CM E

Nutritional Aspects of
Child and Adolescent Psychopharmacology
O
ne challenge faced by physi-
cians in pharmacotherapy of
children and adolescents is the
management of drug-drug interactions.
A second challenge, rarely addressed,
is the potential interaction of drugs with
nutrients. The National Health and Nu-
trition Examination Survey (NHANES)
found 52% of adults taking a dietary
supplement in the previous month.1 In
children with autism spectrum disorders,
nutrient supplementation has also been

CM E EDUCATIONAL OBJECTIVES

1. Describe the scope of nutrients, espe-

cially vitamins and materials, which
have been studied in relationship to
mood, and some of the findings.
2. Relate the four different types of
interactions between medications
and nutrients/foods.
3. Discuss the recommendations for
compensatory supplementation for
specific medication regimens.

Bonnie J. Kaplan, PhD, is Professor, Fac-

ulty of Medicine, University of Calgary,
Calgary, Alberta, Canada. Scott Shan-
© Nikolai Punin / Images.com
non, MD, is Medical Director, Northern
Colorado Center for Holistic Medicine,
Fort Collins, Colorado.
Address correspondence to: Bonnie J.
Kaplan, PhD, Department of Pediatrics,
University of Calgary, Behavioral Research
Unit, Alberta Children’s Hospital, 2888 Sha-
ganappi Trail NW, Calgary AB T3B 6A8; fax Bonnie J. Kaplan, PhD; and Scott Shannon, MD
403-955-2772; e-mail bonnie.kaplan@cal-
garyhealthregion.ca. reported to be about 50%.2 Vitamins, blocks of neuronal structure and func-
Dr. Kaplan and Dr. Shannon have dis- minerals, amino acids, and essential tion, and depending on dose levels, can
closed no relevant financial relationships. fatty acids, of course, are the building be expected to influence brain function

