between abnormally low levels of melatonin and depressive like symptoms could be consequential but not necessarily causal to depression. Yet, some research suggest that it is not the changes in absolute melatonin availability that corresponds with depression, but rather the amplitude of the circadian
11 melatonin rhythm that is blunted in patients that suffer from depression (Malhotra, 2004). The theory that these changes could be associated with depression is further strengthened by the fact that melatonin patterns also follow a circannual rhythm that resonates with the onset of SAD seasonality (Morera, 2006).
Although not widely accepted, the belief that melatonin may act as an inhibitor of corticotrophin releasing hormone (CRH) and vice versa also exists (Kellner, 1997.
Konakchieva, 1998). CRH’s primary function is to stimulate the production of
Adrenocorticotropic hormone (ACTH) which is a central component of the hypothalamic - pituitary - adrenal axis (HPA axis). Increased production of CRH is subsequently linked to the physiological stress response and there appears to be a link between elevated levels of CRH and MDD (Kasckow, 2001). Besides the possible inhibitory effect of melatonin as an “anti - stress constituent”, melatonin production itself partly depends on chemicals that can be associated with psycho -physiological states of stress or high alertness (Mitchell, 2010). One such chemical is a neurotransmitter called norepinephrine. This compound by itself is
capable of stimulating melatonin synthesis (Heather, 2010) (Figure 7).
Figure 7: Serotonin and sequentially Melatonin (Serotonergic pathway) are both synthesized from tryptophan (indicated as TRP). Tryptophan is transported across the Blood-Brain-Barrier (BBB) in a process where it competes with other large neutral amino acids (LNAA). Carbohydrates cause an insulin spike that results in the uptake of LNAA in the skeletal muscles. This results in a more favorable ratio of tryptophan vs. LNAA and increases the uptake of Tryptophan. Inside the brain, tryptophan is biochemically converted into (eventually) serotonin and melatonin in a biosynthesis pathway that is facilitated by vitamin D and the omega 3 fatty acids (EPA & DHA) . Norepinephrine (NE) increases the transcription of the Arylalkamine N-acetyltransferase (AANAT) gene. This gene transcribes for the AANAT enzymes which are necessary for the production of melatonin (Peuhkuri, 2012).
12 5. Vitamin D supplementation in clinical trials
Thus far there appears to be mounting evidence of the importance of vitamin D with regards to living a healthy lifestyle and its relation to depression (Li, 2013. Spedding, 2014) Vitamin D notably appears to be at least partly crucial in the biosynthesis of various neurochemicals (dopamine, serotonin) that are associated with positive emotions and overall feelings of wellbeing (Nutt, 2008). The fact that vitamin D can easily be administered provides a positive outlook for the theory that this compound can be used to combat depression.
Nevertheless, the proposed effectiveness of vitamin D has to be experimentally verified before any treatment strategy can be conceptualized. Besides demonstrating the notion itself, several studies have been conducted that aim to answer questions about whether or not vitamin D simply masks some of the adverse effects of depression or whether it can actually mitigate the disorder altogether. In short, even if vitamin D supplementation is effective, the question remains if it constitutes as a possible cure or whether it is capable to prevent the onset of MDD.
In 2012 an article was released that stated that supplementation with vitamin D was responsible for the mitigation of depression-like symptoms in adolescent patients that had been depressed (Högberg, 2012). Patients (n=48) that were found to be both depressed and vitamin D deficient were administered vitamin D for 3 consecutive months. Serum vitamin D was found to be positively correlated with an increase in “wellness”. A mood and feelings questionnaire was used to determine the emotional state of being. After treatment, patients indicated that they felt less depressed, agitated, tired and suffered less from mood changes.
These findings hint towards a possible correlation between vitamin D treatment and the subsequent attenuation of depressive-like symptoms. However it is important to keep in mind that positive changes were noticed in patients that had previously been observed to be vitamin D deficient, therefore it is unclear whether or not this treatment would actually be beneficial in other cases of depression.
