Depression – The Nutrition Connection

  • 31 Mar 2009
  • Reading time 17 mins
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There is little doubt that the incidence of depression is increasing. The Mynutrition survey we conducted on over 37,000 people found that 42% are frequently depressed, while 15% are clinically depressed, half of which consult their doctor.

Why would nutrition have anything to do with depression? Firstly, we have seen a significant decline in fruit and vegetable intake (rich in folic acid), in fish intake (rich in essential fats) and an increase in sugar consumption, from 2lbs a year in the 1940’s to 150lbs a year in many of today’s teenagers. Each of these nutrients are strongly linked to depression and could, theoretically, contribute to increasing rates of depression. Secondly, if depression is a biochemical imbalance it makes sense to explore how the brain normalises its own biochemistry, using nutrients as the precursors for key neurotransmitters such as serotonin. Thirdly, if 21st century living is extra-stressful, it would be logical to assume that increasing psychological demands would also increase nutritional requirements since the brain is structurally and functionally completely dependent on nutrients. So, what evidence is there to support sub-optimal nutrition as a potential contributor to depression? These are the common imbalances connected to nutrition that are known to worsen your mood and motivation:

• Blood sugar imbalances (often associated with excessive sugar and stimulant intake)
• Lack of chromium
• Lack of amino acids (tryptophan and tyrosine are precursors of serotonin and noradrenalin)
• Lack of B vitamins (vitamin B6, folate, B12)
• Lack of essential fats (omega 3)

One factor that often underlies depression is poor control of blood glucose levels. The symptoms of impaired blood sugar control are many, and include fatigue, irritability, dizziness, insomnia, excessive sweating (especially at night), poor concentration and forgetfulness, excessive thirst, depression and crying spells, digestive disturbances and blurred vision. These symptoms often preceed measurable abnormalities in blood glucose, manifesting first as a decreased sensitivity to insulin, known as insulin resistance. One of the world’s experts on blood sugar problems, Professor Gerald Reaven from Stanford University in California, estimates that 25 per cent of normal, non-obese people have ‘insulin resistance’. Since the brain depends on an even supply of glucose it is no surprise to find that sugar has been implicated in aggressive behaviour, anxiety, hyperactivity and attention deficit, depression, eating disorders, fatigue, and learning difficulties. The second reason excessive consumption of refined sugar is undesirable is that it uses up the body’s vitamins and minerals and provides next to none. Every teaspoon of sugar uses up B vitamins for its catabolism, thereby increasing demand. B vitamins, as we will see, are vital for maintaining mood.

About 98 per cent of the chromium present in sugarcane is lost in turning it into sugar. This mineral is vital for keeping your blood sugar level stable. Thanks to the thorough research psychiatrist Dr. Malcolm McLeod from the University of North Carolina, chromium has also been shown to act as a highly effective antidepressant for people with “atypical” depression, characterised by weight gain, craving for carbohydrates, feeling sleepy or groggy, chronic fatigue, need for sleep and over-sensitive, with onset of depression before age 30. According to McLeod, between 25 and 50 percent of depressed patients have atypical depression. In fact, a survey of several hundred depressed patients at Massachusetts General Hospital, found that atypical depression accounted for one third of depressed men and almost half of all depressed women. 
 McLeod went on to test his theory by running a double-blind study of 15 patients with atypical depression. Five were given a placebo and 10 were given 600 mcg of chromium picolinate. At the end of eight weeks, seven out of the 10 patients on chromium showed major improvement, compared to none on placebo. McLeod’s experiences with chromium are documented in his book’ Lifting Depression—The Chromium Connection’ (Basic Health Publications, 2005). A larger trial confirmed McLeod’s discovery.

Headed by Dr. John Doherty at the Weill Medical College of Cornell University, 113 patients with atypical depression were given either 600 mcg of chromium or placebo. At the end of eight weeks, 65 percent of those on chromium showed a major improvement in their depression, as measured by the Hamilton Rating Scale for depression, compared to 33 percent on placebo. Chromium is a remarkably safe mineral, even at levels a hundred times higher than this for several years. Chromium is best taken in the morning or at lunch. Try 200 mcg of chromium twice a day—at breakfast and lunch, or with a snack.


There are often two sides to depression – feeling miserable, and feeling apathetic and unmotivated. The most prevalent biochemical theory for the cause of these imbalances is a brain imbalance in two families of neurotransmitters. These are:

• Serotonin, thought to primarily influence mood, and
• Dopamine, noradrenalin, and adrenalin, thought to primarily influence motivation.

