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Complementary Approaches to Depression

By Yousry Naguib, Ph.D.
Vitamin Retailer magazine (August 2005)

Depression is a mood disorder that causes feeling sad or hopeless for an extended period of time. Scientific and clinical investigations of mood disorders and depression led into today’s knowledge that depressive disorders are common, serious, and sometimes life-threatening and that their effects are persistent and costly.
Depressive disorders have a high prevalence, around 10% in the general population. According to the Depression and Bipolar Support Alliance, depression is the most common serious brain disease in the United States, affecting more than 23 million adults each year. The World Health Organization projects major depression to be the second leading cause of disability worldwide by the year 2020.
Women are twice as likely as men to experience feelings of depression. Hormonal changes may play a role in these feelings, which may be evident during pregnancy, especially shortly after the birth of a baby (postpartum depression) or shortly before or during menopause.           
Although depression is quite common, its symptoms may go unrecognized and vary from person to person. Its symptoms include getting less enjoyment from usual activities, feeling worthlessness, irritable, desperate, feeling tired or sleepy all of the time, and trouble sleeping.
Medication is often the first treatment choice for adults with moderate or severe depression. Although antidepressant medications don’t cure depression, they can help to achieve remission – the disappearance or nearly complete reduction of symptoms. Antidepressant medications include monoamine oxidase (MAO) inhibitors, tricyclic antidepressants and selective serotonin reuptake inhibitors.
MAO inhibitors increase norepinephrine levels, while tricyclics enhance norepinephrine transmission. Research studies have indicated the importance of serotonin in the pathophysiology of depression. (Rush AJ, et al. Neurobiological basis for psychiatric disorders. In: Rosenberg RN, editor. Comprehensive neurology. New York: Raven Press; 1991).
Despite advances in the pharmacotherapy of depression, only one third of patients respond favorably to antidepressant drugs. And one third does not respond at all, and in clinical trials, at least one third responds to placebo. Because of the poor outcomes of treatment with antidepressant medication, patients are increasingly using complementary and alternative medicine.

Alternatives to antidepressant drugs
St John’s wort (SJW)   
            St John’s wort (Hypericum perforatum) is widely used herbal supplement for mild-to-moderate depression. Clinical studies have shown SJW extracts to have antidepressant action either greater than placebo or equal in action to standard prescription antidepressant drugs.
A review published in 1995 analyzed 12 controlled clinical trials—nine were placebo-controlled and three compared St. John’s wort extract to antidepressant drugs maprotiline or imipramine. All trials showed greater antidepressant effects with SJW compared with placebo and comparable results with SJW as with the antidepressant medications (Ernst E. St. John’s wort, an antidepressant? A systematic, crieteria-based review. Phytomedicine 1995; 2:67).
A recent review published this year analyzed 37 randomized and double-blind controlled clinical trials—twenty six were placebo-controlled and fourteen compared St. John’s wort extract to antidepressant standard drugs. The study concluded that current evidence regarding SJW extracts is inconsistent and confusing. And in patients with major depression, several placebo-controlled trials suggest that the tested SJW extracts have minimal beneficial effects while other trial suggests that SJW and standard antidepressants have similar beneficial effects (Linde K et al. St. John’s wort for depression. Cochrane Database Syst Rev 2005; 18:CD000448).
Most of the clinical studies have used SJW extract standardized to 0.3 percent hypericin at a dose of 300 mg three times daily.
SWJ has an encouraging safety profile. However, recent reports indicate the possibility of interactions with prescribed drugs (Markowitz JS et al. Effect of St. John’s wort on drug metabolism by induction of cytochrome P450 3A4 enzyme. Obstet Gynecol Surv 2004; 59:358). Some of such interactions may cause either adverse effects or treatment failures.
SJW has been shown to lower the plasma concentration of certain drugs, including immunosuppressant drugs (cyclosporine, a drug taken by transplant patients to fend off the immune system’s tendency to reject a transplanted organ), warfarin (anticoagulant), digoxin (is a drug originally derived from the foxglove plant, Digitalis lanata and used for congestive heart failure), birth control pills, and protease inhibitors (used to treat persons with HIV infection). There is clearly a need for safe and natural antidepressants.

