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References

Other Nutrients

Omega-3 fatty acids. Omega-3 fatty acids are long-chain polyunsaturated fatty acids found in fish and various oils, such as flaxseed or canola oil (Logan AC 2003). The brain has a high concentration of polyunsaturated fatty acids (Yehuda S et al 1999; Bourre JM et al 1991), and depressed people have lower levels of omega-3 fatty acids compared with the pro-inflammatory omega-6 fatty acids (Tiemeier H 2003). Adding the omega-3 fatty acid eicosapentaenoic acid (EPA) to conventional antidepressant treatment relieves depressive symptoms (Puri BK et al 2001). Among children with depression, supplementation with omega-3 fatty acids has shown “highly significant” effects on symptom scores (Nemets H et al 2006). In 2006, researchers analyzed results from six published studies on depression and omega-3 fatty acids. They found that omega-3 fatty acids can reduce symptoms of depression among adults (Williams AL et al 2006).

Omega-3 fatty acids are also beneficial because they reduce the risk of cardiovascular disease, which is highly associated with depression (Burr ML et al 1989; Singh RB et al 1997).

Zinc. Zinc is a trace element known to have a regulatory function in the human nervous system (Nowak G et al 2002). It not only promotes creation of new brain cells but acts as an antioxidant, decreasing oxidative stress. Decreased blood levels of zinc are associated with depression (Maes M et al 1994, 1997; McLoughlin IJ et al 1990), and maintaining a healthy zinc level in the brain is essential to normal brain function (Takeda A 2000).

Animal studies show that antidepressants and electroconvulsive shock treatments change zinc concentrations in areas of the brain associated with depression (Nowak G et al 1999). In an animal study, zinc was also shown to enhance antidepressant effects of imipramine (Kroczka B et al 2001).

Vitamin C and vitamin E. Vitamin C is a well-known antioxidant. Studies indicate that levels of vitamin C are lower in people with depression than in those without depression (McKee T et al 1999a; Khanzode SD et al 2003). Ascorbic acid indirectly inhibits oxidative stress by enhancing the activity of other antioxidants, such as vitamin E (McKee T et al 1999b). Low serum levels of vitamin E are linked to major depression (Maes M et al 2000).

St. John’s wort. St. John’s wort (Hypericum perforatum) is a medicinal herb used for the treatment of neurological and psychiatric disorders, including depression (Nangia M et al 2000). Compared to placebo, H. perforatum extract can effectively treat mild to moderate depression, reducing symptoms and recurrence rate (Lecrubier Y et al 2002).

The mechanism of action of St. John’s wort in depression is not entirely clear. One idea is that St. John’s wort affects presynaptic serotonin uptake and inhibits norepinephrine reuptake (Nangia M et al 2000). By affecting or inhibiting reuptake mechanisms of presynaptic neurons, St. John’s wort may increase availability of serotonin and norephinephrine. Clinical trials show positive response rates to treatment with St. John’s wort (Kim HL et al 1999; Linde K et al 1996). Please see the important safety information on St. John’s wort at the end of this chapter.

Ginkgo biloba. The herb Ginkgo biloba has been shown to produce an antioxidant. Ginkgo has been studied in animal models of depression with good results. In one study, rats were subjected to chronic stress—the same kind of stress that may lead to depression in humans. When the rodents were treated with the antidepressant venlafaxine, Ginkgo biloba was able to protect the brain while mitigating the side effects of the synthetic antidepressant (Qin XS et al 2005). Another study examined the ability of ginkgo to reduce the sexual dysfunction that sometimes accompanies conventional antidepressant drugs. Ginkgo was administered at 240 mg daily for 12 weeks. Interestingly, although the researchers didn’t find any statistically significant change across the whole group, they noted “spectacular individual responses” (Wheatley D 2004).