To test the theory that serotonin primarily controlled mood, and adrenalin and noradrenalin control motivation, Antonella Dubini, from the Pharmacia and Upjohn Medical Department in Milan, Italy, gave 203 people suffering from low mood and motivation either an SSRI drug, promoting serotonin, or a NARI drug, promoting noradrenalin. Sure enough, the former was more effective at improving mood, while the latter was more effective at improving motivation.

Depression and Tryptophan

SSRI anti-depressants are thought to work by stopping the reuptake of serotonin, thereby enhancing serotonin action within the synapse. The trouble is that these kinds of drugs induce unpleasant side-effects in as many as a quarter of those who take them and severe reactions in a minority.

An alternative strategy would be to enhance the synthesis of serotonin by providing optimal amounts of precursor nutrients. But, does it work?
 Serotonin is made from the amino acid tryptophan, a constituent of protein. Dr Philip Cowen and colleagues from Oxford University’s psychiatry department wondered what would happen if you deprived people of tryptophan. They gave 15 volunteers who had a history of depression, but were currently not depressed, a nutritionally balanced drink that excluded tryptophan. Within seven hours 10 out of 15 noticed a worsening of their mood and started to show signs of depression. On being given the same drink, but this time with tryptophan added, their mood improved.

Donald Ecclestone, professor of medicine at the Royal Victoria Infirmary in Newcastle in the UK reviewed the available studies and concluded that supplementing tryptophan is an effective anti-depressant, equivalent to tricyclics. 
 While supplementing tryptophan itself has proven a somewhat effective anti-depressant, even more effective is a derivative of tryptophan that is one step closer to serotonin. This is called 5-hydroxytryptophan, or 5-HTP for short. The first study proving the mood-boosting power of 5-HTP was done in the 1970s in Japan, under the direction of Professor Isamu Sano of the Osaka University Medical School. He gave 107 patients 50 to 300mg of 5-HTP per day, and within two weeks, more than half experienced improvements in their symptoms. By the end of the fourth week of the study, nearly three-quarters of the patients reported either complete relief or significant improvement, with no side-effects. This study was repeated by Nakajima et al who also found that 69 per cent of patients improved their mood. A trial in Germany found 5-HTP to be as effective as the tricyclic anti-depressant imipramine, with a fraction of the side-effects. One double-blind trial headed by Dr Poldinger at the Basel University of Psychiatry gave 34 depressed volunteers either the SSRI anti-depressant fluvoxamine, or 300mg of 5-HTP. Each patient was assessed for their degree of depression using the widely accepted Hamilton Rating Scale, plus their own subjective self-assessment.

At the end of the six weeks, both groups of patient had had a significant improvement in their depression. However, those taking 5-HTP had a slightly greater improvement in each of the four criteria assessed – depression, anxiety, insomnia and physical symptoms, as well as the patient's self-assessment. In total, there have been 29 studies on 5-HTP showing it to be highly effective for depression. Given that 5-HTP is less expensive and has significantly fewer side-effects, it is surprising that doctors and psychiatrists virtually never prescribe it. 
 The recommended dosage of this amino acid, available in any health food shop, is 100mg of 5-HTP, two or three times a day, for depression. Some supplements also provide various vitamins and minerals such as B12 and folic acid, which may be even more effective because these nutrients help to turn 5-HTP into serotonin. 

Depression in Women

Women are three times as prone to low moods as men. Many theories as to why this is have been proposed, some psychological, some social, but the truth is that women and men are biochemically very different. The research of Mirko Diksic and colleagues at McGill University in Montreal demonstrates this. They developed a technique using PET neuro-imaging to measure the rate at which we make serotonin in the brain. What they found was that men’s average synthesis rate of serotonin was 52 per cent higher than women. This, and other research, has clearly shown that women are more prone to low serotonin. They also react differently. In women, low serotonin is associated with depression and anxiety, while in men, low serotonin is related to aggression and alcoholism. One possibility is our social conditioning: men ‘act out’ their moods, while women are more conditioned to ‘act in’ their moods. 
 What has been learnt about serotonin in the last few years is that there are a number of potential reasons for deficiency, in addition to a lack of, or increased 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 and irritable, is tired all the time, tends to comfort eat, has sleeping problems and a reduced interest in sex, and some of the above apply, the chances are they are short on serotonin.
 Low oestrogen means low serotonin and low moods. This is because oestrogen blocks the breakdown of serotonin. This may explain why women are more prone to depression pre-menstrually and in the menopause and thereafter. Low testosterone has a similar effect in men.
 Light also stimulates both oestrogen and serotonin and most of us don’t get enough of it. The difference in light exposure outside and inside is massive. Most of us spend 23 out of 24 hours a day indoors, exposed to an average of 100 units (called lux) of light. That’s compared to 20,000 lux on a sunny day and 7,000 lux on an overcast day.