PSYCHIATRIC ANNALS 37:7 | JULY 2007 519

3707Kaplan.indd 519 7/6/2007 10:11:04 AM

 per se. Additionally, supplements can af-
fect pharmaceutical regimens prescribed
for the purposes of influencing the brain,
because of the possibilities for interac-
tions. In this article, we review a) some
fundamentals of nutrition and brain
biochemistry shown to be important in
psychiatric disorders, including the po-
tential therapeutic benefit of nutrient
supplementation, and b) what is known
of drug-nutrient interactions, including
nutrient stress introduced by drugs that
interfere with metabolism and increase
the requirement for specific nutrients.
NUTRITION AND BRAIN
BIOCHEMISTRY IN RELATION TO
PSYCHIATRIC DISORDERS
For millennia, it has been known that
behavioral/psychiatric symptoms can be
the first manifestation of a nutrient de-
ficiency; Hippocrates wrote 2500 years
ago that food is medicine, and medicine
is food. Modern examples include the
1920s description of behavioral irritabil-
ity caused by vitamin B deficiency in the
Journal of the American Medical Asso-
ciation.3 It is now known that zinc plays
a role in more than 100 metabolic path-
ways in the brain. A review of modern
neuropharmacology reveals that micro-
nutrients (vitamins and minerals) func-
tion as cofactors in almost every aspect
of neurotransmitter synthesis. Ames has
suggested that suboptimal micronutrient
levels result in slowed metabolic reac-
tions4 and reported about 50 genetically
influenced errors reversible by providing
high levels of micronutrients.
The following overview provides a
summary of the nutrients of special in-
terest in the research literature on mental
health. The focus here is on micronutri-
ents,3 in part because they have been
relatively neglected in comparison to
the multiple recent review articles and
books about the burgeoning research on
essential fatty acids (EFA), herbs,5 and
amino acids such as valine, isoleucine,
leucine, tyrosine, and phenylalanine.6
520
3707Kaplan.indd 520
We will cover EFAs only as a facet of
nutrition and not as supplementation.
Vitamins
There is a significant research lit-
erature on the B vitamins. For instance,
Bottiglieri said that 52% of a sample
of depressed patients had raised total
plasma homocysteine, indicative of low
functional folate and cobalamine lev-
els.3 Both the symptoms of depression
and poor response to antidepressant
medication have been found to be as-
sociated with low levels of folic acid.7
Depressive symptomatology was stud-
ied in 2,682 middle-aged men, as well as
their dietary folate, cobalamin (vitamin
B12), pyridoxine (vitamin B6), and ri-
boflavin (vitamin B2).3 The participants
in the lowest third of folate intake had
a significantly higher risk of being de-
pressed than those in the highest third of
folate intake, even after adjustment for
a variety of health and socioeconomic
variables.
Some psychiatrists believe that pa-
tients with mood disorders should have
their vitamin B12 (cobalamin) levels
checked. Perhaps less well known are
some documented cases showing B12
reversing some vitamin-deficiency-trig-
gered episodes of mania. For example,
one patient with mixed depressed/manic
features because of vitamin B12 and fo-
late deficiency experienced full remis-
sion, improved cognitive functioning, and
EEG normalization after vitamin supple-
mentation.3 Thiamine (vitamin B1) is im-
portant for the synthesis of acetylcholine,
relevant to both depression and dementia.
In a 2-month randomized controlled trial
(RCT) with 120 women college students
not suffering from diagnosed mental dis-
orders, placebo was compared with those
taking 50 mg thiamine daily. Improved
mood in those who received the thia-
mine was documented with weekly self-
reported scores on the Profile of Mood
States, especially in those who began the
treatment with low thiamine status. Be-
cause there have been some reports that
patients with depression have low levels
of vitamin B6 (pyridoxine), several stud-
ies have examined the therapeutic ef-
fect of supplementation, but the results
have been inconsistent. Biotin, generally
thought to be in the class of B vitamins,
has been studied more recently: biotin
deficiency can cause withdrawn behav-
ior, a delay in cognitive development or
hallucinations.8
Other vitamins have also been studied
in relation to mood. After controlling for
age, sex, low-density lipoprotein choles-
terol and triglycerides, 42 depressed pa-
tients had lower serum levels of vitamin
E than 26 normal controls.3 Choline bitar-
trate is a vitamin-like compound, which
along with its metabolites, is involved in
many aspects of biological functioning
including maintaining structural integ-
rity of cell membranes, cell signaling,
and nerve impulse transmission. It has
been shown to reduce manic symptoms
in people with bipolar disorder, and at the
same time the basal ganglia exhibited a
rise in the concentration of choline-con-
taining compounds.3 Other studies have
documented abnormalities in metabolism
of choline-containing compounds in the
anterior cingulate cortex of patients with
bipolar disorder and in frontal lobe phos-
pholipid metabolism.3
A discussion of S-adenosylmethio-
nine (SAMe) is relevant to a consider-
ation of the B vitamins. Methylation