The effect of vitamin D supplementation has also been examined in individuals that were at risk of developing a depression. Perinatal and antenatal depression are a frequently
occurring form of depression in women that occurs during pregnancy and after childbirth (Alhusen, 2016. Olivier, 2014). They are characterized by strong negative emotions that appear to be “triggered” by the events surrounding childbirth. Although the exact cause is not known, stressful life events and a past history of mental illness likely increase the risk of developing perinatal depression (Silverman, 2017).
A randomized clinical trial in Iranian pregnant women concluded that the consumption of vitamin D was sufficient at effectively lowering depression scores (Vaziri, 2016). These women n=169 (who did not have a history of mental illness) were either given placebo treatment or were subjected to 2000 IU (international unit) vitamin D per day. The Edinburgh Postnatal Depression scale was used to evaluate depression scores on four occasions; 26- 28 and 38-40 weeks of gestation, and 4 and 8 weeks after birth. The vitamin D group showed a greater reduction in depression scores at 38-40 weeks of gestation and 4 and 8 weeks after birth compared to the placebo group. Yet again, the women that were subjected to the treatment already showed a lower than average level of vitamin D before the procedure.
Therefore it is uncertain if such a treatment would be beneficial for most other women. A unique aspect of perinatal depression in this sense is also the fact that supplementation (of any kind of drug) can be potentially damaging to the unborn child. Pregnancy presents a unique physiological situation whereby medicinal intake of the mother may also affect the
13 development / health of the unborn child (Sachdeva, 2009). Therefore, as is the case with other medicinal approaches there will always be a tradeoff between what is possibly beneficial for the mother and harmful for the child.
There are more studies that hint at the possibility of vitamin D as a treatment for depression.
In fact, researchers from Norway utilized the Beck Depression Inventory score (BDI) (a self- scoring questionnaire) to conclude that symptoms of depression are perhaps caused by low levels of vitamin D (Jorde, 2008). In this study either a placebo, 20,000 or 40,000 IU of vitamin D was administered once per week for the duration of 1 year to both men and women. Low levels of vitamin D at the end of the trials was noticeably correlated with relatively higher depression scores. The researchers indicated that raising serum vitamin D levels through supplementation improved BDI scores significantly after one year. Findings such as these are indeed promising, also with regards to the subject size (n=441). However, once again the patients that were treated already suffered from low vitamin D levels and in this particular case were also either overweight or obese.
Several studies have thus far attempted to discover the truth behind the claim that
supplementation with vitamin D might combat depressive symptoms. Yet, in part because of the fact that it is such a difficult endeavor, most scientist remain hesitant to conclude that this is indeed the case. Therefore most studies focus on patients with abnormally low levels of vitamin D and conclude that there does indeed seem to be a causal link or at least a
correlation between vitamin D and depression. Such is also the case in a large cohort study performed in the Netherlands (Milaneschi, 2014). In this study the authors concluded that low levels of vitamin D were associated with the manifestation and severity of MDD. These findings are again compliant with previous findings. The main focus of this study was to assess the blood serum level of vitamin D in both participants from the Netherlands Study of Depression and Anxiety (NESDA) and healthy controls. Researchers found that low levels of vitamin D were not only associated with MDD but that they could also partially predict the reported severity of the depression based on vitamin D serum levels.
However not all studies have reached a similar consensus.
In 2014 the article: Vitamin D supplementation for depressive symptoms: a systematic review and meta-analysis of randomized controlled trials appeared in the journal of psychosomatic medicine (Schaffer, 2014). The aim of this study was to look at the effects of vitamin D supplementation with regards to depressive symptoms across multiple studies.
The leading author (Dr. Jonathan A. Schaffer) states that:
"Although tempting, adding vitamin D supplements to the armamentarium of remedies for depression appears premature based on the evidence available at this time."