Now, more than ever before, many people rarely expose themselves to direct sunlight, and certainly not enough to maximise serotonin production. Of course, light deficiency is worse in the winter.
 Stress also rapidly reduces serotonin levels, while physical exercise improves stress response, and therefore reduces stress-induced depletion of serotonin.

Is Apathy a Catecholamine Deficiency?

Another group of neurotransmitters associated with depression and lack of motivation are the catecholamines – dopamine, noradrenalin and adrenalin. Both adrenalin and noradrenalin are synthesised from dopamine, which is made from the amino acid tyrosine, which is itself made from the amino acid phenylalanine.

It is logical to assume that, if drugs that block the breakdown of these neurotransmitters do elevate mood, then augmenting the amino acid phenylalanine or tyrosine might work too. And they do.
In a double-blind study by Helmut Beckmann and colleagues at the University of Wurzburg, Germany, 150 to 200mg of the amino acid phenylalanine, or the anti-depressant drug Imipramine, were administered to 40 depressed patients for one month. Both groups had the same degree of positive results – less depression, anxiety and sleep disturbance. A group of researchers at the Rush Medical Center, Chicago, screened depressed patients by testing phenythylamine in the blood; low levels mean you need more phenylalanine. They then gave 40 depressed patients supplements of phenylalanine, and 31 of them improved. 
Tyrosine has been shown to work well in those with dopamine-dependent depression.

In a pilot study administering 3200mg tyrosine a day to 12 patients at the Hopital du Vinatier, France, a significant improvement in mood and sleep was observed on the very first day. The military has long known that tyrosine improves mental and physical performance under stress. Recent research from the Netherlands demonstrates how tyrosine gives you the edge in conditions of stress. Twenty-one cadets were put through a demanding one-week military combat training course. Ten cadets were given a drink containing 2g of tyrosine a day, while the remaining 11 were given an identical drink without the tyrosine. Those on tyrosine consistently performed better, both in memorising the task at hand and in tracking the tasks they had performed. 
In our clinical experience the best results are achieved by supplementing all of these amino acids – 5-HTP, phenylalanine and tyrosine – together with the B vitamins that help turn them into neurotransmitters, which are B6, B12 and folic acid.


B vitamins act as co-factors in key enzymes that control both the production and balance of neurotransmitters. For example, serotonin (5-HT) is produced from 5-HTP by the addition of a methyl group (carboxylase), as is adrenalin from noradrenalin. This enzyme process is highly dependent on folate, as well as B12, B6. Folate deficiency is extremely common among depressed patients. In a study of 213 depressed patients at the Depression and Clinical Research Program at Boston’s Massachusetts General Hospital, people with lower folate levels had more ‘melancholic’ depression and were less likely to improve when given anti-depressant drugs. Very depressed people, and also those diagnosed with schizophrenia, are often deficient in folate. A survey of such patients at Kings College Hospital’s psychiatry department in London found that one in three had borderline or definite folate deficiency. These patients then took part in a trial of taking folate for six months in addition to their standard drug treatment.

Those given folate had significantly improved recovery, and the longer they took the folate, the better they felt. 
 One current theory is that genetic differences worsening a person’s ability to methylate may both increase the tendency to depression (and schizophrenia) and their need for folate, which may be better reflected by measuring homocysteine levels than by measuring blood levels of folate. This is because homocysteine is methylated ‘en route’ to s-adenosyl methionine (SAMe) by a folate dependent enzyme methyl-tetrahydrofolatereductase, or MTHFR for short. In one study, more than half (52 per cent) of patients with severe depression were found to have elevated homocysteine and low levels of folate. 
 Homocysteine levels are particularly high in patients with schizophrenia, even in the absence of dietary deficiency in folate or B12.

When comparing 193 mixed-sex patients with schizophrenia and 762 non-schizophrenic subjects, US researchers found that average homocysteine levels were a very high 16.3 µmol/l for schizophrenics compared to 10.6 ¨mol/l in normal subjects. But the difference between groups was almost entirely attributable to the homocysteine levels of young male patients with schizophrenia.

Genes, Homocysteine and Mental Illness

Not everyone is born equal, as far as methylation is concerned. Around one in ten inherit a defective gene that means that the key methylating enzyme MTHFR doesn’t work so well, increasing the need for folate, as well as B12, B6 and zinc. B6 and zinc are involved because those with a MTHFR deficiency accumulate homocysteine, which can also be detoxified by conversion into cystathionine, via an enzyme dependent on pyridoxal-5-phosphate.

