Depression the nutrition connectionPatrick Holford BSc (Psych) Dip ION

Founder of the Institute for Optimum Nutrition Director of the Mental Health ProjectClinical Director of the Brain Bio Centre London UK

There is little doubt that the incidence of depressionin Britain is increasing According to research at theUniversities of London and Warwick the incidenceof depression among young people has doubled inthe past 12 years However whether young or old thequestion is why and what can be done There arethose who argue that the increasingly common phe-nomenon of depression is primarily psychologicaland best dealt with by counselling There are otherswho consider depression as a biochemical phenom-enon best dealt with by antidepressant medicationHowever there is a third aspect to the onset and treat-ment of depression that is given little heed nutrition

Why would nutrition have anything to do withdepression Firstly we have seen a signiregcant declinein fruit and vegetable intake (rich in folic acid) in regshintake (rich in essential fats) and an increase in sugarconsumption from 2 lb a year in the 1940s to 150 lb ayear in many of todayrsquos teenagers Each of these nutri-ents is strongly linked to depression and could theor-etically contribute to increasing rates of depressionSecondly if depression is a biochemical imbalance itmakes sense to explore how the brain normalises itsown biochemistry using nutrients as the precursorsfor key neurotransmitters such as serotonin Thirdly if21st century living is extra-stressful it would be logicalto assume that increasing psychological demandswould also increase nutritional requirements sincethe brain is structurally and functionally completelydependent on nutrients

So what evidence is there to support suboptimalnutrition as a potential contributor to depressionThese are the common imbalances connected tonutrition that are known to worsen your mood andmotivation

blood sugar imbalances (often associated withexcessive sugar and stimulant intake)

lack of amino acids (tryptophan and tyrosine areprecursors of serotonin and noradrenaline)

lack of B vitamins (vitamin B6 folate B12)

lack of essential fats (omega-3)

The sugar blues

One factor that often underlies depression is poor con-trol of blood glucose levels The symptoms of impairedblood sugar control are many and include fatigueirritability dizziness insomnia excessive sweating(especially at night) poor concentration and forget-fulness excessive thirst depression and crying spellsdigestive disturbances and blurred vision These symp-toms often precede measurable abnormalities in bloodglucose manifesting regrst as a decreased sensitivityto insulin known as insulin resistance One of theworldrsquos experts on blood sugar problems ProfessorGerald Reaven from Stanford University in CaliforniaUSA estimates that 25 of normal non-obese peoplehave `insulin resistancersquo Since the brain depends onan even supply of glucose it is no surprise to regnd thatsugar has been implicated in aggressive behaviour1plusmn6

anxiety78 hyperactivity and attention deregcit9 de-pression10 eating disorders11 fatigue10 and learningdifregculties12plusmn15

The second reason excessive consumption of re-regned sugar is undesirable is that it uses up the bodyrsquosvitamins and minerals and provides next to noneEvery teaspoon of sugar uses up B vitamins for itscatabolism thereby increasing demand B vitamins aswe will see are vital for maintaining mood About98 of the chromium present in sugarcane is lost inturning it into sugar This mineral is vital for keepingthe blood sugar level stable

The amino acid connection

There are often two sides to depression feeling mis-erable and feeling apathetic and unmotivated Themost prevalent biochemical theory for the cause ofthese imbalances is a brain imbalance in two familiesof neurotransmitters These are

Invited papers

Primary Care Mental Health (2003) 1 9plusmn16 atilde 2003 Radcliffe Medical Press

serotonin thought to primarily inmacruence mood

dopamine noradrenalineand adrenaline thoughtto primarily inmacruence motivation

To test the theory that serotonin primarily controlsmood and adrenaline and noradrenaline controlmotivation Antonella Dubini from the Pharmaciaand Upjohn Medical Department in Milan Italy gave203 people suffering from low mood and motivationeither a SSRI (selective serotonin reuptake inhibitor)drug promoting serotonin or a NARI (noradrenalinereuptake inhibitor) drug promoting noradrenalineSure enough the former was more effective at im-proving mood while the latter was more effective atimproving motivation16

Figure 1 shows those nutrients that are required forthe production of serotonin dopamine adrenalineand noradrenaline

Depression and tryptophan

SSRI antidepressants are thought to work by stoppingthe reuptake of serotonin thereby enhancing seroto-nin action within the synapse The trouble is thatthese kinds of drugs induce unpleasant side effects inas many as a quarter of those who take them andsevere reactions in a minority An alternative strategy

P Holford10

TRYPTOPHAN

5-HTP

SEROTONIN

PHENYLALANINE

TYROSINE

DOPAMINENORADRENALINE

ADRENALINE

B vitaminsC + Zinc

help theseconversions

TMG + SAMe

helps makethese

OMEGA 3 fatsimprove neurotransmitter

reception

Mood-Enhancing Nutrients

Figure 1 Nutrients that make mood-enhancing neurotransmitters

would be to enhance the synthesis of serotonin byproviding optimal amounts of precursor nutrientsBut does it work

Serotonin is made from the amino acid trypto-phan a constituent of protein Dr Philip Cowen andcolleagues from the University of Oxford UK psy-chiatry department wondered what would happen ifyou deprived people of tryptophan They gave 15 vol-unteers who had a history of depression but werecurrently not depressed a nutritionally balanced drinkthat excluded tryptophan Within seven hours 10out of 15 noticed a worsening of their mood andstarted to show signs of depression On being given thesame drink but this time with tryptophan added theirmood improved17 Supplementing the amino acidtryptophan is already proven to improve mood Don-ald Ecclestone professor of medicine at the RoyalVictoria Inregrmary Newcastle UK reviewed the avail-able studies and concluded that supplementing tryp-tophan is an effective antidepressant equivalent totricyclic antidepressants18

While supplementing tryptophan itself has provena somewhat effective antidepressant even more effec-tive is a derivative of tryptophan that is one step closerto serotonin This is called 5-hydroxytryptophan or5-HTP for short The regrst study proving the mood-boosting power of 5-HTP was done in the 1970s inJapan under the direction of Professor Isamu Sano ofthe Osaka University Medical School19 He gave 107patients 50 to 300 mg of 5-HTP per day and withintwo weeks more than half experienced improve-ments in their symptoms By the end of the fourthweek of the study nearly three-quarters of thepatients reported either complete relief or signiregcantimprovement with no side effects This study wasrepeated by Nakajima et al who also found that 69of patients improved their mood20 A trial in Germanyfound 5-HTP to be as effective as the tricyclic anti-depressant imipramine with a fraction of the sideeffects21 One double-blind trial headed by Dr Poldin-ger at the Basel University of Psychiatry Switzerlandgave 34 depressed volunteers either the SSRI anti-depressant macruvoxamine or 300 mg of 5-HTP Eachpatient was assessed for their degree of depressionusing the widely accepted Hamilton Rating Scale plustheir own subjective self-assessment At the end of thesix weeks both groups of patients had had a signiregcantimprovement in their depression However thosetaking 5-HTP had a slightly greater improvement ineach of the four criteria assessed plusmn depression anxietyinsomnia and physical symptoms as well as thepatientrsquos self-assessment22 Given that 5-HTP is lessexpensive and has signiregcantly fewer side effects it issurprising thatdoctorsand psychiatrists virtually neverprescribe it192023plusmn25

The recommended dosage of this amino acid avail-able in any health food shop is 100 mg of 5-HTP two

or three times a day for depression Some supple-ments also provide various vitamins and mineralssuch as B12 and folic acid which may be even moreeffective because these nutrients help to turn 5-HTPinto serotonin

Depression in women

Women are three times as prone to low moods asmen Many theories as to why this is have beenproposed some psychological some social but thetruth is that women and men are biochemically verydifferent The research of Mirko Diksic and colleaguesat McGill University in Montreal Canada demon-strates this They developed a technique usingpositron emission tomography (PET) neuro-imagingto measure the rate at which we make serotonin in thebrain26 What they found was that menrsquos averagesynthesis rate of serotonin was 52 higher than thatof women This and other research has clearly shownthat women are more prone to low serotonin Theyalso react differently In women low serotonin isassociated with depression and anxiety while in menlow serotonin is related to aggression and alcoholismOne possibility is our social conditioning men `actoutrsquo their moods while women are more conditionedto `act inrsquo their moods

What has been learnt about serotonin in the lastfew years is that there are a number of potentialreasons for deregciency in addition to a lack of orincreased need for tryptophan

not enough oestrogen (in women)

not enough testosterone (in men)

not enough light

not enough exercise

too much stress especially in women

not enough co-factor vitamins and minerals

If a person is suffering from low mood feels tense andirritable is tired all the time tends to comfort eat hassleeping problems and a reduced interest in sex andsome of the above apply the chances are they areshort on serotonin

Low oestrogen means low serotonin and lowmoods1727 This is because oestrogen blocks thebreakdown of serotonin This may explain whywomen are more prone to depression premenstruallyand in the menopause and thereafter Low testoster-one has a similar effect in men

Light also stimulates both oestrogen and serotoninand most of us do not get enough of it The differencein light exposure outside and inside is massive Mostof us spend 23 out of 24 hours a day indoors exposedto an average of 100 units (called lux) of light That iscompared to an outdoor level of 20 000 lux on a sunnyday and 7000 lux on an overcast day Now more than

Depression the nutrition connection 11

ever before many people rarely expose themselves todirect sunlight and certainly not enough to maximiseserotonin production Of course light deregciency isworse in the winter

Stress also rapidly reduces serotonin levels whilephysical exercise improves stress response and there-fore reduces stress-induced depletion of serotonin

Is apathy a catecholaminederegciency

Another group of neurotransmitters associated withdepression and lack of motivation are the catechola-mines plusmn dopamine noradrenaline and adrenaline As

shown in Figure 2 both adrenaline and noradrenalineare synthesised from dopamine which is made fromthe amino acid tyrosine which is itself made from theamino acid phenylalanine It is logical to assumethat if the drugs that block the breakdown of theseneurotransmitters do elevate mood then augmentingthe amino acid phenylalanine or tyrosine might worktoo And they do

In a double-blind study by Helmut Beckmann andcolleagues at the University of Wurzburg Germany150 to 200 mg of the amino acid phenylalanine orthe antidepressant drug imipramine were adminis-tered to 40 depressed patients for one month Bothgroups had the same degree of positive results ETH lessdepression anxiety and sleep disturbance28 A groupof researchers at the Rush Medical Center ChicagoUSA screened depressed patients by testing phenyl-ethylamine in the blood low levels mean you needmore phenylalanine They then gave 40 depressedpatients supplements of phenylalanine and 31 ofthem improved29

Tyrosine has been shown to work well in thosewith dopamine-dependentdepression In a pilot studyadministering 3200 mg tyrosine a day to 12 patientsat the Hopital du Vinatier France a signiregcant im-provement in mood and sleep was observed on thevery regrst day30

The military has long known that tyrosine improvesmental and physical performance under stress Recentresearch from the Netherlands demonstrates howtyrosine gives you the edge in conditions of stressTwenty-one cadets were put through a demandingone-week military combat training course Ten cadetswere given a drink containing 2 g of tyrosine a daywhile the remaining 11 were given an identical drinkwithout the tyrosine Those on tyrosine consistentlyperformed better both in memorising the task athand and in tracking the tasks they had performed31

In our clinical experience the best results areachieved by supplementing all of these amino acids plusmn5-HTP phenylalanine and tyrosine plusmn together withthe B vitamins that help turn them into neurotrans-mitters which are B6 B12 and folic acid

B vitamins methylation anddepression

B vitamins act as co-factors in key enzymes thatcontrol 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(carboxylase) as is adrenaline from noradrenalineThis enzyme process is highly dependent on folate aswell as vitamins B12 and B6 Folate deregciency is

