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Primary Care Mental Health (2003) 1: 916 2003 Radcliffe Medical Press

Invited papers

Depression: the nutrition connection


Patrick Holford BSc (Psych) Dip ION
Founder of the Institute for Optimum Nutrition, Director of the Mental Health Project,
Clinical Director of the Brain Bio Centre, London, UK

There is little doubt that the incidence of depression The sugar blues
in Britain is increasing. According to research at the
Universities of London and Warwick, the incidence
of depression among young people has doubled in One factor that often underlies depression is poor con-
the past 12 years. However, whether young or old, the trol of blood glucose levels. The symptoms of impaired
question is why and what can be done? There are blood sugar control are many, and include fatigue,
those who argue that the increasingly common phe- irritability, dizziness, insomnia, excessive sweating
nomenon of depression is primarily psychological, (especially at night), poor concentration and forget-
and best dealt with by counselling. There are others fulness, excessive thirst, depression and crying spells,
who consider depression as a biochemical phenom- digestive disturbances and blurred vision. These symp-
enon, best dealt with by antidepressant medication. toms often precede measurable abnormalities in blood
However, there is a third aspect to the onset and treat- glucose, manifesting rst as a decreased sensitivity
ment of depression that is given little heed: nutrition. to insulin, known as insulin resistance. One of the
Why would nutrition have anything to do with worlds experts on blood sugar problems, Professor
depression? Firstly, we have seen a signicant decline Gerald Reaven from Stanford University in California,
in fruit and vegetable intake (rich in folic acid), in sh USA, estimates that 25% of normal, non-obese people
intake (rich in essential fats) and an increase in sugar have `insulin resistance. Since the brain depends on
consumption, from 2 lb a year in the 1940s to 150 lb a an even supply of glucose it is no surprise to nd that
year in many of todays teenagers. Each of these nutri- sugar has been implicated in aggressive behaviour,1 6
ents is strongly linked to depression and could, theor- anxiety,7,8 hyperactivity and attention decit,9 de-
etically, contribute to increasing rates of depression. pression,10 eating disorders,11 fatigue,10 and learning
Secondly, if depression is a biochemical imbalance it difculties.12 15
makes sense to explore how the brain normalises its The second reason excessive consumption of re-
own biochemistry, using nutrients as the precursors ned sugar is undesirable is that it uses up the bodys
for key neurotransmitters such as serotonin. Thirdly, if vitamins and minerals and provides next to none.
21st century living is extra-stressful, it would be logical Every teaspoon of sugar uses up B vitamins for its
to assume that increasing psychological demands catabolism, thereby increasing demand. B vitamins, as
would also increase nutritional requirements since we will see, are vital for maintaining mood. About
the brain is structurally and functionally completely 98% of the chromium present in sugarcane is lost in
dependent on nutrients. turning it into sugar. This mineral is vital for keeping
So, what evidence is there to support suboptimal the blood sugar level stable.
nutrition as a potential contributor to depression?
These are the common imbalances connected to
nutrition that are known to worsen your mood and
motivation: The amino acid connection
. blood sugar imbalances (often associated with
excessive sugar and stimulant intake) There are often two sides to depression feeling mis-
. lack of amino acids (tryptophan and tyrosine are erable, and feeling apathetic and unmotivated. The
precursors of serotonin and noradrenaline) most prevalent biochemical theory for the cause of
. lack of B vitamins (vitamin B6 , folate, B12 ) these imbalances is a brain imbalance in two families
. lack of essential fats (omega-3). of neurotransmitters. These are:
10 P Holford

. serotonin, thought to primarily inuence mood Figure 1 shows those nutrients that are required for
. dopamine, noradrenaline, and adrenaline, thought the production of serotonin, dopamine, adrenaline
to primarily inuence motivation. and noradrenaline.

