Psychological Medicine, Page 1 of 13.

© Cambridge University Press 2017 REVIEW ARTICLE

doi:10.1017/S0033291717000022

The effects of vitamin and mineral supplementation

on symptoms of schizophrenia: a systematic review
and meta-analysis

J. Firth1*, B. Stubbs2,3, J. Sarris4,5, S. Rosenbaum6, S. Teasdale7,8, M. Berk9,10 and A. R. Yung1,11

1
Division of Psychology and Mental Health, University of Manchester, Manchester, UK; 2 Physiotherapy Department, South London and Maudsley
NHS Foundation Trust, London, UK; 3 Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience,
King’s College London, UK; 4 Department of Psychiatry, University of Melbourne, The Melbourne Clinic, Melbourne, Australia; 5 Centre for Human
Psychopharmacology, Swinburne University of Technology, Hawthorn, Australia; 6 Department of Exercise Physiology, School of Medical Sciences,
Faculty of Medicine, University of New South Wales, Sydney, Australia; 7 Keeping the Body in Mind Program, South Eastern Sydney Local Health
District, Sydney, Australia; 8 School of Psychiatry, University of New South Wales, Sydney, Australia; 9 Deakin University, IMPACT Strategic
Research Centre, School of Medicine, Victoria, Australia; 10 Department of Psychiatry, Florey Institute of Neuroscience and Mental Health, Orygen,
The National Centre of Excellence in Youth Mental Health and Orygen Youth Health Research Centre, University of Melbourne, Australia; 11 Greater
Manchester West NHS Mental Health Foundation Trust, Manchester, UK

Background. When used as an adjunctive with antipsychotics, certain vitamins and minerals may be effective for
improving symptomatic outcomes of schizophrenia, by restoring nutritional deficits, reducing oxidative stress, or modu-
lating neurological pathways.

Method. We conducted a systematic review of all randomized controlled trials (RCTs) reporting effects of vitamin and/
or mineral supplements on psychiatric symptoms in people with schizophrenia. Random-effects meta-analyses were
used to calculate the standardized mean difference between nutrient and placebo treatments.

Results. An electronic database search in July 2016 identified 18 eligible RCTs, with outcome data for 832 patients.
Pooled effects showed that vitamin B supplementation (including B6, B8 and B12) reduced psychiatric symptoms sign-
ificantly more than control conditions [g = 0.508, 95% confidence interval (CI) 0.01–1.01, p = 0.047, I2 = 72.3%]. Similar
effects were observed among vitamin B RCTs which used intention-to-treat analyses (g = 0.734, 95% CI 0.00–1.49, p =
0.051). However, no effects of B vitamins were observed in individual domains of positive and negative symptoms
(both p > 0.1). Meta-regression analyses showed that shorter illness duration was associated with greater vitamin B effect-
iveness (p = 0.001). There were no overall effects from antioxidant vitamins, inositol or dietary minerals on psychiatric
symptoms.

Conclusions. There is preliminary evidence that certain vitamin and mineral supplements may reduce psychiatric
symptoms in some people with schizophrenia. Further research is needed to examine how the benefits of supplementa-
tion relate to nutrient deficits and the impact upon underlying neurobiological pathways, in order to establish optimal
nutrient formulations for improving clinical outcomes in this population. Future studies should also explore the effects of
combining beneficial nutrients within multi-nutrient formulas.

Received 22 September 2016; Revised 23 December 2016; Accepted 3 January 2017

Key words: Adjunctive, diet, food, nutrition, psychosis.

Introduction hallucinations and delusions) within the first few

months of treatment, long-term outcomes are poor, as
Schizophrenia affects around 1% of the population and
80% of patients relapse within 5 years (Álvarez-
is among the most disabling and costly long-term
Jiménez et al. 2011). Additionally, ‘negative symptoms’
conditions worldwide (Schizophrenia Commission,
(e.g. anhedonia and amotivation) are largely unrespon-
2012). The mainstay of treatment is antipsychotic med-
sive to antipsychotic treatment but have a strong influ-
ications (NICE, 2014). Although patients typically
ence on functional outcomes (Kirkpatrick et al. 2006;
experience remission of ‘positive symptoms’ (such as
Alvarez-Jimenez et al. 2012). Although psychosocial
interventions (such as CBT) are effective for reducing
residual symptoms in people with schizophrenia
* Address for correspondence: Mr J. Firth, Institute of Brain,
Behaviour and Mental Health, University of Manchester, Room 3.306,
(Jauhar et al. 2014), these are costly and inaccessible for
Jean McFarlane Building, Oxford Road, Manchester M13 9PL, UK. the majority of patients (Schizophrenia Commission,
(Email: joseph.firth@postgrad.manchester.ac.uk) 2012). Thus, novel interventions which can provide

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 2 J. Firth et al.

