The psychotropic effect of vitamin D supplementation on schizophrenia symptoms

Schizophrenia is a multifactorial disease involving interactions between genetic and environmental factors. Although various theories have been proposed to explain its etiology, the most accepted one is the neurodevelopmental model. According to this model, based on a genetic liability, environmental factors such as adverse events or potentially harmful stressors in the perinatal period disrupt the brain’s normal maturation process and neuronal development. After a certain latent period, the clinical symptoms appear in adolescence or young adulthood [1]. Schizophrenia prevalence varies in geographic regions. Environmental risk factors such as a high schizophrenia prevalence at higher latitudes, in winter/spring births, and darker-skinned people support the role of vitamin D in the etiology of schizophrenia [2‐5].

Almost all (90–95%) of vitamin D, the only vitamin that can be synthesized in the human body, is synthesized in the skin by the effect of direct sunlight. The amount taken with diet is minimal. Provitamin D turns into vitamin D₃ in the skin with the effect of ultraviolet-B rays. Vitamin D₃ undergoes hydroxylation first in the liver to generate 25-hydroxyvitamin D (25OHD) and then in the kidneys to generate the physiologically active form, 1,25-dihydroxyvitamin D (1,25 OH-2D). It binds to the vitamin D receptor (VDR) in tissues [3, 6‐8]. The amount of synthesized vitamin D depends on age, skin color, season, ethnicity, and duration of sun exposure, the latitude of the place of residence, use of sunscreen, clothing style, and the size of the skin surface exposed to the sun [8, 9]. The best parameter to show vitamin D level is the serum 25OHD level [10].

While a major role of vitamin D concerns calcium balance and bone metabolism, it also serves several other metabolic functions. Recent studies have shown associations between vitamin D and autoimmune, metabolic, neurological, and allergic diseases and malignancies. Vitamin D also has potential links with psychiatric illnesses such as schizophrenia, autism, attention-deficit/hyperactivity disorder (ADHD), depression, premenstrual syndrome, and anxiety [6, 11‐15].

Vitamin D plays essential roles in neuroplasticity, neurotransmitter biosynthesis, neuroprotection, and neurotransmission in developing and adult brains [16‐18]. Vitamin D reduces oxidative stress and inflammation caused by free radicals and reactive oxygen metabolites by inducing certain neurotrophic factors [6, 16, 19, 20].

The enzyme that converts vitamin D into the active form (1-α hydroxylase) and VDRs are found in several parts of the body, including the substantia nigra, hippocampus, thalamus, hypothalamus, amygdala, prefrontal gyrus, and cingulate gyrus. This enzyme plays a role in regulating behavior in the central nervous system [11, 14, 19, 21]. In brain imaging studies about vitamin D, inverse relationships were found among vitamin D levels and total intracranial volume, total cortical gray matter, and cerebral white matter volumes [22, 23]. Decreased hippocampal volume in schizophrenia has been shown in several studies. The hippocampus is the brain region with the highest number of VDRs. Vitamin D plays a crucial role in hippocampal cell life through its neuroprotective effect [16].

Exposure to low maternal vitamin D levels in the fetus and low 25OHD levels in the neonatal period were found to increase the risk of developing schizophrenia in later years [17]. Animal studies reported that dopamine metabolism is affected in the brains of rats that had developmental vitamin D deficiency during the gestational period [24]. The risk of schizophrenia was shown to decrease by 77% in people who had taken vitamin D supplements in the first year of life [11].

Vitamin D deficiency was seen in more than half of the adult population and was considered to be at a pandemic level in several publications [25‐27]. Vitamin D deficiency is more common in patients with schizophrenia due to factors such as social isolation, lack of movement, smoking, spending less time outside, malnutrition, and disruption of vitamin D synthesis by antipsychotic drugs [2, 7, 19, 28‐31].

Studies on vitamin D deficiency in schizophrenia patients usually include the first episode and acute exacerbation periods. Vitamin D levels outside these periods have been rarely studied. Also, there are very few studies in the literature examining the effect of vitamin D replacement on disease symptoms. Therefore, we aimed to investigate the rates of vitamin D deficiency, related factors, and the effect of vitamin D replacement on clinical symptoms and cognitive functions in schizophrenia patients who attended an outpatient treatment facility in our region.

At the beginning of the study, the mean 25OHD levels of 52 schizophrenia patients were 17.89 ± 6.22 ng/mL (n = 52, min: 4.26, max: 34.00); 14.39 ± 6.53 in women (n = 8) and 18.53 ± 6.02 in men (n = 44). Only 3.8% (n = 2) of the patients had 25OHD levels within the normal range. Approximately 96% (n = 50) were below the optimal vitamin D levels.