To test the theory that serotonin primarily controls


mood, and adrenaline and noradrenaline control
motivation, Antonella Dubini, from the Pharmacia Depression and tryptophan
and Upjohn Medical Department in Milan, Italy, gave
203 people suffering from low mood and motivation
either a SSRI (selective serotonin reuptake inhibitor) SSRI antidepressants are thought to work by stopping
drug, promoting serotonin, or a NARI (noradrenaline the reuptake of serotonin, thereby enhancing seroto-
reuptake inhibitor) drug, promoting noradrenaline. nin action within the synapse. The trouble is that
Sure enough, the former was more effective at im- these kinds of drugs induce unpleasant side effects in
proving mood, while the latter was more effective at as many as a quarter of those who take them, and
improving motivation.16 severe reactions in a minority. An alternative strategy

TRYPTOPHAN PHENYLALANINE

B vitamins,
C + Zinc
help these
conversions
5-HTP TYROSINE

TMG + SAMe
helps make
these

DOPAMINE
SEROTONIN NORADRENALINE
ADRENALINE

OMEGA 3 fats
improve neurotransmitter
reception

Mood-Enhancing Nutrients
Figure 1 Nutrients that make mood-enhancing neurotransmitters
Depression: the nutrition connection 11

would be to enhance the synthesis of serotonin by or three times a day, for depression. Some supple-
providing optimal amounts of precursor nutrients. ments also provide various vitamins and minerals
But, does it work? such as B12 and folic acid, which may be even more
Serotonin is made from the amino acid trypto- effective because these nutrients help to turn 5-HTP
phan, a constituent of protein. Dr Philip Cowen and into serotonin.
colleagues from the University of Oxford, UK, psy-
chiatry department, wondered what would happen if
Depression in women
you deprived people of tryptophan. They gave 15 vol-
unteers who had a history of depression, but were Women are three times as prone to low moods as
currently not depressed, a nutritionally balanced drink men. Many theories as to why this is have been
that excluded tryptophan. Within seven hours 10 proposed, some psychological, some social, but the
out of 15 noticed a worsening of their mood and truth is that women and men are biochemically very
started to show signs of depression. On being given the different. The research of Mirko Diksic and colleagues
same drink, but this time with tryptophan added, their at McGill University in Montreal, Canada demon-
mood improved.17 Supplementing the amino acid strates this. They developed a technique using
tryptophan is already proven to improve mood. Don- positron emission tomography (PET) neuro-imaging
ald Ecclestone, professor of medicine at the Royal to measure the rate at which we make serotonin in the
Victoria Inrmary, Newcastle, UK reviewed the avail- brain.26 What they found was that mens average
able studies and concluded that supplementing tryp- synthesis rate of serotonin was 52% higher than that
tophan is an effective antidepressant, equivalent to of women. This, and other research, has clearly shown
tricyclic antidepressants.18 that women are more prone to low serotonin. They
While supplementing tryptophan itself has proven also react differently. In women, low serotonin is
a somewhat effective antidepressant, even more effec- associated with depression and anxiety, while in men,
tive is a derivative of tryptophan that is one step closer low serotonin is related to aggression and alcoholism.
to serotonin. This is called 5-hydroxytryptophan, or One possibility is our social conditioning: men `act
5-HTP for short. The rst study proving the mood- out their moods, while women are more conditioned
boosting power of 5-HTP was done in the 1970s in to `act in their moods.
Japan, under the direction of Professor Isamu Sano of What has been learnt about serotonin in the last
the Osaka University Medical School.19 He gave 107 few years is that there are a number of potential
patients 50 to 300 mg of 5-HTP per day, and within reasons for deciency, in addition to a lack of, or
two weeks, more than half experienced improve- increased need for tryptophan:
ments in their symptoms. By the end of the fourth
week of the study, nearly three-quarters of the . not enough oestrogen (in women)
patients reported either complete relief or signicant . not enough testosterone (in men)
improvement, with no side effects. This study was . not enough light
repeated by Nakajima et al. who also found that 69% . not enough exercise
of patients improved their mood.20 A trial in Germany . too much stress, especially in women
found 5-HTP to be as effective as the tricyclic anti- . not enough co-factor vitamins and minerals.
depressant imipramine, with a fraction of the side
effects. 21 One double-blind trial headed by Dr Poldin- If a person is suffering from low mood, feels tense and
ger at the Basel University of Psychiatry, Switzerland irritable, is tired all the time, tends to comfort eat, has
gave 34 depressed volunteers either the SSRI anti- sleeping problems and a reduced interest in sex, and
depressant uvoxamine, or 300 mg of 5-HTP. Each some of the above apply, the chances are they are
patient was assessed for their degree of depression short on serotonin.
using the widely accepted Hamilton Rating Scale, plus Low oestrogen means low serotonin and low
their own subjective self-assessment. At the end of the moods.17,27 This is because oestrogen blocks the
six weeks, both groups of patients had had a signicant breakdown of serotonin. This may explain why
improvement in their depression. However, those women are more prone to depression premenstrually
taking 5-HTP had a slightly greater improvement in and in the menopause and thereafter. Low testoster-
each of the four criteria assessed depression, anxiety, one has a similar effect in men.
insomnia and physical symptoms, as well as the Light also stimulates both oestrogen and serotonin
patients self-assessment. 22 Given that 5-HTP is less and most of us do not get enough of it. The difference
expensive and has signicantly fewer side effects, it is in light exposure outside and inside is massive. Most
surprising that doctors and psychiatrists virtually never of us spend 23 out of 24 hours a day indoors, exposed
prescribe it.19,20,23 25 to an average of 100 units (called lux) of light. That is
The recommended dosage of this amino acid, avail- compared to an outdoor level of 20 000 lux on a sunny
able in any health food shop, is 100 mg of 5-HTP, two day and 7000 lux on an overcast day. Now, more than
12 P Holford

