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overcoming psychosis naturally
In this article we review the current literature addressing the treatment of schizophrenia with vitamin supplementation. We first describe the important roles that vitamins play in normal metabolism, then review the evidence pertaining to vitamin deficiency and supplementation in patients with schizophrenia. We then describe mounting evidence suggesting that vitamin supplementation, in particular with folic acid, vitamin B12 and vitamin D, may be important in treatment within certain subgroups of patients. We highlight the need for larger, randomized controlled trials, and recommend further studies examining the incidence of schizophrenia in countries with poor prenatal care and malnutrition, as well as in countries that have adopted mandatory folic acid fortification of grain products.
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1) Introduction
Schizophrenia is a devastating and usually chronic illness associated withfunctional disability in social, cognitive, and emotional realms. It is characterized by positive symptoms (hallucinations, delusions), negative symptoms (emotional blunting, apathy), as well as cognitive impairment. While positive symptoms often respond to antipsychotic medication, negative symptoms and cognitive deficits do not. There is an urgent need forpharmacologic treatment beyond current antipsychotic medications to address these residual symptoms, which contribute substantially to functional impairment [1, 2]. Numerous investigators have associated schizophrenia with vitamin deficiencies, either after the illness has been diagnosed or during prenatal development[3-13].Vitamin supplementation could provide therapeutic benefits through separate mechanisms of action than our current medication regimens, which focus largely on monoamine and histamine signaling.
Vitamins are organic compounds that are generallysupplied in the diet; many are unable to be synthesized in adequate amounts by the human body. Vitamins are classified as water-soluble and fat-soluble. Most of the nine water-soluble vitaminsact as coenzymes in metabolic processes; only one (vitamin K) of the fourfat-soluble vitamins has a coenzyme role. Fat-soluble vitamins are absorbed and stored within the liver and adipose tissue[14]. To prevent a variety of medical illnesses caused by vitamin deficiencies, the Food and Drug Administration has issued specific recommendations for daily vitamin intake [15](see Table 1). Of note, patients with schizophrenia often take in a high caloric diet that is high in saturated fats with poor fruit and fiber intake[16].
Table 1
Vitamins
Vitamin Source Function Deficiencies Daily
recommended
values (based
on 2000
calorie diet)
Water Soluble
Thiamine
(Vitamin B1) Cereals, bread,
grains,
legumes, seeds Coenzyme in formation/
degradation of a-ketols and
oxidative decarboxylation
of a keto acids Beriberi; Wernicke-
Korsakoff syndrome 1.5 mg
Riboflavin
(Vitamin B2) Dairy, cereals,
legumes Coenzyme in
oxidation/reduction reactions Dermatitis, cheilosis,
glossitis 1.7 mg
Niacin
(Vitamin B3) Meats, cereals,
whole grains Coenzyme in
oxidation/reduction reactions Pellagra 20 mg
Pyridoxine
(Vitamin B6) Chicken, fish,
pork, eggs,
starchy
vegetables Acts as coenzyme for amino
acid reactions Microcytic anemia,
dermatitis with cheilosis
and glossitis 2 mg
Folate
(Vitamin B9) Liver, leafy
vegetables;
fortified grain
products Key in one-carbon
metabolism Megaloblastic anemia;
neural tube defects 400 μg
Cobalamin
(Vitamin B12) Animal
products (meat,
dairy) Key for remethylation of
homocysteine to methionine;
isomerization to form
succinyl coA; DNA
synthesis Megaloblastic anemia;
pernicious anemia;
neuropsychiatric
symptoms 6 μg
Ascorbic Acid
(Vitamin C) Citrus fruits,
potatoes,
spinach Reducing agent in
hydroxylation reactions;
antioxidant Scurvy (defective
collagen) 60 mg
Biotin Liver, egg yolk Coenzyme in carboxylation
reactions Rare 300 μg
Pantothenic
Acid Eggs, liver,
yeast Part of CoA, transferring
acyl groups Unknown 10 mg
Fat Soluble
Vitamin A Liver, dairy,
kidney, green
vegetables Regulates RNA synthesis;
need for visual cycle,
reproduction
(spermatogenesis), growth,
differentiation of epithelial
cells Xerophtalmia (dryness
of conjunctiva, cornea
→blindness); infertility;
growth abnormality 5,000 IU*
Vitamin D Fish, liver, egg
yolk, fortified
milk Regulates gene expression;
regulates
calcium/phosphorus Rickets/Osteomalacia
(bone demineralization in
children/adults) 400 IU
Vitamin E Vegetable oils,
liver, eggs Antioxidant Mostly in premature
infants; RBC membrane
fragility 30 IU
Vitamin K Greens, egg
yolk, liver Coenzyme in post-
translational modification of
clotting factors Rare
(hypoprothrombinemia);
supplemented in
newborns 80 μg
Open in a separate window
*IU = International units
In this article we review the literature addressing both vitamin deficiency and treatment in patients with schizophrenia. Data for this review were obtained from PubMed searches performed through February 2014 (see Table 2). Keyword searches included “vitamin supplementation schizophrenia” and “vitamin schizophrenia clinical trial.” Additionally a search was performed for each individual vitamin combined with “schizophrenia” (e.g. “vitamin A schizophrenia”). Additional articles were obtained through references listed in the initial article list generated. We included only articles that involved measurement of vitamin levels in cohorts of schizophrenia or human clinical trials addressing the treatment of the primary symptoms of schizophrenia (i.e. not for medication side effect treatment). We did not include individual case reports, The search was limited to articles published in English.
