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File: St. John's Wort (Hypericum perforatum) Folate SAM-e Omega-3 Fatty Acids Acupuncture Exercise Depression HC 071153-434 Date: October 14, 2011 RE: A Review of Dietary Supplement, Therapeutic, and Lifestyle Therapies for Major Depressive Disorder Nahas R, Sheikh O. Complementary and alternative medicine for the treatment of major depressive disorder. Can Fam Physician. 2011;57(6):659-663. Pharmaceuticals do not effectively treat all patients with major depressive disorder (MDD). Many adults with depression use complementary and alternative medicine (CAM). The paper reviews 6 commonly used CAM therapies for MDD. In order to find the most commonly researched therapies, PubMed was searched with the search terms "depressive disorder" and "complementary therapies, diet, dietary supplements, vitamins, minerals, and exercise." The search was conducted from January 1966 to February 2010. St. John's wort (SJW; Hypericum perforatum), folate, Sadenosyl methionine (SAM-e), omega-3 fatty acids, acupuncture therapy, and exercise were identified. The authors reviewed clinical trials, meta-analyses, and review articles for safety and efficacy. St. John's Wort Since the 1980s, SJW has been used to treat depression. The safety and efficacy are well established. The authors focused their discussion on a meta-analysis of 29 randomized, controlled, double-blind studies.1 The meta-analysis included studies of 412 weeks in duration that most often used 500 to 1200 mg/day. The meta-analysis revealed that SJW was more effective than placebo (n = 3064) and as effective as conventional antidepressants (n = 2810). Adverse side effects were less common with SJW compared with conventional antidepressants. The authors only identified one longterm study (52 weeks), which was uncontrolled and showed maintained efficacy up to one year. The authors conclude that long-term studies are needed, and short-term use is effective, with fewer adverse side effects than conventional antidepressants. Though no studies have shown the necessity for hypericin, the authors recommend using

conventional extracts standardized to 0.3% hypericin at a starting dose of 600 mg/day, in three divided doses, increasing to 1200 mg/day as needed. They caution against using SJW with other antidepressants. SJW induces cytochrome P450 enzymes and intestinal P-glycoprotein, which alters the metabolism of hundreds of drugs. The authors state that "this need not be a contraindication for SJW use in most cases, but SJW should be avoided in patients taking certain drugs, such as immunosuppressants, antiretrovirals, and chemotherapeutic agents." Despite the authors' statement, it is prudent to discuss the use of SJW with a healthcare provider prior to initiating use to confirm that no concurrent medications are of special concern for adverse interactions. Folate People with folate deficiency are more likely to have depression, and less likely to respond to antidepressant drugs. Folate was evaluated as an adjunct therapy in three small, randomized controlled studies. The results were mixed with one study showing no effect of 0.2 mg/day folic acid compared with placebo for one year; one study showing a small significant improvement with 15 mg/day L-methylfolate compared with placebo for six months (P < 0.05); and one study showing a small significant improvement with 0.5 mg/day folic acid compared with placebo after ten weeks (P < 0.05). The authors conclude that there is insufficient evidence to recommend folate for treating depression. Rather, they recommend screening patients with depression for folate deficiency. SAM-e SAM-e is naturally occurring in human cells. Patients with depression have low levels of SAM-e. A systematic review reported that SAM-e was found to be beneficial in seven of seven trials evaluating parenteral SAM-e and in four of five trials of oral SAM-e (1600 mg/day). In three of five studies, oral SAM-e was equivalent to tricyclic antidepressants. The authors conclude that the evidence supporting SAM-e must be confirmed by larger studies. They state that the main drawback to SAM-e use is the cost, which is comparable to pharmaceutical antidepressants. Acupuncture A recent Cochrane review identified 30 randomized controlled trials, and the authors identified five more that were not in the Cochrane review. Overall the findings were inconclusive, with some studies reporting a benefit, and others reporting no benefit compared with control (sham procedure or wait list) for patients with MDD. The authors conclude that acupuncture should be considered only by patients who are unwilling or unable to use "traditional antidepressants," or that acupuncture should be used as adjunctive therapy. Exercise Exercise is known to make people feel good, but the mechanism of action is unknown. Several large systematic reviews suggest that exercise improves depression. The authors conclude that the magnitude of effect was unclear. The authors note that many physicians are reluctant to recommend exercise because people with depression typically lack motivation. They state that considering all of the health benefits associated with exercise, exercise should be prescribed for patients with depression. Omega-3 Fatty Acids Depression is less prevalent in societies that consume a lot of fish, which is high in omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]). Also, people with depression have significantly lower levels of omega-3 fatty acids. A

systematic review of pooled data from 16 randomized controlled studies revealed that DHA and EPA (dose not reported) were beneficial for patients diagnosed with MDD, but not for patients without the diagnosis. Further, a larger benefit was seen in patients with more severe depression at baseline. There was no dose-response relationship, and no differences were reported by these authors between DHA and EPA. However, the paper cited for this statement contained only two studies with DHA, and neither one found an antidepressant effect. So how the authors reached this conclusion is not evident. The authors conclude that omega-3 fatty acids are a promising therapy, especially for people with low omega-3 levels. Most physicians recommend at least 1 g/day of EPA and DHA combined. This statement is also not supported by the references or the literature. The most common side effect is fishy taste (only capsulated products were evaluated). [Note: Experts suggest that up to 3 g/day EPA+DHA is safe and effective.] Conclusion Regular exercise should be recommended for all patients, unless contraindicated by a physician. Patients can be screened for folate and omega-3 fatty acid deficiencies, and supplemented to normalize levels. Physicians should query about SJW use, or patients should volunteer the information, so that herb-drug interactions can be minimized. Heather S. Oliff, PhD
Reference 1 Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448. doi:10.1002/14651858.CD000448.pub3.

Referenced article can be found at http://www.cfp.ca/content/57/6/659.full.pdf+html.

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