ever before, many people rarely expose themselves to shown in Figure 2, both adrenaline and noradrenaline
direct sunlight, and certainly not enough to maximise are synthesised from dopamine, which is made from
serotonin production. Of course, light deciency is the amino acid tyrosine, which is itself made from the
worse in the winter. amino acid phenylalanine. It is logical to assume
Stress also rapidly reduces serotonin levels, while that, if the drugs that block the breakdown of these
physical exercise improves stress response, and there- neurotransmitters do elevate mood, then augmenting
fore reduces stress-induced depletion of serotonin. the amino acid phenylalanine or tyrosine might work
too. And they do.
In a double-blind study by Helmut Beckmann and
colleagues at the University of Wurzburg, Germany,
Is apathy a catecholamine 150 to 200 mg of the amino acid phenylalanine, or
the antidepressant drug imipramine, were adminis-
deciency? tered to 40 depressed patients for one month. Both
groups had the same degree of positive results less
depression, anxiety and sleep disturbance.28 A group
Another group of neurotransmitters associated with
of researchers at the Rush Medical Center, Chicago,
depression and lack of motivation are the catechola-
USA screened depressed patients by testing phenyl-
mines dopamine, noradrenaline and adrenaline. As
ethylamine in the blood; low levels mean you need
more phenylalanine. They then gave 40 depressed
patients supplements of phenylalanine, and 31 of
DIETARY PROTEIN them improved.29
Tyrosine has been shown to work well in those
B6 and Zinc with dopamine-dependent depression. In a pilot study
administering 3200 mg tyrosine a day to 12 patients
at the Hopital du Vinatier, France, a signicant im-
provement in mood and sleep was observed on the
L-PHENYLALANINE
very rst day.30
The military has long known that tyrosine improves
Folic Acid, Magnesium, Manganese, Iron, Copper, Zinc, C
mental and physical performance under stress. Recent
research from the Netherlands demonstrates how
tyrosine gives you the edge in conditions of stress.
L-TYROSINE Twenty-one cadets were put through a demanding
one-week military combat training course. Ten cadets
Folic Acid, Magnesium, Manganese, Iron, Copper, Zinc, C were given a drink containing 2 g of tyrosine a day,
while the remaining 11 were given an identical drink
without the tyrosine. Those on tyrosine consistently
L-DOPA performed better, both in memorising the task at
hand and in tracking the tasks they had performed.31
B6 and Zinc In our clinical experience the best results are
achieved by supplementing all of these amino acids
5-HTP, phenylalanine and tyrosine together with
DOPAMINE the B vitamins that help turn them into neurotrans-
mitters, which are B6 , B12 and folic acid.
Vitamin C

