From February 1999 Issue of Nutrition Science News
By Donald Brown, N.D., Alan R. Gaby, M.D., and Ronald Reichert, N.D.
Altering the brain's chemistry to elevate mood
Depression is one of the most frequent psychological problems encountered in medical practice. Some studies say 13 to 20 percent of American adults exhibit some depressive symptoms.  The mortality rate among those who are depressed is four times greater than those without depressionmajor depression accounts for 60 percent of all suicides. 
Yet, despite this professional recognition and the fact that depression is a treatable condition, only about a third of depressed patients receive appropriate intervention. 
While the exact etiology of depression is unknown, numerous factors appear to contribute. These include genetics, life/event sensitization and biochemical changes.
Family, twin and adoption studies demonstrate that predisposition toward depression can be inherited. In addition, stressful life events can contribute to depression; most studies concur that the likelihood of a depressive episode is five to six times greater six months after events such as early parental loss, job loss or divorce. The link between depression and stressful life events has been conceptualized in the form of the sensitization model, which proposes that prior exposure to stressful life events sensitizes the brain's limbic system to the degree that subsequently less stress is needed to produce a mood disorder.  Many of the current biochemical theories of depression focus on the biogenic amines, which are a group of chemical compounds important in neurotransmissionmost importantly norepinephrine, serotonin and, to a lesser extent, dopamine, acetylcholine and epinephrine.
Antidepressant medications, which address the brain's biochemistry, include monoamine oxidase (MAO) inhibitors, tricyclic antidepressants and selective serotonin reuptake inhibitors. MAOs increase norepinephrine levels, while tricyclics essentially enhance norepinephrine transmission. Serotonin, in particular, has been the subject of intense research during the past 25 years, indicating its importance in the pathophysiology of depression. Basically, a functional deficiency in serotonin results in depression. 
Amino Acid Supplements
The nutritional treatment of depression includes dietary modifications, supportive treatment with vitamins and minerals, and supplementation with specific amino acids, which are precursors to neurotransmitters. Dietary modification and vitamin and mineral supplementation in some cases reduce the severity of depression or result in an improvement in general well-being. However, these interventions are usually considered adjunctive, since they are not typically effective by themselves as a treatment for clinical depression. On the other hand, supplementation with the amino acids L-tyrosine and D,L-phenylalanine can in many cases be used as an alternative to antidepressant drugs. Another particularly effective treatment is the amino acid L-tryptophan (see sidebar).
L-Tyrosine is the precursor to the biogenic amine norepinephrine and may therefore be valuable to the subset of people who fail to respond to all medications except amphetamines. Such people excrete much less than the usual amounts of 3-methoxy-4-
hydroxyphenylglycol, the byproduct of norepinephrine breakdown, suggesting a deficiency of brain norepinephrine.
One clinical study detailed two patients with long-standing depression who failed to respond to MAO inhibitor and tricyclic drugs as well as electroconvulsive therapy.  One patient required 20 mg/day of dextroamphetamine to remain depression-free, and the other required 15 mg/day of D,L-amphetamine. Within two weeks of starting L-tyrosine, 100 mg/kg once a day before breakfast, the first patient was able to eliminate all dextroamphetamine, and the second was able to reduce the intake of D,L-amphetamine to 5 mg/day. In another case report, a 30-year-old female with a two-year history of depression showed marked improvement after two weeks of treatment with L-tyrosine, 100 mg/kg/day in three divided doses.  No side effects were seen.
L-Phenylalanine, the naturally occurring form of phenylalanine, is converted in the body to L-tyrosine. D-phenylalanine, which does not normally occur in the body or in food, is metabolized to phenylethylamine (PEA), an amphetaminelike compound that occurs normally in the human brain and has been shown to have mood-elevating effects. Decreased urinary levels of PEA (suggesting a deficiency) have been found in some depressed patients. Although PEA can be synthesized from L-phenylalanine, a large proportion of this amino acid is preferentially converted to L-tyrosine. D-phenylalanine is therefore the preferred substrate for increasing the synthesis of PEAalthough L-phenylalanine would also have a mild antidepressant effect because of its conversion to L-tyrosine and its partial conversion to PEA. Because D-phenylalanine is not widely available, the mixture D,L-phenylalanine is often used when an antidepressant effect is desired.
Studies of D,L-phenylalanine's efficacy show that it has promise as an antidepressant. Additional research is needed to determine the optimal dosage and which types of patients are most likely to respond to treatment.
Vitamin and Mineral Therapy
Vitamin and mineral deficiencies can cause depression. Correcting deficiencies, when present, often relieves depression. However, even if a deficiency cannot be demonstrated, nutritional supplementation may improve symptoms in selected groups of depressed patients.
