course of psychiatric diseases are of recent origin.
This chapter will address four questions:
1. Assuming that psychiatric disorders have a genetic basis, is there a role
for environmental factors?
Simopoulos AP (ed): Nutrition and Fitness: Mental Health and Aging – Components
and Implementation of Diet and Physical Activity and the Role of the Government.
Basel, Karger, 2005, vol 95, pp 1–16
Psychiatric Disorders,Mood and
Cognitive Function:The Influence of
Nutrients and Physical Activity
Regina C. Casper
Department of Psychiatry and Behavioral Sciences, Stanford University School of
Medicine, Stanford, Calif., USA
Human mental function is genetically based, yet modulated during develop-
ment and throughout life by environmental factors. Family and twin studies have
shown that hereditary factors play an important role in the incidence and clinical
expression of affective disorders and schizophrenia . As a result, research has
increasingly focused on linking specific psychiatric disorders to specific genetic
markers. Hereditary studies, however, have revealed a significant environmental
influence on gene expression . Psychological factors are important environ-
mental components which interact with genes or gene products to promote the
expression of a phenotype. For instance, Caspi et al.  reported that a polymor-
phism in the 5-HTT gene, in this case one or one or two copies of the short allele
of the 5-HT T promoter, increased an individual’s chance to react to stressful life
events with depressive symptoms, depressive disorder and suicidal behavior. The
heritability for psychiatric disorders  suggests that there is a significant envi-
ronmental component in the pathogenesis of psychiatric disorders. For nutrition
which powerfully impacts physical health and disease [4, 5], the mechanisms of
the gene-environment interaction are under investigation [6, 7].
In normal populations nutritional factors and physical activity have been
shown to have subtle effects on mood and cognitive ability . Studies explor-
ing possible relationships between nutritional factors and the incidence and
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Early Development:Prenatal Growth and Diseases in Adult Life
2. What are the beneficial effects of the essential ?–3 polyunsaturated fatty
acids (?–3-PUFAS) on human development and what is the evidence that mal-
nutrition during prenatal life affects mental development?
3. In the second part findings from placebo controlled studies and uncon-
trolled trials will be reviewed with the question in mind: do the data support a
role for nutritional compounds, specifically the ?–3-PUFAS, in altering the
prevalence or the occurrence of psychiatric symptoms?
4. Lastly, are there mental health benefits to physical exercise?
Psychiatric Disorders are the Products of
Genetic Regulation and Environmental Influences
The genetic basis of human mental function and dysfunction is complex
and due to the interaction of multiple genes. Genes instruct the development of
the central nervous system (CNS), at the same time environmental factors
promote or in the case of hypoxia, infection or malnutrition may disrupt matu-
rational processes. For schizophrenia, even if 100% genes are shared as would
be the case for an individual with two schizophrenic parents, the risk of devel-
oping the condition is estimated to be no more than 46%, leaving a substantial
portion to environmental factors . Furthermore the recent discovery of the
neuregulin gene which plays a central role in neural development and con-
tributes to schizophrenia in both Icelandic and Scottish populations suggests
the possibility of population based genetic variability . An example of a
gene/nutritional environment interaction would be the APOE gene which has
been linked to schizophrenia in Chinese and seems to confer vulnerability dur-
ing times of malnutrition . A hereditary component for affective disorders is
well documented . Recently, the South Island Bipolar Study demonstrated
an increased prevalence of bipolar and depressive disorders in relatives of bipo-
lar patients , which, nevertheless, leaves ?60% to environmental risk fac-
tors. Another example of a gene/environment interaction would be the variant
of the monoamineoxidase type A (MAOA) gene which has been linked to
aggressive, impulsive and even violent behaviors in monkeys and humans.
Maltreated children with a genotype conferring high levels of MAOA expres-
sion were less likely to develop antisocial problems [12, 13].