Pyridoxine (B6) is converted to pyridoxal-5-phosphate by a zinc dependent enzyme. Supplementing a combination of folate, B12 and B6 has proven three times more effective at lowering homocysteine than folate alone. The combined efficacy of these nutrients on depression warrants investigation.
 While folate deficiency alone can induce depression, the combination of deficiency and a fault in the MTHFR gene is more likely to tip someone over into mental illness. To compensate for this, much higher levels of folate than normal are needed. According to research from Columbia University’s Department of Psychiatry in New York, this also applies to those with schizophrenia. They found increased levels of homocysteine, despite no apparent lack of dietary folate.

The same is true for vitamin B12. Many people with mental illness need more than a normal amount of vitamin B12 despite no obvious signs of deficiency such as anaemia. 
 A far better indicator of personal or individualised increased need for these B vitamins is a person’s homocysteine level. 

SAMe and TMG: the Master Tuners

SAMe & TMG are kinds of amino acids. TMG stands for tri-methyl-glycine and SAMe stands for s-adenosyl methionine. Unlike the B vitamins discussed above, which act as ‘methyl movers’, SAMe and TMG are methyl group donors. Both can lower homocysteine levels by donating methyl groups. Conversely, sufficient folate , by enhancing the MTHFR enzyme, can increase production of SAMe . It’s a two way process. SAMe is one of the most comprehensively studied natural anti-depressants. Over 100 placebo-controlled, double-blind studies show that SAMe is equal to or superior to anti-depressants, works faster, most often within a few days (most pharmaceutical anti-depressants may take three to six weeks to take effect) and with few side-effects. You need 200 to 600mg a day, but the trouble is it’s both very expensive and very unstable.

A lot of SAMe sold in health food shops is pretty ineffective. An alternative that is much more stable and less costly is tri-methyl glycine (TMG). In the body it turns into SAMe, but you need to supplement three times as much - 600 to 2,000mg a day, on an empty stomach or with fruit.

Mood-Boosting Fats

Omega-3 fats have a direct influence on serotonin status, probably by enhancing production and reception. According to Dr J. R. Hibbeln, who discovered that fish eaters are less prone to depression, ‘It’s like building more serotonin factories, instead of just increasing the efficiency of the serotonin you have.’ Dr Basant Puri from London’s Hammersmith Hospital reported the case of a 21-year-old student who had been on a variety of anti-depressants, to no avail. He had a very low sense of self-esteem, sleeping problems, little appetite, found it hard to socialise and often thought of killing himself.

After one month of supplementing ethyle-EPA, a concentrated form of omega-3 fats, he was no longer having suicidal thoughts and after nine months no longer had any depression. 
 Dr Andrew Stoll and colleagues at Harvard Medical School ran a double-blind placebo-controlled trial of omega-3 fats, placing 14 adult manic depressives on the fish oils EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) and compared them with 14 taking an olive oil placebo. Both took the supplement alongside their normal medication. Those taking the omega-3 fats had a substantially longer period in remission than the placebo group. The fish oil group also performed better than the placebo group for nearly every other symptom measured.

The Institute of Psychiatry in London is currently running a large double-blind trial with fish oils to further evaluate the effects of omega 3 fats on bipolar depression.
 Omega 3 fats are effective for severe depression too. A recent trial published in the American Journal of Psychiatry tested the effects of giving 20 people suffering from depression, who were already on anti-depressants but still depressed, a highly concentrated form of omega-3 fat called ethyl-EPA, versus a placebo. By the third week, the depressed patients were showing major improvement in their mood, while those on placebo were not.


There is good logic, and substantial evidence that ensuring optimum nutrition in depressed patients can be highly effective. In addition to simple lifestyle changes such as encouraging exercise and outdoor activity to maximise light, reducing stress and recommending counselling, the following diet and supplement advice may help:


  • Reduce sugar and stimulants (caffeinated drinks and smoking)
  • Increase fruit and vegetables (five servings a day)
  • Eat oily fish (mackerel, tuna, salmon, herring) at least twice a week
  • Ensure sufficient protein from fish, meat, eggs, beans and lentils
  • B Complex, including B6 10mg, folate 400mcg and B12 10mcg
  • Additional folate, 400 to 2,000mcg a day 5-HTP 200-300mg a day
  • Omega 3 rich fish oil, two capsules a day, giving at least 400mg of EPA

The Brain Bio Centre is an outpatient clinical treatment centre, specialising in the 'optimum nutrition' approach to mental health problems. The centre offers a comprehensive assessment of biochemical imbalances that can contribute to mental health problems, and advice to correct these imbalances as a means to restore health. For more information click here