N u trients fo r Preven t i on a nd

Trea tme n t o f M en t al H e a l th
D i s o rd e r s
Shahin Akhondzadeh, PhD, FBPharmacolSa,*,
Patricia L. Gerbarg, MDb, Richard P. Brown, MD
c

KEYWORDS

Vitamins
Minerals
N-Acetylcysteine
Choline
5-Hydroxy-L-tryptophan

g-Aminobutyric acid
Inositol
Neuroprotection

KEY POINTS

Vitamin B6 (pyridoxine) can reduce medication-related extrapyramidal side effects.

Vitamin D3 (cholecalciferol) studies in depression show mixed results; however, patients
with prior history of depression, adolescents with severe mental illness, and people with
reduced sun exposure may benefit.

Medication augmentation with zinc may be beneficial in depression and attention-deficit
disorder, but not in dementia.

In children with low levels of serum ferritin, supplementation may improve learning,
memory, and symptoms of attention-deficit/hyperactivity disorder.

N-Acetylcysteine is an effective treatment for acetaminophen poisoning, antidepressant
augmentation, and reduction of negative symptoms, abnormal movements, and akathisia
in schizophrenia.

Citicoline (CDP-choline) is beneficial in dementia, recovery from head injury, and probably
acute ischemic stroke.

Although studies supporting the use of inositol are small, evidence indicates benefits in
depression, panic disorder, obsessive-compulsive disorder, bipolar depression, groom-
ing disorders, and eating disorders.

Disclosures: None.
a
Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical Sciences, South
Kargar Street, Tehran 13337, Iran; b New York Medical College, 86 Sherry Lane, Valhalla, NY
12401, USA; c Columbia University College of Physicians and Surgeons, 30 East End Avenue,
New York, NY 10028, USA
* Corresponding author.
E-mail address: [email protected]

Psychiatr Clin N Am 36 (2013) 25–36

http://dx.doi.org/10.1016/j.psc.2012.12.003 psych.theclinics.com
0193-953X/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
26 Akhondzadeh et al

INTRODUCTION

The nutrients most relevant to clinical psychiatric practice are those that affect the
central nervous system (CNS) and that are most likely to fall below the levels required
for healthy brain function.1,2 Dietary deficiencies, malabsorption, stress, illness, aging,
brain injury, and genetic polymorphisms affect requirements for essential nutrients.
Under conditions of oxidative stress, hypoxia, inflammation, or mitochondrial insuffi-
ciency, greater amounts of nutrients may be necessary to maintain cellular function
and repair, and to prevent cumulative damage. The clinical research and biochemistry
of S-adenosylmethionine, folate, and vitamin B12 are discussed in the article Folate,
B12, SAM-e by Bottiglieri, and omega-3 fatty acids in the article Omega-3 Fatty Acids
in Psychiatry by Mischoulon and Freeman, elsewhere in this issue.

VITAMINS B1, B6, AND D

Vitamin B1: Thiamine
The discovery of Vitamin B1 (thiamine) deficiency as the cause of beriberi and Wernicke-
Korsakoff syndrome (dementia, confabulation) led to the routine use of intramuscular
and oral thiamine supplementation in the treatment of alcoholism. Critically ill patients
are also at risk for thiamine deficiency and can benefit from supplementation.

Vitamin B6: Pyridoxine

A review of vitamin B6 (pyridoxine) found a lack of evidence to support its use in the
treatment of depression, except in premenopausal women.3 Low levels of pyridoxyl
50 -phosphate (PLP), the active form of vitamin B6, have been significantly associated
with depressive symptoms, but causality has not been established. B6 deficiency
(serum PLP <20 ng/mL) doubled the likelihood of depression in a cross-sectional
study of older adults.4
Reactive carbonyl compounds (RCOs) are thought to contribute to the pathogenesis
of schizophrenia. Vitamin B6 detoxifies RCOs. In a 26-week, double-blind, placebo-
controlled (DBPC) crossover trial, 50 inpatients with schizophrenia or schizoaffective
disorder and tardive dyskinesia (TD) were given either vitamin B6 (1200 mg daily) or
placebo. The mean decreases on the Extrapyramidal Symptom Rating Scale, parkin-
sonism subscale score, and dyskinesia subscale scores were significantly greater in
patients taking vitamin B6 than in controls.5