feasible adjunctive treatment are needed to support and with positive and negative symptom domains. We
sustain full psychosocial recovery. also aimed to use meta-regression analyses to explore
It has been suggested that adjunctive treatment with which nutrient strategies may be most effective, and
certain vitamins and minerals may benefit people with how various patient characteristics may influence
psychiatric disorders (Rucklidge & Kaplan, 2013; nutrient effectiveness.
Kaplan et al. 2015), as there are plausible biological
mechanisms through which these nutrients may exert
Method
positive effects. Improvements may occur from resolv-
ing nutritional deficits, as diet quality is increasingly This meta-analysis followed the PRISMA statement
recognised as a risk for many psychiatric disorders (Moher et al. 2009) for transparent and comprehensive
(Sarris et al. 2015), and people with schizophrenia are reporting.
at much greater risk of poor diet (Dipasquale et al.
2013; Heald et al. 2015). Consequently, patients often Search strategy
have a spectrum of vitamin and mineral deficiencies
We conducted an electronic database search of
(Yanik et al. 2004; Kale et al. 2010; Valipour et al. 2014),
Cochrane Central Register of Controlled Trials,
even prior to antipsychotic treatment. Serum indicators
Health Technology Assessment Database, AMED
of reduced D and B vitamins have been found to hold
(Allied and Complementary Medicine), HMIC Health
significant associations with illness severity, particu-
Management Information Consortium, Ovid
larly with regards to negative symptoms (Kale et al.
MEDLINE, PsycINFO, EMBASE from inception to
2010; Graham et al. 2015). Furthermore, these vitamin
July 2016. We structured our search according to the
deficiencies are associated with neurological abnormal-
PICO framework (Schardt et al. 2007), using search
ities observed in schizophrenia; such as hippocampal
terms relevant to schizophrenia, along with 44 nutrient
deterioration and cognitive impairments (Graham et al.
terms, in order to return all potentially eligible studies
2015; Shivakumar et al. 2015), perhaps due to the essen-
(see Supplement 1). A search of Google Scholar was
tial role these vitamins play in the biosynthesis of pro-
conducted to identify any additional relevant articles,
teins which promote neuronal growth and repair.
and reference lists of retrieved articles were also
Clinical benefits may also result from the anti-
searched.
inflammatory and antioxidant properties of certain
vitamins/minerals (Kaplan et al. 2015), as neuroinflam-
Eligibility criteria
mation and oxidative stress are increasingly implicated
in schizophrenia onset and relapse (Miller et al. 2011; Articles were screened by two independent reviewers
van Berckel et al. 2011). These are potentially treatable (J.F. and B.S.). Disagreements were resolved through
conditions, which have been linked to negative symp- discussion until consensus was reached. We included
toms and cognitive deficits in schizophrenia and all randomized controlled trials (RCTs) reporting psy-
may drive some of the neurological abnormalities chiatric outcomes of vitamin and/or mineral supple-
which arise in schizophrenia (Meyer et al. 2011; ments for people with schizophrenia from database
Mondelli et al. 2011). Indeed, certain anti-inflammatory inception to June 2016. Eligible samples were those in
medications (Chaudhry et al. 2012) and even antioxi- which >90% of participants had a diagnosis of a non-
dant nutrients (Berk et al. 2008) have already demon- affective psychotic disorder (such as schizophrenia,
strated some efficacy as adjunctive treatments for schizoaffective or schizophreniform disorder), regard-
schizophrenia. less of age, ethnicity or sample size. Studies in which
Recent narrative reviews have presented a strong <90% of the sample had a non-affective psychotic dis-
case for the use of adjunctive nutrient treatments in order were only eligible if the data specifically for the
people with schizophrenia (Arroll et al. 2014; Brown non-affective psychosis subgroup was reported separ-
et al. 2016). A 2016 meta-analysis of adjunctive treat- ately. Only English-language research articles were
ments for depression found that certain vitamins and included in the review.
other nutrients can reduce clinical symptoms (Sarris Eligible interventions were those which administered
et al. 2016). However, there is currently no systematic any vitamins and/or essential mineral supplements (here-
evaluation or meta-analytic evidence for the efficacy after referred to as ‘nutrient supplements’) as an adjunct-
of vitamin and mineral supplementation in the treat- ive to usual medication regimens, and compared this to
ment of schizophrenia. placebo nutrients (plus usual medication), or usual medi-
Thus, the aim of this systematic review and meta- cation alone. Studies which compared nutrient supple-
analysis is to establish the efficacy of vitamin and ments to antipsychotic medications were not eligible
mineral supplements for people with schizophrenia; for inclusion. Both studies which used single-nutrient
examining the effects on total symptom scores, along supplements and those which combined two or more

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 Vitamin and mineral supplementation in schizophrenia 3