Schaffer’s team conducted a systematic review of clinical trials that involved both vitamin D treatment and MDD. In total seven trials were investigated with a combined 3,191
participants. Data was reviewed from several earlier studies (randomized trials) that had focussed on vitamin D supplementation in relation to depressive symptoms. Furthermore, the The Cochrane Risk of Bias Tool was used to assess the quality of the studies themselves.
The overall conclusion of the systematic review was that vitamin D treatment itself did little in terms of relieving patients of their symptoms. Combined with standard antidepressant
medication however, it could be beneficial in some cases. Although only a small number of clinical trials were compared in this study, the authors do admit that there appear to be considerable dissimilarities between each of the trials which may obscure some of the supposed benefits of vitamin D.
14 As has been the case for many years, most patients that suffer from MDD are treated by conventional therapies such as SSRI administration. Thus possible therapeutic effects of vitamin D supplementation should always be weighed against current treatment.
However, it remains difficult to directly compare both options. One of the reasons for this disparity is the certitude that dosage is hard to equate. Further complicating a direct comparison is the fact that the assessment for depression is almost exclusively performed via subjective measurement techniques (such as questionnaires) and adding to the complexity are the (often) diverse groups of study participants.
Nevertheless, some studies hint at the fact that vitamin D administration could possibly be regarded as an effective MDD treatment (Spedding, 2014). A meta-study conducted at the University of South Australia identified several randomized controlled trials and concluded that it was mostly studies that featured biological flaws (methodological quality sub-par) that were inconclusive (Spedding, 2014). Studies without flaws however tended to favour the notion that vitamin D supplementation can significantly improve mood scores in MDD patients. In fact, six out of seven studies without flaws showed improvement in depression with vitamin D supplementation. One of these examined studies was performed using adult primary care patients (n=610) who were screened for vitamin D deficiency (mild to moderate;
10-25 ng/mL serum vitamin D levels) and participated in vitamin D replacement therapy (Arvold, 2009). Placebo or 50,000 IU (weekly) of vitamin D was administered for 8 straight weeks. The experiment was initially performed as double-blind, however severely deficient patients (serum vitamin D <10 ng/mL) were treated under the oversight of a knowing observer. Important findings included that severely deficient patients were reported to have improved their depression scores (questionnaire, including seasonal depression) significantly after the clinical trial period.
Ultimately, there exists also the possibility of combining traditional medication with supplementary vitamin D treatment. Fluoxetine (Prozac, Sarafem) is an often used antidepressant belonging to the SSRI class of drugs. It is a compound that is frequently prescribed to patients that suffer from MDD (Sohel, 2018). A double-blind randomized control placebo study (n=42) concluded that a combined administration of fluoxetine and vitamin D supplements was significantly better at lowering depression scores than fluoxetine alone (Khoraminya, 2013). For eight weeks, either 1500 IU vitamin D was administered in combination with 20 mg fluoxetine or fluoxetine alone (no vitamin D). Every 2 weeks the 24-item Hamilton Depression Rating Scale (HDRS) and the 21-item Beck Depression Inventory (BDI) were used as an indication for depression. Serum vitamin D was also measured both before and after the intervention. From the fourth week of treatment until the final measurement, the group that had received the combination treatment showed
significantly better test scores than fluoxetine alone (although both groups improved over time). It is to be noted however that close to 95% of patients had vitamin D levels of less than 30 ng/ml at the start of the intervention (which is considered to be low).
15 6. Conclusion
So far vitamin D supplementation appears promising as a possible treatment option for MDD and SAD. The bio-metabolic pathways that are associated with depression seem to be (sometimes directly) affected by vitamin D. However, not all depressed patients also suffer from low levels of vitamin D. Most studies conclude that low levels of vitamin D are indeed correlated with depression, although cause and effect cannot be clearly distinguished.