L-phenylalanine and tyrosine. Just as tryptophan and 5-hydroxytryptophan are precursors to serotonin, L-phenylalanine and tyrosine are precursors to dopamine and norepinephrine. Although not many clinical studies have examined the effects of these two amino acids, one review study found that people experiencing mild to moderate depression may find it helpful to “preload” with precursors of valuable neurotransmitters (Meyers S 2000).

Tryptophan and 5-hydroxytryptophan. Available as dietary supplements, these two substances are immediate precursors to serotonin. In some countries, tryptophan is licensed as an antidepressant (Murphy SE et al 2006). In one study, healthy women given tryptophan for 14 days experienced increased recognition of happy faces and words and decreased recognition of negative words. The research team concluded that tryptophan had improved the study participants’ supply of serotonin, much like a conventional SSRI (Murphy SE et al 2006). More study is needed on the use of these supplements in depression.

Life Extension Foundation Recommendations

Treatment of depression often takes place on several fronts. Depressed patients may benefit from exercise and other strategies, such as acupuncture, yoga, or meditation. In addition, psychiatric counseling can help people deal with the feelings of sadness and hopelessness that accompany depression.

If there are any underlying conditions, these should also be treated. Heart and vascular disease are associated with depression, and hypothyroidism can also cause depression. For more ideas on how to treat these conditions, please see the chapters on thyroid disorders and heart disease.

The following dietary supplements have been shown to help restore neurotransmitter levels and alleviate depression:

B vitamins—A full complement of B vitamins (including at least 1000 micrograms (mcg) vitamin B12, 250 milligrams (mg) vitamin B6, and 800 mcg of folic acid daily
Zinc—15 to 30 mg daily
TMG—2 to 4 grams (g) daily
Cytidine diphosphate choline—250 to 500 mg daily (alternatively, 1 to 3 teaspoons liquid choline chloride mixed with 2 ounces juice daily, 1 tablespoon pure lecithin granules daily, or 250 mg glyceryl phosphoryl choline daily)
Micronized creatine—500 mg (in capsule form) four to eight times daily
N-acetylcysteine—600 mg (in capsule form) one to two times daily on an empty stomach
Vitamin C—1 to 3 g daily
Vitamin E—400 International Units (IU) daily, with 200 mg gamma tocopherol
EPA/DHA—1400 mg EPA and 1000 mg DHA daily
SAMe—400 to 1200 mg daily without food
St. John’s wort—300 to 900 mg daily
Ginkgo biloba—120 mg daily
L-phenylalanine—500 to 1000 mg early in the day
Tyrosine—500 to 1000 mg daily
Tryptophan—500 to 1000 mg once or twice daily on an empty stomach
DHEA—15 to 75 mg daily, followed by blood testing in three to six weeks to make sure optimal levels are maintained

In addition, hormone therapy may be necessary to balance levels of important hormones, including pregnenolone, estrogen, progesterone, and testosterone. Hormone testing is recommended, followed by hormone supplements if necessary. Progesterone creams are available for application directly to the skin, while testosterone is available in a number of delivery systems. Special compounding pharmacies can help produce estrogen supplements that reflect the natural balance of estrogens rather than the strong animal estrogens used in conventional hormone replacement therapy. For more information, see the chapters Female Hormone Modulation and Male Hormone Modulation.

Product Availability

All the nutrients and supplements discussed in this section are available through the Life Extension Foundation Buyers Club, Inc. For ordering information, call anytime toll-free 1-800-544-4440, or visit us online at www.LifeExtension.com.

The blood tests discussed in this section are available through Life Extension National Diagnostics, Inc. For ordering information, call anytime toll-free 1-800-208-3444, or visit us online at www.LifeExtension.com.

Depression Safety Caveats

An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:

Choline

Do not take choline if you have primary genetic trimethylaminuria.
Choline can cause fishy body odor, excessive perspiration, hypotension (low blood pressure), depression, and gastrointestinal symptoms such as nausea and diarrhea.