NORADRENALINE B vitamins, methylation and


depression
B12, Folic Acid, Niacin

B vitamins act as co-factors in key enzymes that


ADRENALINE control both the production and balance of neuro-
transmitters. For example, serotonin (5-HT) is pro-
duced from 5-HTP by the addition of a methyl group
Dopamine pathway (carboxylase), as is adrenaline from noradrenaline.
This enzyme process is highly dependent on folate, as
Figure 2 The catecholamine pathway well as vitamins B12 and B6 . Folate deciency is
Depression: the nutrition connection 13

SAMe

MTHFR needs TMG and B 12

Methyltransferase needs Folate, B12, B2


and Zinc

METHIONINE
HOMOCYSTEINE
from diet

Cystathionine
Beta-synthase needs B6, B2 and Zinc

Cystathionine
needs B6, B2 and Zinc
Lyase

GLUTATHIONE

Figure 3 How homocysteine is detoxied

extremely common among depressed patients. In a reected by measuring homocysteine levels than by
study of 213 depressed patients at the Depression and measuring blood levels of folate. This is because
Clinical Research Program at Boston Massachusetts homocysteine is methylated `en route to s-adenosyl
General Hospital, USA people with lower folate levels methionine (SAMe) by a folate-dependent enzyme
had more `melancholic depression and were less methyl-tetrahydrofolatereductase, or MTHFR for
likely to improve when given antidepressant drugs.32 short (see Figure 3). In one study, more than half
Very depressed people, and also those diagnosed with (52%) of patients with severe depression were found
schizophrenia, are often decient in folate. A survey to have elevated homocysteine and low levels of
of such patients at Kings College Hospitals psychiatry folate.34
department in London, UK found that one in three Homocysteine levels are particularly high in
had borderline or denite folate deciency. These patients with schizophrenia, even in the absence of
patients then took part in a trial where they took dietary deciency in folate or vitamin B12 .35 When
folate for six months in addition to their standard comparing 193 mixed-sex patients with schizophre-
drug treatment. Those given folate had signicantly nia and 762 non-schizophrenic subjects, US research-
improved recovery, and the longer they took the ers found that average homocysteine levels were a
folate, the better they felt.33 very high 16.3 mmol/l for schizophrenics compared to
One current theory is that genetic differences 10.6 mmol/l in normal subjects.36 However, the dif-
worsening a persons ability to methylate may both ference between groups was almost entirely attribut-
increase the tendency to depression (and schizophre- able to the homocysteine levels of young male
nia) and their need for folate, which may be better patients with schizophrenia.
14 P Holford