Table 2
Vitamin studies in schizophrenia
Publication Study Design Sample
Characteristics Measurement/
Intervention Key Findings Comments
B vitamins
Kepmerman
et al., 2006
[3] Cross-
sectional 61 Dutch
schizophrenia
patients
identified by
chart review,
compared to
age and sex
matched data
from Dutch
National Food
Consumption
Survey Measured serum
vitamin B6, folate
and B12 and
essential fatty
acids; 3 pts with
hyperhomocystein
emia were given
B vitamin
supplementation Patients had lower
vitamin B12 levels
and higher
homocysteine
levels compared to
controls; no
differences in
folate and B6 in
patients compared
to controls Small sample
size, did not
address vitamin
levels in relation
to symptoms, no
strict exclusion
criteria
Muntjeweff
et al., 2003
[4] Cross-
sectional 35 Dutch
outpatients with
schizophrenia,
104 controls Measured plasma
and red blood cell
(RBC) folate
levels and plasma
vitamin B6, B12,
homocysteine
levels Patients had 1)
lower plasma and
higher RBC folate
levels after
adjusting for
homocysteine; 2)
there was increased
risk of
schizophrenia with
decreasing plasma
folate. No
difference between
groups in serum
vitamin B6 and
B12 levels Small sample
size,
homogenous
population
Haidemenos
et al., 2007
[20] Cross-
sectional 97 Greek
inpatients with
schizophrenia,
103 controls Measured plasma
folate, B12,
homocysteine
levels No difference in
folate and B12
levels between
groups; patients
had elevated
homocysteine
levels Did not address
potential
confounding
factors, control
group not age
and sex matched
Kale et al.,
2010 [5] Cross-
sectional,
subjects
compared to
healthy
controls 31 medication
naïve first-
episode
outpatients with
psychosis in
India, 48
healthy controls Measured plasma
folate, B12,
homocysteine,
and cortisol levels Lower plasma
folate and B12
levels in patients
vs. controls, (effect
is independent of
treatment with
antipsychotics);
association with
psychiatric
symptoms Small sample
size
Goff et al.,
2004 [6] Cross-
sectional 91
schizophrenia
outpatients,
compared to
representative
sample from
Framingham
Offspring Study Measured serum
folate, B12,
homocysteine
levels, measured
clinical symptoms Lower folate levels
in schizophrenia
patients compared
to controls, inverse
relationship
between folate
level and negative
symptom severity Inverse
correlation
between negative
symptom
severity and
folate levels was
significant in
nonsmokers but
not smokers
(smoking may
lower folate
levels and
conceal the
relationship)
Roffman et
al., 2008 [21] Cross-
sectional 200 outpatients
with
schizophrenia Obtained MTHFR
genotype,
previously
measured serum
folate and
homocysteine
levels from 85 of
the patients Serum folate levels
did not differ
between genotype;
an increase in the
low functioning
MTHFR (677T)
load conferred risk
for negative
symptoms Suggest lower
serum folate
levels among
T/T carriers
worsen negative
symptoms,
although small
sample size
Roffman et
al., 2008 [22] Cross-
sectional 185 outpatients
with
schizophrenia Obtained MTHFR
and COMT
genotype,
measured
neurocognitive
performance Patients
homozygous for
hyperfunctional
COMT allele and
carrying a low
functioning
MTHFR allele
showed increase in
perseverative errors Population
overlapped with
Roffman et al.