P Holford12

DIETARY PROTEIN

B and Zinc

L-PHENYLALANINE

Folic Acid Magnesium Manganese Iron Copper Zinc C

L-TYROSINE

Folic Acid Magnesium Manganese Iron Copper Zinc C

L-DOPA

B and Zinc

DOPAMINE

Vitamin C

NORADRENALINE

B Folic Acid Niacin

ADRENALINE

Dopamine pathway

6

6

12

Figure 2 The catecholamine pathway

extremely common among depressed patients In astudy of 213 depressed patients at the Depression andClinical Research Program at Boston MassachusettsGeneral Hospital USA people with lower folate levelshad more `melancholicrsquo depression and were lesslikely to improve when given antidepressant drugs32

Very depressed people and also those diagnosed withschizophrenia are often deregcient in folate A surveyof such patients at Kings College Hospitalrsquos psychiatrydepartment in London UK found that one in threehad borderline or deregnite folate deregciency Thesepatients then took part in a trial where they tookfolate for six months in addition to their standarddrug treatment Those given folate had signiregcantlyimproved recovery and the longer they took thefolate the better they felt33

One current theory is that genetic differencesworsening a personrsquos ability to methylate may bothincrease the tendency to depression (and schizophre-nia) and their need for folate which may be better

remacrected by measuring homocysteine levels than bymeasuring blood levels of folate This is becausehomocysteine is methylated `en routersquo to s-adenosylmethionine (SAMe) by a folate-dependent enzymemethyl-tetrahydrofolatereductase or MTHFR forshort (see Figure 3) In one study more than half(52) of patients with severe depression were foundto have elevated homocysteine and low levels offolate34

Homocysteine levels are particularly high inpatients with schizophrenia even in the absence ofdietary deregciency in folate or vitamin B1235 Whencomparing 193 mixed-sex patients with schizophre-nia and 762 non-schizophrenic subjects US research-ers found that average homocysteine levels were avery high 163 mmoll for schizophrenics compared to106 mmoll in normal subjects36 However the dif-ference between groups was almost entirely attribut-able to the homocysteine levels of young malepatients with schizophrenia

Depression the nutrition connection 13

SAMe

MTHFR

Methyltransferase

HOMOCYSTEINE

CystathionineBeta-synthase

CystathionineLyase

GLUTATHIONE

METHIONINEfrom diet

needs TMG and B

needs Folate B B and Zinc

needs B B and Zinc

needs B B and Zinc

12

12 2

26

26

Figure 3 How homocysteine is detoxireged

Genes homocysteine andmental illness

Not everyone is born equal as far as methylation isconcerned Around one in ten inherit a defective genethat means that the key methylating enzyme MTHFRdoes not work so well increasing the need for folateas well as vitamins B12 B6 and zinc Vitamin B6 andzinc are involved because those with an MTHFRderegciency accumulate homocysteine which can alsobe detoxireged by conversion into cystathionine via anenzyme 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 vitaminB6 has proven three times more effective at loweringhomocysteine than folate alone37 The combinedefregcacy of these nutrients for depression warrantsinvestigation

While folate deregciency alone can induce depres-sion the combination of deregciency and a fault in theMTHFR gene is more likely to tip someone over intomental illness To compensate for this much higherlevels of folate than normal are needed According toresearchers from Columbia Universityrsquos Departmentof Psychiatry in New York USA this also applies tothose with schizophrenia They found increased levelsof homocysteine despite no apparent lack of dietaryfolate38 The same is true for vitamin B12 Manypeople with mental illness need more than a normalamount of vitamin B12 despite no obvious signs ofderegciency such as anaemia39

A far better indicator of personal or individualisedincreased need for these B vitamins is a personrsquoshomocysteine level

SAMe and TMG the mastertuners

In Figures 2 and 3 you might have noticed these twostrange-sounding nutrients Both are kinds of aminoacids TMG stands for tri-methyl-glycine and SAMestands for s-adenosyl methionine Unlike the B vita-mins discussed above which act as `methyl moversrsquoSAMe and TMG are methyl group donors Both canlower homocysteinelevels by donating methylgroupsConversely sufregcient folate by enhancingthe MTHFRenzyme can increase production of SAMe40 It is a two-way process

SAMe is one of the most comprehensively studiednatural antidepressants Over 100 placebo-controlleddouble-blind studies have shown that SAMe is equal

to or superior to antidepressants works faster mostoften within a few days (most pharmaceutical anti-depressants may take three to six weeks to take effect)and with few side effects41plusmn43 An intake of 200 to600 mg a day is needed but the trouble is that it isboth very expensive and very unstable A lot of SAMesold in health food shops is pretty ineffective Analternative that is much more stable and less costly istri-methyl-glycine (TMG) In the body it turns intoSAMe but the supplement needed is three times asmuch plusmn 600 to 2000 mg a day on an empty stomachor with fruit

Mood-boosting fats

Omega-3 fats have a direct inmacruence on serotoninstatus probably by enhancing production and recep-tion According to Dr JR Hibbeln who discovered thatregsh eaters are less prone to depression `Itrsquos like build-ing more serotonin factories instead of just increasingthe efregciency of the serotonin you haversquo44 Dr BasantPuri from Londonrsquos Hammersmith Hospital UK re-ported the case of a 21-year-old student who had beenon a variety of antidepressants to no avail He had avery low sense of self-esteem sleeping problems littleappetite found it hard to socialise and often thoughtof killing himself After one month of supplementingethyle-EPA (eicosapentaenoic acid) a concentratedform of omega-3 fats he was no longer having suici-dal thoughts and after nine months no longer had anydepression45

Dr Andrew Stoll and colleagues at Harvard MedicalSchool USA ran a double-blind placebo-controlledtrial of omega-3 fats placing 14 adult manic depres-sives on the regsh oils EPA and DHA (docosahexaenoicacid) and compared them with 14 taking an olive oilplacebo Both took the supplement alongside theirnormal medication Those taking the omega-3 fatshad a substantially longer period in remission thanthe placebo group The regsh oil group also performedbetter than the placebo group for nearly every othersymptom measured46 The Institute of Psychiatry inLondon is currently running a large double-blind trialwith regsh oils to further evaluate the effects of omega-3fats on bipolar depression

Omega-3 fats are effective for severe depression tooA recent trial published in the American Journal ofPsychiatry tested the effects of giving 20 people suffer-ing from depression who were already on antidepres-sants but still depressed a highly concentrated form ofomega-3 fat ethyl-EPA versus a placebo By the thirdweek the depressed patients were showing majorimprovement in their mood while those on placebowere not47

P Holford14

Good mood foods andsupplements

There is good logic and substantial evidence thatensuring optimum nutrition in depressed patients canbe highly effective In addition to simple lifestylechanges such as encouraging exercise and outdooractivity to maximise light reducing stress and recom-mending counselling the following diet and supple-ment advice may help

Diet

Reduce sugar and stimulants (caffeinated drinksand smoking)

Increase fruit and vegetables (regve servings a day)

Eat oily regsh (mackerel tuna salmon herring) atleast twice a week

Ensure sufregcient protein from regsh meat eggsbeans and lentils

Supplements

B complex including vitamin B6 10 mg folate400 mg and vitamin B12 10 mg

Additional folate 400 to 2000 mg a day

5-HTP 200plusmn300 mg a day

Omega-3-rich regsh oil two capsules a day giving atleast 400 mg of EPA

ACKNOWLEDGEMENTS

This article has been adapted from Patrick Holfordrsquosnew book Optimum Nutrition for the Mind (Piatkuspound1699) For further information call Dagger44 (0)20 88712949 or visit wwwmentalhealthprojectcom

REFERENCES

1 Benton D Kumari N and Brain PF (1982) Mild hypo-glycaemia and questionnaire measures of aggressionBiological Psychology 14 129plusmn35

2 Roy A Virkkunen M and Linnoila M (1988) Mono-amines glucose metabolism aggression toward selfand others International Journal of Neuroscience 41261plusmn4

3 Schauss AG (1980) Diet Crime and Delinquency ParkerHouse Berkeley

4 Virkkunen M (1984) Reactive hypoglycaemic ten-dency among arsonists Acta Psychiatrica Scandinavica69 445plusmn52

5 Virkkunen M and Narvanen S (1987) Tryptophanand serotonin levels during the glucose tolerance testamong habitually violent and impulsive offendersNeuropsychobiology 17 19plusmn23

6 Yaryura-Tobias J and Neziroglu F (1975) Violent be-haviour brain dysrhythmia and glucose dysfunctionA new syndrome Journal of Orthopaedic Psychology4 182plusmn5

7 Bruce M and Lader M (1989) Caffeine abstention andthe management of anxiety disorders PsychologicalMedicine 19 211plusmn14

8 Wendel W and Beebe W (1973) Glycolytic activity inschizophrenia In Hawkins D and Pauling L (eds)Orthomolecular Psychiatry treatment of schizophreniaWH Freeman San Francisco

9 Prinz R and Riddle D (1986) Associations betweennutrition and behaviour in 5-year-old children Nutri-tion Reviews 43 (Suppl) 151plusmn8

10 Christensen L (1988) Psychological distress and dieteffects of sucrose and caffeine Journal of AppliedNutrition 40 44plusmn50

11 Fullerton DT and Getto CJ (1985) Sugar opioids andbinge eating Brain Research Bulletin 14 273plusmn80

12 Colgan M and Colgan L (1984) Do nutrient supple-ments and dietary changes affect learning and emo-tional reactions of children with learning difregcultiesA controlled series of 16 cases Nutrition and Health3 69plusmn77

13 Goldman J Lerman RH Controis JH et al (1986)Behavioural effects of sucrose on preschool childrenJournal of Abnormal Child Psychology 14 565plusmn77

14 Lester M Thatcher RW and Monroe-Lord L (1982)Reregned carbohydrate intake hair cadmium levelsand cognitive functioning in children Nutrition andBehaviour 1 3plusmn13

15 Schoenthaler S Doraz WE and Wakeregeld JA (1986)The impact of low food additive and sucrose diet onacademic performance in 803 New York City publicschools International Journal for Biosocial Research8 185plusmn95

16 Dubini A Bosc M and Polin V (1997) Do noradrenalineand serotonin differentially affect social motivationand behaviour European Neuropsychopharmacology 7(Suppl 1) S49plusmn55

17 Smith KA Fairburn CG and Cowen PJ (1997) Relapseof depression after rapid depletion of tryptophanLancet 349 915plusmn19

18 Eccleston D (1993) L-tryptophan and depressive ill-ness Psychiatric Bulletin 17 223plusmn4

19 von Sano I (1972) L-5-hydroxytryptophan (L-5-HTP)therapie Folia Psychiatrica et Neurologica Japonica 267plusmn17

20 Nakajima T Kudo Y and Kaneko Z (1978) Clinicalevaluation of 5-hydroxytryptophan as an antidepres-sant Folia Psychiatrica et Neurologica 32 223plusmn30

21 Woggon A and Schoef J (1977) The treatment ofdepression with L-5-hydroxytryptophan versus imi-pramine Archiv fuEgraver Psychiatrie und Nervenkrankheiten224 175plusmn86

Depression the nutrition connection 15

serotonin thought to primarily inmacruence mood

dopamine noradrenalineand adrenaline thoughtto primarily inmacruence motivation

To test the theory that serotonin primarily controlsmood and adrenaline and noradrenaline controlmotivation Antonella Dubini from the Pharmaciaand Upjohn Medical Department in Milan Italy gave203 people suffering from low mood and motivationeither a SSRI (selective serotonin reuptake inhibitor)drug promoting serotonin or a NARI (noradrenalinereuptake inhibitor) drug promoting noradrenalineSure enough the former was more effective at im-proving mood while the latter was more effective atimproving motivation16

Figure 1 shows those nutrients that are required forthe production of serotonin dopamine adrenalineand noradrenaline

Depression and tryptophan

SSRI antidepressants are thought to work by stoppingthe reuptake of serotonin thereby enhancing seroto-nin action within the synapse The trouble is thatthese kinds of drugs induce unpleasant side effects inas many as a quarter of those who take them andsevere reactions in a minority An alternative strategy

