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.

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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

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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).

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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).

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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

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