Vitamin B6, or pyridoxine, is the cofactor for enzymes that convert L-tryptophan to serotonin and L-tyrosine to norepinephrine. Consequently, vitamin B6 deficiency might result in depression. One person volunteered to eat a pyridoxine-free diet for 55 days. The resultant depression was alleviated soon after supplementation with pyridoxine was begun. 
While severe vitamin B6 deficiency is rare, marginal vitamin B6 status may be relatively common. A study using a sensitive enzymatic assay suggested the presence of subtle vitamin B6 deficiency among a group of 21 healthy individuals.  Vitamin B6 deficiency may also be common in depressed patients. In one study, 21 percent of 101 depressed outpatients had low plasma levels of the vitamin.  In another study, four of seven depressed patients had subnormal plasma concentrations of pyridoxal phosphate, the biologically active form of vitamin B6.  Although low vitamin B6 levels could be a result of dietary changes associated with depression, vitamin B6 deficiency could also be a contributing factor to the depression.
Depression is also a relatively common side effect of oral contraceptives. The symptoms of contraceptive-induced depression differ from those found in endogenous and reactive depression. Pessimism, dissatisfaction, crying and tension predominate, whereas sleep disturbance and appetite disorders are uncommon. Of 22 women with depression associated with oral contraceptive use, 11 showed biochemical evidence of vitamin B6 deficiency. In a double-blind, crossover trial, women with vitamin B6 deficiency improved after treatment with pyridoxine, 2 mg twice a day for two months.  Women who were not deficient in the vitamin did not respond to supplementation.
These studies indicate vitamin B6 supplementation is valuable for a subset of depressed patients. Because of its role in monoamine metabolism, this vitamin should be investigated as possible adjunctive treatment for other patients with depression. A typical vitamin B6 dose is 50 mg/day.
Folic acid deficiency may result from dietary deficiency, physical or psychological stress, excessive alcohol consumption, malabsorption or chronic diarrhea. Deficiency may also occur during pregnancy or with the use of oral contraceptives, other estrogen preparations or anticonvulsants. Psychiatric symptoms of folate deficiency include depression, insomnia, anorexia, forgetfulness, hyperirritability, apathy, fatigue and anxiety. 
Serum folate levels were measured in 48 hospitalized patients: 16 with depression, 13 psychiatric patients who were not depressed and 19 medical patients.  Depressed patients had significantly lower serum folate concentrations than did patients in the other two groups. Depressed patients with low serum folate levels had higher depression ratings on the Hamilton Depression Scale than did depressed patients with normal folate levels.
These findings suggest that folic acid deficiency may be a contributing factor in some cases of depression. Serum folate levels should be determined in all depressed patients who are at risk for folic acid deficiency. The usual dose of folic acid is 0.4 to 1 mg/day. It should be noted that folic acid supplementation can mask the diagnosis of vitamin B12 deficiency when the complete blood count is used as the sole screening test. Patients in whom vitamin B12 deficiency is suspected and who are taking folic acid should have their serum vitamin B12 measured.
Vitamin B12 deficiency can also manifest as depression.  In depressed patients with documented vitamin B12 deficiency, parenteral (intravenous) administration of the vitamin has resulted in dramatic improvement.  Vitamin B12, 1 mg/day for two days (route of administration not specified), also produced rapid resolution of postpartum psychosis in eight women. 
Vitamin C, as the cofactor for tryptophan-5-hydroxylase, catalyzes the hydroxylation of tryptophan to serotonin.  Vitamin C may therefore be valuable for patients with depression associated with low levels of serotonin. In one study, 40 chronic psychiatric inpatients received 1 g/day of ascorbic acid or placebo for three weeks, in double-blind fashion.  In the vitamin C group, significant improvements were seen in depressive, manic and paranoid symptom complexes, as well as in overall functioning.
Magnesium deficiency can cause numerous psychological changes, including depression. The symptoms of magnesium deficiency are nonspecific and include poor attention, memory loss, fear, restlessness, insomnia, tics, cramps and dizziness. Plasma magnesium levels have been found to be significantly lower in depressed patients than in controls.  These levels increased significantly after recovery. In a study of more than 200 patients with depression and/or chronic pain, 75 percent had white blood cell magnesium levels below normal.  In many of these patients, intravenous magnesium administration led to rapid resolution of symptoms. Muscle pain responded most frequently, but depression also improved.
Magnesium has also been used to treat premenstrual mood changes. In a double-blind trial, 32 women with premenstrual syndrome were randomly assigned to receive 360 mg/day of magnesium or placebo for two months.  The treatments were given daily from day 15 of the menstrual cycle until the onset of menstruation. Magnesium was significantly more effective than placebo in relieving premenstrual symptoms related to mood changes.