P Holford10

TRYPTOPHAN

5-HTP

SEROTONIN

PHENYLALANINE

TYROSINE

DOPAMINENORADRENALINE

ADRENALINE

B vitaminsC + Zinc

help theseconversions

TMG + SAMe

helps makethese

OMEGA 3 fatsimprove neurotransmitter

reception

Mood-Enhancing Nutrients

Figure 1 Nutrients that make mood-enhancing neurotransmitters

would be to enhance the synthesis of serotonin byproviding optimal amounts of precursor nutrientsBut does it work

Serotonin is made from the amino acid trypto-phan a constituent of protein Dr Philip Cowen andcolleagues from the University of Oxford UK psy-chiatry department wondered what would happen ifyou deprived people of tryptophan They gave 15 vol-unteers who had a history of depression but werecurrently not depressed a nutritionally balanced drinkthat excluded tryptophan Within seven hours 10out of 15 noticed a worsening of their mood andstarted to show signs of depression On being given thesame drink but this time with tryptophan added theirmood improved17 Supplementing the amino acidtryptophan is already proven to improve mood Don-ald Ecclestone professor of medicine at the RoyalVictoria Inregrmary Newcastle UK reviewed the avail-able studies and concluded that supplementing tryp-tophan is an effective antidepressant equivalent totricyclic antidepressants18

While supplementing tryptophan itself has provena somewhat effective antidepressant even more effec-tive is a derivative of tryptophan that is one step closerto serotonin This is called 5-hydroxytryptophan or5-HTP for short The regrst study proving the mood-boosting power of 5-HTP was done in the 1970s inJapan under the direction of Professor Isamu Sano ofthe Osaka University Medical School19 He gave 107patients 50 to 300 mg of 5-HTP per day and withintwo weeks more than half experienced improve-ments in their symptoms By the end of the fourthweek of the study nearly three-quarters of thepatients reported either complete relief or signiregcantimprovement with no side effects This study wasrepeated by Nakajima et al who also found that 69of patients improved their mood20 A trial in Germanyfound 5-HTP to be as effective as the tricyclic anti-depressant imipramine with a fraction of the sideeffects21 One double-blind trial headed by Dr Poldin-ger at the Basel University of Psychiatry Switzerlandgave 34 depressed volunteers either the SSRI anti-depressant macruvoxamine or 300 mg of 5-HTP Eachpatient was assessed for their degree of depressionusing the widely accepted Hamilton Rating Scale plustheir own subjective self-assessment At the end of thesix weeks both groups of patients had had a signiregcantimprovement in their depression However thosetaking 5-HTP had a slightly greater improvement ineach of the four criteria assessed plusmn depression anxietyinsomnia and physical symptoms as well as thepatientrsquos self-assessment22 Given that 5-HTP is lessexpensive and has signiregcantly fewer side effects it issurprising thatdoctorsand psychiatrists virtually neverprescribe it192023plusmn25

The recommended dosage of this amino acid avail-able in any health food shop is 100 mg of 5-HTP two

or three times a day for depression Some supple-ments also provide various vitamins and mineralssuch as B12 and folic acid which may be even moreeffective because these nutrients help to turn 5-HTPinto serotonin

Depression in women

Women are three times as prone to low moods asmen Many theories as to why this is have beenproposed some psychological some social but thetruth is that women and men are biochemically verydifferent The research of Mirko Diksic and colleaguesat McGill University in Montreal Canada demon-strates this They developed a technique usingpositron emission tomography (PET) neuro-imagingto measure the rate at which we make serotonin in thebrain26 What they found was that menrsquos averagesynthesis rate of serotonin was 52 higher than thatof women This and other research has clearly shownthat women are more prone to low serotonin Theyalso react differently In women low serotonin isassociated with depression and anxiety while in menlow serotonin is related to aggression and alcoholismOne possibility is our social conditioning men `actoutrsquo their moods while women are more conditionedto `act inrsquo their moods

What has been learnt about serotonin in the lastfew years is that there are a number of potentialreasons for deregciency in addition to a lack of orincreased need for tryptophan

not enough oestrogen (in women)

not enough testosterone (in men)

not enough light

not enough exercise

too much stress especially in women

not enough co-factor vitamins and minerals

If a person is suffering from low mood feels tense andirritable is tired all the time tends to comfort eat hassleeping problems and a reduced interest in sex andsome of the above apply the chances are they areshort on serotonin

Low oestrogen means low serotonin and lowmoods1727 This is because oestrogen blocks thebreakdown of serotonin This may explain whywomen are more prone to depression premenstruallyand in the menopause and thereafter Low testoster-one has a similar effect in men

Light also stimulates both oestrogen and serotoninand most of us do not get enough of it The differencein light exposure outside and inside is massive Mostof us spend 23 out of 24 hours a day indoors exposedto an average of 100 units (called lux) of light That iscompared to an outdoor level of 20 000 lux on a sunnyday and 7000 lux on an overcast day Now more than

Depression the nutrition connection 11

ever before many people rarely expose themselves todirect sunlight and certainly not enough to maximiseserotonin production Of course light deregciency isworse in the winter

Stress also rapidly reduces serotonin levels whilephysical exercise improves stress response and there-fore reduces stress-induced depletion of serotonin

Is apathy a catecholaminederegciency

Another group of neurotransmitters associated withdepression and lack of motivation are the catechola-mines plusmn dopamine noradrenaline and adrenaline As

shown in Figure 2 both adrenaline and noradrenalineare synthesised from dopamine which is made fromthe amino acid tyrosine which is itself made from theamino acid phenylalanine It is logical to assumethat if the drugs that block the breakdown of theseneurotransmitters do elevate mood then augmentingthe amino acid phenylalanine or tyrosine might worktoo And they do

In a double-blind study by Helmut Beckmann andcolleagues at the University of Wurzburg Germany150 to 200 mg of the amino acid phenylalanine orthe antidepressant drug imipramine were adminis-tered to 40 depressed patients for one month Bothgroups had the same degree of positive results ETH lessdepression anxiety and sleep disturbance28 A groupof researchers at the Rush Medical Center ChicagoUSA screened depressed patients by testing phenyl-ethylamine in the blood low levels mean you needmore phenylalanine They then gave 40 depressedpatients supplements of phenylalanine and 31 ofthem improved29

Tyrosine has been shown to work well in thosewith dopamine-dependentdepression In a pilot studyadministering 3200 mg tyrosine a day to 12 patientsat the Hopital du Vinatier France a signiregcant im-provement in mood and sleep was observed on thevery regrst day30

The military has long known that tyrosine improvesmental and physical performance under stress Recentresearch from the Netherlands demonstrates howtyrosine gives you the edge in conditions of stressTwenty-one cadets were put through a demandingone-week military combat training course Ten cadetswere given a drink containing 2 g of tyrosine a daywhile the remaining 11 were given an identical drinkwithout the tyrosine Those on tyrosine consistentlyperformed better both in memorising the task athand and in tracking the tasks they had performed31

In our clinical experience the best results areachieved by supplementing all of these amino acids plusmn5-HTP phenylalanine and tyrosine plusmn together withthe B vitamins that help turn them into neurotrans-mitters which are B6 B12 and folic acid

B vitamins methylation anddepression

B vitamins act as co-factors in key enzymes thatcontrol 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(carboxylase) as is adrenaline from noradrenalineThis enzyme process is highly dependent on folate aswell as vitamins B12 and B6 Folate deregciency is

P Holford12

DIETARY PROTEIN

B and Zinc

L-PHENYLALANINE

Folic Acid Magnesium Manganese Iron Copper Zinc C

L-TYROSINE

Folic Acid Magnesium Manganese Iron Copper Zinc C

L-DOPA

B and Zinc

DOPAMINE

Vitamin C

NORADRENALINE

B Folic Acid Niacin

ADRENALINE

Dopamine pathway

6

6

12

Figure 2 The catecholamine pathway

extremely common among depressed patients In astudy of 213 depressed patients at the Depression andClinical Research Program at Boston MassachusettsGeneral Hospital USA people with lower folate levelshad more `melancholicrsquo depression and were lesslikely to improve when given antidepressant drugs32

Very depressed people and also those diagnosed withschizophrenia are often deregcient in folate A surveyof such patients at Kings College Hospitalrsquos psychiatrydepartment in London UK found that one in threehad borderline or deregnite folate deregciency Thesepatients then took part in a trial where they tookfolate for six months in addition to their standarddrug treatment Those given folate had signiregcantlyimproved recovery and the longer they took thefolate the better they felt33

One current theory is that genetic differencesworsening a personrsquos ability to methylate may bothincrease the tendency to depression (and schizophre-nia) and their need for folate which may be better

remacrected by measuring homocysteine levels than bymeasuring blood levels of folate This is becausehomocysteine is methylated `en routersquo to s-adenosylmethionine (SAMe) by a folate-dependent enzymemethyl-tetrahydrofolatereductase or MTHFR forshort (see Figure 3) In one study more than half(52) of patients with severe depression were foundto have elevated homocysteine and low levels offolate34

Homocysteine levels are particularly high inpatients with schizophrenia even in the absence ofdietary deregciency in folate or vitamin B1235 Whencomparing 193 mixed-sex patients with schizophre-nia and 762 non-schizophrenic subjects US research-ers found that average homocysteine levels were avery high 163 mmoll for schizophrenics compared to106 mmoll in normal subjects36 However the dif-ference between groups was almost entirely attribut-able to the homocysteine levels of young malepatients with schizophrenia

Depression the nutrition connection 13

SAMe

MTHFR

Methyltransferase

HOMOCYSTEINE

CystathionineBeta-synthase

CystathionineLyase

GLUTATHIONE

METHIONINEfrom diet

needs TMG and B

needs Folate B B and Zinc

needs B B and Zinc

needs B B and Zinc

12

12 2

26

26

Figure 3 How homocysteine is detoxireged

Genes homocysteine andmental illness

Not everyone is born equal as far as methylation isconcerned Around one in ten inherit a defective genethat means that the key methylating enzyme MTHFRdoes not work so well increasing the need for folateas well as vitamins B12 B6 and zinc Vitamin B6 andzinc are involved because those with an MTHFRderegciency accumulate homocysteine which can alsobe detoxireged by conversion into cystathionine via anenzyme 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 vitaminB6 has proven three times more effective at loweringhomocysteine than folate alone37 The combinedefregcacy of these nutrients for depression warrantsinvestigation

While folate deregciency alone can induce depres-sion the combination of deregciency and a fault in theMTHFR gene is more likely to tip someone over intomental illness To compensate for this much higherlevels of folate than normal are needed According toresearchers from Columbia Universityrsquos Departmentof Psychiatry in New York USA this also applies tothose with schizophrenia They found increased levelsof homocysteine despite no apparent lack of dietaryfolate38 The same is true for vitamin B12 Manypeople with mental illness need more than a normalamount of vitamin B12 despite no obvious signs ofderegciency such as anaemia39

A far better indicator of personal or individualisedincreased need for these B vitamins is a personrsquoshomocysteine level

SAMe and TMG the mastertuners

In Figures 2 and 3 you might have noticed these twostrange-sounding nutrients Both are kinds of aminoacids TMG stands for tri-methyl-glycine and SAMestands for s-adenosyl methionine Unlike the B vita-mins discussed above which act as `methyl moversrsquoSAMe and TMG are methyl group donors Both canlower homocysteinelevels by donating methylgroupsConversely sufregcient folate by enhancingthe MTHFRenzyme can increase production of SAMe40 It is a two-way process

