Depression: The Nutrition Connection: Invited Papers
Depression: The Nutrition Connection: Invited Papers
Invited papers
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.
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
SAMe
METHIONINE
HOMOCYSTEINE
from diet
Cystathionine
Beta-synthase needs B6, B2 and Zinc
Cystathionine
needs B6, B2 and Zinc
Lyase
GLUTATHIONE
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
22 Poldinger W, Calanchini B and Schwarz W (1991) phrenia. Journal of Neural Transmission (Vienna Aus-
A functional-dimensional approach to depression: tria) 100: 1659.
serotonin deciency and target syndrome in a com- 36 Levine J, Stahl Z, Sela BA et al. (2002) Elevated homo-
parison of 5-hydroxytryptophan and uvoxamine. cysteine levels in young male patients with [chronic]
Psychopathology 24: 5381. schizophrenia. The American Journal of Psychiatry 159:
23 van Praag HM, Kort J and Dols LC (1972) A pilot study 17902.
of the predictive value of the probnecid test in appli- 37 Koyama K, Usami T, Takeuchi O et al. (2002) Efcacy
cation of 5-hydroxytryptophan as antidepressant. of methylcobalamin on lowering total homocysteine
Psychopharmacologica (Berlin) 25: 1421. plasma concentrations in haemodialysis patients
24 Kaneko M, Kumashiro H, Takahashi Y et al. (1979) receiving high-dose folic acid supplementation.
L-5-HTP treatment and serum 5-HT level after L-5- Nephrology Dialysis Transplantation 17 (5): 91622.
HTP loading on depressed patients. Neuropsychobiol- 38 Susser E, Brown AS, Klonowski E et al. (1998) Schizo-
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25 van Heile LJ (1980) L-5-hydroxytryptophan in de- a possible association. Biological Psychiatry 44 (2):
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26 Heninger GR (1997) Serotonin, sex, psychiatric ill- Neuropsychiatric disorders caused by cobalamin de-
ness. Proceedings of the National Academy of Sciences of ciency in the absence of anemia or macrocytosis.
the USA 94: 8234. New England Journal of Medicine 318: 1720 8.
27 Shepherd J (2001) Effects of oestrogen on cognition, 40 Crellin R, Bottiglieri T and Renolds EH (1993) Folates
mood and degenerative brain diseases. Journal of the and psychiatric disorders. Clinical potential. Drugs 45:
American Pharmaceutical Association (Washington DC) 62336.
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28 Beckmann H, Athen D, Olteanu M et al. (1979) DL- the 21st century. www.naturallyhigh.co.uk.
phenylalanine versus imipramine: a double-blind 42 Kagan BL, Sultzer DL, Rosenlicht N et al. (1990) Oral
controlled study. Archiv fur Psychiatrie und Nerven- S-adenosylmethionine in depression: a randomized,
krankheiten 227: 4958. double-blind, placebo-controlled trial. American Jour-
29 Sabelli HC, Fawcett J, Gustovsky F et al. (1986) nal of Psychiatry 147: 5915.
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of affective disorder: urine and blood phenylacetic S-adenosyl-methionine (SAMe) in depression: litera-
acid and phenylalanine dietary supplements. Journal ture review and preliminary data. Psychopharmacology
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30 Mouret J, Lemoine P, Minuit MP et al. (1988) 44 Hibbeln JR (1998) Fish consumption and major
L-tyrosine cures, immediate and long term, dopamine- depression. Lancet 351: 1213.
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studies. Comptes Rendus de lAcademie des Sciences. pentaenoic acid in treatment-resistant depression.
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31 Deijen JB, Wientjes CJ, Vullinghs HF et al. (1999) 46 Stoll AL, Severus WE, Freeman MP et al. (1999)
Tyrosine improves cognitive performance and reduces Omega 3 fatty acids in bipolar disorder: a preliminary
blood pressure in cadets after one week of a com- double-blind, placebo-controlled trial. Archives of
bat training course. Brain Research Bulletin 48: 2039. General Psychiatry 56: 40712.
32 Fava M, Borus JS, Alpert JE et al. (1997) Folate, vitamin 47 Nemets B, Stahl Z and Belmaker RH (2002) Addition
B12 and homocysteine in major depressive disorder. of omega-3 fatty acid to maintenance medication
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33 Godfrey PS, Toone BK, Carney MW et al. (1990) American Journal of Psychiatry 159: 4779.
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34 Bottiglieri T, Laundy M, Crellin R et al. (2000) Homo- ADDRESS FOR CORRESPONDENCE
cysteine, folate, methylation, and monoamine meta-
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.