nutrients were eligible, provided that the specific individ- effects model (van der Kemp et al. 2012) to calculate
ual ingredients (and dosage) were reported. However, a standardized mean difference (as Hedges’ g) with
only studies lasting 55 days were included. Where 95% confidence intervals (CI) for nutrient and placebo
reported study data was insufficient to determine eligi- conditions. In cases where raw change scores were
bility, the corresponding authors were contacted twice unavailable, t values or F statistics were used instead.
over a period of 8 weeks to request the necessary infor- Where sufficient data was available (i.e. >2 studies),
mation. Additional information was obtained for one effect sizes were also calculated for individual mea-
study via this method (Bentsen et al. 2013). sures of total symptoms, and subdomains of positive
symptoms, negative symptoms and general symptoms
Data extraction individually.
Between-study heterogeneity was assessed using
A systematic data extraction form was used to extract
Cochran’s Q and I2 estimates, both of which quantify
the following from each study:
the amount of statistical heterogeneity due to variance
(1) Primary outcome: Total psychiatric symptoms. This between studies, rather than by arising by chance. The
was defined as total score on any clinically vali- Cochrane Collaboration’s risk of bias tool (Higgins
dated rating scale used for assessing the severity et al. 2011) was applied for determining the quality of
of psychiatric symptoms in people with schizo- each included study, through assessing six aspects of
phrenia. All psychiatric outcome measures are trial design that could introduce different sources of
shown in Table 1. For studies which applied bias. Sensitivity analyses were then used to investigate
more than one relevant measure, the average if significant effects were still present after removing
change across all measures used for the pooled low-quality trials. To examine the potential of publica-
analysis. For studies which did not use a total tion bias influencing results, Eggers’ t test used. Where
score but instead reported changes in positive, a significant risk of publication bias was detected, a
negative and general symptoms separately, these ‘file draw analysis’ was conducted to calculate a ‘fail-safe
were also pooled to calculate an average overall N’ (Orwin, 1983); the approximate number of unpub-
change score. lished studies which must exist to invalidate the results
(2) Secondary outcomes: Individual symptom domains. of the meta-analysis (i.e. the number of null studies
Changes in individual symptom domains were required to cause the p value to exceed 0.05).
also examined separately to establish the discrete Additionally, a funnel plot for assessing risk of bias
effects of nutrient supplements on positive symp- was generated for each analysis to inspect asymmetry
toms, negative symptoms and general symptoms of effect sizes (Duval & Tweedie, 2000), and Duval &
of schizophrenia. Tweedie’s trim-and-fill analysis was applied to recalcu-
(3) Potential moderators. Factors which may moderate late the effect size after removing any extreme small stud-
the effectiveness of nutrient supplements for ies from the positive side of the funnel plot.
schizophrenia were also extracted from each Subgroup analyses were conducted for different nutri-
study, including intervention details (nutrients ent types, in order to examine relative effectiveness of
used, daily dosage, intervention length), study nutrients within the classes of; (i) trace minerals, (ii)
design (cross-over v. parallel designs, control con- major minerals, (iii) B vitamins, (iv) antioxidant vitamins
dition used, trial quality) and sample characteris- and (v) other vitamins. Subgroup analyses were also
tics (mean age, years of illness, % male, applied to compare intervention effectiveness in inpatient
antipsychotic dosage in chlorpromazine equiva- v. outpatient settings. Additionally, meta-regression ana-
lents; Woods, 1899). lyses were used to examine the relationship between
(4) Adverse events. Any information on adverse events study effect sizes and continuous moderators which
which occurred during the trials or side-effects of may impact upon the outcomes of nutrient interventions.
treatment reported by participants was extracted
for narrative synthesis.
Results
Statistical analyses Search results

Meta-analyses were conducted in Comprehensive The initial database search was performed on 24 July
Meta-Analysis 2.0 (Borenstein et al. 2005) using a 2016. The search returned 2217 results reduced to
DerSimonian–Laird random-effects model (van der 1510 after duplicates were removed. A further 1445
Kemp et al. 2012) to account for heterogeneity between articles were excluded after reviewing the titles and
studies. The mean change in total symptom scores abstracts for eligibility. Full versions were retrieved
were pooled using a DerSimonian–Laird random- for 68 articles, of which 18 articles with unique samples

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Table 1. Details of included studies

4 J. Firth et al.
Sample characteristics Nutrient intervention Study details

Mean Illness
Nutrient, n Control, n age length % male Nutrient name Daily dosage Weeks Country Design Setting Outcome measures

Antioxidant vitamin studies

Adler et al. (1999) 73 85 50.3 24.5 97 Vitamin E 1600 IU 52 USA Parallel Outpatient BPRS Total
Bentsen et al. (2013) 25 24 28.25 4.81 62.7 Vitamin E + 544 IU 16 Norway Parallel N.S. PANSS Total
vitamin C 1000 mg PANSS Positive
PANSS Negative
PANSS General
Dakhale et al. (2005) 20 20 28.4 1 – Vitamin C 500 mg 8 India Parallel Outpatient BPRS Total
Dorfman et al. (1999) 19 20 35 – 48.7 Vitamin E 600 IU 2 Israel Parallel Inpatient BPRS Total
Lam et al. (1994) 12 12 61.8 21.8 41.7 Vitamin E 400–1200 IU 6 China Cross-over Inpatient BPRS Total
Lohr et al. (1988) 15 15 44 24 73.3 Vitamin E 400–1200 IU 4 USA Cross-over Outpatient BPRS Total
Vitamin B studies
Godfrey et al. (1990) 9 8 44.1 – 53 Folate (methyl) 15 mg 24 USA Parallel Mixed Clinical Rating Scale
Hill et al. (2011) 14 14 46.3 19.6 81.3 Folic acid 2 mg 12 USA Parallel Outpatient PANSS Total
SANS
Lerner et al. (2002) 8 7 50 18.6 26.7 Vitamin B6 100–400 mg 4 Israel Cross-over Inpatient PANSS Positive
PANSS Negative
Lerner et al. (2004) 10 10 42.6 10.6 70 Vitamin B6 1200 mg 5 days Israel Parallel Inpatient BPRS Total
CGI Total
Levine et al. (2006) 20 22 40 15.8 95 Folic acid 2 mg 12 Israel Cross-over Inpatient PANSS Total
Vitamin B6 25 mg PANSS Positive
Vitamin B12 400 µg PANSS Negative
PANSS General
Miodownik et al. (2006) 23 17 43.2 16.5 52.5 Vitamin B6 1200 mg 5 days Israel Parallel Inpatient BPRS Total
CGI Total
Roffman et al. (2013a, b) 89 46 45.5 19.5 71.2 Folic acid 2 mg 16 USA Parallel Outpatient PANSS Total
Vitamin B12 400 µg PANSS Positive
SANS
Inositola studies
Levine et al. (1993a) 10 10 36.8 14.7 60 Inositol 6g 4 Israel Cross-over Inpatient BPRS Total
Levine et al. (1993b) 11 11 53.2 28.7 63.6 Inositol 6g 10 days Israel Cross-over Inpatient BPRS Total
 Vitamin and mineral supplementation in schizophrenia 5