SAMe is one of the most comprehensively studiednatural antidepressants Over 100 placebo-controlleddouble-blind studies have shown that SAMe is equal

to or superior to antidepressants works faster mostoften within a few days (most pharmaceutical anti-depressants may take three to six weeks to take effect)and with few side effects41plusmn43 An intake of 200 to600 mg a day is needed but the trouble is that it isboth very expensive and very unstable A lot of SAMesold in health food shops is pretty ineffective Analternative that is much more stable and less costly istri-methyl-glycine (TMG) In the body it turns intoSAMe but the supplement needed is three times asmuch plusmn 600 to 2000 mg a day on an empty stomachor with fruit

Mood-boosting fats

Omega-3 fats have a direct inmacruence on serotoninstatus probably by enhancing production and recep-tion According to Dr JR Hibbeln who discovered thatregsh eaters are less prone to depression `Itrsquos like build-ing more serotonin factories instead of just increasingthe efregciency of the serotonin you haversquo44 Dr BasantPuri from Londonrsquos Hammersmith Hospital UK re-ported the case of a 21-year-old student who had beenon a variety of antidepressants to no avail He had avery low sense of self-esteem sleeping problems littleappetite found it hard to socialise and often thoughtof killing himself After one month of supplementingethyle-EPA (eicosapentaenoic acid) a concentratedform of omega-3 fats he was no longer having suici-dal thoughts and after nine months no longer had anydepression45

Dr Andrew Stoll and colleagues at Harvard MedicalSchool USA ran a double-blind placebo-controlledtrial of omega-3 fats placing 14 adult manic depres-sives on the regsh oils EPA and DHA (docosahexaenoicacid) and compared them with 14 taking an olive oilplacebo Both took the supplement alongside theirnormal medication Those taking the omega-3 fatshad a substantially longer period in remission thanthe placebo group The regsh oil group also performedbetter than the placebo group for nearly every othersymptom measured46 The Institute of Psychiatry inLondon is currently running a large double-blind trialwith regsh oils to further evaluate the effects of omega-3fats on bipolar depression

Omega-3 fats are effective for severe depression tooA recent trial published in the American Journal ofPsychiatry tested the effects of giving 20 people suffer-ing from depression who were already on antidepres-sants but still depressed a highly concentrated form ofomega-3 fat ethyl-EPA versus a placebo By the thirdweek the depressed patients were showing majorimprovement in their mood while those on placebowere not47

P Holford14

Good mood foods andsupplements

There is good logic and substantial evidence thatensuring optimum nutrition in depressed patients canbe highly effective In addition to simple lifestylechanges such as encouraging exercise and outdooractivity to maximise light reducing stress and recom-mending counselling the following diet and supple-ment advice may help

Diet

Reduce sugar and stimulants (caffeinated drinksand smoking)

Increase fruit and vegetables (regve servings a day)

Eat oily regsh (mackerel tuna salmon herring) atleast twice a week

Ensure sufregcient protein from regsh meat eggsbeans and lentils

Supplements

B complex including vitamin B6 10 mg folate400 mg and vitamin B12 10 mg

Additional folate 400 to 2000 mg a day

5-HTP 200plusmn300 mg a day

Omega-3-rich regsh oil two capsules a day giving atleast 400 mg of EPA

ACKNOWLEDGEMENTS

This article has been adapted from Patrick Holfordrsquosnew book Optimum Nutrition for the Mind (Piatkuspound1699) For further information call Dagger44 (0)20 88712949 or visit wwwmentalhealthprojectcom

REFERENCES

1 Benton D Kumari N and Brain PF (1982) Mild hypo-glycaemia and questionnaire measures of aggressionBiological Psychology 14 129plusmn35

2 Roy A Virkkunen M and Linnoila M (1988) Mono-amines glucose metabolism aggression toward selfand others International Journal of Neuroscience 41261plusmn4

3 Schauss AG (1980) Diet Crime and Delinquency ParkerHouse Berkeley

4 Virkkunen M (1984) Reactive hypoglycaemic ten-dency among arsonists Acta Psychiatrica Scandinavica69 445plusmn52

5 Virkkunen M and Narvanen S (1987) Tryptophanand serotonin levels during the glucose tolerance testamong habitually violent and impulsive offendersNeuropsychobiology 17 19plusmn23

6 Yaryura-Tobias J and Neziroglu F (1975) Violent be-haviour brain dysrhythmia and glucose dysfunctionA new syndrome Journal of Orthopaedic Psychology4 182plusmn5

7 Bruce M and Lader M (1989) Caffeine abstention andthe management of anxiety disorders PsychologicalMedicine 19 211plusmn14

8 Wendel W and Beebe W (1973) Glycolytic activity inschizophrenia In Hawkins D and Pauling L (eds)Orthomolecular Psychiatry treatment of schizophreniaWH Freeman San Francisco

9 Prinz R and Riddle D (1986) Associations betweennutrition and behaviour in 5-year-old children Nutri-tion Reviews 43 (Suppl) 151plusmn8

10 Christensen L (1988) Psychological distress and dieteffects of sucrose and caffeine Journal of AppliedNutrition 40 44plusmn50

11 Fullerton DT and Getto CJ (1985) Sugar opioids andbinge eating Brain Research Bulletin 14 273plusmn80

12 Colgan M and Colgan L (1984) Do nutrient supple-ments and dietary changes affect learning and emo-tional reactions of children with learning difregcultiesA controlled series of 16 cases Nutrition and Health3 69plusmn77

13 Goldman J Lerman RH Controis JH et al (1986)Behavioural effects of sucrose on preschool childrenJournal of Abnormal Child Psychology 14 565plusmn77

14 Lester M Thatcher RW and Monroe-Lord L (1982)Reregned carbohydrate intake hair cadmium levelsand cognitive functioning in children Nutrition andBehaviour 1 3plusmn13

15 Schoenthaler S Doraz WE and Wakeregeld JA (1986)The impact of low food additive and sucrose diet onacademic performance in 803 New York City publicschools International Journal for Biosocial Research8 185plusmn95

16 Dubini A Bosc M and Polin V (1997) Do noradrenalineand serotonin differentially affect social motivationand behaviour European Neuropsychopharmacology 7(Suppl 1) S49plusmn55

17 Smith KA Fairburn CG and Cowen PJ (1997) Relapseof depression after rapid depletion of tryptophanLancet 349 915plusmn19

18 Eccleston D (1993) L-tryptophan and depressive ill-ness Psychiatric Bulletin 17 223plusmn4

19 von Sano I (1972) L-5-hydroxytryptophan (L-5-HTP)therapie Folia Psychiatrica et Neurologica Japonica 267plusmn17

20 Nakajima T Kudo Y and Kaneko Z (1978) Clinicalevaluation of 5-hydroxytryptophan as an antidepres-sant Folia Psychiatrica et Neurologica 32 223plusmn30

21 Woggon A and Schoef J (1977) The treatment ofdepression with L-5-hydroxytryptophan versus imi-pramine Archiv fuEgraver Psychiatrie und Nervenkrankheiten224 175plusmn86

Depression the nutrition connection 15

would be to enhance the synthesis of serotonin byproviding optimal amounts of precursor nutrientsBut does it work

Serotonin is made from the amino acid trypto-phan a constituent of protein Dr Philip Cowen andcolleagues from the University of Oxford UK psy-chiatry department wondered what would happen ifyou deprived people of tryptophan They gave 15 vol-unteers who had a history of depression but werecurrently not depressed a nutritionally balanced drinkthat excluded tryptophan Within seven hours 10out of 15 noticed a worsening of their mood andstarted to show signs of depression On being given thesame drink but this time with tryptophan added theirmood improved17 Supplementing the amino acidtryptophan is already proven to improve mood Don-ald Ecclestone professor of medicine at the RoyalVictoria Inregrmary Newcastle UK reviewed the avail-able studies and concluded that supplementing tryp-tophan is an effective antidepressant equivalent totricyclic antidepressants18

While supplementing tryptophan itself has provena somewhat effective antidepressant even more effec-tive is a derivative of tryptophan that is one step closerto serotonin This is called 5-hydroxytryptophan or5-HTP for short The regrst study proving the mood-boosting power of 5-HTP was done in the 1970s inJapan under the direction of Professor Isamu Sano ofthe Osaka University Medical School19 He gave 107patients 50 to 300 mg of 5-HTP per day and withintwo weeks more than half experienced improve-ments in their symptoms By the end of the fourthweek of the study nearly three-quarters of thepatients reported either complete relief or signiregcantimprovement with no side effects This study wasrepeated by Nakajima et al who also found that 69of patients improved their mood20 A trial in Germanyfound 5-HTP to be as effective as the tricyclic anti-depressant imipramine with a fraction of the sideeffects21 One double-blind trial headed by Dr Poldin-ger at the Basel University of Psychiatry Switzerlandgave 34 depressed volunteers either the SSRI anti-depressant macruvoxamine or 300 mg of 5-HTP Eachpatient was assessed for their degree of depressionusing the widely accepted Hamilton Rating Scale plustheir own subjective self-assessment At the end of thesix weeks both groups of patients had had a signiregcantimprovement in their depression However thosetaking 5-HTP had a slightly greater improvement ineach of the four criteria assessed plusmn depression anxietyinsomnia and physical symptoms as well as thepatientrsquos self-assessment22 Given that 5-HTP is lessexpensive and has signiregcantly fewer side effects it issurprising thatdoctorsand psychiatrists virtually neverprescribe it192023plusmn25

The recommended dosage of this amino acid avail-able in any health food shop is 100 mg of 5-HTP two

or three times a day for depression Some supple-ments also provide various vitamins and mineralssuch as B12 and folic acid which may be even moreeffective because these nutrients help to turn 5-HTPinto serotonin

Depression in women

Women are three times as prone to low moods asmen Many theories as to why this is have beenproposed some psychological some social but thetruth is that women and men are biochemically verydifferent The research of Mirko Diksic and colleaguesat McGill University in Montreal Canada demon-strates this They developed a technique usingpositron emission tomography (PET) neuro-imagingto measure the rate at which we make serotonin in thebrain26 What they found was that menrsquos averagesynthesis rate of serotonin was 52 higher than thatof women This and other research has clearly shownthat women are more prone to low serotonin Theyalso react differently In women low serotonin isassociated with depression and anxiety while in menlow serotonin is related to aggression and alcoholismOne possibility is our social conditioning men `actoutrsquo their moods while women are more conditionedto `act inrsquo their moods

What has been learnt about serotonin in the lastfew years is that there are a number of potentialreasons for deregciency in addition to a lack of orincreased need for tryptophan

not enough oestrogen (in women)

not enough testosterone (in men)

not enough light

not enough exercise

too much stress especially in women

not enough co-factor vitamins and minerals

If a person is suffering from low mood feels tense andirritable is tired all the time tends to comfort eat hassleeping problems and a reduced interest in sex andsome of the above apply the chances are they areshort on serotonin

Low oestrogen means low serotonin and lowmoods1727 This is because oestrogen blocks thebreakdown of serotonin This may explain whywomen are more prone to depression premenstruallyand in the menopause and thereafter Low testoster-one has a similar effect in men

Light also stimulates both oestrogen and serotoninand most of us do not get enough of it The differencein light exposure outside and inside is massive Mostof us spend 23 out of 24 hours a day indoors exposedto an average of 100 units (called lux) of light That iscompared to an outdoor level of 20 000 lux on a sunnyday and 7000 lux on an overcast day Now more than

Depression the nutrition connection 11

ever before many people rarely expose themselves todirect sunlight and certainly not enough to maximiseserotonin production Of course light deregciency isworse in the winter

Stress also rapidly reduces serotonin levels whilephysical exercise improves stress response and there-fore reduces stress-induced depletion of serotonin

Is apathy a catecholaminederegciency

Another group of neurotransmitters associated withdepression and lack of motivation are the catechola-mines plusmn dopamine noradrenaline and adrenaline As

shown in Figure 2 both adrenaline and noradrenalineare synthesised from dopamine which is made fromthe amino acid tyrosine which is itself made from theamino acid phenylalanine It is logical to assumethat if the drugs that block the breakdown of theseneurotransmitters do elevate mood then augmentingthe amino acid phenylalanine or tyrosine might worktoo And they do