Creatine

Do not take creatine if you have diabetes, kidney failure, a kidney disorder such as nephrotic syndrome, or are otherwise at risk of having a kidney disorder.
If you take creatine, have your serum creatinine level monitored frequently.
Creatine can cause muscle cramping, muscle strains, and gastrointestinal symptoms such as nausea and diarrhea.

DHEA

Do not take DHEA if you could be pregnant, are breastfeeding, or could have prostate, breast, uterine, or ovarian cancer.
DHEA can cause androgenic effects in woman such as acne, deepening of the voice, facial hair growth and hair loss.

D,L-Phenylalanine

Do not take D,L-phenylalanine if you have phenylketonuria.
Do not take D,L-phenylalanine if you are taking nonselective monoamine oxidase inhibitors (MAOIs).
Do not take D,L-phenylalanine if you have schizophrenia. D,L-phenylalanine can exacerbate tardive dyskinesia (involuntary facial movements) in people who have schizophrenia.
Consult your doctor before taking D,L-phenylalanine if you have high blood pressure. D,L-phenylalanine can exacerbate high blood pressure. D,L-phenylalanine can also cause high blood pressure.

EPA/DHA

Consult your doctor before taking EPA/DHA if you take warfarin (Coumadin). Taking EPA/DHA with warfarin may increase the risk of bleeding.
Discontinue using EPA/DHA 2 weeks before any surgical procedure.

Folic acid

Consult your doctor before taking folic acid if you have a vitamin B12 deficiency.
Daily doses of more than 1 milligram of folic acid can precipitate or exacerbate the neurological damage caused by a vitamin B12 deficiency.

Ginkgo biloba

Individuals with a known risk factor for intracranial hemorrhage, systematic arterial hypertension, diabetes, or seizures should avoid ginkgo.
Do not use prior to or after surgery.
Avoid concomitant use of ginkgo with NSAIDS, blood thinners, diuretics, or SSRI’s.
Gastrointestinal symptoms (nausea and diarrhea) may occur.
Allergic skin reactions may occur.
Elevations in blood pressure may occur.

L-Tryptophan

Do not take L-tryptophan if you have carcinoid tumors.
Do not take L-tryptophan while taking monoamine oxidase inhibitors (MAOIs) (type A) or within 2 weeks of discontinuing MAOIs.
Do not take L-tryptophan with any antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants or MAOIs.
Do not take L-tryptophan with serotonin 5-HT receptor agonists, including naratriptan, sumatriptan and zolmitriptan.
Do not take L-tryptophan if you have ischemic heart disease (e.g., a history of myocardial infarction, angina pectoris or documented silent ischemia), coronary artery spasm (e.g., Prinzmetal sangina), uncontrolled hypertension or any other significant cardiovascular disease.
L-tryptophan can trigger excess serotonin formation in tissues other than the target organ and cause significant adverse reactions.
L-tryptophan can cause nausea, diarrhea, loss of appetite, vomiting, difficulty breathing, pupil dilation, abnormally sensitive reflexes, loss of muscle coordination, blurry vision and cardiac dysrhythmia.

L-Tyrosine

Do not take L-tyrosine if you have inborn errors of metabolism alkaptonuria and tyrosinemia type I and type II.
Do not take L-tyrosine if you are taking non-selective monoamine oxidase (MAO) inhibitors.
Do not take L-tyrosine if you have hypertension.
Do not take L-tyrosine if you have melanoma

NAC

NAC clearance is reduced in people who have chronic liver disease.
Do not take NAC if you have a history of kidney stones (particularly cystine stones).
NAC can produce a false-positive result in the nitroprusside test for ketone bodies used to detect diabetes.
Consult your doctor before taking NAC if you have a history of peptic ulcer disease. Mucolytic agents may disrupt the gastric mucosal barrier.
NAC can cause headache (especially when used along with nitrates) and gastrointestinal symptoms such as nausea and diarrhea.