were eligible for inclusion. The full article screening

BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impressions Scale; IU, international units; N.S., not specified; PANSS, Positive and Negative Syndrome Scale; SANS, Scale
Negative

Negative

Negative
and selection process is detailed in Fig. 1.
Positive

Positive

Positive
General

General
Total

Total

Total
Included studies and participant details
PANSS
PANSS
PANSS
PANSS

PANSS
PANSS
PANSS
PANSS
PANSS
PANSS
PANSS
Study details are displayed in Table 1. Eight studies
were conducted in Israel, five in the USA, and one
each in India, China, UK, Iran and Norway. For asses-
Inpatient

Inpatient
sing total symptoms, eight studies used the Positive
and Negative Syndrome Scale (PANSS; Kay et al.
N.S.

1987), nine used the Brief Psychiatric Rating Scale

(BPRS; Overall & Gorham, 1962) and two used the
Cross-over

Clinical Global Impressions scale (CGI; Guy, 1976).

Parallel

Parallel

Individual domains of positive and negative symp-

toms were assessed using the PANSS subscales in
seven studies, and the Scale for the Assessment
Israel

Negative Symptoms (SANS) in two studies (Andreasen,

Iran
UK

1989). Outcome data for was available for 433 patients

in nutrient treatments, and 399 patients in control
conditions. In the eligible samples, 99.5% had a diag-
12
4

nosis of schizophrenia/schizoaffective disorder, and

0.5% had bipolar disorder. The mean age was 42.8
years (range 28–53 years) and 70.2% were male.
150 mg
400 µg

Duration of illness was reported in 15 studies (n = 747),

12 g

with a mean duration of 17.2 years (range 1–28.8 years).

Antipsychotic dosage was reported in 12 studies (n =
473), with a mean chlorpromazine-equivalent dose of
Chromium

423.7 mg per day (166–900 mg). No studies reported sig-

Inositol

nificant differences in antipsychotic medications at base-

Zinc

line between active and placebo conditions. No studies

selectively recruited participants on the basis of diet qual-
ity at baseline. However, one study selectively recruited
33.3

60.7

participants by blood-folate levels (Godfrey et al. 1990),

93

and another by elevated homocysteine (Levine et al. 2006).

Nutrient treatments lasted an average of 10.3 weeks
18.9

28.8

(range 5 days to 1 year). All nutrient treatments were

–

administered as an adjunctive to antipsychotic medica-

tions. Results of bias assessment are presented in
44.7

41.8

32.9

Supplement 2. The most common risk of bias was due

to missing outcome data with lack of intention-to-treat
(ITT) analyses (seven studies).
12

51

15

Effects of B vitamins on psychiatric symptoms

for the Assessment of Negative Symptoms.

Seven studies examined the effects of vitamin B sup-

Previously considered vitamin B8.

plementation in schizophrenia: vitamin B6 alone

12

49

14

(Lerner et al. 2002, 2004; Miodownik et al. 2006), folate

supplement alone (Godfrey et al. 1990; Hill et al. 2011),
folic acid with vitamin B12 (Roffman et al. 2013b) or
Essential mineral studies

Mortazavi et al. (2015)

Hockney et al. (2006)

folic acid with vitamins B6 and B12 (Levine et al.

Levine et al. (1994)

2006). Dosages are displayed in Table 1. Psychiatric

outcome data from seven pooled vitamin B RCTs
(n = 297) found a significant positive effect on total
symptom scores (g = 0.51, 95% CI 0.01–1.01, p = 0.047).
However, there was significant statistical heterogeneity
a

across the study data (Q = 21.6, p < 0.01, I2 = 72.3%).

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 6 J. Firth et al.

Fig. 1. PRISMA flow diagram of study selection.

Fig. 2. Meta-analysis of the effects of vitamin and mineral supplements on psychiatric symptoms of schizophrenia. Box size
represents study weighting. Diamond represents overall effect size and 95% confidence intervals. * Previously considered
vitamin B8.