reactions and nucleic acid synthesis lie
at the core of the relationship between
folate and cobalamin, as illustrated by
the methylation of homocysteine to me-
thionine and the synthesis of SAMe.
SAMe in the central nervous system
is involved in methylation of proteins,
nucleic acids, phospholipids, and neu-
rotransmitters. If there is a deficiency in
either vitamin B12 or folate, the result
may be insufficient methionine synthase
activity, which disrupts methylation,
and can in turn cause clinical sequelae,
including depression. It is therefore not
PSYCHIATRIC ANNALS 37:7 | JULY 2007
7/6/2007 10:11:06 AM
 surprising that SAMe has been shown
to have antidepressant properties, with a
faster onset of action than conventional
antidepressants. Results of two multi-
center double-blind studies showed that
the efficacy of SAMe as an antidepres-
sant did not differ significantly from
that of imipramine, and SAMe caused
fewer adverse events.7
Inositol
An isomer of glucose, inositol is found
in food as a fiber component known as
phytic acid. Americans eat about 1,000
mg per day of this sweet-tasting nutrient.
Inositol is a pre-
cursor of crucial
intracellular sec-
ond messengers.
What makes it
most interesting
for psychiatry is
that it has been found to be quite use-
ful in a range of psychiatric problems.
RCTs have demonstrated significant
benefits for the treatment of panic dis-
order, depression, obsessive compulsive
disorder, and bulimia.8 Significant dif-
ferences in levels of intracellular inosi-
tol have been isolated in the brains of
children with attention-deficit hyper-
activity disorder (ADHD) as compared
to controls.9 In the STEP-BD study, a
comparison was made between aug-
mentation with inositol, risperidone, or
lamotrigine.10 No separation was found
between the three. Research on inositol
is underway as a treatment for a range
of disorders or as an intracellular target
in treatments for bipolar disorder.
Minerals
Zinc is the second most abundant
transition metal in the brain next to
iron and plays a role in synaptic trans-
mission, DNA synthesis, and the func-
tion of many enzymes. Maes and col-
leagues found lower serum zinc levels
in 48 unipolar depressed patients (16
minor depression, 14 with simple ma-
PSYCHIATRIC ANNALS 37:7 | JULY 2007
3707Kaplan.indd 521
jor depression, and 18 with various
combinations) in comparison with 32
normal volunteers.3 A recent review
found nine published studies on zinc in
ADHD.11 For example, Toren’s group
in Israel reported lower serum zinc in
43 children with ADHD than in com-
parable controls.11 In 44 children with
ADHD, parent and teacher ratings of
inattentiveness correlated inversely
(r = -.45, P = 0.004) with serum zinc.11
A study of 18 boys with ADHD in a pla-
cebo-controlled trial of d-amphetamine
found that higher baseline hair zinc lev-
els predicted a better placebo-controlled
behavioral
response to
the stimulant.
Two placebo-
controlled tri-
als found zinc
Some psychiatrists realize that patients with mood disorders
should have their vitamin B12 (cobalamin) levels checked.
useful in ADHD, one as monotherapy
and one as augmentation of methylphe-
nidate. Examining copper/zinc ratios in
135 assaultive, incarcerated males in
comparison with controls, Walsh and
colleagues found a linear relationship
between the degree of zinc deficiency
and the seriousness of the behavior,
ranging from verbal assault to aggra-
vated and violent assault.3 The zinc
results in humans are consistent with
a large, older literature on lab animals,
which demonstrates that zinc deficiency
is associated with impaired learning and
memory; immunodeficiency, and de-
layed motor development.
The role of other minerals such as
calcium for human mood is also being
explored. Calcium imbalance caused by
hyperparathyroidism affects anxiety, de-
pression, and cognitive function. Some
reports indicate that intracellular cal-
cium signalling systems play a role in
the pathophysiology of bipolar disorder.
Plasma calcium was significantly lower
in 29 unipolar depressed and 11 manic
patients compared with 10 healthy con-
trols, and platelet calcium concentration
was lower in unipolar than bipolar de-
pressed patients.3 Interestingly, a study
by Michelson and colleagues reported
significantly decreased bone mineral
density (measured at hip, spine, and ra-
dius) in 24 women with current major
depressive disorders or with a past his-
tory of depression,3 suggesting a com-
mon pathophysiology involving im-
paired calcium absorption.
Magnesium plays a role in neu-
rotransmitter release as well as post-syn-
aptic receptor function and has a depres-
sant effect at synapses, inhibiting the
release of neurotransmitters such as ace-
tylcholine, and antagonizing receptors
such as the NMDA receptor. There are
relatively few studies of magnesium in
mental health. Physicians have known of
its sedative value since the 1920s. In fact
in the 1930s and ’40s, magnesium was
the preferred treatment for affective psy-
chosis in Europe. Its role in depression
is unclear, because some studies indicate
that higher plasma and erythrocyte con-
centrations of magnesium are associated
with increased severity of depression.
The brain contains a number of iron-
dependent enzymes that are necessary
for the synthesis, function, and degra-