2008a study
Roffman et
al., 2008[23] Cross-
sectional 79 outpatients
with
schizophrenia,
75 matched
healthy controls Obtained MTHFR
and COMT
genotype, subjects
performed
cognitive task
associated with
DLPFC activation
while undergoing
fMRI Low functioning
MTHFR variant
was associated
with decreased
working memory
load dependent
activation DLPFC;
MTHFR genotype
effects stronger in
patients than
controls Mult-site cohort
with different
scanners
Roffman et
al., 2011 [24] Cross-
sectional 31 outpatients
with
schizophrenia,
25 matched
healthy controls MTHFR
genotype, subjects
performed
antisaccade task
while undergoing
fMRI Low functioning
MTHFR genotype
influenced error-
related activation
in dorsal anterior
cingulate cortex
(dACC) in both
patients and
controls Amount of
dACC activation
is predicted by
allele load
Godfrey et
al., 1990 [26] Double blind
placebo-
controlled 123 patients
with major
depression or
schizophrenia,
matched
healthy controls Daily 15 mg
methylfolate
supplementation
for 6 months Symptom and
social recovery in
17 schizophrenia
patients with low
folate levels treated
with methlyfolate Small sample
number, all
patients had low
folate levels at
baseline
Levine et al.,
2006 [27] Double blind
placebo-
controlled
crossover 42 inpatients
with
schizophrenia
and elevated
plasma
homocysteine
completed
study Daily
administration of
2 mg folate, 25
mg pyridoxine,
400 micrograms
for 3 months, then
cross over to
placebo or vice
versa; clinical
rating scales
performed Symptom
improvement and
neuropsychological
testing
improvement in
active treatment
group All patients had
elevated
homocysteine
and lower serum
folate at baseline
Hill et al.,
2011 [28] Double blind
placebo-
controlled 28 outpatients
with
schizophrenia Daily
administration of
folate 1 mg for 3
months, MTHFR
genotype
obtained, assessed
psychopathology,
global
functioning,
quality of life at
4,8,12 weeks;
measured serum
and RBC folate,
serum B12 No effect of folate
supplementation on
symptom response;
subjects with at
least one copy of
the lower
functioning
MTHFR allele had
more negative
symptom
improvement in the
treatment group vs
placebo group at
trend level Small sample
size (low power),
only one patient
was homozygous
and for T allele;
patients were not
folate deficient
Roffman et
al., 2013 [29] Parallel-
group, double
blind
placebo-
controlled 140 outpatients
with
schizophrenia,
randomly
assigned to
group Treatment group
received folate 2
mg/day plus
vitamin B12 400
mcg day for 16
weeks, measured
serum folate, B12,
homocysteine,
RBC folate,
clinical rating
scales performed,
genotype obtained
for genes
regulating folate
metabolism Folate+B12 group
had improvement
in negative
symptom severity
vs. control when
genotype
considered (low
functioning
FOLH1 variant had
strongest effect) Negative
symptom
improvement
was significant
but small
Vitamin D
Menkes et al.,
2012 [7] Cross-
sectional 102 psychiatric
inpatients in
New Zealand Measured serum
vitamin D levels 13 of 19 patients
with severe vitamin
D deficiency had
schizophrenia Small sample
size, patients of
Maori
background were
over-represented
Dealberto et
al., 2013 [36] Retrospective
chart review
followed by
intervention 18 first
generation
immigrants
from Africa and
Haiti who were
inpatients and
psychotic Measured serum
vitamin D levels,
then
supplemented
with 1000 IU/day All patients had
vitamin D levels in
insufficient range Small sample
number, very
specific
population, not
all carried
schizophrenia
diagnosis, no
matched control
group, unclear
duration of
vitamin D
supplementation
Berg et al.,
2010 [8] Cross-
sectional 67 immigrants
living in
Norway and 66
Norwegians –
both groups had
diagnosis of
psychotic
disorder; within
group
comparison and
comparison to
sample from
population-
based health
study Examined serum
vitamin D levels Vitamin D
deficiency present
in 80% of
psychotic
immigrant group
with dark
complexions; 43%
of Norwegians
with psychosis had
vitamin D
deficiency and
lower serum
vitamin D than
Norwegians in
reference group
Gracious et
al., 2012 [9] Cross-
sectional 35 adolescent
inpatients Measured serum
vitamin D (25-
hydroxyvitamin
D) 33.7 % patients
were vitamin D
deficient; of those
40% displayed
psychotic
symptoms vs. 16%
who were not
vitamin D deficient Adolescent
population
Crews et al.,
2013 [10] Case-control 69 inpatients
with first-
episode
psychosis,
matched
healthy controls Measured serum
vitamin D (25-
hydroxyvitamin
D) Vitamin D levels
significantly lower
in psychotic
patients (36%)
