As with omega-3s, the first clue that folate might help treat depression came from population studies showing an association between folate deficiencies and depression. Scientists began to ask whether administering the vitamin to patients would help treat the condition.
Studies have focused on three forms of the vitamin: folic acid, the synthetic version used in supplements and fortified foods; 5-methylene tetrahydrofolate, also known as 5-MTHF, methylfolate or L-methylfolate, which is a breakdown product of folic acid and folate; and folinic acid, a synthetic compound that gets broken down into 5-MTHF.
As in the case of omega-3s, existing studies on the folate compounds have looked at patients with a variety of diagnoses, including major depressive disorder, alcoholism plus depression, dementia with depressive symptoms, bipolar depression and schizophrenia. Most studies examined the compounds' effects when given in conjunction with another drug, such as the antidepressant fluoxetine (Prozac) or lithium. In several studies, the folate compounds appeared to improve the effectiveness of the prescription drugs and in some cases to reduce unwanted side effects.
Mischoulon says many researchers are now focusing on 5-MTHF, or L-methylfolate. Folate is needed to make the brain chemicals dopamine, serotonin and norepinephrine, and L-methylfolate is the only form of folate that can cross the blood-brain barrier. That means a smaller dose of L-methylfolate may be able to exert the same effect as a much larger dose of folate. (Mischoulon is conducting a clinical trial of a commercial form of L-methylfolate called Deplin; the trial is supported by Pamlab, Deplin's maker.)
Last year, the American Psychiatric Assn.'s Task Force on Complementary and Alternative Medicine reviewed the body of evidence on folate and depression and concluded that the folate compounds appeared to be "a low-risk and reasonable part of a treatment plan" for major depression when added to prescription antidepressants. Much more research, they concluded, is needed to determine how useful folate may be on its own.
S-adenosyl-L-methionine, or SAM-e, has a close relationship with folate: the body needs 5-MTHF in order to make SAM-e. SAM-e, in turn, is needed to make key messenger chemicals in the brain.
European scientists first noted SAM-e's antidepressant effects in the 1970s, and the compound has been used as a depression treatment on that continent ever since. In the U.S., SAM-e wasn't commercially available until the 1990s.
Intrigued by reports from Europe, in 2002 the U.S. Agency for Healthcare Research and Quality conducted a review of the evidence on SAM-e and depression, and concluded that the compound was better than a placebo and equivalent to standard antidepressants in improving mood.
But most of the studies reviewed by the agency dated from the 1970s and 1980s and used an intravenous or intramuscular form of SAM-e (a SAM-e shot, that is, instead of a pill). Researchers who studied oral SAM-e in the 1990s noted that the molecule was very unstable and subject to rapid disintegration.
A newer, more stable version of oral SAM-e is now available. But despite this, there have been few recent studies on SAM-e and depression.
One small trial published in 2004 found that oral SAM-e quickly reduced symptoms of depression in a small population of people infected with HIV. Another 2004 study reported that SAM-e improved symptoms in patients with major depression who were taking prescription antidepressants but had experienced little to no relief from the drugs.
Last year, Harvard researchers reported a larger trial in the American Journal of Psychiatry in which 73 patients with major depression whose prescription antidepressants weren't helping received either SAM-e pills or a placebo as an "add-on" treatment. After six weeks, patients who took SAM-e had a greater improvement in symptoms.
Like the majority of studies on omega-3s and folate, SAM-e studies also, on the whole, have tended to focus on a small number of patients for a short time. The American Psychiatric Assn. Task Force's 2010 report called the published studies on SAM-e "promising" but noted that "definitive studies are still required."
Those studies may be a long way off because, as a naturally occurring compound, SAM-e can't be patented, says Papakostas, who was lead author of the Harvard study. For that reason, he says, "research is moving very slowly."
St. John's wort
St. John's wort is one of the most well-studied natural supplements for depression, but opinions on the supplement are split among the psychiatrists who research alternative therapies for depression.
Study results are similarly mixed. Some well-designed studies have shown that St. John's wort relieves depression better than a placebo; others show it doesn't. Ditto for studies comparing St. John's wort with prescription drugs.