Vitamin D deficiency also occurs more frequently in depressed patients compared to those that are not affected. Perhaps the subset of both depressed and vitamin D deficient patients could therefore indeed benefit from vitamin D administration. If vitamin D treatment is to be considered however, more research will first have to be conducted that focusses on
combination treatments (such as fluoxetine). The fact that current studies also vary widely in their approach to dosage makes it difficult to both compare results. Therefore more research is necessary before actual treatment can be advised.
The supposed benefits of vitamin D with regard to depression appear less clear for individuals that are not vitamin D deficient, therefore any advice regarding the
supplementation of vitamin D is at this moment not substantiated for MDD patients that are not vitamin D deficient.
The fact that vitamin D can be easily administered and adhered to does make it so that vitamin D treatment can possibly be considered as low-risk high reward. And in that sense it would be worth considering as a treatment option. However, hard evidence that vitamin D could be used to actually prevent or cure depression altogether is at this point unsupported.
Therefore recommending vitamin D as the sole treatment for depression is not justifiable, at least not until additional studies have been conducted that focus on causation and not just correlation between low vitamin D and depression.
16 Acknowledgements
The author would like to express his sincere gratitude towards dr. ing. J.D.A. Olivier of the Faculty of Science and Engineering, GELIFES (University of Groningen). For her expertise on the subject matter and overall guidance during the full span of the project.
17 7. References
Andre K, Kampman O, Illi A, Viikki M, Setälä-Soikkeli E, Mononen N, Lehtimäki T,
Haraldsson S, Koivisto PA, Leinonen E. SERT and NET polymorphisms, temperament and antidepressant response. Nord J Psychiatry. 2015
Alexander W, Dorland N. Dorland's Illustrated Medical Dictionary. Saunders, 1994 Alhusen JL, Alvarez C. Perinatal depression, A clinical update. Nurse Pract. 2016 Alissa EM, Alnahdi WA, Alama N, Ferns GA. Serum osteocalcin is associated with
dietary vitamin D, body weight and serum magnesium in postmenopausal women with and without significant coronary artery disease. Asia Pac J Clin Nutr. 2014
Alshahrani F, Aljohani N. Vitamin D: Deficiency, Sufficiency and Toxicity. Nutrients. 2013 Arias-Carrión O, Stamelou M, Murillo-Rodríguez E, Menéndez-González M, Pöppel E.
Dopaminergic reward system: a short integrative review. Int Arch Med. 2010 Arias-Carrión O, Pŏppel E. Dopamine, learning, and reward-seeking behavior. Acta Neurobiol Exp (Wars). 2007
Arvold DS, Odean MJ, Dornfeld MP, Regal RR, Arvold JG, Karwoski GC, Mast DJ, Sanford PB, Sjoberg RJ. Correlation of symptoms with vitamin D deficiency and symptom
response to cholecalciferol treatment: a randomized controlled trial. Endocr Pract. 2009 Ayers JW, Althouse BM, Allem JP, Rosenquist JN, Ford DE. Seasonality in Seeking Mental Health Information on Google. American Journal of Preventive Medicine. 2013
Ayers JW. Seasonality in Seeking Mental Health Information on Google American Journal of Preventive Medicine. 2013
Baggerly CA, Cuomo RE, French CB, Garland CF, Gorham ED, Grant WB, Heaney RP, Holick MF, Hollis BW, McDonnell SL, Pittaway M, Seaton P, Wagner CL, Wunsch A, Sunlight and Vitamin D: Necessary for Public Health. J Am Coll Nutr. 2015 Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011
Berridge MJ. Vitamin D and Depression: Cellular and Regulatory Mechanisms.