Aside from genetic factors, the maternal environment influences fetal devel-
opmental milestones. In the late eighties, epidemiological studies began to point
WRN95001.qxd 4/18/05 6:14 PM Page 2
of malnutrition for schizophrenia. First trimester exposure to severe malnutri-
tion during the Dutch hunger winter has also been reported to double the risk of
schizoid personality disorders , schizophrenia spectrum disorders , and
antisocial personality disorder . Malnutrition during the second trimester
appears to double the risk for affective disorders in adulthood .
Nutrients, Neurodevelopment and Psychiatric Disorder3
to the conclusion that adults who had been born with normal, yet low birth weight
have an increased susceptibility to diseases in adult life. Barker’s  analyses of
birth and death certificates of people born in Hertfordshire, UK revealed that 2.3-
kg babies had double the rate of death from coronary heart disease, hypertension,
stroke and type II diabetes, compared to 4.5-kg babies. These observations which
were subsequently confirmed  generated the fetal origins hypothesis that pro-
poses that the fetus adapts to a limited supply of nutrients, and in doing so, per-
manently alters its physiology and metabolism. The new set point appears to
increase the risk of disease in later life. There is one report  which found a
relationship between low weight gain in infancy and suicide in adult life.
Observations that growth restriction during fetal life is associated with
increased adrenocortical and adrenomedullary activity  and a higher preva-
lence of autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin
(TgSAb)  are important in view of the presence of similar endocrine abnor-
malities in major depressive disorders. Remarkably, an excess of protein may
also modulate lifelong changes in the hypothalamic-pituitary-adrenal (HYPAC)
axis. Herrick et al.  described hypercortisolemia in 28- to 30-year-old sub-
jects whose mothers had been advised to consume 0.45kg of red meat daily and
avoid carbohydrates during pregnancy, an intriguing finding given the popular-
ity of the Atkins diet. Another report  that described epigenetic metastabil-
ity following excess intake of folic acid, vitamin B12, choline, and betaine leading
to possible deleterious influences on the establishment of epigenetic gene regu-
lation in humans deserves further study in view of current recommendations for
large doses of folic acid in particular for patients taking antiepileptic drugs.
Epidemiological studies of psychiatric disorders  have linked severe
malnutrition during the first trimester to the risk of schizophrenia by analyzing
the incidence of schizophrenia in birth cohorts born between January-February
1944 and November–December 1946 in Holland during the German occupa-
tion. Those conceived during the height of the Dutch famine and exposed to
very low food rations during the first trimester (from February to April 1945)
had an excess of neural tube defects  and double the relative risk for schiz-
ophrenia . Brain imaging studies  have shown decreased intracranial
volume and double the rate of brain abnormalities, in particular focal white
matter hyperintensities in a subset of these patients compared to controls born
during the Dutch hunger winter. As noted previously, Liu et al.  suggested
that the epsilon-4 genotype of the APOE gene may be associated with the risk
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Nutritional Factors in Affective Disorders
Interaction between Nutrition,Growth and Development
Bourre et al.  have documented during cerebral development in
rodents a linear relationship between brain content of (?–3) acids and the (?–3)
content of the diet up to 200mg of ?-linolenic acid levels per 100g food intake,
however DHA levels remained unaltered following ALA . They observed
that a diet low in (?–3) acids affects learning in rodents. In rhesus monkeys,
Connor et al.  showed more fatty acid lability when ?–3-deficient monkeys
were fed fish oil diets rich in DHA and other ?–3 fatty acids. An earlier study
 described that rhesus monkeys long term deficient in ?–3 fatty acids
displayed bouts of stereotyped behavior typical of monkeys raised in social
isolation compared to monkeys fed a matched control diet abundant in ?–3
Fish oil supplements given from week 30 of the pregnancy extended the
pregnancy duration on average 4 days in Danish women compared to women
receiving olive oil supplements . Low consumption of seafood has been
associated with premature delivery . Cheruku et al.  found that higher
maternal DHA levels were associated with more mature infant sleep and wake
states in newborns. Maternal supplementation with cod liver oil (total 1.2g
DHA ?0.8g EPA) versus corn oil (4.7g linoleic acid (LA) and 0.09g ?-
linolenic acid (ALA) from week 18 of pregnancy until 3 months after delivery
increased children’s mental processing composite score significantly at 4 years
of age. Intelligence correlated with head circumference at birth, but not with
birth weight or gestational length . Maternal supplementation with 2.8g
ALA did not prevent decreases in maternal DHA and AA concentrations, yet
did increase EPA and DPA levels, with no difference in birth outcome .