dation of neurotransmitters as well as
other cellular processes. Low levels of
serum iron have been found in people
with major depression, and women with
low postpartum hemoglobin levels had
higher depression scores at 28 days post-
partum.12 In a RCT conducted in South
521
7/6/2007 10:11:07 AM
 Africa, anemic mothers who were sup-
plemented with iron (125 mg/day) from
10 weeks to 9 months postpartum had a
25% improvement in depressive scores
over the placebo group.13
Although less is known about the role
of chromium in mammalian brain, there
is research linking it to mood also. In a
RCT, 113 subjects with atypical depres-
sion received chromium or placebo for
8 weeks; there were no significant im-
provements in mood with chromium sup-
plementation, although the supplement-
ed group did experience improvements
in appetite and carbohydrate craving.14
In a small RCT in atypical depression,
the investigators reported that seven of
10 patients taking chromium for 8 weeks
responded positively to the chromium
treatment with a significant reduction in
depression scores, compared with no re-
sponse in the pla-
cebo group.7
Selenium is
believed to play
an important role
in brain function,
suspected from
its selective retention by the brain in
times of deficiency. The functions of se-
lenium within the brain are not clear but
may be related to its antioxidant proper-
ties. A 5-week RCT involving 50 healthy
participants indicated that selenium im-
proved mood scores and decreased anxi-
ety as compared with placebo.3 How-
ever, a recent, large RCT involving 501
healthy older adults showed no effect of
selenium supplementation on mood after
6 months, despite increased plasma con-
centrations of selenium.15
Multi-ingredient Supplementation
Several examples of single-nutrient
supplementation trials were presented
above, showing therapeutic benefit of
B vitamins, choline, SAMe, zinc, mag-
nesium, iron, chromium, and selenium.
Recently, a literature on multi-ingredient
supplementation has developed, based
522
3707Kaplan.indd 522
on the logic that nutrients work together
in the central nervous system. Therefore,
providing an array of micronutrients will
replace multiple coexisting deficiencies
and thus allow optimal brain function.
Benton’s double blind evaluation of
a high daily dose of multivitamins (10
times the recommended daily dose) in
129 healthy young volunteers involved
daily doses of either the supplement or
a placebo for one year.3 The improve-
ments in mood reported after a year oc-
curred even though the blood status of
nine vitamins reached a plateau after 3
months. In the female participants, there
was a positive correlation between thia-
mine status and mood.
Gesch and colleagues conducted a
RCT involving both vitamins and miner-
als in 231 young offenders: there was a
35.1% decrease in disciplinary incidents
for those re-
ceiving the
active mi-
cronutrient
supplement
(which in-
Calcium imbalance caused by hyperparathyroidism affects anxiety,
depression, and cognitive function.
cluded 25 vitamins and minerals, plus
some essential fatty acids), compared
with a reduction of only 6.7% in those
receiving placebo.3
Five different open reports have
suggested that a broad spectrum mul-
tivitamin/mineral formula called Em-
powerplus deserves further study as a
potential treatment for unstable mood
symptoms in both children and adults.
In an ABAB reversal design, on-off
control of mood and temper symptoms
were demonstrated in two children,
who were then followed for more than
4 years.16 Two open label case series,
one in children with mood and anxiety
disorders17 and another in adults with
bipolar disorder18 provided positive
results with large effect sizes. These
results have been replicated in cases
series in clinical settings by two inde-
pendent psychiatrists using the same
nutrient supplement.19,20 Children and
adolescents were included in both these
replications. A randomized controlled
trial in adults with bipolar disorder is
underway in Calgary, Alberta, Canada,
and San Diego, California.
DRUG-NUTRIENT INTERACTIONS
The interface of nutrition, psycho-
pharmacology, nutrient biochemistry,
and clinical management in child psy-
chiatry presents a daunting yet crucial
arena of concern. On one hand, we have
mounting evidence that key nutrients
can play a significant role in psychiat-
ric illness and their treatment. On the
other hand, we have the extremely com-
mon clinical observation that psychiat-
ric medications alter nutritional status
in children by changing appetite, food
selection, and weight. Appetite sup-
pression may induce parents to allow a
switch from micronutrient-rich foods to
the “empty calories” found in sugar and
fat in order to maintain weight. There
is significant research that indicates
that many psychiatric medications shift
the metabolism of key nutrients. Con-
versely, nutrients can create alterations
in the bioavailability of psychiatric
medications. This complex biochemis-
try comes into clinical psychiatric rel-
evance in the child’s brain.
The complexity of nutrient-drug-nu-
trition interactions forces the need for a
more exact manner to describe the myr-
iad of interactions possible. One method
PSYCHIATRIC ANNALS 37:7 | JULY 2007
7/6/2007 10:11:08 AM