compared to
controls (16%) Not all patients
with confirmed
diagnosis of
schizophrenia
Graham et al.,
2014 [37] Cross-
sectional 20 first episode
schizophrenia
outpatients, 20
healthy controls Measured serum
vitamin D levels,
clinical symptom
evaluation Association
between vitamin D
insufficiency and
more severe
negative symptoms
and cognitive
deficits Small sample
size
Belvederi
Murri et al.,
2013 [11] Meta-analysis 7 studies; 523
patients with
schizophrenia,
7545 controls Examined serum
vitamin D levels Patients with
psychotic disorders
(mostly
schizophrenia) had
consistently lower
levels of serum
vitamin D Heterogeneity of
effect size, most
were
observational
studies
McGrath et
al., 2010 [38] Case-control 424 Danish
patients with
schizophrenia,
424 controls
from Danish
national health
registers and
neonatal
biobank Examined vitamin
D (25
hydroxyvitamin
D3) levels in
neontatal dried
blood samples Those in lower 3
quintiles of vitamin
D had 2-fold
increased risk of
schizophrenia;
highest quintile
also had increased
schizophrenia risk Unclear why
hypervitaminosis
D is correlated
with increased
schizophrenia
risk
Sullivan et
al., 2013 [39] Prospective
cohort 2047 maternal-
offspring pairs
in UK Examined
maternal serum
vitamin D levels
and offspring that
developed
psychosis No association
between maternal
vitamin D levels
and risk of
psychotic illness at
age 18 Likely some
offspring have
not yet
experienced
onset of
psychotic
symptoms at age
of evaluation
(18)
McGrath et
al., 2004 [40] Prospective
cohort Finnish birth
cohort of >9000
people Examined vitamin
D
supplementation
in the first year of
life; looked at
incidence of
schizophrenia and
non-psychotic
disorders at age
31 Among males,
either regular or
irregular vitamin D
supplementation
reduced
schizophrenia risk;
supplementation
with at least
2000IU/day
reduced risk by
77%; no reduction
in risk among
females Wide confidence
intervals; women
may have later
onset illness (i.e.
after age 31)
Brown et. al,
2007 [35] Nested case-
control Population-
based
birth
cohort; 63
schizophrenia
patients and 122
controls Measured serum
homocysteine
levels from
banked sera from
cohort of mothers Elevated 3rd
trimester
homocysteine
levels (inversely
related to folate)
associated with
twofold increase
risk of
schizophrenia in
offspring Elevated
homocysteine
levels can
contribute to
schizophrenia
development
through other
mechanisms than
disruption in
folate
metabolism
Vitamins C
and E
Suboticanec
et al., 1986
[12] Cross-
sectional,
then
interventional Group 1: 20
inpatients with
schizophrenia,
15 controls
Group 2: 15
inpatients with
schizophrenia
and 15 controls Examined serum
and urinary
vitamin C levels;
then
supplemented
with vitamin C
(70 mg/day for 4
weeks) in a new
group of
cases/controls Patients had lower
serum and urinary
vitamin C
excretion after oral
vitamin C load;
after
supplementation
for 4 weeks no
difference in
vitamin C serum
levels between
groups, but urinary
excretion lower in
patients Suggest
impairment in
vitamin C
metabolism in
patients with
schizophrenia
D’Souza et
al., 2003 [13] Cross-
sectional 14 inpatients
with
schizophrenia,
18 controls Measured plasma
vitamin E and C
levels Vitamin E and C
levels were
significantly lower
in patients vs
controls Small sample
size
Arvindakshan
et al., 2003
[41] Case-control 28 outpatients
with
schizophrenia,
45 healthy
controls Supplementation
with vitamin e
and C, omega-3
fatty acids,
measured clinical
symptoms using
scales Improvement in
symptomatology
after
supplementation Unclear effects
of vitamin
supplementation
alone due to
combination
treatment, small
sample size
Beauclair et
al., 1987 [43] Open-label
trial 13 outpatients
with
schizophrenia
with residual
symptoms Measured plasma
vitamin C levels,
given increasing
doses of vitamin
C (1 g – 8 g
daily) over 8
weeks 10 of 13 patients
showed clinical
improvement after
supplementation,
plasma vitamin C
levels increased No control
group, small
sample size
Dakhale et
al., 2005 [44] Double-blind
placebo-
controlled 40 outpatients
with
schizophrenia
in India taking
antipsychotic
medications Measured serum
vitamin C,
malondialdehyde
(MDA),
supplemented
with vitamin C
(500 mg/day) for
8 weeks,
measured clinical
symptoms At baseline,
increased serum
MDA and lower
vitamin C among
patients; after
treatment reduction
in MDA and
increase in vitamin
C; decrease in
symptoms (all
significant changes
compared to
placebo group) Potential
interaction
between second
generation
antipsychotics