Apocynum venetum
            A standardized extract from Apocynum venetum, sold under the trade name PosinolTM by Soft Gel Technologies, Inc., has been found to shorten the immobility time in an animal model (forced swimming test) for antidepressant activity at the dosage of 15 mg/kg body weight, indicating possible antidepressant activity. This effect was comparable to that of the antidepressant drug Imipramine (15 mg/kg), and to St. John’s Wort extracts (250 mg/kg). This antidepressant effect might be related to the bioactive flavonoids hyperoside and isoquercitrin in PosinolTM, which are also present in St. John’s wort extract (Butterweck V et al. Antidepressant effects of apocynum venetum leaves in a forced swimming test. Biol Pharm Bull 2001; 24:848).

S-Adenosyl-L-methionine (SAMe)
SAMe is widely used dietary supplement with antidepressant properties. The bioavailability and lack of toxicity of SAMe has been demonstrated in a clinical trial involving fifteen healthy volunteers, who received oral SAMe for 4 weeks; the dosage was titrated over 5 days to 1600 mg/day. Serum levels of SAMe were significantly elevated, no significant toxic metabolites were detected and no subject exhibited elevated homocysteine levels during SAMe treatment (Goren JL et al. Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans. Pharmacotherapy 2004; 24:1501).

Ginkgo biloba
A recent clinical trial on healthy older volunteers showed that supplementation with ginkgo biloba extract (GBE) at a dosage of 120 mg per day continuously for 10 months improved mood and the self-assessed performance of the tasks of everyday living. These improvements were diminished on cessation of treatment with GBE (Trick L et al. The effects of Ginkgo biloba (LI 1370) supplementation and discontinuation on activities of daily living and mood in free living older volunteers. Phytother Res 2004; 18:531).

Omega-3 fatty acids
Depression has been associated with significantly low levels of EPA and DHA in cell tissue contents (red blood cell membrane, plasma). In an 8-week, double-blind, placebo-controlled trial, comparing omega-3 polyunsaturated fatty acids (PUFA, 9.6 g/day) with placebo in 28 patients with major depressive disorder; patients in the omega-3 PUFA group showed a significant improvement in the symptoms as compared to those in the placebo group. The study suggested that omega-3 PUFA could improve the short-term course of illness and were well tolerated in patients with major depressive disorder (Birch EE et al. A randomized controlled trial of early dietary supply of long-chain polyunsaturated fatty acids and mental development in term infants. Dev Med Child Neurol 2000; 42:174)