Pharmacol Rev. 2017
Berridge KC, Kringelbach ML. Pleasure systems in the brain. Neuron. 2015 Bikle DD. Vitamin D and Bone. Curr Osteoporos Rep. 2012
Bracken P, Thomas P, Timimi S, Asen E, Behr G, Beuster C, Bhunnoo S, Browne I, Chhina N, Double D, Downer S, Evans C, Fernando S, Garland MR, Hopkins W, Huws R, Johnson B, Martindale B, Middleton H, Moldavsky D, Moncrieff J, Mullins S, Nelki J, Pizzo M, Rodger J, Smyth M, Summerfield D, Wallace J, Yeomans D. Psychiatry beyond the current paradigm. Br J Psychiatry. 2012
Brookshire BR. The dopamine side(s) of depression. Scientific American. 2012 Burke RE, Antonelli M, Sulzer D. Glial cell line-derived neurotrophic growth factor
18 inhibits apoptotic death of postnatal substantia nigra dopamine neurons in primary culture. J Neurochem. 1998
Carlberg C. The physiology of vitamin D—far more than calcium and bone. Front Physiol. 2014
Cass WA, Smith MP, Peters LE. Calcitriol protects against the dopamine- and serotonin depleting effects of neurotoxic doses of methamphetamine. Ann N Y Acad Sci. 2006 Cherney K. What Medications Help Treat Depression? Healthline. 2017
Claustrat B, Leston J. Melatonin: Physiological effects in humans. Neurochirurgie. 2015 Cowen PJ, Browning M. What has serotonin to do with depression? World Psychiatry.
2015
Cui X, Pelekanos M, Burne TH, McGrath JJ, Eyles DW. Maternal vitamin D deficiency alters the expression of genes involved in dopamine specification in the developing rat mesencephalon. Neurosci Lett. 2010
Dailly E, Chenu F, Renard CE, Bourin M. Dopamine, depression and antidepressants.
Fundam Clin Pharmacol. 2004
DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004
DeLuca HF. The metabolism and functions of vitamin D. Adv Exp Med Biol. 1986
Eserian JK. Vitamin D as an effective treatment approach for drug abuse and addiction.
Journal of Medical Hypotheses and Ideas. 2013
Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Prim Care Companion J Clin Psychiatry. 2001
Fernandes de Abreu DA, Eyles D, Féron F. Vitamin D, a neuro-immunomodulator:
implications for neurodegenerative and autoimmune diseases.
Psychoneuroendocrinology. 2009
Gallagher JC. Vitamin D and Aging. Endocrinol Metab Clin North Am. 2013 Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-
hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009
Groves NJ, Burne THJ. The impact of vitamin D deficiency on neurogenesis in the adult brain. Neural Regen Res. 2017
Groves NJ, Kesby JP, Eyles DW, McGrath JJ, Mackay-Sim A, Burne TH. Adult vitamin D deficiency leads to behavioural and brain neurochemical alterations in C57BL/6J and BALB/c mice. Behav Brain Res. 2013
Gupta A, Sharma PK, Garg VK, Singh AK, Mondal SC. Role of serotonin in seasonal affective disorder. Eur Rev Med Pharmacol Sci. 2013
Harris SS. Vitamin D and African Americans. J Nutr. 2006
Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc. 2012
19 Högberg G, Gustafsson SA, Hällström T, Gustafsson T, Klawitter B, Petersson M.
Depressed adolescents in a case-series were low in vitamin D and depression was ameliorated by vitamin D supplementation. Acta Paediatr. 2012
Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with healthconsequences1– 4. Am J Clin Nutr 2008
Informed Health Online [Internet]. Depression: How effective are antidepressants? IQWiG (Institute for Quality and Efficiency in Health Care). 2017
Informed Health Online [Internet]. Depression: Overview. IQWiG (Institute for Quality and Efficiency in Health Care). 2017
Jaber M, Robinson SW, Missale C, Caron MG. Dopamine receptors and brain function.
