Is vitamin D actually helpful for your mental health?
The Trifecta of Mental Health Supplements: Vitamin D, Probiotics & Fish Oil
This post is the first in a series of three in which we will thoroughly explore the darlings of supplementation for mental health: vitamin D, probiotics and fish oil. Read on to learn it all – the good, the bad and the ugly.
Whether it’s a mood disorder, an eating disorder, schizophrenia, autism, or even the adverse effects from earthquakes (yes, it’s been studied!) there is something promising enough about vitamin D that makes us ask:
Will vitamin D help me/my child feel better?
The first consideration to make when examining studies on vitamin D is that we can have low levels of vitamin D for a number of reasons aside from inadequate sun exposure.
In looking at mental illness we have to remember to see the patient as a whole person. This is not just about the brain. This could be about inflammation, anemia, gut dysbiosis, thyroid dysfunction…and supplementing with vitamin D, while making lab values look better or possibly improving symptoms, may completely miss the root cause of the problem.
In addition to that, did you know that getting your vitamin D from a supplement will not give you the same benefits as getting your vitamin D from the sun?
Naturally the next question is:
Are there some scenarios in which boosting vitamin D
through supplementation may be an appropriate consideration?
For this question, we’ll focus on several mental health conditions with links to low vitamin D levels and the outcomes of supplementation in each of these conditions. This post covers schizophrenia, depression, autism, eating disorders and ADHD – if you’re primarily interested in just one of these conditions please feel free to scroll down to the appropriate topic.
Schizophrenia
Early Life Vitamin D Status
During the earliest years of our lives, there is potential for vitamin D deficiency due to the lack of vitamin D in breast milk. Interestingly, vitamin D deficient rats will produce offspring that have changes in brain structure eerily similar to the changes we see in schizophrenia [1]. In humans, there does not seem to be a link between prenatal vitamin D levels and psychotic episodes [2], but there is some relationship between childhood vitamin D deficiency and the later development of schizophrenia [3].
As one would therefore expect, vitamin D supplementation during infancy has long ago been linked to a reduced risk of schizophrenia in males [3,4]. However, correlational study, where the two variables of vitamin D supplementation and the development of schizophrenia are studied as they naturally occur without intervention, is slightly problematic. This type of study cannot rule out other factors that would influence both schizophrenia risk and vitamin D status. These factors include nutrition, toxicant exposure, socioeconomic status, and other lifestyle factors.
What is perhaps most fascinating is one study that actually found a correlation between higher levels (in addition to lower levels) of vitamin D as an infant and psychosis [3]! More is not always better!
Vitamin D and the Onset of Psychotic Symptoms
Once we get into adolescence and young adulthood, we see that lower bioavailable vitamin D correlates to the severity of patients’ symptoms in their first episode of psychosis [5].
There are conflicting reports on vitamin D status depending on whether patients are in a first episode of psychosis (which also affects how long they have been on medication), if they have had schizophrenia for a longer period of time, and how their vitamin D levels were measured.
The overall consensus is that those with schizophrenia have significantly lower total vitamin D levels than healthy populations [6,7].
Once a treatment regimen of antipsychotic drugs begins, serum levels of vitamin D will likely deteriorate further, as these drugs interfere with vitamin D synthesis and contribute to obesity. Other factors playing a role in vitamin D status are decreased sun exposure (either through withdrawal from activities or through psychiatric hospitalization), poor nutrition and malabsorption issues.
Is Supplementation the Answer?
With all the data on low vitamin D levels in patients with schizophrenia, many claim that we need to establish appropriate vitamin D supplementation protocols for this group of people. Yet the existence of such trials (on vitamin D3 supplementation specifically) remains almost nonexistent.
One trial that used 600,000 IU of vitamin D over two treatments found improvement in negative symptoms (blunted emotions, poor rapport, apathy, etc) at three months but the correlation did not reach levels of significance [8].
This trend is important to note, even if it was not significant. The little research that has been done may not be terribly promising but perhaps we are studying the wrong patient population. Could there be a subset of patients that would respond to vitamin D supplementation?
It is possible that there are some patients that would benefit more from supplementation than others, and this study was not designed to account for differences in proline dehydrogenase or COMT. You’ll see why these are important in the next section.
Too little vitamin D, or too much proline?
