The very first issue of The Carlat Report (TCR 1:1) featured an article on St. John’s Wort for the treatment of depression. While this may be the most famous of the “natural” antidepressants, we are hearing more and more about others, including those surveyed in this article.

Omega-3 Fatty Acids.
Understanding the omega-3 fatty acid story is simple enough, but it will require that you revisit some of your more traumatic memories from organic chemistry. It's all about lipids. Recall that fatty acids (hereafter abbreviated as "FAs") are long hydrocarbon chains with a lipophilic methyl end and a hydrophilic hydroxyl end. Because of these chemical properties, they naturally form a "lipid bilayer" in our cell membranes. A bunch of big proteins are lodged within this layer, providing receptor sites for all those neurotransmitters that allow us psychiatrists to make a living.

Omega-3s are great for your heart; the evidence is not as clear for mood disorders

There are many different FAs required by humans, but through a quirk of biology, our metabolic factories are only equipped to manufacture some of them. The ones that we can't make on our own we have to get from our diet, and these are called "essential FAs." The omega-3 FAs fall in this category.

Not all omega-3s are created equal: there are three different varieties: EPA, DHA, and ALA (I'll spare you the full chemical names, as no one in their right mind would ever use them). EPA and DHA are derived from fish, and are what are normally found in the capsules that your patients are likely to buy when they ask for omega-3 at the pharmacy. ALA is usually derived from flax seed oil, and has not been studied as much as EPA and DHA for medical indications.

In cardiology, omega-3s are widely considered a boon. Large epidemiological studies and clinical trials beginning in the late 1970s have endorsed the value of omega-3s in protecting against heart attacks. In one of the most widely cited studies, patients were randomized to a Mediterranean style diet with a special margarine enriched with omega-3s; at 27 month follow-up, these patients had a 76% lower risk of MI and death than the control group, a result that compares favorably with the effects of lipid-lowering agents like the statins (Lancet 1994; 344:1383- 1389). For cardiovascular protection, the American Heart Association recommends doses from 1 g to 4 g per day, depending on your cardiac risk status.

In psychiatry, there is much less agreement. A study published in the Archives of General Psychiatry caused a stir in 1999, because it was written by such a reputable research group. Patients with bipolar disorder on conventional medication (n = 30) were randomized to either adjunctive omega-3s (at a very high dose of 6.2 grams of EPA and 3.4 grams of DHA, requiring seven capsules twice a day), or placebo (olive oil capsules) for four months. Those receiving omega-3s stayed in remission significantly longer than those on placebo (Arch Gen Psychiatry 1999; 56(5):407-412). However, two recent studies attempted to replicate this finding with much larger numbers of bipolar subjects (121 in the two combined studies). Neither study found any separation between adjunctive EPA and placebo (Keck et al, Bipolar Disord 2003; 5(suppl 1):58).

What about omega-3 for depression? Three placebo-controlled studies have evaluated adjunctive EPA for depression, and all showed some benefit for the fatty acid. The only monotherapy trial done to date has shown no separation from placebo, but the version of omega-3 used in this study was pure DHA, rather than a combination of EPA and DHA (Marangell et al, Am J Psychiatry 2003; 160(5):996-998). Thus, the evidence so far is promising but mixed on omega-3s in mood disorders.

In general, most of the studies cited above have used either pure EPA or EPA/DHA combinations with larger proportions of EPA. Doses in these studies have ranged from 1g to 6 g per day. In standard formulations, two capsules of fish oil deliver 1 gram of EPA/DHA, so your patient may end up taking two to twelve capsules per day. Side effects include GI disturbances, most notably diarrhea, and can be minimized by dividing the dose BID or TID, and taking it with food or ginger root. Some people complain of a fishy aftertaste, but this is minimized with high-quality formulations. Even if taken in extremely high doses, it seems to be safe. Eskimos may eat more than 16 g of omega-3s per day, and they suffer no dangerous side effects as a result.

SAMe.
SAMe is S-Adenosyl-L-Methionine and until recently was just another chunk of information that physicians had been forced to memorize for regurgitation during biochem finals. Well, like Freddy Krueger in Nightmare on Elm Street, "Heeeee's Back!"

We have the Italians to thank for SAMe's newfound prominence, since the very first clinical study of SAMe for depression was published by Italian researchers. Over the years, SAMe has become something of an Italian institution, as evidenced by the fact that in a 1995 survey, SAMe emerged as the third most frequently prescribed antidepressant, behind Prozac and Elavil (Acta Psychiatr Scand, 1995; 92:7-9).