and vitamin C
Bentsen et al.,
2013 [42] Randomized
double-blind
placebo
controlled 99 patients with
schizophrenia
or
schizoaffective
disorder within
four weeks of
hospitalization Treated with
omega-3 fatty
acid or vitamin E
364 mg/day +
vitamin C 1000
mg/day or placebo
for 4 months,
measured
polyunsaturated
fatty acids
(PUFAs), clinical
symptoms
measured Treatment with
vitamins C and E
impaired course of
improvement of
psychotic
symptoms in
patients with low
red blood cell
PUFAs Study was done
in acute-subacute
patients; difficult
to generalize to
more stabilized
patients
Bao et al.,
2012 [45] Nested case-
control Population-
based birth
cohort (Prenatal
Determinants of
Schizophrenia
study); 55
schizophrenia
patients and 106
controls Measured serum
vitamin A levels
from banked sera
from cohort of
mothers Low 2nd trimester
vitamin A levels
associated with
three fold increase
in schizophrenia
spectrum illnesses;
no association
found during 3rd
trimester Analysis not
done on first-
trimester
samples
Open in a separate window
MTHFR = Methylenetetrahydrofolate reductase, COMT = Catechol-o-methyltranferase, DLPFC = Dorsolateral prefrontal cortex, FOLH1 = Folate hydrolase 1, fMRI = functional magnetic resonance imaging
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2) Brief Historical Perspective
While this review focuses primarily on thecurrent body of literature, it is worth putting it into some historical context. One of the earliest investigators to examine vitamin treatment for schizophrenia was Canadian psychiatrist Abraham Hoffer, who began his work in the 1950s and was a proponent of “orthomolecular psychiatry,”which included treating with high doses of vitamins and nutrients. He argued that standard treatment of schizophrenia plus treatment with vitamin B3 “doubled recovery rates of acute and subacute cases” [17], since vitamin B3 reduced the production of adrenochrome (an oxidized derivative of adrenaline that is neurotoxic) [18]. Hiscontemporary, Thomas Ban, argued against vitamin treatment for schizophrenia, citing no replicable evidence from placebo-controlled trials to support vitamin supplementation [19]. Thus, the benefits of vitamin treatment in schizophrenia have long been debated, and as discussed below, no clear-cut answer has yet emerged, although there has been progresstowards a more clear answer.
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3) Vitamins
i. B Vitamins
B vitamins play an essential role in cellular metabolism, including transmethylation and oxidation/reduction reactions. Low blood levels of B vitamins are a relatively consistent finding in patients with schizophrenia. Ina cross-sectional study, Kemperman and colleagues reported lower levels of serum vitamin B12 in 61 Dutch patients with schizophrenia when compared to healthy controls; no difference was found in folate and vitamin B6 levels between the groups [3]. In an earlier cross-sectional study, alsoina Dutch population, Muntjeweff and colleaguesdemonstrated lower plasma folate levels in 35 schizophrenia patients compared to controlsafter adjusting for homocysteine levels, and an increased risk of schizophrenia with decreasing plasma folate levels; they found no difference in vitamin B6 and vitamin B12 levels [4]. In another cross-sectional study among Greek inpatients, there was no difference in plasma folate and B12 levels between patients and controls [20]. However, among medicationnaïve first-episode outpatients with psychosis in India (with diagnosis of schizophrenia, schizoaffective disorder or schizophreniform after 6 months follow-up), Kale et alshowed lower plasma folate and B12 levels in patients versus controls[5], suggesting an effect independent of antipsychotic medication treatment. Goff and associates[6]also reported low folate levels in a cohort of 91 schizophrenia outpatients, and found a significant inverse relationship between folate level and negative symptom severity among non-smoking patients; further work in this group has specifically related a common, low-functioning variant in MTHFR, a key enzyme in the folate metabolic pathway, to risk for negative symptoms[21], related cognitive impairment[22], and reduced prefrontal activation during executive function[23, 24]. The same variant in MTHFR, known as 667C>T (rs1801133), has also been associated with increased schizophrenia risk in a large meta-analysis[25], although at this time it has yet to emerge as a significant risk factor in genome-wide studies.