Genes, homocysteine and to or superior to antidepressants, works faster, most


often within a few days (most pharmaceutical anti-
mental illness depressants may take three to six weeks to take effect)
and with few side effects.41 43 An intake of 200 to
600 mg a day is needed, but the trouble is that it is
Not everyone is born equal, as far as methylation is
both very expensive and very unstable. A lot of SAMe
concerned. Around one in ten inherit a defective gene
sold in health food shops is pretty ineffective. An
that means that the key methylating enzyme MTHFR
alternative that is much more stable and less costly is
does not work so well, increasing the need for folate,
tri-methyl-glycine (TMG). In the body it turns into
as well as vitamins B12 , B6 and zinc. Vitamin B6 and
SAMe, but the supplement needed is three times as
zinc are involved because those with an MTHFR
much 600 to 2000 mg a day, on an empty stomach
deciency accumulate homocysteine, which can also
or with fruit.
be detoxied by conversion into cystathionine, via an
enzyme dependent on pyridoxal-5-phosphate. Pyri-
doxine (vitamin B6 ) is converted to pyridoxal-5-
phosphate by a zinc-dependent enzyme. Supplement-
ing a combination of folate, vitamin B12 and vitamin Mood-boosting fats
B6 has proven three times more effective at lowering
homocysteine than folate alone.37 The combined
Omega-3 fats have a direct inuence on serotonin
efcacy of these nutrients for depression warrants
status, probably by enhancing production and recep-
investigation.
tion. According to Dr JR Hibbeln, who discovered that
While folate deciency alone can induce depres-
sh eaters are less prone to depression, `Its like build-
sion, the combination of deciency and a fault in the
ing more serotonin factories, instead of just increasing
MTHFR gene is more likely to tip someone over into
the efciency of the serotonin you have.44 Dr Basant
mental illness. To compensate for this, much higher
Puri from Londons Hammersmith Hospital, UK re-
levels of folate than normal are needed. According to
ported the case of a 21-year-old student who had been
researchers from Columbia Universitys Department
on a variety of antidepressants, to no avail. He had a
of Psychiatry in New York, USA this also applies to
very low sense of self-esteem, sleeping problems, little
those with schizophrenia. They found increased levels
appetite, found it hard to socialise and often thought
of homocysteine, despite no apparent lack of dietary
of killing himself. After one month of supplementing
folate.38 The same is true for vitamin B12 . Many
ethyle-EPA (eicosapentaenoic acid), a concentrated
people with mental illness need more than a normal
form of omega-3 fats, he was no longer having suici-
amount of vitamin B12 despite no obvious signs of
dal thoughts and after nine months no longer had any
deciency such as anaemia.39
depression.45
A far better indicator of personal or individualised
Dr Andrew Stoll and colleagues at Harvard Medical
increased need for these B vitamins is a persons
School, USA ran a double-blind placebo-controlled
homocysteine level.
trial of omega-3 fats, placing 14 adult manic depres-
sives on the sh oils EPA and DHA (docosahexaenoic
acid) and compared them with 14 taking an olive oil
placebo. Both took the supplement alongside their
SAMe and TMG: the master normal medication. Those taking the omega-3 fats
tuners had a substantially longer period in remission than
the placebo group. The sh oil group also performed
better than the placebo group for nearly every other
In Figures 2 and 3 you might have noticed these two symptom measured.46 The Institute of Psychiatry in
strange-sounding nutrients. Both are kinds of amino London is currently running a large double-blind trial
acids. TMG stands for tri-methyl-glycine and SAMe with sh oils to further evaluate the effects of omega-3
stands for s-adenosyl methionine. Unlike the B vita- fats on bipolar depression.
mins discussed above, which act as `methyl movers, Omega-3 fats are effective for severe depression too.
SAMe and TMG are methyl group donors. Both can A recent trial published in the American Journal of
lower homocysteine levels by donating methyl groups. Psychiatry tested the effects of giving 20 people suffer-
Conversely, sufcient folate, by enhancingthe MTHFR ing from depression, who were already on antidepres-
enzyme, can increase production of SAMe.40 It is a two- sants but still depressed, a highly concentrated form of
way process. omega-3 fat, ethyl-EPA, versus a placebo. By the third
SAMe is one of the most comprehensively studied week, the depressed patients were showing major
natural antidepressants. Over 100 placebo-controlled, improvement in their mood, while those on placebo
double-blind studies have shown that SAMe is equal were not.47
Depression: the nutrition connection 15