Another study found similar visual, cognitive and language scores in breastfed
and DHA- and DHA?AA-enriched formula-fed children at 39 months . In
a cross-sectional study phospholipid (DHA and AA) status at birth was not
associated with cognitive development at 4 years of age  or with cognitive
performance at 7 years .
Studies on the effects of amino acids, protein and carbohydrates on
mood and the effects of caloric restriction on life span have been reviewed pre-
WRN95001.qxd 4/18/05 6:14 PM Page 4
gave EPA/DHA 2:1, a total of 6.6g daily after a placebo washout in a 12-week
study and showed improvement in the HAMD score by 4 weeks with further
symptom reduction by 12 weeks. Cross-sectional analyses  found elderly
patients with MDD and with normal C-reactive protein levels to have lower ?–3
plasma levels and higher ?–6/?–3 ratios. A population-based study of all males,
Nutrients, Neurodevelopment and Psychiatric Disorder5
Polyunsaturated Fatty Acids (PUFAS) and Major Depressive
Phospholipids as components of membrane structure play a critical role in
signal transduction via receptor mediated phospholipid derived second messen-
gers such as prostaglandins or arachidonic acid. A role for the eicasonoids and
immune activation in the pathophysiology of MDD [39, 40] is supported by
findings that antidepressants of several classes decrease the production of
pro-inflammatory cytokines such as interferon-gamma and tumor necrosis fac-
tor-?, and increase that of interleukin-10, an anti-inflammatory cytokine .
Significant decreases of plasma polyunsaturated ?–3 fatty acids and/or
increases of the ?–6/?–3 plasma ratio in and/or in red cell membranes of
patients with major depression  which correlated inversely with depression
severity and was not due to reduced dietary intake have provided the rationale
for treating depressions with essential fatty acids. The comprehensive review by
Hibbeln and Salem  makes it abundantly clear that testing of the therapeu-
tic efficacy of PUFAS has underdone few double-blind trials, in fact most data
derive from case reports, pilot studies, open trials, cross-sectional analyses and
Omega–3 Fatty Acids in Major Depressive Disorder (table 1)
On the other hand, placebo-controlled studies typically have included
treatment resistant or partially improved patients who may not be representative
and who are by definition difficult to treat.
Four placebo-controlled studies have randomly assigned patients on
antidepressant medication to receive ?–3 fatty acids. Administration of 2g EPA
daily reduced depressive symptoms by week 3 in a 4-week study of Nemets et
al. . Peet and Horrobin  found that 1g EPA daily, but not 2 or 4g EPA
ameliorated depression scores in mostly female medicated patients by week 4
on the Hamilton rating scale (HRS) and the Montgomery Asberg depression
rating scale (MDRS) with the greatest improvement occurring at 12 weeks,
when patients rated themselves as improved on the BDI. Marangell et al.’s
6-week  study failed to show benefit from 2g DHA daily on the MDRS,
even though the placebo group was more depressed at baseline. Su et al. 
WRN95001.qxd 4/18/05 6:14 PM Page 5
ence measures of depression in a study by Llorente et al. . This study was
not a valid test, since too few (15%) women with MDD were included. In a
small open label trial  which administered 2.96g of fish oil (EPA/DHA
ratio 1.3) during the last 4 weeks of pregnancy, 4/7 women experienced post-
partum depression, not different from the relapse rate expected in untreated
50–69 years old residing in southwestern Finland  found no evidence
between fish consumption or overall ?–3 dietary intake and depressed mood,
MDD or suicide.