Niacin (nicotinic acid)

Do not take high doses of nicotinic acid (1.5 to 5 grams daily or more) if you have liver dysfunction, an unexplained elevation in your serum aminotransferase (transaminase) level, active peptic ulcer disease, arterial bleeding, or if you consume large amounts of alcohol.
Consult your doctor before taking high doses of nicotinic acid if you have a history of jaundice, peptic ulcer disease, gastritis, disease of the liver or bile ducts, gout, kidney dysfunction, or cardiovascular disease (especially acute myocardial infarction or unstable angina).
Consult your doctor before taking high doses of nicotinic acid if you have diabetes. High doses of nicotinic acid can negatively affect glucose tolerance. Monitor your serum glucose level frequently if you take nicotinic acid and have diabetes.
Have your doctor monitor your serum aminotransferase level if you take high-doses of nicotinic acid.
Nicotinic acid may cause flushing, principally of the face, neck, and chest. This flushing is thought to be prostaglandin-prostacyclin mediated. Histamine may also play a role in the flushing.
Nicotinic acid can cause dizziness, palpitations, rapid heartbeat, shortness of breath, sweating, chills, insomnia, nausea, vomiting, abdominal pain, and muscle pain.
High doses of nicotinic acid can cause blurred vision, macular edema, toxic amblyopia, and cystic maculopathy.

PABA (Para-aminobenzoic Acid)

Do not take PABA if you are taking sulfonamides or have a kidney disease.
PABA can cause anorexia, nausea, vomiting, fever, and rash.

Saint John’s Wort

St. John's wort can increase sensitivity to sunlight. To avoid a sunburn while taking St. John’s wort, minimize your exposure to the sun.
St. John's wort can cause bloating and constipation.

SAMe

Consult your doctor before taking SAMe if you have bipolar disorder. See your doctor frequently if you take SAMe and you have bipolar disorder.
Consult your doctor before taking SAMe if you take antidepressants. See your doctor frequently if you take SAMe in place of or in addition to antidepressants.
Consult your doctor before taking SAMe if you have cancer. Nucleic acid methylation patterns may change in people who have cancer and take SAMe.
Do not take SAMe if you are undergoing gene therapy.
SAMe can cause anxiety, hyperactive muscle movement, insomnia, hypomania, and gastrointestinal symptoms such as nausea and diarrhea.

Vitamin B1 (Thiamin)

Consult your doctor before taking vitamin B1 for a thiamin deficiency, lactic acidosis secondary to thiamin deficiency, Wernicke-Korsakoff syndrome, Wernicke's encephalopathy, or Korsakoff's psychosis.

Vitamin B2 (riboflavin)

High doses of vitamin B2 (riboflavin) may interfere with the Abbott TDx drugs-of-abuse assay.
Riboflavin absorption is increased in hypothyroidism and decreased in hyperthyroidism.
If you are taking nucleoside reverse-transcriptase inhibitors, even a mild riboflavin deficiency can increase your risk of lactic acidosis.

Vitamin B6

Individuals who are being treated with levodopa without taking carbidopa at the same time should avoid doses of 5 milligrams or greater daily of vitamin B6.

Vitamin B12 (cyanocobalamin)

Do not take cyanocobalamin if you have Leber's optic atrophy.

Vitamin C

Do not take vitamin C if you have a history of kidney stones or of kidney insufficiency (defined as having a serum creatine level greater than 2 milligrams per deciliter and/or a creatinine clearance less than 30 milliliters per minute.
Consult your doctor before taking large amounts of vitamin C if you have hemochromatosis, thalassemia, sideroblastic anemia, sickle cell anemia, or erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency. You can experience iron overload if you have one of these conditions and use large amounts of vitamin C.

Vitamin E

Consult your doctor before taking vitamin E if you take warfarin (Coumadin).
Consult your doctor before taking high doses of vitamin E if you have a vitamin K deficiency or a history of liver failure.
Consult your doctor before taking vitamin E if you have a history of any bleeding disorder such as peptic ulcers, hemorrhagic stroke, or hemophilia.
Discontinue using vitamin E 1 month before any surgical procedure.

For more information see the Safety Appendix

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