In a double-blind study by Helmut Beckmann andcolleagues at the University of Wurzburg Germany150 to 200 mg of the amino acid phenylalanine orthe antidepressant drug imipramine were adminis-tered to 40 depressed patients for one month Bothgroups had the same degree of positive results ETH lessdepression anxiety and sleep disturbance28 A groupof researchers at the Rush Medical Center ChicagoUSA screened depressed patients by testing phenyl-ethylamine in the blood low levels mean you needmore phenylalanine They then gave 40 depressedpatients supplements of phenylalanine and 31 ofthem improved29

Tyrosine has been shown to work well in thosewith dopamine-dependentdepression In a pilot studyadministering 3200 mg tyrosine a day to 12 patientsat the Hopital du Vinatier France a signiregcant im-provement in mood and sleep was observed on thevery regrst day30

The military has long known that tyrosine improvesmental and physical performance under stress Recentresearch from the Netherlands demonstrates howtyrosine gives you the edge in conditions of stressTwenty-one cadets were put through a demandingone-week military combat training course Ten cadetswere given a drink containing 2 g of tyrosine a daywhile the remaining 11 were given an identical drinkwithout the tyrosine Those on tyrosine consistentlyperformed better both in memorising the task athand and in tracking the tasks they had performed31

In our clinical experience the best results areachieved by supplementing all of these amino acids plusmn5-HTP phenylalanine and tyrosine plusmn together withthe B vitamins that help turn them into neurotrans-mitters which are B6 B12 and folic acid

B vitamins methylation anddepression

B vitamins act as co-factors in key enzymes thatcontrol 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(carboxylase) as is adrenaline from noradrenalineThis enzyme process is highly dependent on folate aswell as vitamins B12 and B6 Folate deregciency is

P Holford12

DIETARY PROTEIN

B and Zinc

L-PHENYLALANINE

Folic Acid Magnesium Manganese Iron Copper Zinc C

L-TYROSINE

Folic Acid Magnesium Manganese Iron Copper Zinc C

L-DOPA

B and Zinc

DOPAMINE

Vitamin C

NORADRENALINE

B Folic Acid Niacin

ADRENALINE

Dopamine pathway

6

6

12

Figure 2 The catecholamine pathway

extremely common among depressed patients In astudy of 213 depressed patients at the Depression andClinical Research Program at Boston MassachusettsGeneral Hospital USA people with lower folate levelshad more `melancholicrsquo depression and were lesslikely to improve when given antidepressant drugs32

Very depressed people and also those diagnosed withschizophrenia are often deregcient in folate A surveyof such patients at Kings College Hospitalrsquos psychiatrydepartment in London UK found that one in threehad borderline or deregnite folate deregciency Thesepatients then took part in a trial where they tookfolate for six months in addition to their standarddrug treatment Those given folate had signiregcantlyimproved recovery and the longer they took thefolate the better they felt33

One current theory is that genetic differencesworsening a personrsquos ability to methylate may bothincrease the tendency to depression (and schizophre-nia) and their need for folate which may be better

remacrected by measuring homocysteine levels than bymeasuring blood levels of folate This is becausehomocysteine is methylated `en routersquo to s-adenosylmethionine (SAMe) by a folate-dependent enzymemethyl-tetrahydrofolatereductase or MTHFR forshort (see Figure 3) In one study more than half(52) of patients with severe depression were foundto have elevated homocysteine and low levels offolate34

Homocysteine levels are particularly high inpatients with schizophrenia even in the absence ofdietary deregciency in folate or vitamin B1235 Whencomparing 193 mixed-sex patients with schizophre-nia and 762 non-schizophrenic subjects US research-ers found that average homocysteine levels were avery high 163 mmoll for schizophrenics compared to106 mmoll in normal subjects36 However the dif-ference between groups was almost entirely attribut-able to the homocysteine levels of young malepatients with schizophrenia

Depression the nutrition connection 13

SAMe

MTHFR

Methyltransferase

HOMOCYSTEINE

CystathionineBeta-synthase

CystathionineLyase

GLUTATHIONE

METHIONINEfrom diet

needs TMG and B

needs Folate B B and Zinc

needs B B and Zinc

needs B B and Zinc

12

12 2

26

26

Figure 3 How homocysteine is detoxireged

Genes homocysteine andmental illness

Not everyone is born equal as far as methylation isconcerned Around one in ten inherit a defective genethat means that the key methylating enzyme MTHFRdoes not work so well increasing the need for folateas well as vitamins B12 B6 and zinc Vitamin B6 andzinc are involved because those with an MTHFRderegciency accumulate homocysteine which can alsobe detoxireged by conversion into cystathionine via anenzyme 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 vitaminB6 has proven three times more effective at loweringhomocysteine than folate alone37 The combinedefregcacy of these nutrients for depression warrantsinvestigation

While folate deregciency alone can induce depres-sion the combination of deregciency and a fault in theMTHFR gene is more likely to tip someone over intomental illness To compensate for this much higherlevels of folate than normal are needed According toresearchers from Columbia Universityrsquos Departmentof Psychiatry in New York USA this also applies tothose with schizophrenia They found increased levelsof homocysteine despite no apparent lack of dietaryfolate38 The same is true for vitamin B12 Manypeople with mental illness need more than a normalamount of vitamin B12 despite no obvious signs ofderegciency such as anaemia39

A far better indicator of personal or individualisedincreased need for these B vitamins is a personrsquoshomocysteine level

SAMe and TMG the mastertuners

In Figures 2 and 3 you might have noticed these twostrange-sounding nutrients Both are kinds of aminoacids TMG stands for tri-methyl-glycine and SAMestands for s-adenosyl methionine Unlike the B vita-mins discussed above which act as `methyl moversrsquoSAMe and TMG are methyl group donors Both canlower homocysteinelevels by donating methylgroupsConversely sufregcient folate by enhancingthe MTHFRenzyme can increase production of SAMe40 It is a two-way process

SAMe is one of the most comprehensively studiednatural antidepressants Over 100 placebo-controlleddouble-blind studies have shown that SAMe is equal

to or superior to antidepressants works faster mostoften within a few days (most pharmaceutical anti-depressants may take three to six weeks to take effect)and with few side effects41plusmn43 An intake of 200 to600 mg a day is needed but the trouble is that it isboth very expensive and very unstable A lot of SAMesold in health food shops is pretty ineffective Analternative that is much more stable and less costly istri-methyl-glycine (TMG) In the body it turns intoSAMe but the supplement needed is three times asmuch plusmn 600 to 2000 mg a day on an empty stomachor with fruit

Mood-boosting fats

Omega-3 fats have a direct inmacruence on serotoninstatus probably by enhancing production and recep-tion According to Dr JR Hibbeln who discovered thatregsh eaters are less prone to depression `Itrsquos like build-ing more serotonin factories instead of just increasingthe efregciency of the serotonin you haversquo44 Dr BasantPuri from Londonrsquos Hammersmith Hospital UK re-ported the case of a 21-year-old student who had beenon a variety of antidepressants to no avail He had avery low sense of self-esteem sleeping problems littleappetite found it hard to socialise and often thoughtof killing himself After one month of supplementingethyle-EPA (eicosapentaenoic acid) a concentratedform of omega-3 fats he was no longer having suici-dal thoughts and after nine months no longer had anydepression45

Dr Andrew Stoll and colleagues at Harvard MedicalSchool USA ran a double-blind placebo-controlledtrial of omega-3 fats placing 14 adult manic depres-sives on the regsh oils EPA and DHA (docosahexaenoicacid) and compared them with 14 taking an olive oilplacebo Both took the supplement alongside theirnormal medication Those taking the omega-3 fatshad a substantially longer period in remission thanthe placebo group The regsh oil group also performedbetter than the placebo group for nearly every othersymptom measured46 The Institute of Psychiatry inLondon is currently running a large double-blind trialwith regsh oils to further evaluate the effects of omega-3fats on bipolar depression

Omega-3 fats are effective for severe depression tooA recent trial published in the American Journal ofPsychiatry tested the effects of giving 20 people suffer-ing from depression who were already on antidepres-sants but still depressed a highly concentrated form ofomega-3 fat ethyl-EPA versus a placebo By the thirdweek the depressed patients were showing majorimprovement in their mood while those on placebowere not47

P Holford14

Good mood foods andsupplements

There is good logic and substantial evidence thatensuring optimum nutrition in depressed patients canbe highly effective In addition to simple lifestylechanges such as encouraging exercise and outdooractivity to maximise light reducing stress and recom-mending counselling the following diet and supple-ment advice may help

Diet

Reduce sugar and stimulants (caffeinated drinksand smoking)

Increase fruit and vegetables (regve servings a day)

Eat oily regsh (mackerel tuna salmon herring) atleast twice a week

Ensure sufregcient protein from regsh meat eggsbeans and lentils

Supplements

B complex including vitamin B6 10 mg folate400 mg and vitamin B12 10 mg

Additional folate 400 to 2000 mg a day

5-HTP 200plusmn300 mg a day

Omega-3-rich regsh oil two capsules a day giving atleast 400 mg of EPA

ACKNOWLEDGEMENTS

This article has been adapted from Patrick Holfordrsquosnew book Optimum Nutrition for the Mind (Piatkuspound1699) For further information call Dagger44 (0)20 88712949 or visit wwwmentalhealthprojectcom

REFERENCES

1 Benton D Kumari N and Brain PF (1982) Mild hypo-glycaemia and questionnaire measures of aggressionBiological Psychology 14 129plusmn35

2 Roy A Virkkunen M and Linnoila M (1988) Mono-amines glucose metabolism aggression toward selfand others International Journal of Neuroscience 41261plusmn4

3 Schauss AG (1980) Diet Crime and Delinquency ParkerHouse Berkeley

4 Virkkunen M (1984) Reactive hypoglycaemic ten-dency among arsonists Acta Psychiatrica Scandinavica69 445plusmn52

5 Virkkunen M and Narvanen S (1987) Tryptophanand serotonin levels during the glucose tolerance testamong habitually violent and impulsive offendersNeuropsychobiology 17 19plusmn23

6 Yaryura-Tobias J and Neziroglu F (1975) Violent be-haviour brain dysrhythmia and glucose dysfunctionA new syndrome Journal of Orthopaedic Psychology4 182plusmn5

7 Bruce M and Lader M (1989) Caffeine abstention andthe management of anxiety disorders PsychologicalMedicine 19 211plusmn14

8 Wendel W and Beebe W (1973) Glycolytic activity inschizophrenia In Hawkins D and Pauling L (eds)Orthomolecular Psychiatry treatment of schizophreniaWH Freeman San Francisco

9 Prinz R and Riddle D (1986) Associations betweennutrition and behaviour in 5-year-old children Nutri-tion Reviews 43 (Suppl) 151plusmn8

10 Christensen L (1988) Psychological distress and dieteffects of sucrose and caffeine Journal of AppliedNutrition 40 44plusmn50

11 Fullerton DT and Getto CJ (1985) Sugar opioids andbinge eating Brain Research Bulletin 14 273plusmn80

12 Colgan M and Colgan L (1984) Do nutrient supple-ments and dietary changes affect learning and emo-tional reactions of children with learning difregcultiesA controlled series of 16 cases Nutrition and Health3 69plusmn77

13 Goldman J Lerman RH Controis JH et al (1986)Behavioural effects of sucrose on preschool childrenJournal of Abnormal Child Psychology 14 565plusmn77

14 Lester M Thatcher RW and Monroe-Lord L (1982)Reregned carbohydrate intake hair cadmium levelsand cognitive functioning in children Nutrition andBehaviour 1 3plusmn13

15 Schoenthaler S Doraz WE and Wakeregeld JA (1986)The impact of low food additive and sucrose diet onacademic performance in 803 New York City publicschools International Journal for Biosocial Research8 185plusmn95