Omega-3 Fatty Acids in Pregnancy and Postpartum
Hibbeln  analyzed prevalence rates for postpartum depressive disorder
(PPD) across countries and found an inverse relationship to seafood consump-
tion. Higher DHA, but not AA or EPA, breast milk concentrations predicted a
lower prevalence of PPD. Stronger evidence for a role of ?–3 fatty acid defi-
ciencies in postnatal MDD comes from a study by De Vriese et al.  who
found lower ?–3 PUFAS and lower ?–3/?–6 ratio in plasma lipids of women
who developed postpartum depression compared to controls. Yet, a placebo-
controlled study supplementing breast-feeding women with 200mg DHA daily
for 4 months postdelivery, even if it raised DHA lipid content, failed to influ-
Table 1. Placebo-controlled treatment studies of ?–3 fatty acids
Author Type,dosage, durationSubjects, nResults
Major depressive disorders
Nemets et al. 
Peet and Horrobin ,
Ethyl-EPA 2g/day 4 weeks
Ethyl-EPA 1,2 or
4g/day 12 weeks
DHA 2g/day 6 weeks
↓HRSD scores week 2
1g/day ↓HRSD MADRS
Response rates similar
↓HSRD scores week 4 & 8
Marangell et al. 36
Su et al. EPA 4.4g/day
8 weeks ? DHA 2.2g/day
Breast-feeding women with postnatal depressive disorder
Llorente et al. DHA 200mg/day101No difference; only 14%
of patients had MDD or
HRSD ? Hamilton rating scale for depression; MADRS ? Montgomery-Asberg depression rating
scale; MDD ? major depressive disorder.
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Schizophrenia is currently conceptualized as a neurodevelopmental disor-
der . Among the nutritional deficiencies low vitamin D has been hypothe-
sized to underlie the relationships to excess of winter births, increased rates of
schizophrenia in urban versus rural settings and increased rates in dark-skinned
migrants to colder climates .
Nutrients, Neurodevelopment and Psychiatric Disorder7
women. Considering the high rates of breast-feeding among current mothers
and the benefits from nursing, PPD merits further investigation in better
designed placebo controlled studies which ought to include an infant assess-
ment. Remarkably, infant monkeys fed a formula containing 1% DHA and 1%
AA displayed better visual orienting and motor skills by day 7 and day 14 than
breast-fed or standard formula-fed infant monkeys .
Omega–3 Fatty Acids in Bipolar Disorder (table 2)
Two studies have described either reduced erythrocyte membrane AA or
DHA content in bipolar disorder patients  or an increased prevalence of
bipolar I, bipolar II bipolar spectrum disorder in countries with less than 50lb
seafood consumption per year . These findings notwithstanding, only one
report found some benefit from ?–3 fatty acids in bipolar disorders. Stoll et al.
 who compared time to relapse over 4 months in 14 bipolar patients who
received 6.2g EPA?3.4g DHA daily to that in 16 bipolar patients receiving
olive oil placebo found more patients in the PUFA supplemented group to
remain stable at 4 months than in the placebo group. Two studies by Keck et al.
 found no benefits from 6g EPA added for 4 months to the medication
regime of bipolar patients.
Omega–3 Fatty Acids in Schizophrenia (table 3)
Table 2. Placebo-controlled treatment studies of ?–3 fatty acids in bipolar disorders
AuthorType, duration, dosageSubjects, nResults
Stoll et al. 6.2g EPA? 3.4g DHA or
placebo; 4 months
30 bipolar I and
62 bipolar rapid
Longer time to
Keck et al. 
Keck et al. 
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In four out of five placebo-controlled add-on trials to standard antipsychotic
medication EPA, but not DHA, reduced positive symptoms . In a monother-
apy trial , 12 placebo-treated patients, but only 8/14 EPA treated patient
required antipsychotic medication after 3 months. Another analysis  in which
2g EPA, but not 1 or 4g EPA were found to be better than placebo was based on
The rationale to use PUFAS in schizophrenia is based on Horrobin’s theory
 of abnormal lipid metabolism in schizophrenia and on findings that schiz-
ophrenic patients as opposed to normal controls and depressed patients display
a deficient flushing response to niacin subdermally suggesting reduced
membrane arachidonic acid levels and reduced production of prostaglandin D2
(PGD2) in schizophrenia. Noaghiul and Hibbeln  observed no relationship
between seafood consumption and lifetime prevalence rates of schizophrenia.