Vitamin D deficiency was found in 65.4% (n = 34) of the patients with vitamin D values below the normal limit, and vitamin D insufficiency was found in 30.8% (n = 16). Serum calcium, phosphorus, creatinine, parathyroid hormone, and alkaline phosphatase levels were within normal limits in all patients. In our study, no side effect related to vitamin D replacement was observed.

Our study is one of the few studies in the literature examining the effects of vitamin D replacement on schizophrenia symptoms. Of three other studies, one has not yet been completed [37‐39]. In our study, significant improvements in total SANS, SAPS, and their subscale scores and TASs were found after vitamin D replacement compared to the values before replacement in schizophrenia patients. To the best of our knowledge, this study is the first to show improvement in negative and positive symptoms in schizophrenia patients with the treatment of vitamin D deficiency.

Previous studies in schizophrenia patients found vitamin D deficiency rates varying between 22 and 65% and insufficiency rates between 30 and 66% during the acute exacerbation period and during hospitalization [7, 19, 30, 40]. These rates were even higher in the treatment-resistant patient group (79–90%) [41]. These data have also been confirmed by meta-analysis and review studies examining vitamin D levels in patients with schizophrenia [2, 42]. In our study, 65.4% of the patients had vitamin D deficiency (< 20 ng/dL), 30.8% had vitamin D insufficiency (20–29.9 ng/dL), and only 3.8% of the patients had an optimal level of vitamin D. Similar to our study, Bulut et al. (2016) conducted a study with schizophrenia patients in an outpatient clinic. They found that vitamin D levels were deficient in 20%, insufficient in 13.75%, and sufficient in 61.25% of the patients [43]. Yuksel et al. (2014) found vitamin D deficiency in 22%, vitamin D insufficiency in 68.3%, and adequate vitamin D levels in only 9.8% of the patients. Although our study population consisted of outpatients and blood samples were taken between May and July when sunlight is more intense, the rates of low vitamin D levels were found to be high, similar to those in studies conducted during the acute exacerbation period [7]. Vitamin D synthesis varies according to geographic location and seasonal characteristics [5, 42]. Trabzon is located in northern Turkey (38° 30′ – 40° 30′ East and 40° 30′ – 41° 30′ North). Based on the data provided by the Governorship of Trabzon, the average number of sunny days during the year is very low [44]. The results obtained in this study may be due to the geographical characteristics of the city where the study was conducted.

In our study, vitamin D levels in schizophrenia patients were found to be associated with the duration of sunlight exposure. No relationship was found between vitamin D levels and other variables such as smoking, tea and coffee consumption, skin color, physical activity level, diet (fish consumption), clothing style, and BMI. The duration of sunlight exposure positively affects vitamin D levels in patients with schizophrenia [42]. A meta-analysis study found that vitamin D levels in psychotic patients were only related to the season in which blood samples were taken and parathyroid hormone levels [4]. Since 90–95% of vitamin D is synthesized in the skin through exposure to direct sunlight, other variables may not affect vitamin D levels. Our findings suggest that sunlight is more critical than other factors for vitamin D synthesis.

The trials about the association between vitamin D deficiency and disease severity in schizophrenia patients were generally conducted with patients in the acute exacerbation period, and the results vary. Although vitamin D levels were found to be low in psychotic patients, this was reported to be independent of the severity of the disease [19, 30, 45, 46]. Several studies are reporting that low vitamin D is associated with negative symptoms of schizophrenia [9, 11, 20, 47‐50]. In some studies, low vitamin D levels were found to be associated with both positive and negative symptoms [7, 43, 51, 52]. No association was found between vitamin D levels and SANS and SAPS scale and subscale scores in our study. Studies reporting an association between vitamin D levels and symptom severity were usually conducted with patients in the acute exacerbation period. Since the patients included in our study were outpatients, the association between vitamin D levels and disease severity might have been missed.

Vitamin D deficiency has been reported to cause attention and memory deficiencies and cognitive impairment [30]. VDR and 1α-hydroxylase are expressed at high levels in brain areas important for cognitive functions, such as the hippocampus and cortex. Vitamin D also affects the production of various neurotransmitters, such as acetylcholine, dopamine, and serotonin [53]. Therefore, a relationship between 25OHD and cognitive functions is possible. Vitamin D deficiency is associated with various neurodegenerative disorders in which cognitive impairment is an important feature (i.e., schizophrenia, depression, attention deficit hyperactivity disorder, autism spectrum disorders, and Alzheimer’s disease) [15]. Low vitamin D in schizophrenia is associated with increased symptom severity, more severe negative symptoms, and more severe cognitive impairment (11; 48, 50).