Fig. 2 displays the effectiveness of vitamin B supple- to exceed 0.05. The results remained unchanged after
ments for reducing psychiatric symptoms in schizo- applying the trim-and-fill analysis, as this did not iden-
phrenia at each dosage studied. Eggers’ regression tify any extreme small studies affecting results.
test found no evidence of publication bias (p = 0.11), Sensitivity analyses were performed to examine
and the fail-safe N was 14, indicating that 14 additional effects of vitamin B supplements among the high-
‘null’ studies would be needed for the observed p value quality RCTs which used ITT analyses (or had complete

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 Vitamin and mineral supplementation in schizophrenia 7

outcome data). In these high-quality trials (N = 5, n = used in earlier years of illness (N = 6, n = 280, B = −0.166,
227), there was a moderate-to-large positive effect of B Z = −3.2, p = 0.001). However, there were no
S.E. = 0.052,
vitamins on total symptom scores (g = 0.734), although associations of effectiveness with sample size, age,
the p value fell short of statistical significance (p = 0.051, study duration or gender (all p > 0.01). There was insuffi-
95% CI 0.00–1.49), again with significant heterogeneity cient study data to examine relationship between anti-
across studies (Q = 19.6, p < 0.01, I2 = 79.6). Eggers’ test psychotic dose and treatment effect size.
provided no evidence of publication bias influencing Three studies (n = 66) examined the effects of inositol
this analysis (p = 0.13). supplementation on psychiatric symptoms in schizo-
The effects of B vitamins in individual domains of phrenia (Levine et al. 1993a, b, 1994). These were ana-
positive and negative symptoms were reported in lysed separately, but still included in this review
three (n = 192) and four (n = 220) studies, respectively. section since inositol was previously considered vita-
Meta-analyses found no significant effect of B vitamins min B8 and is still used as a nutritional supplement.
on either positive symptoms (g = 0.26, 95% CI −0.24 to Meta-analyses found no overall effect of 6–12 g daily
0.76, p = 0.31) or negative symptoms (g = 0.154, 95% CI inositol on total symptoms scores (g = 0.115, 95% CI
−0.12 to 0.42, p = 0.26). Furthermore, no significant −0.35 to 0.58, p = 0.63).
effects of B vitamins were observed when restricting
analyses to include only those studies which measured
Effects of antioxidant vitamins on psychiatric
total psychiatric symptoms using the PANSS total scale
symptoms
(N = 3, n = 247, g = 0.320, 95% CI −0.5 to 1.14, p = 0.45).
Vitamin B6 was the only B vitamin to be examined Six studies used antioxidant vitamins: vitamin E and
alone in two or more studies (N = 3, n = 75), and thus vitamin C combined (Bentsen et al. 2013), vitamin E
suitable for individual meta-analysis. The effect of vita- alone (Lohr et al. 1988; Lam et al. 1994, Adler et al.
min B6 alone on psychiatric symptoms did not reach 1999; Dorfman-Etrog et al. 1999), or vitamin C alone
statistical significance (g = 0.682, 95% CI −0.09 to (Dakhale et al. 2005). As shown in Table 2 and Fig. 2,
1.45, p = 0.08). There was also no effect of vitamin B6 there was no effect from antioxidant vitamins on
on positive and negative symptom subdomains total symptom scores across all trials (N = 6, n = 340,
(Lerner et al. 2002). g = 0.296, 95% CI −0.39 to 0.98, p = 0.40, Q = 40.6, I2 =
Vitamin B9 (folate) was used in four studies, 87.7), or in high-quality trials (N = 3, n = 247, g = 0.44,
although was not suitable for individual meta-analysis 95% CI −0.95 to 1.83, p = 0.54, Q = 39.3, I2 = 94.9).
as it was administered in combination with other B The four studies examining vitamin E alone pri-
vitamins. Individual studies found that there were no marily aimed to reduce extrapyramidal side-effects of
benefits of folic acid alone (2 mg) or folic acid plus medications, however there was no effect on total
B12 (2 mg and 400 µg) for either PANSS total scores, psychiatric symptoms (n = 251, g = 0.018, 95% CI
the PANSS positive subscale, or SANS scores (Hill −0.23 to 0.26, p = 0.89). The sole study of vitamin C
et al. 2011; Roffman et al. 2013a). However, in the alone observed significantly greater reductions in
study which selected participants with low blood-folate BPRS symptom scores in the nutrient group (n = 20)
at baseline, 15 mg methylfolate daily for 6 months sign- than the placebo condition (n = 20) after 8 weeks of
ificantly reduced total symptom scores (Godfrey et al. treatment with 500 mg vitamin C daily (p < 0.01).
1990). Additionally, a vitamin B combination supple- Effects of antioxidant vitamins on total symptoms
ment (2 mg folic acid, 400 μg B12, 25 mg B6) signifi- scored using the BPRS were reported in five studies,
cantly reduced PANSS total scores after 3 months and found no overall effect (n = 291, g = 0.514, 95% CI
among 42 patients with schizophrenia who had ele- −0.23 to 1.26, p = 0.18). PANSS symptom domains
vated homocysteine (p = 0.019) (Levine et al. 2006). were only reported one study, which combined vita-
Subgroup analyses showed that effects of B vitamins min E (544 IU daily) with vitamin C (1000 mg daily)
on total symptom scores of inpatients (N = 4, n = 117, in acute psychosis patients (Bentsen et al. 2013). The
g = 0.584, 95% CI 0.06 to 1.11, p = 0.03) were signifi- study observed significant negative effects from vita-
cantly greater than effects for outpatients (N = 2, n = min treatment in positive and negative symptoms in
163, g = −0.051, 95% CI −0.37 to 0.27, p = 0.75). comparison to placebo conditions.
Meta-regression found that publication year was nega- Antioxidant supplementation was equally ineffective
tively associated with observed effect size (Supplement in both inpatient and outpatient studies (Table 2).
3); as effects of vitamin B interventions on total symptom Meta-regression analyses found no relationship between
scores decreased in more recent studies (B = −0.086, S.E. = antioxidant effectiveness with age, sample size, illness
0.028, Z = −3.08, p = 0.002). Vitamin B effectiveness was duration, study duration or year of publication (all p >
also significantly correlated with illness duration, as 0.1). However, among the four studies which reported
B vitamins reduced symptoms to a greater extent when chlorpromazine-equivalent antipsychotic dosages,

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 8 J. Firth et al.