Known Medication Effects on Specific Nutrients8
Medication
Carbamazepine, phenytoin, valproic acid
Carbamazepine
Valproic acid
Valproic acid
Anti-epileptic drugs
Anti-epileptic drugs
Anti-epileptic drugs
Anti-epileptic drugs
Multiple anti-epileptic drugs and valproic acid
Long term anti-epileptic drug treatment
Paroxetine
MAOI
Dextroamphetamine
Lithium
Lithium
Non-selective beta blockers
Thioridazine
Haloperidol
to classify these interactions employs
the following four categories:
1. Drug-nutrient interaction. In this
case the prescribed medication alters
the bioavailability of the nutrient either
through adjustments in absorption, me-
tabolism, or excretion.
2. Nutrient-drug interaction. Here,
the nutrient alters the effectiveness of
the medication through absorption, me-
tabolism, or excretion.
3. Drug-nutrition interaction. In
this case the medication alters the pa-
tient’s nutrition by altering the types and
amounts of food consumed.
4. Nutrition-nutrient interaction.
Here, the patient’s nutrition shifts the
bioavailability of the nutrient. This shift
can be an effect of the food mechanical-
ly or chemically altering the absorption.
More often it comes from a significant
dietary shift such as outlined in number
three above. These last two steps (drug-
PSYCHIATRIC ANNALS 37:7 | JULY 2007
3707Kaplan.indd 523
TABLE 1.
Nutrient
Folic acid
B-12
Folic acid
B-12
Copper, selenium, and zinc
B-6
Vitamin E
Vitamin K
Carnitine
Biotin
Serum sodium
Tyramine
Magnesium
Inositol
Serum sodium
Potassium
Vitamin A
Iron, magnesium
nutrition and nutrition-nutrient) are of-
ten closely linked.
Effects of Drugs on Nutrients
Psychiatric medications may signifi-
cantly alter many other factors that influ-
ence the status of the child’s neurochem-
istry such as absorption and excretion of
key nutrients. A large number of child
and adolescent psychiatry patients ex-
hibit many characteristics of being at
high risk for drug-nutrient interactions:
ongoing growth, high levels of stress,
two or more medications at once, tak-
ing medications over extended periods
of time, smoking or drinking alcohol,
making poor dietary choices, experienc-
ing medication-induced appetite, and
weight change. Ultimately, the psychiat-
ric medication alters the bioavailability
of the selected nutrient (see Table 1).
The most widely known is reduced
folic acid levels in patients taking anti-
Effect
Reduction
Reduction
Decreased intestinal wall transfer
Reduction in serum B-12
Reduction
Reduction
Reduction
Reduction in fetal levels
Dramatic reductions in levels
Reduced serum levels
Reduction
Hypertensive crisis
Elevation of serum levels
Decreased brain stores
Depletion
Hyperkalemia
Serum elevation
Decreased serum levels
epileptic drugs (AED). Several AEDS
when administered alone reduce folic
acid, as well as B12: carbamazepine,
phenytoin, and valproic acid.8 Inter-
estingly, a Mexican study showed that
treatment with phenytoin or carbamaze-
pine alone reduced both folic acid and
verbal memory skills, while treatment
with 5 mg of folic acid significantly
improved verbal memory and folate
levels.21 Although the mechanism is not
clearly documented, one study found
clear differences between medications
that induced hepatic metabolism (phe-
nobarbital and carbamazepine) versus
those that did not (valproic acid and
zonisamide). Multiple AED therapy has
also been shown to have similar effects,
such as reduced blood levels of folic
acid, and a dramatic increase in homo-
cysteine levels, a marker of folic acid
and B12 deficiency.8 Long term AED
treatment can also reduce serum biotin
523
7/6/2007 10:11:08 AM
 levels. People taking multiple AEDs
have demonstrated a drug-induced vita-
min D deficiency and decreased serum
calcium. The correlation of 25-hydroxy-
vitamin D deficiency and depressed
mood in SAD (seasonal affective disor-
der) or fibromyalgia makes this finding
psychiatrically relevant.
Carnitine plays a role in energy me-
tabolism by assisting in the oxidation
of fatty acids and phospholipids me-
tabolism. Carnitine has been shown in
double blind controlled studies to be
helpful in treating major depression and
dysthymia,22 and
blood levels are
reduced in pa-
tients treated with
multiple AEDs
or valproic acid
alone.8 A recent
review article suggested the value of L-