Arvindakshan et al.  a described lower than normal AA and DHA in drug
naïve unmedicated compared to medicated schizophrenia patients and controls
as well as modestly significant negative correlations between AA. An open
trial  found symptomatic improvement of negative symptoms in 20 schizo-
phrenia patients following 6 weeks of 10g EPA/DHA- ratio 1.3. Another
uncontrolled study (180/120mg EPA/DHA, as well as vitamins C and E) found
clinical improvement in 33 patients .
Table 3. Polyunsaturated fatty acids in the treatment with schizophrenia: placebo-
controlled studies of medicated patients
AuthorSubjects, n Type, dosage, duration Outcome
Mellor et al. 20 10g EPA/DHA ratio:
1.3; 6 weeks
EPA 360mg? DHA
vitamins C and E
Sustained 4 months
et al. 
Peet et al. 
Peet et al. 
452g EPA vs. 2g
DHA 3 months
1, 2, 4g EPA/placebo,
3g EPA 12 weeks
EPA ? DHA
Fenton et al. 87 No difference
Peet and Horrobin  115 2g improvement in
Emsley et al. 40
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Impulsivity and Irritability (table 5)
Nutrients, Neurodevelopment and Psychiatric Disorder9
9 clozapine-treated patients, only. The strongest evidence for consistent improve-
ment from week 3 to 12 based on total PANSS scores and involuntary movement
scores was presented by Emsley et al.  who in contrast to Peet and Horrobin
 found a trend for patients on conventional antipsychotic drugs to fare better.
Fenton et al.  found no differences over the 12-week period between the
placebo- and EPA-treated group in an older chronically ill population.
Although several uncontrolled studies [68–73] have reported reductions in
aggressive behavior or hostility scores after administration of DHA or EPA, no
Table 4. Case studies and case control studies of nutritional factors in aging, dementia, and AD
Authors Number of subjects
Type, dosage Outcome/results
Fletcher et al.  1,214 (75–84) Ascorbate levels
AD disliked fish
and green vegetable
Intake vitamins C, E, A
EPA at 900mg
Otsuka 64AD/80 NC
Conquer et al. AD/other dementias
81 AD/81 NCTabet et al. 
↓vitamins C and
E in severe AD
↓60% AD 3.9-year
Morris et al. 815 (65–94 ) Fish once/week
Grodstein et al.  14,968 (70–79)
63 AD, 25 CI vs. 53 NC
Long-term vitamin C
and E users
Vitamins E, C, A, etc.Rinaldi et al. 
Tully et al. 148 AD/45 NC↓EPA
and DHA in AD vs. NC
MMSE: 19.5 AD/
Vitamin C ? ?500mg/day
Upper quartile DHA 180mg
DHA daily fish twice/week
Zandi et al. 
Schaefer et al. 
MMSE ? Mini mental status examination.
WRN95001.qxd 4/18/05 6:14 PM Page 9
Clinical and experimental evidence from studies in elite athletes and in
moderately depressed patient populations suggests that vigorous exercise
of 30min or more of moderate intensity physical activity on most, preferably
all days, improves energy levels and reduces anxiety, tension and depressive
firm conclusions can be drawn without more and better designed double blind
controlled studies. DHA supplements for 2 months in a placebo-controlled
study  did not improve concentration or the behavior of children with atten-
tion deficit disorder.
Mild Cognitive Impairment and Alzheimer’s Disease (table 5)
Epidemiological studies, summarized in table 4, suggest better cognitive
function with long-term use of vitamin C and vitamin E [74, 75]. A decreased
risk for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) was
found in individuals who used both vitamin C and vitamin E [76, 77]. Plasma
?–3 PUFA and phospholipid levels were found to be reduced in AD and other
dementias . Four studies found a relationship between fish and PUFA
intake and the incidence of AD [79–81].