Table 2. Meta-analyses of vitamin and mineral supplements on psychiatric symptoms in people with schizophrenia

Publication bias
Sample Meta-analysis Heterogeneity (Eggers’)

Studies Total, n Hedges’ g 95% CI p value Q value p value I2 Intercept p value

B vitamins: all 7 297 0.508 0.01 to 1.01 0.047 21.6 <0.01 72.3 3.00 0.11
B vitamins: HQ studies 5 227 0.734 0.00 to 1.49 0.051 19.6 <0.01 79.6 3.45 0.13
B vitamins: Inpatients 4 117 0.584 0.06 to 1.11 0.028 5.44 0.14 44.9 – –
B vitamins: Outpatients 2 163 −0.051 −0.37 to 0.27 0.752 0.20 0.65 0.00 – –
Vitamin B6 alone 3 75 0.682 −0.09 to 1.45 0.082 4.81 0.09 58.4 −0.17 0.98
B vitamins: Positive symptoms 3 192 0.260 −0.24 to 0.76 0.310 4.20 0.12 52.3 0.65 0.87
B vitamins: Negative symptoms 4 220 0.154 −0.12 to 0.42 0.262 1.22 0.75 0.00 −1.39 0.10
B vitamins: PANSS totals only 3 247 0.320 −0.50 to 1.14 0.446 16.4 <0.01 87.8 0.73 0.95
Antioxidant vitamins: all 6 340 0.296 −0.39 to 0.98 0.396 40.6 <0.01 87.7 3.18 0.39
Antioxidants: HQ studies 3 247 0.440 −0.95 to 1.83 0.535 39.3 <0.01 94.9 5.07 0.65
Antioxidants: Inpatients 2 63 0.153 −0.33 to 0.64 0.535 0.57 0.45 0.00 – –
Antioxidants: Outpatients 2 188 1.070 −1.27 to 3.41 0.371 30.5 <0.01 96.7 – –
Antioxidants: BPRS totals only 5 291 0.514 −0.23 to 1.26 0.177 31.3 <0.01 87.2 3.99 0.27
Vitamin E alone 4 251 0.018 −0.23 to 0.26 0.886 2.01 0.55 0.00 1.32 0.30
Inositol: all 3 66 0.155 −0.35 to 0.58 0.629 0.46 0.78 0.0 1.79 0.32
Minerals: all 2 129 0.324 −0.48 to 1.3 0.430 3.81 0.05 73.8 – –

CI, Confidence interval; BPRS, Brief Psychiatric Rating Scale; HQ, high quality; PANSS, Positive and Negative Syndrome
Scale.

lower doses were associated greater symptomatic no side-effects/adverse events at all. Two studies did
improvements following antioxidant supplementation observe serious adverse events during the trials (hospi-
(N = 4, n = 221, B = −0.009, S.E. = 0.003, Z = −2.84, p = talization due to psychosis), but determined that these
0.004) (Supplement 3). were unrelated to the treatment and did not differ
between nutrient and placebo conditions (Bentsen
Effects of mineral supplements on psychiatric et al. 2013; Roffman et al. 2013b). One study withdrew
symptoms a single participant from zinc treatment following a
Two studies investigated the effects of mineral supple- maculopapular reaction, although causality was
ments (zinc and chromium) on psychiatric symptoms unclear (Mortazavi et al. 2015). Furthermore, one vita-
(Hockney et al. 2006; Mortazavi et al. 2015). min E study observed minor side-effects (including
Random-effects meta-analyses found no overall effect flu-like symptoms and stomach complaints) in 11–
(N = 2, n = 129, g = 0.324, 95% CI −0.48 to 1.30, p = 22% of patients over 12 months of treatment, but
0.430), although there was significant heterogeneity reported that no serious adverse events occurred dur-
between studies (Q = 3.81, p = 0.05, I2 = 73.8%). ing the trial (Adler et al. 1999).
Specifically, 150 mg zinc per day significantly reduced
total PANSS scores after 6 weeks in comparison to pla- Discussion
cebo treatment (n = 29, p = 0.003), with significant ben- This is the first meta-analysis to examine the effects of
efits also evident in individual domains of positive vitamin and mineral supplements as an adjunctive
(p = 0.04) and negative (p = 0.02) symptom subscales, treatment for people with schizophrenia. The system-
but not for general symptoms (Mortazavi et al. 2015). atic search identified 18 RCTs with a combined sample
Conversely, there were no significant differences across size of 832 patients receiving antipsychotic treatment
100 patients with schizophrenia after 12 weeks of for schizophrenia (Table 1). Overall, antioxidant vita-
receiving either 400 µg chromium daily or placebo sup- mins, inositol, and minerals were no more effective
plements in PANSS total scores (p = 0.88), or positive than placebo treatments for reducing psychiatric symp-
and negative symptoms (Hockney et al. 2006). toms. On the other hand, pooled effects of vitamin B
interventions showed these were moderately more
Adverse effects of nutrient interventions
effective than placebo treatments.
Ten of the 18 studies reported on side-effects and/or However, there was significant heterogeneity among
adverse events during the trial. Six studies observed trial outcomes, as data from different types, doses and