carnitine in treating valproic acid toxic-
ity and serious side effects.
Depressed levels of copper, selenium
and zinc have also been reported fol-
lowing AED treatment.8 It is possible
that the copper, selenium, and zinc de-
ficiency are connected with some of the
adverse drug reactions to AEDs, in par-
ticular hair loss, suggesting that mineral
supplementation may be useful for cor-
recting this problem.
AEDs can also dramatically decrease
serum levels of vitamin B6,8 which is
concerning, because B6 is a necessary
co-factor in serotonin metabolism. De-
pressed B12 levels are a common finding
in psychiatric patients and can be caused
by AEDs. When supplemented with 30
mcg of B12, these patients noted an im-
provement in their mental status.8
Recent studies indicate that vitamin E
levels are reduced in patients with major
depression,23 which may be related to
an inflammatory basis of severe depres-
sion. Two studies indicated that patients
using AEDs had lower vitamin E levels
than those who received no treatment for
their seizures.8
524
3707Kaplan.indd 524
For other psychiatric medications the
level of research and the relevant findings
are much more limited. In anti-depres-
sants, the numbers of known interactions
are few. A number of studies have dem-
onstrated that tricyclic antidepressants
(TCAs) inhibit enzymes that require co-
enzyme Q10, needed in normal cardiac
function.8 This finding may relate to the
potential cardiac toxicity of TCAs. A
variety of selective serotonin reuptake
inhibitors (SSRI) including paroxetine
have been found to cause sodium deple-
tion. Phenelzine has a chemical structure
quite similar
to isoniazid
and hydrala-
zine, which
cause B6 de-
ficiency.
Five different open reports have suggested that a broad spectrum
multivitamin/mineral formula called Empowerplus deserves
further study as a potential treatment for unstable mood
symptoms in both children and adults.
Finally, a variety of different drug-nu-
trient interactions have been noted with
varied psychiatric implications. Dex-
troamphetamine may cause increased
levels of serum magnesium, known to
have mood effects.8 Lithium has report-
edly depleted brain stores of inositol
and caused serum sodium depletion.
Propranolol inhibits enzymes dependent
on coenzyme Q10. Haloperidol may de-
crease serum levels of iron and magne-
sium. One study found that infants born
to women taking AEDs had low serum
levels of vitamin K.8
Effects of Nutrients on Drugs
The interaction between medications
and nutrients appears to be common and
potentially concerning. One study in Ar-
chives of Internal Medicine found that
43% of patients studied in an outpatient
clinic were taking a supplement in addi-
tion to a prescription medication,24 45%
of which had the potential for a signifi-
cant nutrient-drug interaction. Taking
medications with food increases the ab-
sorption of propranolol and other beta-
blockers, while high protein foods may
interfere with the metabolism of pro-
pranolol.8 Foods that alkalinize the urine
will increase the elimination of lithium,
lowering serum levels. The notorious
tyramine-monoamine oxidase inhibitor
(MOAI) interaction causing a potential
hypertensive crisis is a well-known ex-
ample of an extremely relevant nutrient-
drug conflict. Certain medications will
be absorbed more slowly in the face of a
full meal: trazodone, amitriptyline, zol-
pidem, and diazepam.
The absorption of nutrients, ions, and
drug molecules from the gut into the he-
patic circulation is a complex process
involving dissolution, diffusion, active
transport, and pre-systemic metabolism.
Drugs and nutrients interact by compet-
ing for the transport mechanism across
the enterocytes or by forming complexes
that are not adsorbed. Also, drug-metab-
olizing enzymes are found in the gastric
and intestinal tissues. For example, cyto-
chrome P450 (CYP) 3A4 isoenzyme is
present in the small bowel and plays a
role in the regulation of bioavailability
for about 50% of the prescription drugs
now used. Induction or inhibition of this
enzyme in the gut by nutrients may cre-
ate significant alterations in the bioavail-
ability of these medications. Compounds
found in grapefruit juice significantly
PSYCHIATRIC ANNALS 37:7 | JULY 2007
7/6/2007 10:11:09 AM
 TABLE 2.