Vitamin D3: Cholecalciferol

Vitamin D deficiency during brain development has been linked to autism spectrum
disorders and schizophrenia. In preclinical studies vitamin D deficiency affected differ-
entiation of neurons, connectivity, dopamine pathways, and brain function. Evidence
also suggests that vitamin D affects neurotransmitters, inflammatory markers, homeo-
stasis of brain calcium, hypothalamic-pituitary-adrenocortical axis response to threat,
and synthesis of nerve growth factor.6 Adult population studies indicate that subop-
timal vitamin D levels may increase risks for depression, Alzheimer’s disease (AD), Par-
kinson’s disease, and cognitive decline.7 Although controversial, Vitamin D status is
usually based on serum concentrations of 25-hydroxyvitamin D (25(OH)D): deficiency
at less than 20 ng/mL; insufficiency at 20 to 30 ng/mL; and optimal at 30 to 80 ng/mL.
A review of 42 case-control, cohort, and randomized trials found a prevalence of
vitamin D insufficiency in 40% to 100% of community-dwelling adults aged 65 years
or older.8 Among 104 adolescents seeking treatment for serious acute mental illness,
vitamin D deficiency was found in 34% and insufficiency in 38%, with a strong asso-
ciation between vitamin D deficiency and psychotic features.9
 Nutrients: Nutrients for Treatment of Mental Health Disorders 27

Small clinical trials show positive effects of vitamin D on symptoms of depression.

However, larger-scale epidemiological studies report mixed results. The heterogeneity
of findings may be explained by differences in test measures, population characteris-
tics, vitamin D doses, and study duration. For example, a cross-sectional study of
12,594 adults at a primary care clinic found that higher levels of vitamin D were asso-
ciated with significantly reduced risk of depression. Individuals with a prior history of
depression showed a strong correlation compared with no significant correlation in
those without a prior history of depression.6 Studies not taking this distinction into
account might produce less valid results. Higher dietary intake of vitamin D correlated
with a reduced risk of AD over 7 years in 480 community-dwelling women aged
75 years and older. The risk of other dementias showed no significant association.10
Methodological weaknesses included the use of self-administered food-frequency
questionnaires and lack of serum 25(OH)D measurements.
Current evidence is not sufficient to justify vitamin D supplementation in all
depressed individuals. Assessment of 25(OH)D levels and supplementation with
vitamin D may be indicated in patients with the following risks: older than 65 years;
prior history of depression; adolescents with severe mental illness; lifestyle without
regular outdoor activity; and residence in northern latitudes. In patients with docu-
mented insufficiency of vitamin D, a daily dose of 800,000 IU/d vitamin D3 (cholecal-
ciferol) for several weeks is recommended.11 Once serum levels return to normal,
a lower maintenance dose of 2000 to 6000 IU/d is usually adequate. Small trials of
vitamin D for seasonal affective disorder have produced mixed results.12,13

MINERALS: ZINC, IRON, COPPER

Zinc
Zinc is important for immune regulation, energy metabolism, sexual function, insulin
storage, and macromolecule stabilization; and modulation of protein synthesis, DNA
transcription,14 neuronal precursor cell activity, neurotrophins, neurotransmitters,
and antioxidants.15

Major depression
Evidence from animal and human studies suggests an association between zinc
status and mood disorders. A systematic review16 identified 4 eligible randomized
controlled trials (RCTs) of moderate quality. In 2 studies antidepressant augmentation
with zinc (7–25 mg/d) for 10 to 12 weeks significantly improved depressive symptoms
in comparison with placebo add-on. However, evidence for efficacy of zinc monother-
apy was insufficient. The third RCT of 674 Guatemalan elementary school children (no
DSM-IV diagnosis) at risk for zinc deficiency found no effect of zinc supplementation
on mental health. However, increases in serum zinc concentrations were associated
with decreases in internalizing symptoms (depression and anxiety). The fourth study
found weak evidence of beneficial effects of zinc on mood in nondepressed
subjects.17

