Steve Balt, MD
Research fellow, Addiction Pharmacology Research Laboratory, California Pacific Medical Center
Dr. Balt discloses that his spouse is employed as a sales representative for Bristol Myers Squibb.
Patients are probably asking you about Deplin, or L-methylfolate, a version of folic acid that is being marketed by Pamlab as an adjunctive treatment for depression. In a prior issue of TCPR (June 2009) we reviewed available information on Deplin, concluding that there’s little evidence it is any more helpful for depression than much cheaper folic acid. Have we learned anything new in the last two years?
Interest in folate began in a landmark study by Victor Herbert in 1962. After eating a folate-free diet for four months, Herbert developed depressive symptoms and numerous hematologic abnormalities, all of which were reversed by folate supplementation (Herbert V, Trans Assoc Am Physicians 1962;307–320). While Herbert’s symptoms may have been nonspecific and due to poor nutritional status, several epidemiologic studies over the years have shown a relationship between low serum and/or red blood cell folate and depression and other neuropsychiatric conditions (Frankenburg F, Harv Rev Psychiatry 2007;15(4):146–160). It isn’t clear whether the correlation is due to a general nutritional deficiency—as in Herbert’s case—but it is tempting to conclude that supplemental folate may help to treat mental illness.
L-methylfolate (Pamlab’s Deplin) is also known as methyltetrahydrofolate (MTHF), a derivative of folic acid. Deplin is marketed as a “medical food,” which is defined by the FDA as “a food which is formulated to be consumed under the supervision of a physician and which is intended for the specific dietary management of a condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”
There are no recognized “distinctive nutritional requirements” for depressed patients, but based on neurochemistry, it makes sense that folate might help. How? Well, folate is first converted into dihydrofolate (DHF), and then into L-methylfolate (Deplin). L-methylfolate is the “active” form of folate in the brain; it helps to form tetrahydrobiopterin (BH4), a crucial cofactor in the synthesis of serotonin, norepinephrine, and dopamine. In theory then (even though this has not been proven), low levels of folate could cause neurotransmitter deficiencies, which could then be corrected by L-methylfolate supplementation. Because L-methylfolate is involved in the synthesis of three monoamines, Dr. Stephen Stahl has dubbed Deplin a “trimonoamine modulator” (Stahl SM, CNS Spectrums 2007;12(10):739–744).
The promotional literature for Deplin, as well as several articles published over the last few years (many underwritten by Pamlab), imply that L-methylfolate is essential for BH4 synthesis, and that it is the only form of folate that can cross the blood-brain barrier. However, neither of these propositions is entirely true. BH4 can be generated in at least three ways unrelated to L-methylfolate, and it is unknown how significant the L-methylfolate pathway is (Ponzone A et al, Med Res Rev 2004;24(2)127–150). Furthermore, regular folic acid can, in fact, enter the brain without being transformed to L-methylfolate, although L-methylfolate may be the preferred substrate for the blood-brain barrier transporters (Hermann W and Obeid O, Clin Chem Lab Med 2007;45(12):1614–1620).
But is any of this even relevant for neurotransmitter synthesis? Probably not, since it’s well known that the CSF folate level stays at a relatively constant concentration across wide variations in the serum folate (and, presumably, L-methylfolate) level (Obeid et al, Clin Chem 2007 53(2):326–333). So for the vast majority of our patients—except for those eating a folate-free diet for four months, perhaps—there’s probably sufficient folate in the brain for monoamine synthesis, regardless of serum folate status.
A tenuous biochemical explanation notwithstanding, the key question is whether folate supplementation actually works for depression. A few small studies over the years have shown that folate and L-methylfolate may be somewhat helpful as adjunctive agents in the treatment of depression and other neuropsychiatric phenomena, but with no obvious advantage of L-methylfolate (see TCPR, June 2009). Earlier this year, however, at the 2011 European Congress of Psychiatry, two controlled studies of Deplin were made public. Neither has been published, but the results are available by request from Pamlab as a poster (Papakostas GI et al, EPA 2011, Vienna, Austria; 13 March 2011).
In the first study, 148 patients with SSRI-resistant depression were randomized to one of three groups. In each group, patients continued their SSRIs and used Deplin or placebo as an adjunct: 1. Deplin 7.5 mg/d for 30 days, then 15 mg/d for 30 days; 2. placebo for 30 days, then Deplin 7.5 mg/day for 30 days; or 3. placebo for 60 days. There was no statistically significant difference in outcomes among any of the three groups.
The second study was simpler. Seventy-five patients, also with SSRI-resistant depression, were randomized to 60 days of adjunctive treatment with either 15 mg/d of Deplin or placebo. In this trial, Deplin separated from placebo: 32.3% of Deplin-treated patients showed a response (ie, 50% reduction in HAM-D score), vs 14.6% of placebo patients (p=0.04), with a number needed to treat (NNT) of approximately 6. Mean reduction in HAM-D score was 5.6 points, vs 3 points for placebo (p=0.05). Deplin was well-tolerated, with only one dropout (vs two on placebo).
Thus, we have one positive study, and one larger negative study. Neither study compared Deplin with generic folic acid—and such a study is unlikely to be done (presumably because Pamlab is concerned that folic acid would be equivalent to Deplin). Thus, at this point, the clinical trial data on Deplin is suggestive, but by no means clear. We would need another positive controlled trial before being convinced it is effective.
But assuming for a moment that Deplin does successfully augment antidepressants, to whom should we prescribe it? Pamlab’s answer is that Deplin is especially appropriate for patients who have a mutation that slows the conversion of folic acid to L-methylfolate. This is called the MTHFR C677T mutation, found in 10% of whites and up to 22% of Hispanics and those of Mediterranean descent (Farah A, CNS Spectrums 2009;14(1 supp 2):2–7). Theoretically, if your body is genetically inefficient at converting folate to L-methylfolate, you might make fewer neurotransmitters, and you might be more vulnerable to depression (the tenuous biochemical argument that we reviewed above).
But there are problems with the mutation story, too. In heterozygotes for the mutation, the conversion rate is reduced only a little—to 70%–80% of the normal rate. Even in homozygotes, the conversion rate is reduced to 30%–40%. Given all the uncertainties about the role of L-methylfolate in neurotransmitter synthesis, it is not clear that mutations decreasing its production have any clinical ramifications.
Furthermore, this mutation is more likely to occur in bipolar disorder and schizophrenia than in depression (Gilbody S et al, Am J Epidem 2006;165(1):1–13), meaning that these patients may need Deplin more than depressed patients—if you believe Pamlab’s biochemical hypothesizing. Should we therefore be “Deplinizing” patients with mood disorders and psychosis? Pamlab hasn’t weighed in on this one yet.
Finally, there is the possibility that the folate tail is wagging the homocysteine dog. It turns out that folate deficiency causes an elevation in homocysteine, a nonessential amino acid thought to be involved in thrombosis, cardiovascular disease, stroke, and other morbidities. Homocysteine is itself an NMDA receptor agonist and a pro-oxidant, and elevated homocysteine has been found to be strongly associated with depression in several studies totaling nearly 11,000 individuals (Kronenberg G et al, Curr Molec Med 2009;9(3):315–323). This wouldn’t argue against using folic acid supplementation, but it does call into question the neat, convenient “trimonoamine modulator” model for Deplin’s presumed efficacy.
TCPR Verdict: Folate supplementation may help some depressed patients, but it’s hard to say why, and it’s even harder to prove that Deplin is more effective than folic acid. Deplin has a nice story, but the threads tying the story together remain weak, the clinical data are unconvincing, and the price tag is just too high.