Since our last review of the evidence for natural treatments in April of 2006, several new studies have been published, though they haven’t necessarily clarified the efficacy picture. Here, we’ll look at how the most popular natural treatments stack up.

Omega-3 fatty acids
Omega-3 fatty acids are still considered effective for the prevention of cardiovascular disease, including arrhythmias, atherosclerosis, and hypertriglyceridemia. The American Heart Association recommends that everybody eat two servings of fish per week, and that patients with coronary artery disease consume 1 gm of omega-3 per day. But as more data on omega-3 for mood disorders has emerged, we are losing confidence. The largest study of omega-3 for adjunctive treatment of depression, which included 77 patients, was negative (Silvers KM et al., Prostaglandins Leukot Essent Fatty Acids 2005;72 (3):211–218).

Recently, a particularly trendy use of omega-3 is for the treatment of depression in pregnant women. This is based on the reasonable theory that since omega-3 is thought to aid the neurodevelopment of the fetus, it would be an unusually safe perinatal antidepressant. Unfortunately, two out of three placebo-controlled trials of omega-3 monotherapy in this population were negative (see Freeman M, J Clin Psychiatry 2009;70[suppl 5]:7–11 for a review of this literature). Finally, a meta-analysis of all randomized trials of omega-3 for depression showed little if any overall effect (Appleton K et al., Am J Clin Nutrition 2006;84(6):1308–1316).
TCPR Verdict: Effective for heart health, but for depression, a placebo?

Folate
In the June 2009 issue of TCPR we reviewed the mixed evidence for the use of folate in depression. Some may recall that Pamlab has begun to market an expensive form of folate, methylfolate (brand name Deplin), on the theory that since it crosses the blood brain barrier (and folate does not), it is more effective. Pamlab must be encountering some success, because it recently funded a fancy CME supplement published by the Journal of Clinical Psychiatry (Volume 70, suppl 5, 2009). But no study has actually compared the two formulations to prove that Deplin is worth the money. In fact, only three randomized trials of Deplin for depression have been published, all with small numbers of subjects, and all with flawed research designs.

For example, the largest of these studies randomly assigned 96 elderly patients with dementia and depression to either methylfolate 50 mg/day or to trazodone 50 mg BID. The two treatments performed equally well on the primary outcome variable, indicating that methylfolate works as well as a standard antidepressant…right? Not really. A very robust dose of methylfolate (more than six times the recommended dose of 7.5 mg/day) was compared to a baby dose of trazodone—100 mg/day (trazodone’s antidepressant dose is 150 mg–400 mg/day)—and trazodone is rarely used as an antidepressant.

Essentially, this study found that methylfolate cured depression as well as a sleeping pill (Passeri M et al., Aging 1993;5:63–71), an interesting piece of trivia, perhaps, but not the evidence upon which our treatment decisions should be made.
TCPR Verdict: Antidepressant data thus far are limited and unimpressive.

Kava
Kava (150–300 mg/day) is the only herbal medication with solid evidence of efficacy for anxiety in placebo-controlled trials. (See a brief recent review in Sarris J et al., Hum. Psychopharmacol Clin Exp 2009;24:41–48, page 2.) However, few patients are likely to take it once they hear about the possibility of hepatic toxicity. The side effect is thought to be rare, mild, and reversible, with an incidence of about one case per million monthly doses (Bauer R., Planta Med 2003;69:971–972). Nonetheless, the 2002 FDA warning of the possibility of hepatotoxicity seems to have scared away most patients.
TCPR Verdict: Effective, probably safe, but with a scary reputation.

Chamomile
There is some evidence that chamomile may be effective for generalized anxiety disorder (GAD). A 2009 randomized double-blind placebo-controlled study of 57 patients with mild to moderate GAD found that treatment with chamomile extract (Matricaria recutita) resulted in a significant reduction in Hamilton Anxiety Rating (HAM-A) scores (Amsterdam J et al., J Clin Psychopharmacol 2009;29:378–382).

Participants in the study took up to five 220 mg chamomile capsules per day. There is some variation in the concentration of chamomile in a tea bag, but some contain 600 mg or more, so a cup of tea might have the same effect. (To learn more, read “Chamomile May Be Effective For GAD,” TCPR October 2009.)
TCPR Verdict: A small sample size could have created false results. Nonetheless, it won’t hurt and it might help.

Acupuncture
Recently, a systematic review of acupuncture for depression was published, and the authors located nine randomized controlled trials. The results were mixed. Two studies found acupuncture as effective as tricyclic antidepressants, but three other studies found it to be no more effective than placebo (sham) acupuncture; in one of these studies sham beat the real thing (Leo RJ et al., Journal of Affective Disorders 2003;97:13–22). The problem here is that it’s very hard to devise a good placebo for testing acupuncture. The common method is to compare genuine acupuncture, in which needles are placed along specific energy “meridians,” with fake acupuncture in which needles are placed at random locations. It turns out that this sham acupuncture is often effective. This implies either that real acupuncture does not work, or that acupuncture is so effective that it works no matter where you place the needles.
TCPR Verdict: For depression, it sometimes works, sometimes doesn’t.

SAMe and St. John’s Wort: See this month’s interview of Dr. Richard Brown on page 4 for coverage of these treatments.