Several recent B vitamin supplementation strategiesshow promise in schizophrenia. In a small double blind placebo-control study, Godfrey et al., showed symptom and social recovery in 17 schizophrenia patients with baseline low folate levels who received daily methylfolate supplementation (15 mg/day) for six months[26] in addition to standard pharmacologic treatment. In a more recent crossover study, Levine and colleagues demonstrated symptom improvement in 42 schizophrenic patients with elevated homocysteine levels, supplemented with folic acid(2 mg/day), vitamin B6 (25 mg/day) and vitamin B12 (400 mcg/day) [27] in addition to regular antipsychotic treatment. However, it is not evident from this study whether elevated homocysteine levels are required for the symptomatic benefits of treatment with folic acid, since all of the patients had hyperhomocysteinemia. In a small study of 28 patients on a stable dose of antipsychotic medication, Hill and colleagues found no difference in symptom response among patients who received folic acid (2 mg/day) versus placebo (both groups improved); however, among patients with at least one copy of the low functioning variant in the MTHFR gene (677T), negative symptoms improved more in the active treatment group than in the placebo group at trend level (p=.06)[28]. In one of the largest randomized multicenter control trials examining vitamin supplementation, Roffman et al. randomly assigned 140 patients with schizophrenia on a stable antipsychotic dose to either treatment for 16 weeks with folic acid (2 mg/day) and vitamin B12 (400 mcg/day) or placebo[29]. The folate+B12 group showed significant improvement in negative symptom severity, but only when genotype was considered. Specifically, treatment response was strongly influenced by a genetic variant in FOLH1 (rs202676), which facilitates the translocation of dietary folates across the intestinal lumen. While transport of supplemental (synthetic) folic acid does not require FOLH1, patients with the low-functioning variant had lower levels of blood folate (i.e., reflecting pre-trial dietary folate intake) at baseline. This may account for the diminished response to supplementation in this subset of patients, as it may have taken longer to achieve a therapeutic CNS folate level, and sustained folate exposure was necessary to achieve negative symptom reduction.
An important limitation of the cross-sectional studies described above is that nutrient deficiency may reflect a downstream consequence of symptoms (e.g., impaired motivation to eat a healthy diet), rather than a primary cause of pathophysiology. However, somewhat stronger evidence – albeit still correlational – comes from longitudinal studies of populations exposed to famine during neurodevelopment. Although its age of onset is not usually until the second or third decade of life, schizophrenia is widely posited to reflect a delayed consequence of altered neurodevelopment[30]. Local incidence of schizophrenia transiently doubled two decadesafterthe Dutch Hunger Winter of 1944-1945[31]and the Chinese famine in the late 1950s[32]. Among the birth cohort conceived while exposed to the peak of the Dutch famine, there was also an increase in neural tube defects[31]. Given that neural tube defects are strongly associated with prenatal folate deficiency[33], a parsimonious explanation for both diagnoses would be a perturbation in the folate metabolic pathway.
While a more thorough discussion of the mechanisms by which prenatal folate deficiency contribute to the development of schizophrenia is outside of the scope of this article, we emphasize three ideas proposed by Brown and Susser[34] who elaborate that folate deficiency: 1)interferes with DNA synthesis and repair, leading to an increase in de novo mutations; 2) interferes with DNA methylation and gene expression; and 3)limits the conversion of homocysteine to methionine, resulting in a buildup of homocysteine in the developing brain. Further, investigators in the Prenatal Determinants of Schizophrenia (PDS) study analyzed banked sera from a US cohort of mothers during pregnancy, finding that elevated third trimester homocysteine (which is inversely related to folate) was associated with a twofold increase in schizophrenia risk in offspring[35]. However, Brown and Susser also point out that elevated homocysteine levels may contribute to the development of schizophrenia through other mechanisms (dysfunction of NMDA receptor, placental vasculopathy leading to fetal hypoxia) than by disruption in folate metabolism[34].