Dementia
In healthy states zinc, copper, and amyloid-b (Ab) metabolism are in a fine balance.
Zinc may protect against Ab-mediated oxidative cytotoxicity. Paradoxically, accumu-
lation of either zinc or Ab could lead to zinc-induced and/or Ab-mediated oxidative and
cytotoxic damage.18 Histopathological and case-control studies show increased
levels of brain zinc, mostly in parietal lobes,19 and reduced levels of serum zinc in
patients with AD.20 In a systematic review of 55 studies, no conclusive evidence for
any effect of zinc on AD was found.20
28 Akhondzadeh et al

Mental health in children

An 8-week double-blind randomized controlled trial (DBRCT) of low-birth-weight
infants in Brazil found no significant impact on mental or psychomotor development
with zinc 1 mg or 5 mg/d, or placebo at age 6 and 12 months. However, by year 1,
infants given zinc 5 mg/d had the highest ratings on behavioral assessment.21 A
combination of iron 20 mg/d and zinc 20 mg/d for 6 months may improve motor devel-
opment and exploratory behavior in infants at risk for micronutrient deficiency.22
Several RCTs found no effect of zinc alone or in combination with iron on cognitive
performance in children.
Zinc plays a role in attention-deficit/hyperactivity disorder (ADHD), possibly through
modulation of neurotransmitters (particularly dopamine and norepinephrine), prosta-
glandins, and fatty acids.23 Two of 3 RCTs reported that zinc modestly reduced hyper-
activity and impulsivity, but not attention. The first compared 6 weeks of zinc sulfate
(15–150 mg/d) monotherapy (n 5 400) with placebo.24 The second compared
12 weeks of zinc augmentation of methylphenidate (n 5 44) with placebo add-on.25
A third study in 52 children showed no effect of zinc glycinate (15 or 30 mg/d) after
8 weeks either alone or with methylphenidate on symptoms of ADHD, although zinc
30 mg/d lowered the required dose of methylphenidate by 37%.26 Tolerability of
zinc was comparable with placebo in all 3 studies.

Sexual dysfunction
Zinc is important for gonadal and sexual function. A systematic review of 4 parallel
trials in patients with uremia and sexual dysfunction surmised that zinc supplementa-
tion significantly increased testosterone levels but had inconsistent, nonsignificant
effects on libido and nocturnal penile tumescence.27

Wilson disease
Wilson disease (WD) is a genetic disorder characterized by hepatic and neuropsychi-
atric symptoms caused by excess deposition of copper. A systematic review,
including 1 RCT and 12 heterogeneous observational studies, concluded that in
general chelating agents were the most effective treatment. By contrast, zinc therapy
was favored for presymptomatic patients and neurological symptoms because it had
better tolerability and equal efficacy in these conditions.28 In a retrospective study of
288 patients (median follow-up of 17.1 years), zinc therapy was associated with signif-
icantly more hepatic treatment failure and less transplantation-free survival in compar-
ison with chelation. Patients with inadequate response to zinc generally responded
better to chelating agents.29

Zinc toxicity
Zinc is generally well tolerated. At toxic levels zinc can interfere with copper metabo-
lism, causing symptoms of copper deficiency such as microcytic anemia and
neutropenia. Acute zinc intoxication can also cause gastrointestinal disturbances,
tachycardia, shock, and damage to pancreas and liver. Toxic doses exceed
150 mg/kg body weight, which is considerably more than clinical doses.14

Clinical guidelines
Based on the studies reviewed, the following guidelines are suggested:
1. Zinc supplementation of antidepressants might be beneficial in the treatment of
depression.
2. Zinc alone or in combination with stimulants might improve hyperactivity and
impulsivity symptoms of ADHD.
 Nutrients: Nutrients for Treatment of Mental Health Disorders 29

3. Zinc is a good choice for treatment of presymptomatic WD as well as its neurolog-

ical symptoms.
4. Zinc is not beneficial for the treatment of dementia.
5. Zinc has minimal impact on intelligence quotient or mental health in children,
except possibly in those with zinc deficiency.