Neuropharmacology. 1996
Jäpelt RB, Jakobsen J. Vitamin D in plants: a review of occurrence, analysis, and biosynthesis. Front Plant Sci. 2013
Jhee JH, Kim H, Park S, Yun HR, Jung SY, Kee YK, Yoon CY, Park JT, Han SH, Kang SW, Yoo TH. Vitamin D deficiency is significantly associated with depression in patients with chronic kidney disease. PLoS One. 2017
Jorde R, Sneve M, Figenschau Y, Svartberg J, Waterloo K. Effects of vitamin D supplementation on symptoms of depression in overweight and obese subjects:
randomized double blind trial. J Intern Med. 2008
Káradóttir R, Axelsson J. Melatonin secretion in SAD patients and healthy subjects matched with respect to age and sex. Int J Circumpolar Health. 2001
Kasckow JW, Baker D, Geracioti TD Jr. Corticotropin-releasing hormone in depression and post-traumatic stress disorder. Peptides. 2001
Kellner M, Yassouridis A, Manz B, Steiger A, Holsboer F, Wiedemann K. Corticotropin- releasing hormone inhibits melatonin secretion in healthy volunteers--a potential link to low-melatonin syndrome in depression? Neuroendocrinology. 1997
Kesby JP, Cui X, Ko P, McGrath JJ, Burne TH, Eyles DW. Developmental vitamin D deficiency alters dopamine turnover in neonatal rat forebrain. Neurosci Lett. 2009 Kesby JP, Turner KM, Alexander S, Eyles DW, McGrath JJ, Burne THJ. Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain.
Int J Dev Neurosci. 2017
Kesby JP, Eyles DW, Burne TH, McGrath JJ. The effects of vitamin D on brain development and adult brain function. Mol Cell Endocrinol. 2011
Khan A, Faucett J, Lichtenberg P, Kirsch I, Brown WA. A Systematic Review of
Comparative Efficacy of Treatments and Controls for Depression. PLoS One. 2012 Khanal R, Nemere I. Membrane receptors for vitamin D metabolites. Crit Rev Eukaryot Gene Expr. 2007
Khoraminya N, Tehrani-Doost M, Jazayeri S, Hosseini A, Djazayery A. Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. Aust N Z J Psychiatry. 2013
20 Kim SH, Seok H, Kim DS, MDcorresponding author. Relationship Between Serum Vitamin D Levels and Symptoms of Depression in Stroke Patients. Ann Rehabil Med. 2016 Kirsch I. Antidepressants and the Placebo Effect. Z Psychol. 2014
Konakchieva R, Mitev Y, Almeida OF, Patchev VK. Chronic melatonin treatment counteracts glucocorticoid-induced dysregulation of the hypothalamic-pituitary- adrenal axis in the rat. Neuroendocrinology. 1998
Koo W, Walyat N. Vitamin D and skeletal growth and development. Curr Osteoporos Rep.
2013
Kumar R. Metabolism of 1,25-dihydroxyvitamin D3. Physiol Rev. 1984
Leonard BE. The concept of depression as a dysfunction of the immune system. Curr Immunol Rev. 2010
Li G, Mbuagbaw L, Samaan Z, Zhang S, Adachi JD, Papaioannou A, Thabane L. Efficacy of vitamin D supplementation in depression in adults: a systematic review protocol. Syst Rev. 2013
Lin SH, Lee LT, Yang YK. Serotonin and Mental Disorders: A Concise Review on Molecular Neuroimaging Evidence. Clin Psychopharmacol Neurosci. 2014
Lu M, Taylor BV, Körner H. Genomic Effects of the Vitamin D Receptor: Potentially the Link between Vitamin D, Immune Cells, and Multiple Sclerosis. Front Immunol. 2018 Luan W, Hammond LA, Cotter E, Osborne GW, Alexander SA, Nink V, Cui X, Eyles DW.
Developmental Vitamin D (DVD) Deficiency Reduces Nurr1 and TH Expression in Post- mitotic Dopamine Neurons in Rat Mesencephalon. Mol Neurobiol. 2018
Madsen MT, Isbrand A, Andersen UO, Andersen LJ, Taskiran M, Simonsen E, Gögenur I.