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 Vitamin and mineral supplementation in schizophrenia 9

durations of vitamin B treatment were pooled for this effects of antipsychotic treatments (Soares &
analysis, which limits the strength of these findings. McGrath, 1999), this meta-analysis found no significant
Nonetheless, systematic review of individual study effects on psychiatric symptoms. Vitamin E alone was
findings provides some further insight into which vita- consistently ineffective (Lohr et al. 1988; Adler et al.
min B interventions may be most effective. Vitamin B 1999; Dorfman-Etrog et al. 1999; Lam et al. 1994),
interventions which used higher dosages (Godfrey whereas vitamin C alone had a large positive effect
et al. 1990; Lerner et al. 2004; Miodownik et al. 2006) (Dakhale et al. 2005). Meta-regression analyses indi-
or combined several vitamins (Levine et al. 2006) cated that antioxidant vitamins were most effective
were consistently effective for reducing psychiatric among patients taking lower doses of antipsychotic
symptoms, whereas those which used lower doses treatment. Although there is insufficient data to deter-
were ineffective (Lerner et al. 2002; Hill et al. 2011; mine why this is the case, it is possible this may be due
Roffman et al. 2013b). The hypothesized mechanisms to a ‘ceiling-limit’ effect, as antipsychotics such as clo-
for these improvements is the reduction of folate defic- zapine have antioxidant properties (Libera et al. 1998)
iencies and hyperhomocysteinaemia, as both of these which, at higher doses, may prevent any observable
are prevalent among people with schizophrenia, and benefits from further antioxidant supplementation.
could contributed to impaired mental health and It should be also noted that significant negative
brain functioning in this population (Misiak et al. effects of antioxidant supplementation was observed
2014; Moustafa et al. 2014). Indeed, the two trials by one study; which combined high-dose vitamin C
which selected participants on the basis of indicated (1000 mg daily) with vitamin E (544 IU daily) as an
nutritional deficits (i.e. elevated homocysteine or low adjunctive intervention for acute patients (Bentsen
blood-folate) found that reductions in psychiatric et al. 2013). The authors suggest this may be due to
symptoms where accompanied by improvements in the vitamin E acting as a pro-oxidant among acute
these variables (Godfrey et al. 1990; Levine et al. patients when administered alongside high-dose vita-
2006). It makes intuitive sense that a nutrient is likely min C, and thus exacerbating symptoms. Research in
to be of greater value in the presence of insufficiency. other populations has also raised concerns around
However, the role of genetic variation should also be antioxidant vitamins, as over-supplementation may
considered, since two folate supplementation studies induce further oxidative damage and even increase
which found no overall effects (Hill et al. 2011; mortality risk (Rietjens et al. 2002; Guallar et al. 2013).
Roffman et al. 2013a) did observe significantly reduced Interestingly however, the Bentsen et al. (Bentsen
symptoms when stratifying the sample by genotype; as et al. 2013) study additionally found that adding EPA
participants with low-functioning variants of a gene (2 g daily) to the vitamin E + C combination amelio-
which regulates folate metabolism benefitted most rated the negative effects (Bentsen et al. 2013).
from vitamin B supplementation (Hill et al. 2011; Previous open-label studies which combined vitamins
Roffman et al. 2013a). This is the premise of biomarker E and C with EPA have also shown significant positive
stratification of therapy and personalised medicine, effects on psychiatric outcomes among stabilized
and the next generation of nutritional interventions patients with residual symptoms (Arvindakshan et al.
may well need to index baseline diet quality, nutri- 2003; Sivrioglu et al. 2007).
tional status and genotype as entry criterions. Several limitations must be considered when inter-
The available evidence also suggests that vitamin B preting the findings of this meta-analysis. First,
supplements may be most beneficial when implemen- although vitamin interventions reduced total symp-
ted early on, as duration of illness was negatively toms, we were unable to provide any meta-analytic
correlated with treatment effectiveness. Studies of evidence of significant benefits within any individual
fish oils have also reported benefits for people with measure (i.e. PANSS totals or BPRS totals alone), or
first-episode psychosis (Pawelczyk et al. 2016), as in any specific subdomain of positive/negative symp-
opposed to the lack of efficacy observed in long-term toms (all p > 0.1) (Table 2). These null effects may be
patients (Fusar-Poli & Berger, 2012). The first-episode due to the smaller sample sizes available for these ana-
phase may present an optimal period for using lyses. Future trials should aim to establish which vita-
adjunctive nutrient supplements to improve mental mins and minerals interventions (if any) can be used to
health, as antipsychotics also work better during the treat specific symptoms of schizophrenia. For instance,
early stages of illness (Barnes, 2011; Berk et al. 2011; individual trials to date have shown significant reduc-
NICE, 2010), and there is the possibility of maximising tions in residual positive symptoms from a combin-
functional recovery during this time (Alvarez-Jimenez ation vitamin B supplement (Levine et al. 2006) and
et al. 2012). zinc (Mortazavi et al. 2015), whereas folic acid has
Although certain antioxidants (such as vitamin E) been found to be effective in reducing negative symp-
may be beneficial for reducing extrapyramidal side- toms among patients with genetic variations which