Now consider this: the trial that used 600,000 IU found an improvement in negative symptoms. Negative symptoms also happen to be correlated with high proline levels [9]. Coincidence? Likely not. One of the areas of greatest genetic risk for schizophrenia involves the enzyme proline dehydrogenase, an enzyme that breaks down proline. Vitamin D is involved in the expression of proline dehydrogenase. When vitamin D is suboptimal, proline levels can increase because this enzyme isn’t functioning at its best. It makes sense that giving vitamin D could upregulate expression of proline dehydrogenase and decrease proline levels, impacting negative symptoms specifically.
Elevated proline levels may be a better predictor of schizophrenia risk than actual vitamin D insufficiency itself, as it can account for one third of the relationship between schizophrenia and low vitamin D [10].
Perhaps vitamin D supplementation to stimulate increased expression of proline dehydrogenase would be beneficial for the quarter of schizophrenia patients estimated to have hyperprolinemia (so long as there is not a loss of function for that enzyme) [10].
While this is an interesting consideration, more research is needed to evaluate vitamin D supplementation at an appropriate dosage, long enough follow-up interval, and in the context of proline levels, vitamin D levels, proline dehydrogenase functioning, and COMT mutations.
COMT mutations? How does that affect proline?
You may be familiar with the COMT SNP rs4680 as the Worrier or Warrior SNP. Those with homozygous A/A (or Met/Met) are simplistically referred to as the “worriers” and those with homozygous G/G (or Val/Val) as the “warriors”. These don’t necessarily confer risks on their own in the context of schizophrenia, but they can interact with other variables to impact symptom severity and response to treatment. COMT is responsible for an enzyme involved in catecholamine (for example, dopamine) inactivation.
Those with the Val/Val version of COMT have lower dopamine in the front of their brain (involved in decision making and executive functioning tasks) than those with the Met/Met version. More dopamine may (theoretically) lead to cognitive rigidity and negative symptoms in schizophrenia.
If we combine Met/Met (i.e. slower dopamine inactivation and higher dopamine levels) with high proline levels we get significantly increased negative symptoms [9]. Here we have more proline leading to more dopamine without good enzyme activity for inactivating the excess dopamine.
High proline + Higher dopamine (Met/Met version) increased negative symptom severity
If we combine Val/Val (more dopamine inactivation) with high proline levels we actually get lower negative symptoms [9]. Here we have more proline leading to more dopamine but with increased enzyme activity for inactivating dopamine. In this case high proline may be helpful in keeping the increased COMT enzyme activity from dropping dopamine levels below their narrow functional range.
High proline + Lower dopamine (Val/Val version) decreased negative symptom severity
Clearly, context matters in determining the effects of proline levels. In some people, high proline may be protective while in others it is detrimental. Drugs like Valproate that increase proline may have a beneficial effect on Val/Val patients by further increasing proline, while having negative effects on those who are Met/Met [9]. In addition, gender can influence COMT activity through testosterone (increasing activity) and estrogen [11]. Cannabis use and childhood maltreatment also interact with the COMT genotype and psychosis risk [12].
Could vitamin D supplementation be dangerous for infection-related psychosis?
Even if you decide to supplement vitamin D, and see the levels rise on your labs, that increased vitamin D may not be able to be used by the body. Some infections, for example, cause vitamin D receptors to be downregulated, meaning the body can’t “see” that vitamin D.
How might this be problematic? Well here’s an example specific to schizophrenia. One infection associated with schizophrenia is Toxoplasma gondii, a miserable little parasite you can get from food.
Work by one group of researchers suggests that treating cells with vitamin D could prevent the Toxoplasma from growing and spreading in a petri dish of cells [13]. However, adding vitamin D actually reduced survival in the animal model [14]! It is thought that vitamin D suppresses the necessary immune response for controlling early infection [14].
Supplementing yourself into acute toxoplasmosis could hardly be considered a helpful recommendation!
And that’s just one infection implicated in conditions like schizophrenia. Others may also interfere with vitamin D and this is why we must be careful to address the root cause.
So far we’ve gone through one situation (hyperprolinemia) in which vitamin D may be beneficial with further study and one situation (Toxoplasma or other infection) in which vitamin D may be rather detrimental. This point about finding the root cause of an illness really can’t be reiterated enough.
Depression
While vitamin D supplementation trials in schizophrenia are few, there are numerous studies on vitamin D supplementation for depression. However, after years of trials we still have mixed results [15–17], which, again, really highlights the need to assess the root cause.