The effect of MElatonin on Depressive symptoms, Anxiety, CIrcadian and Sleep
disturbances in patients after acute coronary syndrome (MEDACIS): study protocol for a randomized controlled trial. Trials. 2017
Malhotra S, Sawhney G, Pandhi P. The Therapeutic Potential of Melatonin: A Review of the Science. MedGenMed. 2004
Matchar DB, Chei CL, Yin ZX, Koh V, Chakraborty B, Shi XM, Zeng Y. Vitamin D Levels and the Risk of Cognitive Decline in Chinese Elderly People: the Chinese Longitudinal Healthy Longevity Survey. J Gerontol A Biol Sci Med Sci. 2016
Mayo Clinic Staff. Seasonal affective disorder (SAD). Mayo Clinic. 2017
Meana-Pañeda R, Fernández-Ramos A. Tunneling and conformational flexibility play critical roles in the isomerization mechanism of vitamin D. J Am Chem Soc. 2012 Melrose S. Seasonal Affective Disorder: An Overview of Assessment and Treatment Approaches. Depress Res Treat. 2015
Milaneschi Y, Hoogendijk W, Lips P, Heijboer AC, Schoevers R, van Hemert AM, Beekman AT, Smit JH, Penninx BW. The association between low vitamin D and depressive disorders. Mol Psychiatry. 2014
Mitchell HA, Weinshenker D. Good Night and Good Luck: Norepinephrine in Sleep Pharmacology. Biochem Pharmacol. 2010
21 Montañez S, Daws LC, Gould GG, Frazer A. Serotonin (5-HT) transporter (SERT) function after graded destruction of serotonergic neurons. J Neurochem. 2003
Morera AL, Abreu P. Seasonality of psychopathology and circannual melatonin rhythm.
J Pineal Res. 2006
Nair R, Maseeh A. Vitamin D: The “sunshine” vitamin. J Pharmacol Pharmacother. 2012 Nair S. Vitamin D Deficiency and Liver Disease. Gastroenterol Hepatol (N Y). 2010 Nomura M, Kaneko M, Okuma Y, Nomura J, Kusumi I, Koyama T, Nomura Y. Involvement of Serotonin Transporter Gene Polymorphisms (5-HTT) in Impulsive Behavior in the Japanese Population. PLoS One. 2015
Nutt DJ. Relationship of neurotransmitters to the symptoms of major depressive disorder. J Clin Psychiatry. 2008
Mitchell NC, Koek W, Daws LC. Antidepressant-like effects and basal immobility depend on age and serotonin transporter genotype. Genes Brain Behav. 2015
Okereke OI, Singh A. The Role of Vitamin D in the Prevention of Late-life Depression. J Affect Disord. 2016
Olivier JDA, Åkerud H, Skalkidou A, Kaihola H, Sundström-Poromaa I. The effects of antenatal depression and antidepressant treatment on placental gene expression.
Front Cell Neurosci. 2014
Parker GB, Brotchie H, Graham RK. Vitamin D and depression. J Affect Disord. 2017 Patrick RP, Ames BN. Vitamin D and the omega-3 fatty acids control serotonin
synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB J. 2015
Patrick RP, Ames BN. Vitamin D hormone regulates serotonin synthesis. Part 1:
relevance for autism. FASEB J. 2014
Pertile RAN, Cui X, Hammond L, Eyles DW. Vitamin D regulation of GDNF/Ret signaling in dopaminergic neurons. FASEB J. 2018
Peuhkuri K, Sihvola N, Korpela R. Dietary factors and fluctuating levels of melatonin.