Physical Exercise and Emotional Health
Table 5. Studies examining the relationship between irritability, hostility and/or aggression and ?–3
Authors, year Number of subjects
Hamazaki et al.  22 vs.19 students
231 male offenders
?18 years – 142 days
BPD 20/10 women;
ADHD 20/20 children
LA, ALA, DHA
172, EPA 320mg
EPA 1g mineral 1g
26% reduction in
Gesch et al. 
Zanarini et al. 
Iribaren et al. 
Hirayam et al. 
DHA levels ?1 SD
DHA food 3.6g/week
↓high hostility score
↑visual memory ↓errors
Raine et al. 83 children; 355
NC 3–5 years
WRN95001.qxd 4/18/05 6:14 PM Page 10
begun at 34 weeks of pregnancy  found a bimodal relationship with exercise;
women at the higher end, those who exercised ? or ? 5 times per week and
women at the lower end, those who exercised ?or ? 2 times per week were at
increased risk (odds ratios 4.61 and 2.64, respectively) to deliver babies with a low
birth weight. A much larger study using data from the National Maternal and
Nutrients, Neurodevelopment and Psychiatric Disorder 11
symptoms . Table 6 lists the physiological and psychological mechanisms
which have been hypothesized to contribute to the improved wellbeing.
The benefits of daily physical exercise in healthy and depressed popula-
tions have been reviewed previously by Casper . The lack of motivation and
interest, and the sense of leaden paralysis and lethargy in severe depressive dis-
orders reduce the possibility of exercise in these populations.
Antenatal Exercise and Birth Weight
Studies on the impact of exercise on birth outcome are of increasing impor-
tance considering that more young women now engage in strenuous exercise daily.
In a prospective controlled study  that compared pregnant women who exer-
cised ?5 times per week with women who exercised 3 times or less per week, no
statistically significant difference in the mean birth weight of babies born was
found. However, the fact that at randomization 52% of women refused to be
assigned to the lower exercise group limits the generalizability. Another study
Table 6. Physical activity and mental health theories regarding physiological and
Physical activity induces physiological changes
Neurotransmitters – noradrenalin, serotonin, dopamine- increase vigor and reduce
anxiety and tension
Increases steroid reserves which counteracts stress
Increases cerebral blood flow
Increases alpha rhythm and hemispheric synchronization
Lowers muscle action potential-reduces tension
Increases body temperature – sedative effects
Releases endorphins – analgesic properties
Physical activity induces psychological changes
Increases self-efficacy, self-esteem and self-sufficiency
Induces a meditative, relaxed state
Distracts from daily stress and anxiety
Repeatedly experiencing physical symptoms (sweating, hyperventilation, increased
heart rate) without an emotional disturbance helps desensitize
Individuals to the physiological correlates of anxiety
WRN95001.qxd 4/18/05 6:14 PM Page 11
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Infant Health Survey  found that women who failed to exercise and previously
active women who stopped physical activity during pregnancy were more likely to
have very low birth weight babies and low birth weight babies. No significant rela-
tionship between the duration of gestation and physical activity was observed.
Nutrients, specifically the ?–3 fatty acids, but also vitamins, have a critical
role in the structural and functional development and operation of the central
nervous system (CNS). Placebo controlled studies in medicated patients suggest
that add-on treatment with eicosapentaenoic acid (EPA) in doses varying from 1
to 4g daily may ameliorate symptoms of major depressive disorders and reduce
the abnormal movements and positive and negative symptoms in schizophrenia.
There is preliminary evidence from epidemiological studies that high plasma
levels of ?–3 fatty acids combined with high intakes of antioxidants, such as
vitamins C and E protect against age related cognitive decline. Compared with
the well documented cardioprotective effects associated with ?–3 fatty acid rich
diets, the antidepressant and antipsychotic effects of ?–3 fatty acids seem to be
primarily associated with EPA and not to fit a dose-response curve. The data are
conflicting as to whether immune and inflammatory pathways mediate the asso-
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