ii. Vitamin D
Vitamin D is a critical regulator of calcium metabolism, and also plays roles in gene expression and immune function. Vitamin D deficiency has been implicated by several schizophrenia investigators, although conclusions are limited by small sample size and the lack of comparison to healthy individuals. Within a cross-sectional study of 102 psychiatric inpatients in New Zealand, of 19 patients who had severe vitamin D deficiency, 13 had schizophrenia (34% vs. 9.4% other psychiatric diagnoses)[7]. Vitamin D deficiency and associated psychosis has been noted in dark-skinned immigrant populations. In a retrospective chart review of 18first generation immigrants from Africa and Haitiwith acute psychosis, all patients had vitamin D levels in the insufficient range[36]; however many of the clinical descriptions of the episodes were not consistent with a schizophrenia diagnosis, and only seven of these patients went on to be diagnosed with schizophrenia. Similarly, in a cross-sectional study of Norwegian patients, vitamin D deficiency was present in 80% of the psychotic immigrant population with dark complexions. Among native-born Norwegians with psychosis, 43% had vitamin D deficiency and had lower serum vitamin D levels compared to reference sample [8]. In a cross-sectional study of 35 adolescent inpatients, 33.7% patients were vitamin D deficient; of those deficient 40% exhibited psychotic features compared to 16% of patients who were not vitamin D deficient[9]. In a case-control study, Crews et. al found significantly lower levels of serum vitamin D among 69 first-episode psychosis inpatients compared to matched healthy controls[10] (OR of being vitamin D deficient was 2.99 in patients relative to controls). In another small study of first-episode patients, more severe negative symptoms and cognitive impairment were correlated with lower vitamin D levels. These patients had not received more than a total of four months of antipsychotic treatment[37]. Finally, in a recent meta-analysis, BelvederiMurri et al. found that patients with psychotic disorders (mainly schizophrenia) had consistently lower vitamin D levels compared to healthy controls[11]. The authors examined 7 studies overall for a total of 523 patients and 7545 controls. Of note there was heterogeneity of effect size, and most studies were case-control or cross-sectional. As with all observational studies, we emphasize that the results have to be taken with caution, given there may be many potential confounding variables that are present in patients with schizophrenia and also affect vitamin D levels such as insufficient nutrient intake or little sunlight exposure.
Vitamin D deficiency early in life may also contribute to schizophrenia risk. McGrath et al. examined a Danish cohort of over 400 patients with schizophrenia and carefully matched controls in which neonatal dried blood spots had been collected[38]. Among individuals in the lowest quintiles of neonatal vitamin D there was a two-fold elevated risk of schizophrenia compared to those in higher quintiles. Interestingly, those neonates with the highest vitamin D levels also had an increased risk of schizophrenia. In a birth cohort of over 2000 people in the UK, Sullivan et al. did not find an association between maternal vitamin D levels and risk of psychotic illness at age 18[39]. However, it is likely that some individuals at this age have not yet experienced onset of the illness; it will be important to follow the cohort over the subsequent years.
Intervention studies have had mixed results. In a Finnish birth cohort of over 9000 people, vitamin D supplementation with at least 2000 IU/day in males in the first year of life reduced the risk of schizophrenia by 77% (RR .23) compared to those receiving less than 2000 IU/day; these findings did not hold true in females[40]. The authors hypothesize that early vitamin D supplementation is crucial for pro-differentiating signals in the developing brain, and potentially also for normal brain recovery after insult. In the study of immigrant population discussed above[36], Dealberto provided daily vitamin D supplementation of 1000 IU/dayin addition to ongoing antipsychotic treatment, and concluded there were no changes in psychiatric symptoms after vitamin supplementation.
iii. VitaminsC and E
Vitamins C and E are antioxidants that protect against cellular damage due to inflammation or highly reactive oxygen-containing molecules. In a small cross-sectional study among 20 inpatients with schizophrenia and 15 controls, patients had lower fasting vitamin C levels and lower urinary vitamin C excretion after 1.0 g oral vitamin C load[12].The investigators then examined plasma vitamin C levels in a separate group of schizophrenia patients (n=15) vs controls after vitamin C supplementation (70 mg/day for four weeks in addition to antipsychotic treatment); the plasma vitamin C levels were similar in both groups, but urinary excretion was lower among patient sample, suggesting an impairment in vitamin C metabolism. In another small study among 14 inpatients with schizophrenia in India, plasma vitamin E and C levels were significantly lower when compared to control subjects[13].