What do vitamin D levels indicate about root cause?
There are many conditions that could contribute to depression and/or that could contribute to low serum vitamin D levels. If vitamin D levels are already adequate, further supplementation may not improve symptoms of depression as other contributing factors are clearly at play.
Now if vitamin D levels are low, supplementation may still not improve symptoms. After all, vitamin D status can simply reflect an underlying pathology that will continue unchecked if supplementation is used as a band-aid approach without further investigation.
One way in which low vitamin D can contribute to depression is through increased calcium levels within cells [18]. These elevated calcium levels have a negative effect on GABAergic neurons (inhibitory neurons) and are associated with depression, as well as Alzheimer’s disease. Vitamin D binds to the vitamin D receptor within cells and reduces this calcium by increasing processes involved in calcium homeostasis. If vitamin D levels are low, we may have trouble controlling runaway calcium levels.
How effective is vitamin D supplementation in treating depression?
Unfortunately, many studies of vitamin D and depression do not use study populations of clinically severe depression, and the dosing and follow-up intervals are highly variable [16]. This poses a challenge in determining the effectiveness of the interventions.
While vitamin D supplementation may be a widely accepted treatment in the clinical realm, its use is not so widely supported by the research world. Existing data suggests little benefit in study populations overall, although supplementation may be of use for severely depressed patients specifically [17].
It is also valuable to differentiate between youth populations and adult populations. As one review pointed out, vitamin D deficiency could cause alterations early in life that supplementation in adulthood will be unable to correct [15]. It will be interesting to see the results of a newer trial focused on vitamin D supplementation in a pediatric and adolescent population presenting with both clinical depression and low vitamin D.
In the meantime, what do we do? Well we can always focus on prevention and lifestyle. Going outside and getting some sunshine provides a myriad of benefits that taking a supplement won’t give you.
Autism
Behavioural effects on vitamin D levels
We mentioned earlier that low vitamin D could be a signal of other issues like inflammation and infection. In the case of autism spectrum disorders, low vitamin D levels may partly be due to behavioural changes affecting dietary vitamin D intake (picky eating) and sunshine exposure [15].
Many factors are involved in the vitamin D status of children with autism spectrum disorders. These include sedentary behaviour, medical conditions, medications, picky eating, late intro of solid foods, a less varied diet, decreased sun exposure, and autoantibody production [15, 19].
Associations with vitamin D and serotonin levels
However, vitamin D definitely has some important associations with serotonin, a neurotransmitter involved in social behaviours and reading other people’s emotional and social cues. This association begins prenatally when adequate levels of vitamin D prevent the mother’s body from attacking her growing child. A large number of pregnant women do not have sufficient levels of vitamin D [20,21]. The association continues as the baby’s brain grows and vitamin D is needed to activate the enzyme responsible for producing serotonin in the brain.
There are two enzymes used in serotonin production. One is used in the brain and one is used in tissues outside of the brain. Vitamin D promotes serotonin production in the brain and inhibits serotonin production outside of the brain. Interestingly, serotonin produced via the enzyme used by gastrointestinal cells creates inflammation whereas the serotonin produced via the enzyme used by the gastrointestinal nervous system stimulates gastrointestinal motility [20].
Children with autism spectrum disorders have more activity of the enzyme for serotonin synthesis outside of the brain, and less activity of the enzyme used for serotonin synthesis inside the brain. This is important because serotonin cannot cross the blood brain barrier and must be produced in the brain to be used in the brain. Vitamin D is also important for the proper functioning of oxytocin and vasopressin, both of which are related to the behaviours seen in autism [20].
Effects of vitamin D supplementation
With the relationship to low vitamin D levels, one might expect supplementation to provide benefit. Unfortunately there isn’t enough research to draw that conclusion at this point. While vitamin D insufficiency has clear links to autism, we don’t actually know how beneficial supplementation would be [19].
While one study found improvement in autism scores with the use of vitamin D supplementation, the trial did not include a control group [22]. This questions how effective the supplementation actually was because another intervention trial found improvement in both a group of children who received vitamin D supplementation, as well as in the control group of children who did not receive supplementation [23]. This suggests two alternate explanations for the improvement found in the uncontrolled study: The possibility that the children given vitamin D could have improved anyways (without the supplementation), and the possibility of a placebo effect.