Recommended Supplements and Dietary Considerations for Specific Medication Regimens

Medication Regimen Recommended Supplements
Valproic acid, carbamazepine, multiple anti-epileptic drugs Folic acid, biotin, carnitine, calcium, zinc, copper, selenium, vitamins A, B6, B12, D, E, K

Fluoxetine Melatonin
Paroxetine, SSRIs B6
Lithium Inositol
Haloperidol Iron and magnesium
Stimulants Wait one hour before or after taking orange juice or vitamin C
Atypical antipsychotics Exercise, diet low in low refined sugar and simple carbohydrates, monitoring of
macronutrient balance and calories, regular monitoring of weight, body mass index
(BMI), fasting glucose, and lipid profile
Other psychiatric medications Routine monitoring of weight, BMI, and macronutrient balance
All psychiatric medications Avoid grapefruit juice
All psychiatric medications Reference daily intake (RDI) multivitamin and mineral, 1 to 2 grams of omega 3
essential fatty acids (EFA)
These recommendations are an attempt to make sense of confusing claims for practical use by clinicians. They are based on the scant data currently available and might change in light of future
research findings.

inhibit this isoenzyme. For example, in
a study of healthy volunteers the inges-
tion of 250 mL of grapefruit juice in-
creased the serum levels of fluvoxamine
by 60%.8 This mechanism will affect all
psychiatric medications metabolized by
CYP 3A4: alprazolam, diazepam, mid-
azolam, triazolam, buspirone, aripipra-
zole, haloperidol, methadone, pimozide,
propranol, quetiapine, risperidone, tra-
zodone, ziprasidone, and zolpidem. It
will inhibit the presystemic metabolism
and enhance serum levels significantly.
Another study found that cows’ milk-
based formula induced cytochrome
P450 1A,25 whereas human milk did
not. This research was prompted by the
finding that some infants have a caf-
feine clearance (metabolized by CYP
1A) that is three times that found in
other infants. CYP 1A is involved in the
metabolism of many psychiatric medi-
cations: amitriptyline, clomiprimine,
clozapine, fluvoxamine, haloperidol,
imiprimine, olanzapine, and proprano-
lol. Cows’ milk, brassica, and char-
grilling meat all induce CYP 1A with
the similar consequence of reducing
serum levels of these medications.
One of the key mediators of nutrition-
al effects appears to be insulin. Insulin
(released in proportion to the glycemic
load of a meal) inhibits the reuptake of
norepinephrine and enhances the blood-
brain transport of tryptophan, the precur-
sor of serotonin. Insulin resistance sec-
ondary to obesity, type 2 diabetes, and
prediabetic conditions such as the meta-
bolic syndrome and polycystic ovarian
disease may predispose to depression. In
these cases the person will have impaired
monoamine metabolism. Davidson spec-
ulated that the impairment of monoamine
metabolism by impaired insulin func-
tion underlies atypical depression with
hyperphagia, hypersomnia, and weight
gain.26 A further complication is the fact
that lithium acts like insulin. Thus, cer-
tain common dietary patterns (obesity,
insulin sensitivity) may ultimately create
a depression-prone metabolism. Increas-
ingly, researchers are finding that obesity
predisposes to depression, anxiety and
a range of other psychiatric disorders.27
Given that some psychiatric medications
predispose a patient to obesity and meta-
bolic syndrome, a vicious cycle may eas-
ily develop, and clinicians need to guard
against this by appropriate diet and exer-
cise counseling.
The most significant and common
nutrient-drug interaction is the de-
creased effectiveness of stimulants in
the presence of vitamin C. The inges-
tion of vitamin C (ascorbic acid) re-
sults in the acidification of the intes-
tinal contents. Even a large glass of
orange juice may be sufficient to trig-
ger this effect in a child taking morning
stimulant medication. The acidification
decreases the absorption of mixed am-
phetamine salts and methylphenidate.8
Magnesium hydroxide supplements
have been shown to increase the re-
tention of amphetamines in the body,
possibly causing elevated blood levels.
Currently, this is an area with very lim-
ited research as of yet. Another exam-
ple relates to sodium: the potential for
low sodium diets to decrease lithium
clearance is well known.