Food Nutr Res. 2012
Pies R. Are Antidepressants Effective in the Acute and Long-term Treatment of Depression? Innov Clin Neurosci. 2012
Pizzagalli DA. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol. 2014
Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and Immune Function. Nutrients. 2013 Quinn B. Seasonal Affective Disorder and Beyond: Light Treatment for SAD and Non- SAD Conditions. edited by Raymond W. Lam, M.D. Washington, D.C., American Psychiatric Press, 1998. Prim Care Companion J Clin Psychiatry. 2000
Reevy G, Ozer YM, Ito Y. Encyclopedia of Emotion, Volume 1. Greenwood, copyright by Gretchen Reevy. 2010
22 Roecklein KA, Rohan KJ. Seasonal Affective Disorder: An Overview and Update.
Psychiatry (Edgmont). 2005
Roff A, Wilson RT. A novel SNP in a vitamin D response element of the CYP24A1 promoter reduces protein binding, transactivation, and gene expression. J Steroid Biochem Mol Biol. 2008
Ross AC, Taylor CL, Yaktine AL. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Washington (DC): National Academies Press (US); 2011.
Sachdeva P, Patel BG, Patel BK. Drug use in pregnancy; a point to ponder! Indian J Pharm Sci. 2009
Shaffer JA, Edmondson D, Wasson LT, Falzon L, Homma K, Ezeokoli N, Li P, Davidson KW.
Vitamin D supplementation for depressive symptoms: a systematic review and meta- analysis of randomized controlled trials. Psychosom Med. 2014
Shoenfeld N, Amital H, Shoenfeld Y. The effect of melanism and vitamin D synthesis on the incidence of autoimmune disease. Nat Clin Pract Rheumatol. 2009
Sidney H. Kennedy, MD. Core symptoms of major depressive disorder: relevance to diagnosis and treatment Dialogues. Clin Neurosci. 2008
Silverman ME, Reichenberg A, Savitz DA, Cnattingius S, Lichtenstein P, Hultman CM, Larsson H, Sandin S. The risk factors for postpartum depression: A population-based study. Depress Anxiety. 2017
Sohel AJ, Molla M. Fluoxetine. StatPearls Publishing, 2018
Spedding S. Vitamin D and Depression: A Systematic Review and Meta-Analysis Comparing Studies with and without Biological Flaws. Nutrients. 2014
Trinko JR, Land BB, Solecki WB, Wickham RJ, Tellez LA, Maldonado-Aviles J, de Araujo IE, Addy NA, DiLeone RJ. Vitamin D3: A Role in Dopamine Circuit Regulation, Diet-Induced Obesity, and Drug Consumption. eNeuro. 2016
Tsai HY, Chen KC, Yang YK, Chen PS, Yeh TL, Chiu NT, Lee IH. Sunshine-exposure variation of human striatal dopamine D(2)/D(3) receptor availability in healthy volunteers. Prog Neuropsychopharmacol Biol Psychiatry. 2011
Tsai HY, Chen KC, Yang YK, Chen PS, Yeh TL, Chiu NT, Lee IH. Sunshine-exposure variation of human striatal dopamine D(2)/D(3) receptor availability in healthy volunteers. Prog Neuropsychopharmacol Biol Psychiatry. 2011
Vaziri F, Nasiri S, Tavana Z, Dabbaghmanesh MH, Sharif F, Jafari P. A randomized controlled trial of vitamin D supplementation on perinatal depression: in Iranian pregnant mothers. BMC Pregnancy Childbirth. 2016
Virk G, Reeves G, Rosenthal NE, Sher L, Postolache TT. Short exposure to light
treatment improves depression scores in patients with seasonal affective disorder: A brief report. Int J Disabil Hum Dev. 2009
23 Vukić M, Neme A, Seuter S, Saksa N, de Mello VDF, Nurmi T, Uusitupa M, Tuomainen TP, Virtanen JK, Carlberg C. Relevance of Vitamin D Receptor Target Genes for Monitoring the Vitamin D Responsiveness of Primary Human Cells. PLoS One. 2015
Wacker M, Holick MF. Sunlight and Vitamin D A global perspective for health.
Dermatoendocrinol. 2013
World Health Organisation [Internet]. Depression. 2017
Zhang R, Naughton DP. Vitamin D in health and disease: Current perspectives. Nutr J.
2010