Studies on the effect of vitamin D deficiency on cognitive functions are confusing. Low 25OHD levels have been shown to cause more severe cognitive impairment in the elderly and patients with schizophrenia [11, 54]. However, low vitamin D levels were not associated with cognitive impairment in two studies with large samples [54, 55]. It is unclear which cognitive functions are affected by vitamin D deficiency and whether chronic deficiency alters brain functions in the long term [56]. No relationship was found between the vitamin D level and TASs or WCST-CV sub-dimension scores, which may be related to the duration of vitamin D deficiency of the patients in our study. We found a significant improvement in the TASs measured by WCST after vitamin D replacement compared to those before replacement levels. Krivoy et al. (2014) conducted a double-blind placebo-controlled study and found that cognitive symptoms improved with vitamin D treatment in chronic schizophrenia patients using clozapine [37]. The improvement achieved in TASs in our study is consistent with the data in the literature, indicating that vitamin D deficiency may cause attention disorders through the frontal cortex.

We could find two studies investigating the effect of vitamin D replacement on disease symptoms [37, 38]. A recent double-blind, placebo-controlled, multicenter study in first-episode schizophrenia patients aims to evaluate the effects of high-dose vitamin D on early psychosis, but it has not been completed yet [39]. In a randomized controlled trial, Sheikhmoonesi et al. (2016) found that increased serum vitamin D levels did not improve negative or positive symptoms in male residual schizophrenia patients with low vitamin D who received fixed-dose antipsychotic therapy [38]. In a double-blind placebo-controlled study, Krivoy et al. (2014) found no improvement with vitamin D treatment in psychotic symptoms in schizophrenia patients treated with clozapine [37]. We found a significant improvement in both positive and negative symptoms after eliminating vitamin D deficiency in outpatient schizophrenia patients. In addition to its neurodevelopmental effects in the intrauterine period, vitamin D provides neuroprotection in the adult brain [57]. In recent years, studies provided increasing evidence that vitamin D provides neuroprotective, anti-inflammatory, and immunomodulatory effects by reducing oxidative stress in the brain. Animal studies supported the idea that vitamin D deficiency is associated with behavioral and cognitive impairments [58]. Low vitamin D levels may influence schizophrenia patients’ symptom severity through inflammatory effects [9].

In summary, our findings support that vitamin D levels may be low in schizophrenia outside the first episode or acute exacerbation period, and symptomatic recovery can be achieved independent of antipsychotic treatment after vitamin D level returns to normal.

Debate continues as to whether vitamin D deficiency is the cause or the result of schizophrenia. Vitamin D, which plays a role in the neurodevelopmental etiopathogenesis of schizophrenia, seems to affect the severity of schizophrenia in the period after the disease emerges. In clinical practice, the evaluation of vitamin D levels is usually overlooked. Vitamin D deficiency should be kept in mind, and vitamin D replacement should be considered as necessary in patients whose clinical findings cannot be improved despite regular use of adequate doses of drug therapy. In patients with schizophrenia, it is necessary to measure vitamin D levels regularly and keep vitamin D levels in the optimal range, in addition to the current antipsychotic treatment.

In addition to oral supplementation of low vitamin D levels, these patients should be encouraged to have more sunlight, which is an inexpensive resource to maintain the optimal vitamin D levels. Thus, the risk of metabolic and cardiovascular complications caused by vitamin D deficiency can be reduced in patients with schizophrenia who are already at risk due to reduced activity and antipsychotic drugs.

Our study has several limitations, including the small sample size and the lack of an evaluation of the type of antipsychotic when measuring vitamin D levels and evaluating the effects of replacement therapy on disease severity. Moreover, although patients using antiepileptics were excluded, the effects of other medications used for somatic diseases on vitamin D levels were not evaluated.

To the best of our knowledge, this is the first study that investigated the effects of vitamin D replacement on disease symptoms. Our study provides evidence about psychotropic effects and the possible benefits of adding vitamin D to the antipsychotic treatment for psychotic symptoms. Schizophrenia causes high rates of disability, and correction of vitamin D deficiency may be a low-cost alternative, especially in patients whose symptoms do not improve despite adequate antipsychotic therapy. Our findings may be promising, especially for the negative symptoms that do not sufficiently improve in most patients. Since research examining the effect of vitamin D replacement on schizophrenia symptoms is scarce, our study’s contribution to the descriptive studies literature is significant. However, to prove that vitamin D provides a clinical improvement in schizophrenia, the data we have obtained should be repeated in placebo-controlled studies with larger sample sizes.