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https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S0033291717000022
 10 J. Firth et al.

inhibit folate absorption (Hill et al. 2011; Roffman et al. (Dipasquale et al. 2013; Heald et al. 2015). As indicated
2013b). Further research in this area this would increase by our meta-regression, nutritional supplements may
our understanding of using nutrients for targeting be most effective among patients in the earlier stages
residual symptoms on a patient-by-patient basis. of illness. Dietary interventions may also be most
The positive results of the vitamin B meta-analysis effective during this time, and would confer the add-
may also have been influenced by a lack of ITT ana- itional benefit of reducing the weight-gain and meta-
lyses, publication bias, and the heterogeneity between bolic dysfunction associated with the initiation of
included studies. However, there was no evidence of antipsychotic treatment (Teasdale et al. 2016).
publication bias, and no alteration of effect size after Further efforts should also be made to establish the
applying a trim-and-fill analysis. Furthermore, we mechanisms by which nutrients improve mental health
used sensitivity analyses to show that benefits of B in schizophrenia, and to measure effects on other out-
vitamins were still indicated by five high-quality comes such as neurocognition and metabolic health.
RCTs with complete outcome data (g = 0.734, p = Increasing our understanding of nutrients’ effects will
0.051). Although subgroup and regression analyses help to develop optimal dietary regimes and even sup-
were conducted to investigate the possible sources of plement formulas for schizophrenia, which may in
heterogeneity, there was insufficient data reported to turn present a novel adjunctive intervention for redu-
examine other putative factors which may influence cing residual symptoms and improving long-term
nutrient effectiveness, including the presence of meta- recovery. All of the studies to date have only examined
bolic syndrome, obesity, diabetes and smoking. the benefits of nutrient treatments as an adjunctive to
In conclusion, high-dose B vitamins may be useful antipsychotic medications. However, future research
for reducing residual symptoms in people with schizo- could also explore the feasibility of combining key vita-
phrenia, although there was significant heterogeneity mins/minerals with other beneficial nutrients, such as
among study findings, and some indication that certain amino acids (Berk et al. 2008; O’Donnell et al.
these overall effects may be driven by larger benefits 2016), and comparing these multi-nutrient treatments
among subgroups of patients who have relevant gen- to sustained antipsychotic treatment as stand-alone
etic or dietary nutritional deficiencies. Vitamin C and maintenance therapy in stabilised patients.
zinc have also been found to reduce symptoms of
schizophrenia, although both of these effects have
Supplementary material
only been observed in single studies to date, which
have yet to be replicated. Additionally, despite the The supplementary material for this article can be
growing evidence base for neonatal vitamin D defic- found at https://doi.org/10.1017/S0033291717000022.
iency and developmental onset of psychosis (McGrath
et al. 2010a, b) along with the evidence for considerable
Acknowledgements
vitamin D deficiency in FEP (Graham et al. 2015) and
established schizophrenia (Lally et al. 2016), we found J.F. is funded by an MRC Doctoral Training Grant. S.R. is
no RCT that investigated the influence of vitamin D on funded by a Society for Mental Health Research Early
psychiatric symptoms. Clearly, this is an area which Career Fellowship (Australia). J.S. is supported by a
warrants future research (McGrath, 2010). C. R. Roper Fellowship. M.B. is supported by a
While determining the relative effectiveness of indi- NHMRC Senior Principal Research Fellowship 1059660.
vidual nutrients for schizophrenia is important, B.S. is supported by Stanley Medical Research Institute
large-scale RCTs in other populations have shown Grant 13T-006.
that general broad-spectrum micronutrient formulas
can improve various aspects of mental health and
Declaration of Interest
functioning, including; treating symptoms of ADHD
in adults (Rucklidge et al. 2014), reducing psycho- J.S. has received either presentation honoraria, travel
logical distress following traumatic events (Rucklidge support, clinical trial grants, book royalties from Integ-
et al. 2012), and lowering risk of criminal behaviour ria Healthcare & MediHerb, Pfizer, Taki Mai, Bioceuti-
(Gesch et al. 2002). Furthermore, this approach may cals & Blackmores, Soho-Flordis, Healthworld,
be less likely to result in imbalances which can occur HealthEd, Elsevier, Chaminade University, Inter-
from single-nutrient treatments (Rucklidge & Kaplan, national Society for Affective Disorders, ANS, Society
2013; Rucklidge et al. 2013). It should also be consid- for Medicinal Plant and Natural Product Research,
ered that dietary interventions, which address whole the National Health and Medical Research Council.
diet quality, may be more able to treat the range of All authors declare no conflict of interests. MB has
deficiencies which may affect patients, while also redu- received Grant/Research Support from the NIH,
cing the excessive consumption of high-calorie foods Cooperative Research Centre, Simons Autism

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 Vitamin and mineral supplementation in schizophrenia 11

Foundation, Cancer Council of Victoria, Stanley Med- treatment data and their implication for the staging model
ical Research Foundation, MBF, NHMRC, Beyond and early intervention. Bipolar Disorders 13, 87–98.
Blue, Rotary Health, Geelong Medical Research Foun- Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I,
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S (2008). N-acetyl cysteine as a glutathione precursor for
line, Meat and Livestock Board, Organon, Novartis,
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placebo-controlled trial. Biological Psychiatry 64, 361–368.
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declare no competing financial interests.
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