A more recent study also found improvement in autism scores but had a huge drop out rate and again, no placebo control [24]. This gives rise to concerns of healthy user bias, differences between the kids that remained in the study and those that wouldn’t or couldn’t cooperate, and biased reporting of improvements. One interesting trend that can be taken from this study was a greater improvement in younger children (3 years old and younger) than older children [24].
These studies may have some promise, but don’t give a clear sense of effectiveness over placebo. To ameliorate this problem, randomized, controlled trials of vitamin D supplementation in children with autism are needed. Two such studies have been published in the last two years.
The first demonstrated that vitamin D supplementation (300 IU/kg/day with a max dose of 5000 IU/day) over four months was effective in improving scores of aberrant behaviour and social responsiveness [25]. The second was a smaller study, and found no effect of vitamin D supplementation over five months [26].
What are some possible reasons for these conflicting results?
First of all, as a recent review points out, it is possible that vitamin D deficiency prenatally may have effects that cannot be countered by later supplementation [27]. In addition, autism spectrum disorders are multifactorial. Not all of the children in the first study saw improvement with vitamin D supplementation, although most did [25,27]. While vitamin D may play a big role for one child, it may not be the proverbial straw that broke the camel’s back for another child. In addition, it’s possible that a combination of therapies may be needed. Vitamin D may not improve production of serotonin in the brain if there is not enough tryptophan to produce it from. Trials using a combination of vitamin D and tryptophan supplementation may reveal completely different results.
That pesky COMT business makes another appearance
We explored the impact of proline levels and COMT polymorphisms in the context of schizophrenia, and given the similarities between schizophrenia and autism it shouldn’t be terribly shocking that these two variables play a role in autism as well.
High proline combined with a Met/Met genotype has been found to correlate to severity of symptoms in children with autism [28]. Understanding the relationships between proline, COMT and vitamin D, we can see how low levels of vitamin D could impact these children.
Less vitamin D More proline
More proline + More dopamine (Met/Met) increased symptom severity
Regardless of debate around how effective supplementation is and the mechanism by which low vitamin D is linked to autism, addressing problems in natural routes of obtaining vitamin D may be a useful first step in removing obstacles to health. Further studies that differentiate between supplementation in younger versus older children, that supplement vitamin D along with tryptophan, or that include evaluations of COMT and proline levels would also allow us to see which specific populations with autism could most benefit.
Eating Disorders
When it comes to eating disorders, an immediate consideration would be the role of vitamin D in bone health for a severely malnourished population. However, let’s start from the very beginning.
Prenatal Vitamin D Status and Eating Disorders
Low maternal vitamin D levels (18.30-45.98 nmol/l) during the second trimester have been linked to twice the risk of a child developing an eating disorder by age 20 [29]. This effect was seen with female children, but was not significant for male children [29].
An interesting point regarding this finding is the different effects low vitamin D might have on the developing brain during different trimesters. For example, this study examined vitamin D levels in the second trimester, but others studies have looked at the relationship between low vitamin D in the third trimester and disorders such as schizophrenia [29].
Vitamin D Deficiency in Eating Disorders
While vitamin D may be low prenatally, vitamin D and parathyroid hormone levels may actually be better in or comparable between adolescents with anorexia nervosa and healthy controls [30,31]. This could be partially due to the decreased fat available for storage of vitamin D and the higher amount of vitamin D remaining in circulation, the increased proportion who are supplementing with vitamin D and/or the fairly high compliance with supplementation in this group [30].
Bone Health in those with Eating Disorders
In those with eating disorders, such as anorexia nervosa, vitamin D deficiency is related to low bone mineral density in the spine, the hips and the legs [32]. Correcting this low bone mineral density in adolescence gives the best chances for improving bone health in adulthood, but although vitamin D supplementation is important, it is not enough by itself [32,33]. Some would even argue that low vitamin D levels are not actually a factor in anorexia-related bone loss [31]. This finding may depend on the particular patient population studied.
Poor bone health in adolescents is a challenging issue because treatments used for adults with osteoporosis are not necessarily effective in a younger population [32,33]. Gaining weight, transdermal estrogen and the return of menses have the strongest effect in improving bone mineral density, while SSRI use and oral contraceptives are detrimental [32,33]. It has been suggested that adequate vitamin D status is needed for weight gain to have the desired effect on bone health [34].