Iron
Iron is essential for energy production, DNA and neurotransmitter synthesis, myelina-
tion, and phospholipid metabolism. Iron deficiency has been linked to movement
disorders, including restless leg syndrome (RLS), possibly attributable to effects on
dopamine synthesis. The diagnosis of iron-deficiency RLS is easily missed, particu-
larly in children with ADHD in whom leg movements may be misinterpreted as
a sign of hyperactivity. Iron deficiency is more common in children with ADHD. One
study documented low levels of serum ferritin (a measure of iron stores) in 84% of
53 children with ADHD compared with 18% of 27 children who did not have ADHD.
Lower ferritin levels correlated with more severe cognitive deficits and ADHD
ratings.30
Studies of iron supplementation for the treatment of RLS have shown mixed results,
which may be due to lack of measurement of serum ferritin levels, differences in pop-
ulations studied, poor gastrointestinal absorption or brain uptake of supplements,
genetic polymorphisms, or other dietary factors. A study of intravenous ferric carbox-
ymaltose showed significant benefits in adults with RLS and low levels of ferritin.31 In
adolescents with iron deficiency, iron supplements improved learning and memory.32
In a controlled study of 23 children (age 5–8 years) with low levels of serum ferritin, iron
supplementation (80 mg/d) reduced ADHD symptoms.33 Iron therapy was well toler-
ated. Larger studies are needed to explore the role of iron supplements in the treat-
ment of ADHD.

Copper
Copper is essential in the synthesis of dopamine and norepinephrine. A Canadian
study found that about 23% of children with ADHD were deficient in copper.34 The
role of copper in ADHD needs further study.

AMINO ACIDS, PRECURSORS, AND METABOLITES: N-ACETYLCYSTEINE, CHOLINE,

L-TRYPTOPHAN, g-AMINOBUTYRIC ACID, INOSITOL
N-Acetylcysteine
N-Acetylcysteine (NAC) is a precursor to the essential amino acid, cysteine. Unlike
cysteine, NAC can penetrate the blood-brain barrier such that by oral supplementa-
tion, it can increase blood and brain levels of cysteine. Preclinical data, case reports,
and clinical studies indicate potential benefits of NAC for the treatment of addictions,
bipolar depression, schizophrenia, autism, obsessive-compulsive disorder (OCD), tri-
chotillomania, nail biting, skin picking, overdoses, and environmental toxic
exposures.35
NAC plays important roles in metabolic pathways believed to contribute to psychi-
atric disorders:
1. By increasing levels of brain cysteine, NAC was able to modulate glutamatergic and
dopaminergic pathways. In vitro studies show a reduction in synaptic release of
glutamate and an increase in dopamine release.35
2. Oxidative stress has been implicated as contributing to psychiatric disorders.
Glutathione (GSH) is the body’s main endogenous antioxidant. As a precursor to
30 Akhondzadeh et al

GSH, NAC has been widely used to replenish GSH, for example in the treatment of
acetaminophen overdose. In addition, NAC directly scavenges reactive oxygen
species.
3. Inflammatory cytokines play a role in brain aging and psychiatric disorders. NAC
has anti-inflammatory effects that may occur via antioxidant activities or other
direct effects on inflammatory pathways.

Substance abuse
In an open-label study, 24 cannabis-dependent adults given NAC (2400 mg/d) showed
no significant change in levels of urine cannabinoid. Nevertheless, scores on the
Marijuana Craving Questionnaire improved.36 In an 8-week DBRPC study, 116
cannabis-dependent adolescents were given NAC (1200 mg twice a day) as adjunct
to contingency management and brief weekly cessation counseling. Compared with
placebo, subjects taking NAC had more than twice the odds of negative urine tests.37
In a 4-week open pilot study of 23 cocaine-dependent patients, higher doses of NAC
(2400 mg/d or 3600 mg/d) improved retention rates compared with lower doses.38 A
small RCT of heavy smokers given NAC for 3 and a half days showed no statistically
significant change in craving compared with placebo, but revealed a trend toward
fewer withdrawal symptoms and reduced pleasure in smoking after abstinence.39

