REVIEW OF: Maruf AA et al, Pharmacopsychiatry 2022;55(3):139–147

STUDY TYPE: Meta-analysis

L-methylfolate is a metabolite of dietary folate and is approved by the FDA as a medical food for the adjunctive treatment of depression. Approval of medical foods does not require the same level of rigor as actual approval of a medication, and therefore researchers conducted a meta-analysis scrutinizing the strength of the available empirical evidence for L-methylfolate in depression.

A systematic literature search turned up only four randomized placebo-controlled trials of methylfolate as an adjunct to antidepressant treatment. Most of the trials added methylfolate after failure of an antidepressant, usually an SSRI or SNRI. Two enrolled patients with treatment-resistant depression (n=265), while the other two included patients without treatment resistance (n=284). Three trials used 15 mg/day dosing, while one used 7.5 mg. Trial duration ranged from one month to six months. Results showed a modest treatment effect on Hamilton Depression Rating Scale scores (effect size 0.38, p<0.001) and a similar effect on response rate (RR=1.26, p=0.005). The 7.5 mg dose showed no efficacy—only the 15 mg dose was effective.

The analysis had several limitations. One of the trials lacked clarity on the psychiatric medications that subjects were taking in addition to L-methylfolate, and two of the trials lacked specific data on adverse events. Two were industry sponsored, and the small number of published studies leaves open the possibility that any (unknown) unpublished studies with negative findings could greatly reduce the apparent effect of L-methylfolate.

On the other hand, the authors did not include a large randomized controlled monotherapy trial (n=330) of Enlyte, presumably because this FDA-cleared product contains other folate and B vitamins in addition to 7.5 mg of L-methylfolate. Enlyte had a large effect size (0.88) as monotherapy in this clinical trial. The patients had moderate depression, some treatment resistant and some not, but all were selected for genetic polymorphisms on the MTHFR gene (C677T or A1298C), making it difficult to compare the results with those of the traditional L-methylfolate studies. In theory, these patients may be more likely to respond to L-methylfolate, but that theory has not been clinically tested, and we do not recommend routine genetic testing before starting L-methylfolate (Mech AW and Farah A, J Clin Psychiatry 2016;77(5):668–671).

L-methylfolate is available by prescription or over the counter (eg, Opti-Folate is available as 15 mg tabs for $8/month), while Enlyte is prescription-only ($52/month if not covered by insurance, at www.enlyterx.com).

CARLAT TAKE

Coprescribing L-methylfolate may offer a modest boost to antidepressants and is a reasonable choice for patients who want a natural or well-tolerated option. Both standard L-methylfolate and Enlyte are reasonable options.