16 Dubini A Bosc M and Polin V (1997) Do noradrenalineand serotonin differentially affect social motivationand behaviour European Neuropsychopharmacology 7(Suppl 1) S49plusmn55

17 Smith KA Fairburn CG and Cowen PJ (1997) Relapseof depression after rapid depletion of tryptophanLancet 349 915plusmn19

18 Eccleston D (1993) L-tryptophan and depressive ill-ness Psychiatric Bulletin 17 223plusmn4

19 von Sano I (1972) L-5-hydroxytryptophan (L-5-HTP)therapie Folia Psychiatrica et Neurologica Japonica 267plusmn17

20 Nakajima T Kudo Y and Kaneko Z (1978) Clinicalevaluation of 5-hydroxytryptophan as an antidepres-sant Folia Psychiatrica et Neurologica 32 223plusmn30

21 Woggon A and Schoef J (1977) The treatment ofdepression with L-5-hydroxytryptophan versus imi-pramine Archiv fuEgraver Psychiatrie und Nervenkrankheiten224 175plusmn86

Depression the nutrition connection 15

ever before many people rarely expose themselves todirect sunlight and certainly not enough to maximiseserotonin production Of course light deregciency isworse in the winter

Stress also rapidly reduces serotonin levels whilephysical exercise improves stress response and there-fore reduces stress-induced depletion of serotonin

Is apathy a catecholaminederegciency

Another group of neurotransmitters associated withdepression and lack of motivation are the catechola-mines plusmn dopamine noradrenaline and adrenaline As

shown in Figure 2 both adrenaline and noradrenalineare synthesised from dopamine which is made fromthe amino acid tyrosine which is itself made from theamino acid phenylalanine It is logical to assumethat if the drugs that block the breakdown of theseneurotransmitters do elevate mood then augmentingthe amino acid phenylalanine or tyrosine might worktoo And they do

In a double-blind study by Helmut Beckmann andcolleagues at the University of Wurzburg Germany150 to 200 mg of the amino acid phenylalanine orthe antidepressant drug imipramine were adminis-tered to 40 depressed patients for one month Bothgroups had the same degree of positive results ETH lessdepression anxiety and sleep disturbance28 A groupof researchers at the Rush Medical Center ChicagoUSA screened depressed patients by testing phenyl-ethylamine in the blood low levels mean you needmore phenylalanine They then gave 40 depressedpatients supplements of phenylalanine and 31 ofthem improved29

Tyrosine has been shown to work well in thosewith dopamine-dependentdepression In a pilot studyadministering 3200 mg tyrosine a day to 12 patientsat the Hopital du Vinatier France a signiregcant im-provement in mood and sleep was observed on thevery regrst day30

The military has long known that tyrosine improvesmental and physical performance under stress Recentresearch from the Netherlands demonstrates howtyrosine gives you the edge in conditions of stressTwenty-one cadets were put through a demandingone-week military combat training course Ten cadetswere given a drink containing 2 g of tyrosine a daywhile the remaining 11 were given an identical drinkwithout the tyrosine Those on tyrosine consistentlyperformed better both in memorising the task athand and in tracking the tasks they had performed31

In our clinical experience the best results areachieved by supplementing all of these amino acids plusmn5-HTP phenylalanine and tyrosine plusmn together withthe B vitamins that help turn them into neurotrans-mitters which are B6 B12 and folic acid

B vitamins methylation anddepression

B vitamins act as co-factors in key enzymes thatcontrol 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(carboxylase) as is adrenaline from noradrenalineThis enzyme process is highly dependent on folate aswell as vitamins B12 and B6 Folate deregciency is

P Holford12

DIETARY PROTEIN

B and Zinc

L-PHENYLALANINE

Folic Acid Magnesium Manganese Iron Copper Zinc C

L-TYROSINE

Folic Acid Magnesium Manganese Iron Copper Zinc C

L-DOPA

B and Zinc

DOPAMINE

Vitamin C

NORADRENALINE

B Folic Acid Niacin

ADRENALINE

Dopamine pathway

6

6

12

Figure 2 The catecholamine pathway

extremely common among depressed patients In astudy of 213 depressed patients at the Depression andClinical Research Program at Boston MassachusettsGeneral Hospital USA people with lower folate levelshad more `melancholicrsquo depression and were lesslikely to improve when given antidepressant drugs32

Very depressed people and also those diagnosed withschizophrenia are often deregcient in folate A surveyof such patients at Kings College Hospitalrsquos psychiatrydepartment in London UK found that one in threehad borderline or deregnite folate deregciency Thesepatients then took part in a trial where they tookfolate for six months in addition to their standarddrug treatment Those given folate had signiregcantlyimproved recovery and the longer they took thefolate the better they felt33

One current theory is that genetic differencesworsening a personrsquos ability to methylate may bothincrease the tendency to depression (and schizophre-nia) and their need for folate which may be better

remacrected by measuring homocysteine levels than bymeasuring blood levels of folate This is becausehomocysteine is methylated `en routersquo to s-adenosylmethionine (SAMe) by a folate-dependent enzymemethyl-tetrahydrofolatereductase or MTHFR forshort (see Figure 3) In one study more than half(52) of patients with severe depression were foundto have elevated homocysteine and low levels offolate34

Homocysteine levels are particularly high inpatients with schizophrenia even in the absence ofdietary deregciency in folate or vitamin B1235 Whencomparing 193 mixed-sex patients with schizophre-nia and 762 non-schizophrenic subjects US research-ers found that average homocysteine levels were avery high 163 mmoll for schizophrenics compared to106 mmoll in normal subjects36 However the dif-ference between groups was almost entirely attribut-able to the homocysteine levels of young malepatients with schizophrenia

Depression the nutrition connection 13

SAMe

MTHFR

Methyltransferase

HOMOCYSTEINE

CystathionineBeta-synthase

CystathionineLyase

GLUTATHIONE

METHIONINEfrom diet

needs TMG and B

needs Folate B B and Zinc

needs B B and Zinc

needs B B and Zinc

12

12 2

26

26

Figure 3 How homocysteine is detoxireged

Genes homocysteine andmental illness

Not everyone is born equal as far as methylation isconcerned Around one in ten inherit a defective genethat means that the key methylating enzyme MTHFRdoes not work so well increasing the need for folateas well as vitamins B12 B6 and zinc Vitamin B6 andzinc are involved because those with an MTHFRderegciency accumulate homocysteine which can alsobe detoxireged by conversion into cystathionine via anenzyme 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 vitaminB6 has proven three times more effective at loweringhomocysteine than folate alone37 The combinedefregcacy of these nutrients for depression warrantsinvestigation

While folate deregciency alone can induce depres-sion the combination of deregciency and a fault in theMTHFR gene is more likely to tip someone over intomental illness To compensate for this much higherlevels of folate than normal are needed According toresearchers from Columbia Universityrsquos Departmentof Psychiatry in New York USA this also applies tothose with schizophrenia They found increased levelsof homocysteine despite no apparent lack of dietaryfolate38 The same is true for vitamin B12 Manypeople with mental illness need more than a normalamount of vitamin B12 despite no obvious signs ofderegciency such as anaemia39

A far better indicator of personal or individualisedincreased need for these B vitamins is a personrsquoshomocysteine level

SAMe and TMG the mastertuners

In Figures 2 and 3 you might have noticed these twostrange-sounding nutrients Both are kinds of aminoacids TMG stands for tri-methyl-glycine and SAMestands for s-adenosyl methionine Unlike the B vita-mins discussed above which act as `methyl moversrsquoSAMe and TMG are methyl group donors Both canlower homocysteinelevels by donating methylgroupsConversely sufregcient folate by enhancingthe MTHFRenzyme can increase production of SAMe40 It is a two-way process

SAMe is one of the most comprehensively studiednatural antidepressants Over 100 placebo-controlleddouble-blind studies have shown that SAMe is equal

to or superior to antidepressants works faster mostoften within a few days (most pharmaceutical anti-depressants may take three to six weeks to take effect)and with few side effects41plusmn43 An intake of 200 to600 mg a day is needed but the trouble is that it isboth very expensive and very unstable A lot of SAMesold in health food shops is pretty ineffective Analternative that is much more stable and less costly istri-methyl-glycine (TMG) In the body it turns intoSAMe but the supplement needed is three times asmuch plusmn 600 to 2000 mg a day on an empty stomachor with fruit

Mood-boosting fats

Omega-3 fats have a direct inmacruence on serotoninstatus probably by enhancing production and recep-tion According to Dr JR Hibbeln who discovered thatregsh eaters are less prone to depression `Itrsquos like build-ing more serotonin factories instead of just increasingthe efregciency of the serotonin you haversquo44 Dr BasantPuri from Londonrsquos Hammersmith Hospital UK re-ported the case of a 21-year-old student who had beenon a variety of antidepressants to no avail He had avery low sense of self-esteem sleeping problems littleappetite found it hard to socialise and often thoughtof killing himself After one month of supplementingethyle-EPA (eicosapentaenoic acid) a concentratedform of omega-3 fats he was no longer having suici-dal thoughts and after nine months no longer had anydepression45

Dr Andrew Stoll and colleagues at Harvard MedicalSchool USA ran a double-blind placebo-controlledtrial of omega-3 fats placing 14 adult manic depres-sives on the regsh oils EPA and DHA (docosahexaenoicacid) and compared them with 14 taking an olive oilplacebo Both took the supplement alongside theirnormal medication Those taking the omega-3 fatshad a substantially longer period in remission thanthe placebo group The regsh oil group also performedbetter than the placebo group for nearly every othersymptom measured46 The Institute of Psychiatry inLondon is currently running a large double-blind trialwith regsh oils to further evaluate the effects of omega-3fats on bipolar depression

Omega-3 fats are effective for severe depression tooA recent trial published in the American Journal ofPsychiatry tested the effects of giving 20 people suffer-ing from depression who were already on antidepres-sants but still depressed a highly concentrated form ofomega-3 fat ethyl-EPA versus a placebo By the thirdweek the depressed patients were showing majorimprovement in their mood while those on placebowere not47

P Holford14

Good mood foods andsupplements

There is good logic and substantial evidence thatensuring optimum nutrition in depressed patients canbe highly effective In addition to simple lifestylechanges such as encouraging exercise and outdooractivity to maximise light reducing stress and recom-mending counselling the following diet and supple-ment advice may help

Diet

Reduce sugar and stimulants (caffeinated drinksand smoking)

Increase fruit and vegetables (regve servings a day)

Eat oily regsh (mackerel tuna salmon herring) atleast twice a week

Ensure sufregcient protein from regsh meat eggsbeans and lentils

Supplements

B complex including vitamin B6 10 mg folate400 mg and vitamin B12 10 mg

Additional folate 400 to 2000 mg a day

5-HTP 200plusmn300 mg a day

Omega-3-rich regsh oil two capsules a day giving atleast 400 mg of EPA

ACKNOWLEDGEMENTS

This article has been adapted from Patrick Holfordrsquosnew book Optimum Nutrition for the Mind (Piatkuspound1699) For further information call Dagger44 (0)20 88712949 or visit wwwmentalhealthprojectcom

REFERENCES

1 Benton D Kumari N and Brain PF (1982) Mild hypo-glycaemia and questionnaire measures of aggressionBiological Psychology 14 129plusmn35

2 Roy A Virkkunen M and Linnoila M (1988) Mono-amines glucose metabolism aggression toward selfand others International Journal of Neuroscience 41261plusmn4

3 Schauss AG (1980) Diet Crime and Delinquency ParkerHouse Berkeley

4 Virkkunen M (1984) Reactive hypoglycaemic ten-dency among arsonists Acta Psychiatrica Scandinavica69 445plusmn52

5 Virkkunen M and Narvanen S (1987) Tryptophanand serotonin levels during the glucose tolerance testamong habitually violent and impulsive offendersNeuropsychobiology 17 19plusmn23