Obsessive-compulsive disorder, trichotillomania, nail biting, skin picking

In OCD, glutamatergic dysfunction has been implicated and glutamate modulating
agents may be efficacious. It is postulated that NAC, by increasing extracellular gluta-
mate concentration in the nucleus accumbens, could exert a therapeutic effect on
OCD. Isolated case reports describe a significant response to NAC in patients with
OCD and related grooming disorders.35,40 One DBRPC trial of NAC for 50 patients
with trichotillomania tested NAC 1200 mg/d for 6 weeks followed by NAC 2400 mg/
d for 6 weeks more. Those given NAC showed reduced hair-pulling symptoms (P 5
.001) in comparison with placebo.41

Bipolar disorder
Increased oxidative stress has been associated with manic states and illness duration
in bipolar disorder. Hyperdopaminergic states have been reported during mania. Both
the antioxidant and dopaminergic modulatory effects of NAC might be beneficial in
stabilizing patients with bipolar disorder. A 6-month DBRPC study of 75 patients
with bipolar disorder demonstrated that NAC (2000 mg/d) as adjunct to established
medication regimens resulted in significantly large improvements in depressive symp-
toms and global function when compared with placebo.42

Schizophrenia
Neurotransmitter abnormalities identified in schizophrenia patients include increased
dopaminergic metabolism in the striatum, hypodopaminergia in the prefrontal cortex,
and decreased glutamate levels in the prefrontal cortex. Oxidative stress has been
associated with symptom severity, alterations in lipid membranes, mitochondrial
dysfunction, and abnormalities in DNA, proteins, and dendritic sprouting.35 In
a 6-month DBRPC study of NAC (1000 mg twice a day) as adjunctive treatment to
ongoing standard medications in 140 treatment-refractory schizophrenic patients
with an average duration of symptoms of 12 years or more, those given NAC showed
significant improvements in negative symptoms, global function, abnormal move-
ments, and akathisia in comparison with placebo. Qualitative data revealed that
patients in the NAC group achieved greater improvements in insight, self-care, social
interaction, motivation, volition, psychomotor stability, mood stability, and auditory
 Nutrients: Nutrients for Treatment of Mental Health Disorders 31

sensory processing.43 NAC is a promising adjunctive treatment for schizophrenia and

for reducing the side effects of psychotropic medications, particularly akathisia.

Detoxification following overdose or environmental exposures

Intravenous or oral NAC has been used for decades to treat acetaminophen
poisoning. Acetaminophen is oxidized to N-acetyl-p-benzoquinoneimine (NAPQI),
which binds to molecules inside hepatocytes, causing apoptosis and eventual hepatic
necrosis. Glutathione (GSH) detoxifies NAPQI.44 The depletion of GSH by acetamino-
phen toxicity can be reversed by NAC, leading to recovery and prevention of further
damage. In addition to hepatoprotective properties, NAC is known to be renoprotec-
tive. It has been used to treat nephropathy caused by contrast injections during radio-
logical studies. Considering its renoprotective effects and its benefits for bipolar
disorder, it would be worth studying the use of NAC in preventing or treating renal
dysfunction secondary to lithium treatment.

Side effects and adverse reactions

At clinically relevant doses, side effects of NAC are infrequent and generally mild.
Occasionally allergic reactions and rarely anaphylactic reactions to intravenous NAC
have been reported, but these rarely led to discontinuation. Longer-term and dose-
finding studies would help clarify the maximum safe doses. In animal studies very
high doses caused pulmonary hypertension, but this has not been reported in human
studies. Overdose of NAC was associated with seizures. However, in low doses NAC
is antiepileptic.