One study reported a decrease in the Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Syndrome Scale (PANSS) scores among patients on antipsychotic treatment after supplementation with vitamin C, vitamin E, and omega-3 fatty acids[41]; however given the combination treatment it is difficult to conclude what effects are due to vitamin supplementation alone. A randomized placebo-control study by Bentsen et al.[42] also supplemented vitamin C (364 mg/day) and vitamin E (1000 mg/day) to patients with schizophrenia on antipsychotic medication; among those patients with low red blood cell polyunsaturated fatty acids (PUFAs), the vitamin supplementation actuallyimpaired recovery from acute psychosis compared to placebo. The authors hypothesize that vitamin E at a high enough dose can act as a pro-oxidant if there is inadequate antioxidant activity, thus increasing oxidative stress; it could also inhibit the beneficial γ- and δ tocopherols.They posit that vitamin C may counteract some detrimental effects of vitamin E. Beauclair et al. performed an 8-week open label trial of progressively increasing doses of vitamin C (max dose 8 g/day) among 13 patients with residual symptoms of schizophrenia despite antipsychotic treatment[43]. Ten of the thirteen patients showed improvement on CGI scores and plasma vitamin C levels increased over the eight weeks of treatment. The authors report that most of the symptomatic improvement occurred in the positive symptom domain. Notably, there was no control group in this study, and the weekly study visits with medical staff may also contribute to improvement in psychotic symptoms.
In a prospective double-blind placebo-controlled study of forty outpatients in India, Dakhale et al.[44]examined vitamin C supplementation (500 mg/day) for eight weeks in patients with schizophrenia taking second generation antipsychotics. The authors found that in the vitamin C group, there was a reduction in serum malondiahldehyde (MDA)levels (a measure of antioxidants), an increase in plasma ascorbic acid levels, and a decrease in BPRS scores. Of note, similar trends were also present in the placebo group. When the two groups were compared, the vitamin C group had a significantly greater decrease in MDA and BPRS scores and significant increase in ascorbic acid levels. It is a not clear whether there is some interaction between second generation antipsychotic medications and vitamin C, or if vitamin C acts through another mechanism. The authors propose that vitamin C may inhibit peroxidation of phospholipids and act as a free radical scavenger. While the overall study is well designed, the results must be taken cautiously given the small number of patients.
iv. Vitamin A
Vitamin A is converted to retinoic acid, which plays critical role in neuronal differentiation and migration; a disruption in the process could contribute to the underlying pathophysiology of schizophrenia. In the PDS study (detailed above)[35], investigators found that low maternal vitamin A levels during the second trimester of pregnancy are associated with a three-fold increase in schizophrenia spectrum disorders; no association was found during the third trimester (analysis not done on first trimester samples)[45]. The study finding is consistent with the hypothesis that prenatal vitamin deficiency plays a role in the development of schizophrenia. Further, the finding of elevated homocysteine levels (associated with low folate levels) in this cohort was present only in the third trimester, suggesting specific vitamin levelsare crucial at different stages of development for the prevention of schizophrenia.
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4.) Conclusions and Future Directions
Vitamin supplementation, particularly with folic acid, vitamin B12 and vitamin D, may play an important role in the treatment of schizophrenia within certain subgroups. In those patients who are vitamin D deficient (darker skin, living at latitude with less sunlight)supplementation with vitamin D may be protective among those vulnerable to psychosis.. Among those patients with specific genetic variants in the folate metabolic pathway, supplementation with both folate and vitamin B12 can be beneficial, especially in improving negative symptoms. While there is less compelling evidence for treatment with other vitamins, and even some evidence to the contrary, further studies are necessary to make treatment decisions.
A number of questions remain. For example, should it be common practice to supplement patients’ antipsychotic medications with a cocktail of vitamins? For how long should treatment be continued? There is a clear need for larger, randomized control trials examining vitamin treatment, in particular in relation to dosing, genotype, and specific types of symptoms (e.g. negative symptoms or cognitive symptoms), and in combination with specific antipsychotic medications. It would also be informative to examine the incidence of schizophrenia in underdeveloped countries with poor prenatal care and malnutrition; blood samples and prenatal serum could help determine levels of deficiency, and ideally response to supplementation. Further, it may be valuable to examine patterns of schizophrenia incidence and severity in countries that have recently adopted mandatory folic acid fortification of grain products. Finally, while vitamins generally are generally considered safe and well tolerated, several investigators have linked high doses of vitamin intake to cancer risk[46] although this has been disputed in other meta-analyses[47]. Additionally, it must be noted that there is always the possibility of a publication bias given the lack of negative studies published. Although recent studies demonstrate promise for vitamin supplementation in schizophrenia, as with all interventions, patients and their providers will ultimately need to consider both the risk and benefit sides of the equation prior to initiating treatment.
Key Points
Patients with schizophrenia have lower serum concentrations of certain vitamins compared to healthy individuals.
Vitamin supplementation may play arole in the treatment of schizophrenia within certain subgroups of patients.
Further studies, including larger, randomized control trials are needed to fully elucidate the role of vitamin supplementation in the treatment of schizophrenia.