These studies suggest that magnesium deficiency may be a factor in some cases of depression. Dietary surveys have shown that many Americans fail to achieve the Recommended Dietary Allowance for magnesium. [24, 25] As a result, subtle magnesium deficiency may be common in the United States. A nutritional supplement that contains 200400 mg/day of magnesium may therefore improve mood in some patients with depression.
St. John's wort (Hypericum perforatum) as a standardized extract is licensed in Germany and other European countries as a treatment for mild to moderate depression, anxiety and sleep disorders.
St. John's wort has a complex and diverse chemical makeup. Hypericin and pseudohypericin have received most of the attention based on their contributions to both the antidepressive and antiviral properties of St. John's wort. This explains why most modern St. John's wort extracts are standardized to contain measured amounts of hypericin. Recent research, however, indicates that the medicinal actions of St. John's wort can be ascribed to other mechanisms of action and also to the complex interplay of many constituents. 
While St. John's wort's ability to act as an antidepressant is not fully understood, previous literature points to its ability to inhibit MAOs. MAOs act by inhibiting MAO-A or -B isozymes, thereby increasing synaptic levels of the biogenic amines, especially norepinephrine. This earlier research showed that St. John's wort extracts not only inhibit MAO-A and MAO-B but also reduce the availability of serotonin receptors, resulting in the impaired uptake of serotonin by brain neurons. 
More than 20 clinical studies have been completed using several different St. John's wort extracts. Most have shown antidepressant action either greater than placebo or equal in action to standard prescription antidepressant drugs.  A recent review analyzed 12 controlled clinical trialsnine were placebo-controlled and three compared St. John's wort extract to antidepressant drugs maprotiline or imipramine.  All trials showed greater antidepressant effect with St. John's wort compared with placebo and comparable results with St. John's wort as with the standard antidepressant medications. The first U.S. government-sanctioned clinical trial of St. John's wort, a three-year study sponsored by the Center for Complementary and Alternative Medicine, based in Washington, D.C., began last year.
Dosage is typically based on hypericin concentration in the extract. The minimum daily hypericin dosage recommended is approximately 1 mg. For example, an extract standardized to contain 0.2 percent hypericin would require a daily dosage of 500 mg, usually given in two divided dosages. Clinical studies have used a St. John's wort extract standardized to 0.3 percent hypericin at a dose of 300 mg three times daily.
The German Commission E Monograph for St. John's wort lists no contraindications to its use during pregnancy and lactation. However, more safety studies are needed before St. John's wort is recommended for this population.
Ginkgo (Ginkgo biloba) extract, while clearly not a primary treatment of choice for most patients with major depression, should be considered an alternative for elderly patients with depression resistant to standard drug therapy. This is because depression is often an early sign of cognitive decline and cerebrovascular insufficiency in elderly patients. Frequently described as resistant depression, this form of depression is often unresponsive to standard antidepressant drugs or phytomedicines like St. John's wort. One study showed a global reduction in regional cerebral blood flow in depressed patients older than 50 when compared with age-matched, healthy controls. 
In that study, 40 patients, ages 51 to 78, with a diagnosis of resistant depression (insufficient response to treatment with tricyclic antidepressants for at least three months), were randomized to receive either Ginkgo biloba extract or placebo for eight weeks.  Patients in the ginkgo group received 80 mg of the extract three times daily. During the study, patients remained on their antidepressant drugs. In patients treated with ginkgo, there was a decline in the median Hamilton Depression Scale scores from 14 to 7 after four weeks. This score was further reduced by 4.5 at eight weeks. There was a one-point reduction in the placebo group after eight weeks. In addition to the significant improvement in symptoms of depression for the ginkgo group, there was also a noted improvement in overall cognitive function. No side effects were reported.
Many nutrition-oriented practitioners have found that the answer to depression is as simple as one's diet. A diet low in sugar and refined carbohydrates (with small, frequent meals) can produce symptomatic relief in some depressed patients. Individuals most likely to respond to this dietary approach are those who develop symptoms in the late morning or late afternoon or after missing a meal. In these patients, ingestion of sugar provides transient relief, followed by an exacerbation of symptoms several hours later.
Donald Brown, N.D., teaches herbal medicine and therapeutic nutrition at Bastyr University, Bothell, Wash. Alan R. Gaby, M.D., is past president of the American Holistic Medical Association. Ronald Reichert, N.D., is an expert in European phytotherapy and has an active medical practice in Vancouver, B.C.
5-HTP and the Serotonin Connection
Excerpted with permission from Depression (Natural Product Research Consultants, 1997).
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