Tryptophan: 5-Hydroxy-L-Tryptophan
5-Hydroxy-L-tryptophan (5-HTP) is the immediate precursor of serotonin (5-hydroxy-
tryptamine; 5-HT). Supplemental 5-HTP is used by many consumers for depression,
insomnia, and fibromyalgia. 5-HTP replaced L-tryptophan, which was taken off the
market in 1989 when a contaminated product from one manufacturer was associated
with eosinophilia malignant syndrome. The absence of toxicity in 5-HTP has been
documented in extensive studies.45
A review of 27 studies of 5-HTP for depression found that of the 11 DBRPC trials,
7 reported superiority over placebo, but only 5 of these showed statistical signifi-
cance.46 Studies have shown that 5-HTP augments the response to prescription anti-
depressants such as nialamide, clomipramine, and nomifensine. The average dosage
of 5-HTP in adults is 200 to 300 mg/d in divided doses taken twice or 3 times per day.
Limited evidence supports the use of 5-HTP as augmentation to antidepressant
medications.
Common side effects of 5-HTP include nausea, vomiting, and diarrhea; less
frequent are headache and insomnia. In rodents, doses below 50 mg/kg/d produce
no toxicity, but doses above 100 mg/kg/d induce serotonin syndrome. There are no
case reports of serotonin syndrome in humans taking 5-HTP alone or in combination
with selective serotonin reuptake inhibitors. Studies report no adverse effects from
a combination of 5-HTP and monoamine oxidase inhibitors.

g-Aminobutyric Acid
g-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA
inhibitory pathways help modulate overactivity of the amygdala, for example in anxiety
disorders and posttraumatic stress disorder. It also has a regulatory role in cardiovas-
cular, pituitary, renal, and immune function, as well as fertilization. In Japan, GABA is
produced by fermentation and is used as a food supplement.
32 Akhondzadeh et al

In a DBPC crossover study of 13 healthy adults, the effects on the electroenceph-

alogram (EEG) of 100 mg GABA (Pharma-GABA) were compared with the effects of
200 mg L-theanine or placebo. GABA intake resulted in a significantly greater increase
in alpha waves (associated with relaxed alertness) and decrease in beta waves (asso-
ciated with high stress and difficulty concentrating) in comparison with L-theanine or
placebo.47 Low levels of salivary immunoglobulin A (IgA) occurring in highly anxious
individuals decrease further under stress. In a DBRPC study, 8 patients with acro-
phobia (fear of heights) walked across a suspension bridge 54 m above the ground
and 300 m long. In the placebo group, IgA levels (marker of stress and immune
response) dropped substantially halfway across and at the end of the bridge. In the
group given 100 mg GABA, IgA levels dropped only slightly midway and rose above
baseline by the end of the bridge. GABA prevented decline in IgA, indicating reduced
anxiety and stress effects.47
A synthetic analogue of GABA, pregabalin, approved by the US Food and Drug
Administration for the treatment of neuropathic pain and partial-onset seizures, is
being considered for approval as an adjunctive treatment for generalized anxiety
disorder (GAD). Several RCTs confirm that in moderate to severe GAD, the anxiolytic
effect of pregabalin is comparable with that of lorazepam (Ativan), alprazolam (Xanax),
and venlafaxine (Effexor). Pregabalin is generally safe and well tolerated. Side effects
include dizziness, somnolence, cognitive interference, incoordination, and headache.
Drawbacks are the potential for some dependence and the slow onset of anxiolytic
effect, which requires 1 week of daily treatment.48 Starting with 50 mg 3 times daily,
doses can be increased as tolerated.