6 Yaryura-Tobias J and Neziroglu F (1975) Violent be-haviour brain dysrhythmia and glucose dysfunctionA new syndrome Journal of Orthopaedic Psychology4 182plusmn5

7 Bruce M and Lader M (1989) Caffeine abstention andthe management of anxiety disorders PsychologicalMedicine 19 211plusmn14

8 Wendel W and Beebe W (1973) Glycolytic activity inschizophrenia In Hawkins D and Pauling L (eds)Orthomolecular Psychiatry treatment of schizophreniaWH Freeman San Francisco

9 Prinz R and Riddle D (1986) Associations betweennutrition and behaviour in 5-year-old children Nutri-tion Reviews 43 (Suppl) 151plusmn8

10 Christensen L (1988) Psychological distress and dieteffects of sucrose and caffeine Journal of AppliedNutrition 40 44plusmn50

11 Fullerton DT and Getto CJ (1985) Sugar opioids andbinge eating Brain Research Bulletin 14 273plusmn80

12 Colgan M and Colgan L (1984) Do nutrient supple-ments and dietary changes affect learning and emo-tional reactions of children with learning difregcultiesA controlled series of 16 cases Nutrition and Health3 69plusmn77

13 Goldman J Lerman RH Controis JH et al (1986)Behavioural effects of sucrose on preschool childrenJournal of Abnormal Child Psychology 14 565plusmn77

14 Lester M Thatcher RW and Monroe-Lord L (1982)Reregned carbohydrate intake hair cadmium levelsand cognitive functioning in children Nutrition andBehaviour 1 3plusmn13

15 Schoenthaler S Doraz WE and Wakeregeld JA (1986)The impact of low food additive and sucrose diet onacademic performance in 803 New York City publicschools International Journal for Biosocial Research8 185plusmn95

16 Dubini A Bosc M and Polin V (1997) Do noradrenalineand serotonin differentially affect social motivationand behaviour European Neuropsychopharmacology 7(Suppl 1) S49plusmn55

17 Smith KA Fairburn CG and Cowen PJ (1997) Relapseof depression after rapid depletion of tryptophanLancet 349 915plusmn19

18 Eccleston D (1993) L-tryptophan and depressive ill-ness Psychiatric Bulletin 17 223plusmn4

19 von Sano I (1972) L-5-hydroxytryptophan (L-5-HTP)therapie Folia Psychiatrica et Neurologica Japonica 267plusmn17

20 Nakajima T Kudo Y and Kaneko Z (1978) Clinicalevaluation of 5-hydroxytryptophan as an antidepres-sant Folia Psychiatrica et Neurologica 32 223plusmn30

21 Woggon A and Schoef J (1977) The treatment ofdepression with L-5-hydroxytryptophan versus imi-pramine Archiv fuEgraver Psychiatrie und Nervenkrankheiten224 175plusmn86

Depression the nutrition connection 15

extremely common among depressed patients In astudy of 213 depressed patients at the Depression andClinical Research Program at Boston MassachusettsGeneral Hospital USA people with lower folate levelshad more `melancholicrsquo depression and were lesslikely to improve when given antidepressant drugs32

Very depressed people and also those diagnosed withschizophrenia are often deregcient in folate A surveyof such patients at Kings College Hospitalrsquos psychiatrydepartment in London UK found that one in threehad borderline or deregnite folate deregciency Thesepatients then took part in a trial where they tookfolate for six months in addition to their standarddrug treatment Those given folate had signiregcantlyimproved recovery and the longer they took thefolate the better they felt33

One current theory is that genetic differencesworsening a personrsquos ability to methylate may bothincrease the tendency to depression (and schizophre-nia) and their need for folate which may be better

remacrected by measuring homocysteine levels than bymeasuring blood levels of folate This is becausehomocysteine is methylated `en routersquo to s-adenosylmethionine (SAMe) by a folate-dependent enzymemethyl-tetrahydrofolatereductase or MTHFR forshort (see Figure 3) In one study more than half(52) of patients with severe depression were foundto have elevated homocysteine and low levels offolate34

Homocysteine levels are particularly high inpatients with schizophrenia even in the absence ofdietary deregciency in folate or vitamin B1235 Whencomparing 193 mixed-sex patients with schizophre-nia and 762 non-schizophrenic subjects US research-ers found that average homocysteine levels were avery high 163 mmoll for schizophrenics compared to106 mmoll in normal subjects36 However the dif-ference between groups was almost entirely attribut-able to the homocysteine levels of young malepatients with schizophrenia

Depression the nutrition connection 13

SAMe

MTHFR

Methyltransferase

HOMOCYSTEINE

CystathionineBeta-synthase

CystathionineLyase

GLUTATHIONE

METHIONINEfrom diet

needs TMG and B

needs Folate B B and Zinc

needs B B and Zinc

needs B B and Zinc

12

12 2

26

26

Figure 3 How homocysteine is detoxireged

Genes homocysteine andmental illness

Not everyone is born equal as far as methylation isconcerned Around one in ten inherit a defective genethat means that the key methylating enzyme MTHFRdoes not work so well increasing the need for folateas well as vitamins B12 B6 and zinc Vitamin B6 andzinc are involved because those with an MTHFRderegciency accumulate homocysteine which can alsobe detoxireged by conversion into cystathionine via anenzyme 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 vitaminB6 has proven three times more effective at loweringhomocysteine than folate alone37 The combinedefregcacy of these nutrients for depression warrantsinvestigation

While folate deregciency alone can induce depres-sion the combination of deregciency and a fault in theMTHFR gene is more likely to tip someone over intomental illness To compensate for this much higherlevels of folate than normal are needed According toresearchers from Columbia Universityrsquos Departmentof Psychiatry in New York USA this also applies tothose with schizophrenia They found increased levelsof homocysteine despite no apparent lack of dietaryfolate38 The same is true for vitamin B12 Manypeople with mental illness need more than a normalamount of vitamin B12 despite no obvious signs ofderegciency such as anaemia39

A far better indicator of personal or individualisedincreased need for these B vitamins is a personrsquoshomocysteine level

SAMe and TMG the mastertuners

In Figures 2 and 3 you might have noticed these twostrange-sounding nutrients Both are kinds of aminoacids TMG stands for tri-methyl-glycine and SAMestands for s-adenosyl methionine Unlike the B vita-mins discussed above which act as `methyl moversrsquoSAMe and TMG are methyl group donors Both canlower homocysteinelevels by donating methylgroupsConversely sufregcient folate by enhancingthe MTHFRenzyme can increase production of SAMe40 It is a two-way process

SAMe is one of the most comprehensively studiednatural antidepressants Over 100 placebo-controlleddouble-blind studies have shown that SAMe is equal

to or superior to antidepressants works faster mostoften within a few days (most pharmaceutical anti-depressants may take three to six weeks to take effect)and with few side effects41plusmn43 An intake of 200 to600 mg a day is needed but the trouble is that it isboth very expensive and very unstable A lot of SAMesold in health food shops is pretty ineffective Analternative that is much more stable and less costly istri-methyl-glycine (TMG) In the body it turns intoSAMe but the supplement needed is three times asmuch plusmn 600 to 2000 mg a day on an empty stomachor with fruit

Mood-boosting fats

Omega-3 fats have a direct inmacruence on serotoninstatus probably by enhancing production and recep-tion According to Dr JR Hibbeln who discovered thatregsh eaters are less prone to depression `Itrsquos like build-ing more serotonin factories instead of just increasingthe efregciency of the serotonin you haversquo44 Dr BasantPuri from Londonrsquos Hammersmith Hospital UK re-ported the case of a 21-year-old student who had beenon a variety of antidepressants to no avail He had avery low sense of self-esteem sleeping problems littleappetite found it hard to socialise and often thoughtof killing himself After one month of supplementingethyle-EPA (eicosapentaenoic acid) a concentratedform of omega-3 fats he was no longer having suici-dal thoughts and after nine months no longer had anydepression45

Dr Andrew Stoll and colleagues at Harvard MedicalSchool USA ran a double-blind placebo-controlledtrial of omega-3 fats placing 14 adult manic depres-sives on the regsh oils EPA and DHA (docosahexaenoicacid) and compared them with 14 taking an olive oilplacebo Both took the supplement alongside theirnormal medication Those taking the omega-3 fatshad a substantially longer period in remission thanthe placebo group The regsh oil group also performedbetter than the placebo group for nearly every othersymptom measured46 The Institute of Psychiatry inLondon is currently running a large double-blind trialwith regsh oils to further evaluate the effects of omega-3fats on bipolar depression

Omega-3 fats are effective for severe depression tooA recent trial published in the American Journal ofPsychiatry tested the effects of giving 20 people suffer-ing from depression who were already on antidepres-sants but still depressed a highly concentrated form ofomega-3 fat ethyl-EPA versus a placebo By the thirdweek the depressed patients were showing majorimprovement in their mood while those on placebowere not47

P Holford14

Good mood foods andsupplements

There is good logic and substantial evidence thatensuring optimum nutrition in depressed patients canbe highly effective In addition to simple lifestylechanges such as encouraging exercise and outdooractivity to maximise light reducing stress and recom-mending counselling the following diet and supple-ment advice may help

Diet

Reduce sugar and stimulants (caffeinated drinksand smoking)

Increase fruit and vegetables (regve servings a day)

Eat oily regsh (mackerel tuna salmon herring) atleast twice a week

Ensure sufregcient protein from regsh meat eggsbeans and lentils

Supplements

B complex including vitamin B6 10 mg folate400 mg and vitamin B12 10 mg

Additional folate 400 to 2000 mg a day

5-HTP 200plusmn300 mg a day

Omega-3-rich regsh oil two capsules a day giving atleast 400 mg of EPA

ACKNOWLEDGEMENTS

This article has been adapted from Patrick Holfordrsquosnew book Optimum Nutrition for the Mind (Piatkuspound1699) For further information call Dagger44 (0)20 88712949 or visit wwwmentalhealthprojectcom

REFERENCES

1 Benton D Kumari N and Brain PF (1982) Mild hypo-glycaemia and questionnaire measures of aggressionBiological Psychology 14 129plusmn35

2 Roy A Virkkunen M and Linnoila M (1988) Mono-amines glucose metabolism aggression toward selfand others International Journal of Neuroscience 41261plusmn4

3 Schauss AG (1980) Diet Crime and Delinquency ParkerHouse Berkeley

4 Virkkunen M (1984) Reactive hypoglycaemic ten-dency among arsonists Acta Psychiatrica Scandinavica69 445plusmn52

5 Virkkunen M and Narvanen S (1987) Tryptophanand serotonin levels during the glucose tolerance testamong habitually violent and impulsive offendersNeuropsychobiology 17 19plusmn23

6 Yaryura-Tobias J and Neziroglu F (1975) Violent be-haviour brain dysrhythmia and glucose dysfunctionA new syndrome Journal of Orthopaedic Psychology4 182plusmn5

7 Bruce M and Lader M (1989) Caffeine abstention andthe management of anxiety disorders PsychologicalMedicine 19 211plusmn14

8 Wendel W and Beebe W (1973) Glycolytic activity inschizophrenia In Hawkins D and Pauling L (eds)Orthomolecular Psychiatry treatment of schizophreniaWH Freeman San Francisco

9 Prinz R and Riddle D (1986) Associations betweennutrition and behaviour in 5-year-old children Nutri-tion Reviews 43 (Suppl) 151plusmn8

10 Christensen L (1988) Psychological distress and dieteffects of sucrose and caffeine Journal of AppliedNutrition 40 44plusmn50

11 Fullerton DT and Getto CJ (1985) Sugar opioids andbinge eating Brain Research Bulletin 14 273plusmn80

12 Colgan M and Colgan L (1984) Do nutrient supple-ments and dietary changes affect learning and emo-tional reactions of children with learning difregcultiesA controlled series of 16 cases Nutrition and Health3 69plusmn77