Although not a plant product, SAMe qualifies as "natural" because it is naturally produced by our bodies, being a derivative of the amino acid Lmethionine. Biochemically, SAMe is quite the workhorse for us all, specializing in donating methyl groups to all manner of crucial molecules. Without SAMe, we could not produce norepinephrine or serotonin, nor could we create phospholipids.

The first batch of SAMe studies used intravenous (IV) SAMe, a route of administration that is more reliable because the oral preparation tends to get transformed in the gut to a less active metabolite. These studies of IV SAMe were quite impressive, with results better than placebo and as good as tricyclic antidepressants (Am J Psychiatry 1988; 145:1110-1114).

Of course, studies endorsing IV use of SAMe don't help us much, as few of us are equipped to jab patients in our offices, and compliance with that mode of treatment might be an issue. The double-blind studies of oral SAMe have been pretty consistently positive, with four of five double-blind trials endorsing its effectiveness (Alpert and Mischoulon, "One-Carbon Metabolism and the Treatment of Depression," in Natural Medications for Psychiatric Disorders, Lippincott Williams & Wilkins, 2002). The one negative study was conducted by an influential group at Mass. General (Acta Psychiatr Scand, 1992; 86:42-45) who found no separation between oral SAMe and placebo, but there was evidence that the preparations they used had degraded, leading to underdosing relative to other studies. A large review published by the Quality (AHRQ) involved a metaanalysis of 28 studies, and concluded that SAMe is as effective as conventional antidepressants (www.ahcpr.gov/clinic/epcsums/samesum.htm).

Generally, the positive studies have used a dose of 1600 mg QD of SAMe. Tablets are available in 200 and 400 mg dose strengths, and a recent internet search found prices ranging from $3 to $5 per day, assuming 1600 mg QD. Side effects are basically non-existent (including a refreshing lack of sexual side effects), although there's a theoretical risk of a buildup of homocysteine, since we convert SAMe to this amino acid normally. So far there have been no documented problems. Many physicians recommend that patients on SAMe play it safe by taking folate and vitamin B supplements, which help metabolize homocysteine.

By the way, a potential "two-fer" is the depressed patient with osteoarthritis, as SAMe appear to be just as effective as NSAIDS for the pain accompanying this condition (www.ahcpr.gov/clinic/epcsums/samesum.htm).

Inositol.
Inositol looks structurally like the purest of all placebos, glucose, and it is in fact an isomer of that sweet molecule. Considered by some to be a B-vitamin, inositol is involved in some pretty heavy duty biochemical machinery, including the phosphatidylinositol (PI) cycle, which is a second messenger system that tells the interior of our cells that serotonin, norepinephrine, and dopamine have hopped onto receptor sites. Given its premiere position in the neurocircuitry of emotion, it is no surprise that researchers have tried megadoses of inositol in depressed patients to see what would happen.

A group of researchers in Israel has become very enthusiastic about its use, and has published just about all of the half dozen or so placebo-controlled studies of inositol for a variety of conditions. These have all been double-blind, controlled studies, with the interesting twist that both the active medication and the placebo are some version of sugar. These trials were all small, ranging from 12 to 27 subjects. Doses of inositol ranged from 12 grams QD to 18 grams QD. These studies found benefits of inositol over placebo for major depression (Am J Psychiatry 1995; 152:792-794), panic disorder (Am J Psychiatry 1995; 152:1084-1086) obsessive-compulsive disorder (Am J Psychiatry 1996; 153:1219-1221), and bulimia and binge eating disorder (Int J Eating Disord 2001; 29:345-348).

If you choose to give inositol a try, you should know that the typical dose used in studies has been 12 grams per day, split into two or three doses (i.e., 6 grams BID or 4 grams TID). Most common side effects are flatulence, diarrhea, and nausea. The most cost effective way to take it is in powder form, which is usually 2 grams per teaspoon. This is usually dissolved in fruit juice and gradually increased from a starting dose of 1 teaspoon BID to 2 teaspoons TID. If your patient shops around enough online for pure inositol powder, he or she should be able to get it for about $1 to $2 per day.

TCR VERDICT:
SAMe works for depression; Omega-3s are great for the heart, fair for the brain; Inositol may have that SSRI spectrum of efficacy but we need more studies to be sure!