Choline and its Precursors

Acetylcholine is derived from choline and acetyl coenzyme A. Neurons cannot synthe-
size choline and therefore must obtain it from the bloodstream following food
absorption.49,50 Dysfunction in cholinergic neurotransmission in the hippocampus
and cortex is associated with dementia, particularly AD. Agents are being studied
that could increase central cholinergic activity and thereby improve brain function in
AD, other dementias, cerebrovascular accident, and other brain disorders.51
Trials of choline chloride (up to 200 mg/kg/24 h) failed to enhance acetylcholine
biosynthesis or improve symptoms in patients with mild to moderate AD despite
increasing levels of plasma choline.52–54 Other supplements tested for the treatment
of dementia by potentially increasing acetylcholine content and release include
lecithin, cytidine 50 -diphosphocholine (CDP-choline), choline alphoscerate, and
phosphatidylserine.50 In a systematic review of 12 randomized studies, no study
showed significant objective benefit of lecithin for AD or dementia of Parkinson’s
disease. Only 1 trial reported significant improvement following lecithin administration
for subjective memory problems.55
Five trials of phosphatidylserine (average dose 300 mg/d) reported a modest benefit
over placebo in the treatment of AD.56–60 The effect of phosphatidylserine appears to
be short term in light of the long-term disease progression.60 Phosphatidylserine
demonstrates mixed results in studies of age-associated cognitive impairment in non-
demented individuals.61–63 Differences in outcomes may be attributed to variations in
study design, subject selection, duration, assessment instruments, and preparations
of phosphatidylserine. A safety study reported no negative effects using 100 mg/d
phosphatidylserine for 30 weeks.64
A review of 13 trials (total of 4054 patients), including 10 of patients with dementias,
concluded that choline alphoscerate showed higher efficacy than placebo for
 Nutrients: Nutrients for Treatment of Mental Health Disorders 33

cognitive symptoms and higher or similar efficacy in comparison with active treatment.
Three other uncontrolled studies suggested that it might improve functional recovery
in patients with acute cerebrovascular accident.65 Results of a later open-label study
noted improvement of cognitive function in Parkinson’s dementia (n 5 60) when
compared with piracetam.66
CDP-choline (citicoline), a widely studied choline precursor, has been comprehen-
sively reviewed.67 A Cochrane systematic review of 14 studies with up to 12 months of
follow-up concluded that CDP-choline improved memory and behavior, but showed
no beneficial effect for attention.68 Studies have demonstrated that citicoline can
lead to resolution of brain edema, restoration of consciousness, and improvement
in survival. Several trials have consistently demonstrated a beneficial role of citicoline
(usual doses of 500–2000 mg/d) in prevention of head-injury sequelae,67 including
faster recovery of consciousness and memory function, accelerated resolution of neu-
ropsychological disorders, shorter hospital stays, and improved EEG, quality of life,
and motor recovery. Of importance, citicoline (intraperitoneal, intravenous, intramus-
cular, or oral) was tolerated well. Meta-analysis of 10 studies of cerebrovascular acci-
dents (total of 2279 patients) concluded that receiving citicoline was associated with
reduced morbidity and mortality.69 Two drug-surveillance studies in more than 4300
patients with acute ischemic stroke showed that administration of oral citicoline
(500–4000 mg/d) was associated with better outcomes, with no safety concerns.70,71
Despite the previous reports on the benefit of citicoline in acute stroke, a recent multi-
center DBRCT conducted in 2298 patients with moderate to severe acute ischemic
stroke in 49 centers of 3 European countries did not provide any evidence for the
superior effect of citicoline (1000 mg every 12 hours for 6 weeks) over placebo in
global recovery.72 There could be several reasons for these discrepant findings.
Doses of 2000 mg/d were used in the study by Davalos and colleagues,72 whereas
the authors’ clinical experience and the previous studies suggest better response
to doses above 2000 mg/d. Furthermore, the effect of CDP-choline becomes evident
usually after 9 to 12 weeks, whereas in the study by Davalos the duration was
6 weeks. In subgroup analysis, however, Davalos found evidence for the efficacy
of citicoline in older patients (>70 years), in those with moderate stroke severity,
and in patients not treated with a fibrinolytic. There is also some evidence for the
role of citicoline in the treatment of cocaine addiction. In a 12-week RCT of 44
patients with a history of bipolar disorder and cocaine dependence, citicoline
improved scores on the Rey Auditory Verbal Learning Test alternative word list (but
not mood status) and reduced the probability of cocaine-positive urine significantly
more than the placebo.73 Not all studies, however, showed a beneficial effect on
drug addiction.67,74