4 Virkkunen M (1984) Reactive hypoglycaemic ten-


Good mood foods and dency among arsonists. Acta Psychiatrica Scandinavica
supplements 69: 44552.
5 Virkkunen M and Narvanen S (1987) Tryptophan
and serotonin levels during the glucose tolerance test
There is good logic, and substantial evidence that among habitually violent and impulsive offenders.
ensuring optimum nutrition in depressed patients can Neuropsychobiology 17: 1923.
be highly effective. In addition to simple lifestyle 6 Yaryura-Tobias J and Neziroglu F (1975) Violent be-
changes such as encouraging exercise and outdoor haviour, brain dysrhythmia and glucose dysfunction.
activity to maximise light, reducing stress and recom- A new syndrome. Journal of Orthopaedic Psychology
4: 1825.
mending counselling, the following diet and supple-
7 Bruce M and Lader M (1989) Caffeine abstention and
ment advice may help:
the management of anxiety disorders. Psychological
Medicine 19: 21114.
8 Wendel W and Beebe W (1973) Glycolytic activity in
schizophrenia. In: Hawkins D and Pauling L (eds)
Diet Orthomolecular Psychiatry: treatment of schizophrenia.
WH Freeman: San Francisco.
9 Prinz R and Riddle D (1986) Associations between
. Reduce sugar and stimulants (caffeinated drinks nutrition and behaviour in 5-year-old children. Nutri-
and smoking). tion Reviews 43 (Suppl): 1518.
. Increase fruit and vegetables (ve servings a day). 10 Christensen L (1988) Psychological distress and diet
effects of sucrose and caffeine. Journal of Applied
. Eat oily sh (mackerel, tuna, salmon, herring) at
Nutrition 40: 4450.
least twice a week.
11 Fullerton DT and Getto CJ (1985) Sugar, opioids and
. Ensure sufcient protein from sh, meat, eggs,
binge eating. Brain Research Bulletin 14: 27380.
beans and lentils. 12 Colgan M and Colgan L (1984) Do nutrient supple-
ments and dietary changes affect learning and emo-
tional reactions of children with learning difculties?
A controlled series of 16 cases. Nutrition and Health
Supplements 3: 6977.
13 Goldman J, Lerman RH, Controis JH et al. (1986)
Behavioural effects of sucrose on preschool children.
. B complex, including vitamin B6 10 mg, folate Journal of Abnormal Child Psychology 14: 56577.
400 mg and vitamin B12 10 mg. 14 Lester M, Thatcher RW and Monroe-Lord L (1982)
Rened carbohydrate intake, hair cadmium levels
. Additional folate, 400 to 2000 mg a day.
and cognitive functioning in children. Nutrition and
. 5-HTP 200300 mg a day.
Behaviour 1: 313.
. Omega-3-rich sh oil, two capsules a day, giving at 15 Schoenthaler S, Doraz WE and Wakeeld JA (1986)
least 400 mg of EPA. The impact of low food additive and sucrose diet on
academic performance in 803 New York City public
schools. International Journal for Biosocial Research
ACKNOWLEDGEMENTS 8: 18595.
16 Dubini A, Bosc M and Polin V (1997) Do noradrenaline
This article has been adapted from Patrick Holfords and serotonin differentially affect social motivation
new book Optimum Nutrition for the Mind (Piatkus, and behaviour? European Neuropsychopharmacology 7
(Suppl 1): S4955.
16.99). For further information call 44 (0)20 8871
17 Smith KA, Fairburn CG and Cowen PJ (1997) Relapse
2949 or visit www.mentalhealthproject.com.
of depression after rapid depletion of tryptophan.
Lancet 349: 91519.
18 Eccleston D (1993) L-tryptophan and depressive ill-
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bolism in depression. Journal of Neurology, Neurosurgery Patrick Holford, Mental Health Project, Carters Yard,
and Psychiatry 69: 22832. London SW18 4JR, UK. Tel: 44 (0)20 8871 2949; fax:
35 Regland B, Johansson BV, Grenfeldt B et al. (1995) 44 (0)20 8874 5003; email: patrick@patrickholford.
Homocysteinemia is a common feature of schizo- com.