Those with anorexia not only have low bone mineral density, but they also have poor bone microarchitecture, providing another risk for fractures. Interestingly enough, weight-bearing exercise does not seem to improve bone health in those with anorexia until after recovery [33]. There are additional concerns with recommending exercise in this patient population, one of which would be the potential for appetite suppression [35].
ADHD
Prenatal Vitamin D Levels
In attention deficit hyperactivity disorder we see again the importance of prenatal vitamin D levels. Low prenatal vitamin D levels are associated with an increased risk for ADHD problem scores in toddlers while higher vitamin D levels are associated with a lower risk [36,37]. There are some discrepancies amongst studies of prenatal vitamin D levels and risk of ADHD symptoms depending on the ages studied and the symptom reports used. Vitamin D alone is not the only risk factor [38]. Having a young mother, a mother with low or high BMI, a mother who smoked or drank alcohol during pregnancy, a parent with a psychiatric condition and being a male child are all factors associated with ADHD [36].
Vitamin D Levels in Childhood
Whether or not prenatal vitamin D levels are lower for children who go on to exhibit ADHD-like behaviours, we see that children with ADHD have significantly lower vitamin D levels than healthy children and maybe even lower than children with autism spectrum disorders [39,40]. Does this mean we should supplement with vitamin D? Not necessarily, but it should call into question dietary and lifestyle factors that may have an influence on normalizing these levels [41].
Vitamin D Supplementation as a Complementary Therapy
Disregarding the reasons for low vitamin D for a moment, could it be that supplementing with vitamin D is useful in ADHD? Vitamin D is needed for the production of serotonin, a neurotransmitter involved in behaviour, impulse control and decision-making. Omega 3’s are also needed for optimal serotonin functioning and these will be discussed in a future post. Low serotonin levels have also been implicated in autism spectrum disorders and schizophrenia.
If we have a particular situation (whether it be infection, inflammation etc) leading to low levels of vitamin D, we’re going to see a negative effect on serotonin production. Supplementing with vitamin D would theoretically be useful in these cases because it would allow for enhanced serotonin production. This may be beneficial in the short-term, while underlying causes are investigated and addressed if possible.
Let’s look at vitamin D deficient children taking methylphenidate (Ritalin) for ADHD. What happens when we add 2000 IU of vitamin D to their daily routine? After two months, we may see some improvement in symptoms later in the day [42]. However, the effects of the pharmaceutical may overpower any strong effects of vitamin D and studies are needed to examine how much of an effect vitamin D supplementation would have on its own.
Final Thoughts
There may be severe cases (or other conditions) or subsets of patient populations where supplementation is useful. These studies aren’t perfect, and until we have better trials, we don’t really know the effectiveness of vitamin D supplementation for schizophrenia, depression, eating disorders, ADHD or autism spectrum disorders. Current research does not provide a ton of support for the use of vitamin D supplementation [for review see 16].
In particular, it would be great to see more research on specific subsets of patients, such as the combinations of schizophrenia with high proline levels, various conditions with screening for key infections that alter vitamin D status, depression at a severe level, and autism with different age groups.
As always, we do want to investigate the root cause of illness and long-term supplementation may not be the appropriate answer. In fact, low vitamin D levels may be a very real indicator that something else is wrong.
There is no dispute that vitamin D is critical for many aspects of health, or that it has associations with many mental health conditions. The dispute is whether supplementation is useful or not. Would we be better off attempting to remove obstacles to health (i.e. things that could be lowering our vitamin D levels) and increasing vitamin D through diet and sunshine? And are there specific cases in which supplementation is helpful or needed?
In mental health there are times when acute measures are taken to effect change quickly and keep a patient safe, so it is important to investigate which supplements could be of use. In addition, we must still consider the effect of vitamin D on the developing brain and the possibility that supplementation may have benefits prenatally or at an early age that it would not have later on in life.
Then again, is it really vitamin D levels that are the problem? Because that’s a number we could change on paper, but why silence with supplementation a signal that the body needs help? Will supplementation actually provide complete relief on its own? Or can we use supplementation in the short-term while removing obstacles to health? Tolle causum. Tolle totum. Treat the cause, treat the whole person.
Further Reading
Vitamin D: Chasing a myth?
Nutritional Deficiencies: Could infection be the culprit?
Vitamin D Supplements: What you miss out on
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