Picamilon
Picamilon, a cerebral vasodilator, is a composite of GABA and vitamin B3 (niacin) that
increases cerebral blood flow by reducing blood-vessel tone.75 Most picamilon
research is published in Slavic languages. This paragraph is based on abstracts,
one review in English,76 and clinical experience. In animal studies, picamilon is re-
ported to exert mild tranquilizing action (reduced aggressive behavior) and mild stim-
ulative activity that can improve alertness and cognitive function. It showed low
toxicity (median lethal oral dose 10 g/kg of body weight). Additional controlled trials
are indicated. In practice the authors (R.P.B. and P.G.) find that for patients with cere-
bral vascular impairment, picamilon can substantially improve alertness, confusion,
anxiety, and depression. Side effects are mild, with occasional decreases in blood
pressure.
34 Akhondzadeh et al

Inositol
Inositol (cyclohexane-1,2,3,4,5,6-hexol), a carbohydrate, is a precursor of phosphaty-
linositol, a component of neuronal membranes, essential for effective signaling in
adrenergic, cholinergic, serotonergic, and glutaminergic pathways. Although some-
times listed as a B vitamin, inositol is not a vitamin because it can be synthesized by
the body. Several studies, including RCTs, show benefits greater than placebo in indi-
viduals with depression, panic, and OCD. A 1-month crossover DBRCT in 20 patients
with panic disorder found similar improvements with inositol (18,000 mg/d) and fluvox-
amine (up to 150 mg/d). However, inositol had fewer side effects.77 Another DBRPC
crossover study of 24 nondepressed patients with bulimia nervosa or binge-eating
disorder compared inositol (18,000 mg) with placebo over 6 weeks. No other psycho-
tropic medications were administered. In 5 patients side effects (mild abdominal
pain, flatulence, or soft stools) remitted on reducing inositol to 12,000 mg/d. Compared
with placebo, inositol significantly improved Global Clinical Impression and Visual
Analog Scale scores, as well as showing a borderline significant effect on the Eating
Disorders Inventory. Benefits were independent of anxiety or depression.78
In a DBRPC pilot study of 24 adults with bipolar depression (21 with bipolar I and
3 with bipolar II) whose mood stabilizers (lithium, valproate, and carbamazepine) were
maintained, those given inositol (12,000 mg/d) augmentation showed greater improve-
ment in depression ratings than those given placebo.79 Another RCT of mood-stabilizer
augmentation in 66 bipolar I patients and 11 patients with treatment-resistant depres-
sion demonstrated a recovery rate of 23.8% with lamotrigine versus 17.4% with
inositol.80 Although inositol can cause gastrointestinal side effects, particularly flatu-
lence, it would be worth considering in bipolar patients requiring augmentation who
experience side effects or lack of response with lamotrigine.
Although studies of inositol to date are few, evidence supports the use of this natural
phospholipid precursor as an adjunctive treatment for depression, panic, OCD,
bipolar depression, binge eating, and bulimia nervosa.

SUMMARY

Vitamins, minerals, and natural metabolites are essential for physical and mental
health. In certain populations, such as children, those with ADHD, the elderly, patients
with serious psychiatric or medical conditions, and substance abusers, vitamin defi-
ciencies are not uncommon. For example, vitamin B1 supplementation can reverse
neurological symptoms in critically ill patients and in those with alcoholism. NAC
and vitamin B6 exemplify nutrients that are crucial for normal metabolism as well as
for cellular protection and repair. By repairing neurological damage from antipsy-
chotics and other psychotropics, NAC and B6 can alleviate movement disorders
and akathisia. Considerable evidence supports the use of citicoline (CDP-choline) in
dementia, recovery from head injury, and probably acute ischemic stroke. Picamilon
is a potentially useful vasodilator for the treatment of cerebrovascular insufficiency.
Studies suggest that inositol can be beneficial in depression, panic disorder, OCD,
bipolar depression, and eating disorders. Clinicians may opt to include nutrients in
treatments offered to patients whose symptoms are not fully responsive to medica-
tions or in whom medications cause adverse effects.

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10.1016/j.psc.2012.12.003.
 Nutrients: Nutrients for Treatment of Mental Health Disorders 35

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