5-Hydroxy-L-tryptophan (5-HTP)
Research has shown that oral administration of tryptophan can modify sleep and mood via its actions to stimulate neuronal serotonin production and release (Borbely A, Youmbi-Balderer G. Effects of tryptophan on human sleep. Interdisciplinary Top Gerontol 1987; 22:111). Unfortunately, the outbreak 10 years ago of a toxic response to non-prescription preparations of L-tryptophan diminished interest in this supplement. The toxic response, termed eosiniphilia myalgia syndrome (EMS), was characterized by neurologic and pulmonary complications that resulted in a small number of deaths. Because the occurrence of the syndrome appeared to be correlated with the use of tryptophan, it was thought that a contaminant (termed peak X) in the product, not tryptophan itself, was responsible for EMS.
5-HTP is a close relative to tryptophane and is the immediate precursor in the biosynthesis of the neurotransmitter (brain’s signal carrier) 5-hydroxy-tryptamine (serotonin) from the amino acid L-tryptophan (L-Trp). 5-HTP is derived from the seed pods of Griffonia simplicifolia, a West African plant.
            In one study, 5-HTP was found to be as effective as the antidepressant drug fluvoxamine. Researchers used the Hamilton Depression Rating Scale and a self-assessment scale to gauge the effectiveness of the two treatments. Both scales revealed a gradual reduction in depressive symptoms through time with both medications (Poldinger W et al. A functional dimensional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophane and fluvoxamine. Psychopathology 1991; 24:53).
L-tyrosine is a nonessential amino acid that the body synthesizes from the amino acid phenylalanine. Tyrosine is the precursor of the neurotransmitters dopamine, norepinephrine, and epinephrine (main stress-related hormones). L-tyrosine may affect several health conditions, including Parkinson’s disease and depression. Studies have suggested that tyrosine may help people with depression (Gelenberg AJ et al. Neurotransmitter precursors for the treatment of depression. Psychopharmacol Bull 1982; 18:7).
In one study, tyrosine administration was shown to improve cognition and performance in soldiers under stressful conditions (Banderet LE, Lieberman HR. Treatment with tyrosine, a neurotransmitter precursor, reduces environmental stress in humans. Brain Res Bull 1989; 22:759) and (Ahlers ST et al. Tyrosine and glucose modulation of cognitive deficits resulting from cold stress. In: Marriot BM, ed. Food components to enhance performance: Washington, DC: National Academy Press, 1995: 301)

Folic Acid
Studies investigating plasma folic acid levels showed association between depression disorder (particularly severe depression) and low folic acid levels. Research studies also suggest folic acid has either antidepressant properties or can act as an augmenting agent for standard antidepressant treatment. (Paul RT et al. Folic acid: neurochemistry, metabolism and relationship to depression. Hum Psychopharmacol 2004; 19:477)

Vitamin B6
Vitamin B6 (Pyridoxine) is a cofactor for enzymes that catalyze the conversions of L-tryptophan to serotonin and L-tyrosine to norepinephrine. It is suggested that vitamin B6 deficiency might result in depression. In one study, 21 percent of 101 depressed patients had low plasma levels of vitamin B6 (Stewart JW et al. Low B6 levels in depressed outpatients. Biol Psychiatry 1984; 19:613).
In another double-blind, crossover study, women with vitamin B6 deficiency associated with oral contraceptives improved after treatment with B6, 2 mg twice a day for two months. Women who were not deficient in B6 did not respond to supplementation (Adams PW et al. Effect of pyridoxine hydrochloride (vitamin B6) upon depression associated oral contraceptives. Lancet 1973; 1:897).

Vitamin B12
Vitamin B12 deficiency might also result in depression. In one study, intravenous administration of vitamin B12 has resulted in significant improvement in depressed patients with vitamin B12 deficiency. Geagea K et al. Response of a psychiatric patient to vitamin B12 therapy. Dis Nerv Syst1975; 35:343)

Vitamin C
Vitamin C is involved in the enzymatic hydroxylation of tryptophan to serotonin. In one study, supplementation with 1 g of ascorbic acid daily for three weeks to 40 chronic psychiatric patients showed significant improvements in depressive symptoms, as well as in overall functioning (Milner G. Ascorbic acid in chronic psychiatric patients: a controlled trial. Br J Psychiatry 1963; 109:294).

Myo-inositol is the active form of nine distinct isomers of inositol. It is vital to many biological processes of the body. The major dietary forms of myo-inositol are inositol hexaphosphate or phytic acid, which is widely found in cereals and legumes. Myo-inositol has been shown to exhibit positive effects in a number of studies related to depression, and panic attacks. Levels of myo-inositol in cerebrospinal fluid have been reported to be lower in people suffering from depression as compared to general populations. In one double-blind study, 28 depressed patients received placebo or high-dose (12 grams) myo-inositol for four weeks. Overall, significant improvement was achieved in the treatment group but not in the placebo group. Levine J et al. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 1995; 152:792).