13 Goldman J Lerman RH Controis JH et al (1986)Behavioural effects of sucrose on preschool childrenJournal of Abnormal Child Psychology 14 565plusmn77

14 Lester M Thatcher RW and Monroe-Lord L (1982)Reregned carbohydrate intake hair cadmium levelsand cognitive functioning in children Nutrition andBehaviour 1 3plusmn13

15 Schoenthaler S Doraz WE and Wakeregeld JA (1986)The impact of low food additive and sucrose diet onacademic performance in 803 New York City publicschools International Journal for Biosocial Research8 185plusmn95

16 Dubini A Bosc M and Polin V (1997) Do noradrenalineand serotonin differentially affect social motivationand behaviour European Neuropsychopharmacology 7(Suppl 1) S49plusmn55

17 Smith KA Fairburn CG and Cowen PJ (1997) Relapseof depression after rapid depletion of tryptophanLancet 349 915plusmn19

18 Eccleston D (1993) L-tryptophan and depressive ill-ness Psychiatric Bulletin 17 223plusmn4

19 von Sano I (1972) L-5-hydroxytryptophan (L-5-HTP)therapie Folia Psychiatrica et Neurologica Japonica 267plusmn17

20 Nakajima T Kudo Y and Kaneko Z (1978) Clinicalevaluation of 5-hydroxytryptophan as an antidepres-sant Folia Psychiatrica et Neurologica 32 223plusmn30

21 Woggon A and Schoef J (1977) The treatment ofdepression with L-5-hydroxytryptophan versus imi-pramine Archiv fuEgraver Psychiatrie und Nervenkrankheiten224 175plusmn86

Depression the nutrition connection 15

Genes homocysteine andmental illness

Not everyone is born equal as far as methylation isconcerned Around one in ten inherit a defective genethat means that the key methylating enzyme MTHFRdoes not work so well increasing the need for folateas well as vitamins B12 B6 and zinc Vitamin B6 andzinc are involved because those with an MTHFRderegciency accumulate homocysteine which can alsobe detoxireged by conversion into cystathionine via anenzyme 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 vitaminB6 has proven three times more effective at loweringhomocysteine than folate alone37 The combinedefregcacy of these nutrients for depression warrantsinvestigation

While folate deregciency alone can induce depres-sion the combination of deregciency and a fault in theMTHFR gene is more likely to tip someone over intomental illness To compensate for this much higherlevels of folate than normal are needed According toresearchers from Columbia Universityrsquos Departmentof Psychiatry in New York USA this also applies tothose with schizophrenia They found increased levelsof homocysteine despite no apparent lack of dietaryfolate38 The same is true for vitamin B12 Manypeople with mental illness need more than a normalamount of vitamin B12 despite no obvious signs ofderegciency such as anaemia39

A far better indicator of personal or individualisedincreased need for these B vitamins is a personrsquoshomocysteine level

SAMe and TMG the mastertuners

In Figures 2 and 3 you might have noticed these twostrange-sounding nutrients Both are kinds of aminoacids TMG stands for tri-methyl-glycine and SAMestands for s-adenosyl methionine Unlike the B vita-mins discussed above which act as `methyl moversrsquoSAMe and TMG are methyl group donors Both canlower homocysteinelevels by donating methylgroupsConversely sufregcient folate by enhancingthe MTHFRenzyme can increase production of SAMe40 It is a two-way process

SAMe is one of the most comprehensively studiednatural antidepressants Over 100 placebo-controlleddouble-blind studies have shown that SAMe is equal

to or superior to antidepressants works faster mostoften within a few days (most pharmaceutical anti-depressants may take three to six weeks to take effect)and with few side effects41plusmn43 An intake of 200 to600 mg a day is needed but the trouble is that it isboth very expensive and very unstable A lot of SAMesold in health food shops is pretty ineffective Analternative that is much more stable and less costly istri-methyl-glycine (TMG) In the body it turns intoSAMe but the supplement needed is three times asmuch plusmn 600 to 2000 mg a day on an empty stomachor with fruit

Mood-boosting fats

Omega-3 fats have a direct inmacruence on serotoninstatus probably by enhancing production and recep-tion According to Dr JR Hibbeln who discovered thatregsh eaters are less prone to depression `Itrsquos like build-ing more serotonin factories instead of just increasingthe efregciency of the serotonin you haversquo44 Dr BasantPuri from Londonrsquos Hammersmith Hospital UK re-ported the case of a 21-year-old student who had beenon a variety of antidepressants to no avail He had avery low sense of self-esteem sleeping problems littleappetite found it hard to socialise and often thoughtof killing himself After one month of supplementingethyle-EPA (eicosapentaenoic acid) a concentratedform of omega-3 fats he was no longer having suici-dal thoughts and after nine months no longer had anydepression45

Dr Andrew Stoll and colleagues at Harvard MedicalSchool USA ran a double-blind placebo-controlledtrial of omega-3 fats placing 14 adult manic depres-sives on the regsh oils EPA and DHA (docosahexaenoicacid) and compared them with 14 taking an olive oilplacebo Both took the supplement alongside theirnormal medication Those taking the omega-3 fatshad a substantially longer period in remission thanthe placebo group The regsh oil group also performedbetter than the placebo group for nearly every othersymptom measured46 The Institute of Psychiatry inLondon is currently running a large double-blind trialwith regsh oils to further evaluate the effects of omega-3fats on bipolar depression

Omega-3 fats are effective for severe depression tooA recent trial published in the American Journal ofPsychiatry tested the effects of giving 20 people suffer-ing from depression who were already on antidepres-sants but still depressed a highly concentrated form ofomega-3 fat ethyl-EPA versus a placebo By the thirdweek the depressed patients were showing majorimprovement in their mood while those on placebowere not47

P Holford14

Good mood foods andsupplements

There is good logic and substantial evidence thatensuring optimum nutrition in depressed patients canbe highly effective In addition to simple lifestylechanges such as encouraging exercise and outdooractivity to maximise light reducing stress and recom-mending counselling the following diet and supple-ment advice may help

Diet

Reduce sugar and stimulants (caffeinated drinksand smoking)

Increase fruit and vegetables (regve servings a day)

Eat oily regsh (mackerel tuna salmon herring) atleast twice a week

Ensure sufregcient protein from regsh meat eggsbeans and lentils

Supplements

B complex including vitamin B6 10 mg folate400 mg and vitamin B12 10 mg

Additional folate 400 to 2000 mg a day

5-HTP 200plusmn300 mg a day

Omega-3-rich regsh oil two capsules a day giving atleast 400 mg of EPA

ACKNOWLEDGEMENTS

This article has been adapted from Patrick Holfordrsquosnew book Optimum Nutrition for the Mind (Piatkuspound1699) For further information call Dagger44 (0)20 88712949 or visit wwwmentalhealthprojectcom

REFERENCES

1 Benton D Kumari N and Brain PF (1982) Mild hypo-glycaemia and questionnaire measures of aggressionBiological Psychology 14 129plusmn35

2 Roy A Virkkunen M and Linnoila M (1988) Mono-amines glucose metabolism aggression toward selfand others International Journal of Neuroscience 41261plusmn4

3 Schauss AG (1980) Diet Crime and Delinquency ParkerHouse Berkeley

4 Virkkunen M (1984) Reactive hypoglycaemic ten-dency among arsonists Acta Psychiatrica Scandinavica69 445plusmn52

5 Virkkunen M and Narvanen S (1987) Tryptophanand serotonin levels during the glucose tolerance testamong habitually violent and impulsive offendersNeuropsychobiology 17 19plusmn23

6 Yaryura-Tobias J and Neziroglu F (1975) Violent be-haviour brain dysrhythmia and glucose dysfunctionA new syndrome Journal of Orthopaedic Psychology4 182plusmn5

7 Bruce M and Lader M (1989) Caffeine abstention andthe management of anxiety disorders PsychologicalMedicine 19 211plusmn14

8 Wendel W and Beebe W (1973) Glycolytic activity inschizophrenia In Hawkins D and Pauling L (eds)Orthomolecular Psychiatry treatment of schizophreniaWH Freeman San Francisco

9 Prinz R and Riddle D (1986) Associations betweennutrition and behaviour in 5-year-old children Nutri-tion Reviews 43 (Suppl) 151plusmn8

10 Christensen L (1988) Psychological distress and dieteffects of sucrose and caffeine Journal of AppliedNutrition 40 44plusmn50

11 Fullerton DT and Getto CJ (1985) Sugar opioids andbinge eating Brain Research Bulletin 14 273plusmn80

12 Colgan M and Colgan L (1984) Do nutrient supple-ments and dietary changes affect learning and emo-tional reactions of children with learning difregcultiesA controlled series of 16 cases Nutrition and Health3 69plusmn77

13 Goldman J Lerman RH Controis JH et al (1986)Behavioural effects of sucrose on preschool childrenJournal of Abnormal Child Psychology 14 565plusmn77

14 Lester M Thatcher RW and Monroe-Lord L (1982)Reregned carbohydrate intake hair cadmium levelsand cognitive functioning in children Nutrition andBehaviour 1 3plusmn13

15 Schoenthaler S Doraz WE and Wakeregeld JA (1986)The impact of low food additive and sucrose diet onacademic performance in 803 New York City publicschools International Journal for Biosocial Research8 185plusmn95

16 Dubini A Bosc M and Polin V (1997) Do noradrenalineand serotonin differentially affect social motivationand behaviour European Neuropsychopharmacology 7(Suppl 1) S49plusmn55

17 Smith KA Fairburn CG and Cowen PJ (1997) Relapseof depression after rapid depletion of tryptophanLancet 349 915plusmn19

18 Eccleston D (1993) L-tryptophan and depressive ill-ness Psychiatric Bulletin 17 223plusmn4

19 von Sano I (1972) L-5-hydroxytryptophan (L-5-HTP)therapie Folia Psychiatrica et Neurologica Japonica 267plusmn17

20 Nakajima T Kudo Y and Kaneko Z (1978) Clinicalevaluation of 5-hydroxytryptophan as an antidepres-sant Folia Psychiatrica et Neurologica 32 223plusmn30

21 Woggon A and Schoef J (1977) The treatment ofdepression with L-5-hydroxytryptophan versus imi-pramine Archiv fuEgraver Psychiatrie und Nervenkrankheiten224 175plusmn86

Depression the nutrition connection 15

Good mood foods andsupplements

There is good logic and substantial evidence thatensuring optimum nutrition in depressed patients canbe highly effective In addition to simple lifestylechanges such as encouraging exercise and outdooractivity to maximise light reducing stress and recom-mending counselling the following diet and supple-ment advice may help

Diet

Reduce sugar and stimulants (caffeinated drinksand smoking)

Increase fruit and vegetables (regve servings a day)

Eat oily regsh (mackerel tuna salmon herring) atleast twice a week

Ensure sufregcient protein from regsh meat eggsbeans and lentils

Supplements

B complex including vitamin B6 10 mg folate400 mg and vitamin B12 10 mg

Additional folate 400 to 2000 mg a day

5-HTP 200plusmn300 mg a day

Omega-3-rich regsh oil two capsules a day giving atleast 400 mg of EPA

ACKNOWLEDGEMENTS

This article has been adapted from Patrick Holfordrsquosnew book Optimum Nutrition for the Mind (Piatkuspound1699) For further information call Dagger44 (0)20 88712949 or visit wwwmentalhealthprojectcom

REFERENCES

1 Benton D Kumari N and Brain PF (1982) Mild hypo-glycaemia and questionnaire measures of aggressionBiological Psychology 14 129plusmn35

2 Roy A Virkkunen M and Linnoila M (1988) Mono-amines glucose metabolism aggression toward selfand others International Journal of Neuroscience 41261plusmn4

3 Schauss AG (1980) Diet Crime and Delinquency ParkerHouse Berkeley

4 Virkkunen M (1984) Reactive hypoglycaemic ten-dency among arsonists Acta Psychiatrica Scandinavica69 445plusmn52

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