PSYCHIATRIC ANNALS 37:7 | JULY 2007 525

3707Kaplan.indd 525 7/6/2007 10:11:10 AM

 Different nutrients may enhance or
augment the clinical effect of psychiat-
ric medications. Most of these involve
the combination of anti-depressants
with B vitamins, folic acid, or SAMe.
In a 4-week RCT, Bell and colleagues
tested the augmentation of serum nor-
triptyline levels in 16 elderly depressed
patients28 with the use of 10 mg of three
B vitamins (thiamine, riboflavin, and
pyridoxine). Only marginal clinical im-
provement was noted. Heiden in Austria
administered intravenous magnesium
sulphate to 10 patients with severe treat-
ment resistant
mania. They con-
tinued their prior
treatment with
lithium (n = 10),
haloperidol (n =
5), and/or clonaz-
epam (n = 10). Seven out of 10 patients
demonstrated marked improvements in
mood.29 In one small RCT, 20 male par-
ticipants with prior manic episodes were
assigned to receive either 375 mg of
magnesium oxide or placebo in addition
to verapamil treatment for 120 days; the
magnesium supplement in combination
with verapamil was significantly more
effective in reducing manic symptoms
than the verapamil plus placebo.30
Other studies have demonstrated
that low levels of folic acid are con-
nected with depressive symptoms
but also with an impaired response to
conventional anti-depressants.3 In one
RCT with 127 patients with major
depression, the addition of 500 µg of
folic acid daily created a significant
enhancement of the anti-depressant ef-
fects of fluoxetine.7 In another study
of 213 outpatients with major depres-
sive disorder, those with low folate
levels exhibited a diminished response
to fluoxetine.3 In 44 Iranian children
with ADHD addition of zinc enhanced
response to a standard dose of methyl-
phenidate compared to placebo supple-
mentation of methylphenidate.11
526
3707Kaplan.indd 526
Drug-Nutrition Interaction
Drugs can alter the patient’s nutrition-
al status, an interaction which is not yet
well-studied. We know that many medi-
cations alter appetite, food intake, food
selection, and body mass index (BMI)
and/or weight. In child psychiatry, the
majority of medications are documented
to trigger weight gain or loss: stimulants,
atypical anti-psychotics, lithium, val-
proic acid, and many anti-depressants. In
fact, only a few medications are felt to be
weight neutral: aripiprazole, ziprasidone,
and oxycarbazepine. A recent review in-
dicated that
many anti-
depressants,
mood stabi-
lizers, and
anti-psychot-
Other studies have demonstrated that low levels of folic acid are
connected with depressive symptoms but also with an impaired
response to conventional anti-depressants.
ics cause serious problems with weight
gain.31 Atypical anti-psychotics often
cause weight gain of such significance
that this class of medication now carries a
black box warning indicating the elevat-
ed risk of weight gain, dyslipidemia, and
type 2 diabetes mellitus. SSRIs appear to
be associated with initial weight loss and
then with weight gain. In addition to the
known physical health risks of weight
gain, many patients experience psycho-
logical consequences, which can be de-
moralizing and intolerable. Stimulants
typically trigger weight loss and appetite
reduction. (These medications were used
as weight loss agents before the inadvis-
ability of that process became appar-
ent.) With weight loss, impaired states
of nutrient intake are often seen. Large
numbers of the normal child and adoles-
cent population are deficient in vitamins,
minerals, trace elements, and omega 3
EFAs. Stang et al found that more than
one-third of teens had intakes of vita-
mins A and E, calcium, and zinc that fell
below 75% of the U.S. Recommended
Daily Allowance,32 and even those who
consumed vitamin supplements fell short
of the ideal for these nutrients. A calo-
rically deficient stimulant-treated child
will be at even higher risk.
This issue of appetite change alone
would be reason for grave concern in a
growing and developing child. However,
in addition to appetite suppression there
are the known alterations in diet and
food selection that occur with significant
weight gain or loss. As adults become
obese they are plagued with more narrow
food cravings.33 The most extreme form
is sleep-related eating disorder (SRED),
where the person will awake at night,
consume large quantities of high calorie
carbohydrate foods that are low in mi-
cronutrient density, and return to sleep,
often with no memory of the event. (The
typical patient with SRED is 40, obese,
and depressed.) An association has been
reported with atypical anti-psychotics,
specifically olanzapine. Some speculate
that the recent dramatic rise in recogni-
tion of this disorder mirrors the recent
rise in the use of atypical anti-psychotic
medications. Psychiatric medications
may play a significant role in the altera-
tion of a child’s diet and nutrient intake.
Obese and overweight individuals
have altered liver health characterized
by fatty infiltrates and decreased meta-
bolic potency for detoxification. With
PSYCHIATRIC ANNALS 37:7 | JULY 2007
7/6/2007 10:11:10 AM
 the rates of overweight and obese chil-
dren rising rapidly, we should remember
that they will metabolize medications
more slowly and be at higher risk for
side effects related to high blood levels
or toxic metabolites for medications that
are eliminated via hepatic metabolism.
Nutrition-Nutrient Interaction
In this section we consider the effects
of alterations in nutrient intake created
by altered nutritional status. The child
who is overweight tends to eat a diet nar-
rower in nutrients and more dominated
by sugar, processed foods and simple
carbohydrates. These food choices pre-
dispose the child to deficiencies in B-vi-
tamins, EFAs, and other nutrients known
to be important in mood disorders.
Lower serum levels of long-chain
polyunsaturated fatty acids, particularly
omega-3 fatty acids, have repeatedly been
associated with a variety of behavioral dis-
orders including ADHD.34 Omega 3 fatty
acid levels correlate inversely with the se-
verity of illness being proportional to the
deficiency documented. In a recently pub-
lished study, one researcher found a sig-
nificant association between SNP (single
nucleotide polymorphisms) of the desatu-
rase enzymes involved in omega 3 EFA
metabolism and ADHD patients.35 This
finding makes more sense of the field be-
cause many researchers have documented
no dietary differences between ADHD
and controls despite finding diminished
tissue levels of fatty acids. Hibbeln has
documented a nearly linear inverse corre-
lation between fish intake (high in omega
3s) and depression worldwide.36
Magnesium deficiency is wide-
spread in the United States,37 and in the
past 50 years the magnesium content
of foods has fallen.38 Magnesium has
a variety of mood-related effects and
has many functional similarities to the
mood stabilizer lithium in the CNS.39
In a population deficient in magnesium
one might expect to find problems with
mood instability or dysregulation.
PSYCHIATRIC ANNALS 37:7 | JULY 2007
3707Kaplan.indd 527
CONCLUSION
Many psychiatric medications al-
ter nutrient levels. This is particularly
true for AEDs, which have a range of
drug-nutrient interaction. Many other
drug-nutrient interactions have been
documented. Unfortunately, this entire
topic (outside of AEDs) is character-
ized by inadequate research. Foods,
in particular grapefruit juice, can alter
cytochrome P450 metabolism and thus
psychiatric medication levels. Psychi-
atric medications frequently alter appe-
tite, weight and nutritional status, which
may in turn have significant mood and
behavioral effects for the treated child.
Recent JAMA articles recommended
vitamin supplementation for the gener-
al adult population as deficiencies were
found to be common and a risk factor
for chronic illness.40 In a growing child
with risk factors for psychiatric illness,
the importance of supplementation
would likely be magnified, given the
escalation of nutrient demands found
in the stressed or symptomatic child.
Thus it seems reasonable to recom-
mend vitamin/mineral supplementa-
tion at RDA/RNI (reference nutrient
intake) levels (see Table 2, page 525)
for all child and adolescent psychiatric
patients. The risk benefit ratio is low,
and the potential prevention of psychi-
atric illness is significant.
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