Insufficient response to SSRI: would adding folate help? Am J Psychiatry: Dec: 2012


It has long been suggested that folate deficiency could increase the risk of depression and that low levels would predict poor response to treatment.L-Methylfolate is the biologically active form of folate and the only form of folate that crosses the blood-brain barrier. It regulates the formation of Tetrahydrobiopterin (BH4), which activates key enzymes in monoamine synthesis.

Papakostas and colleagues report the outcome of two separate trials of l-methylfolate as an adjunct to an SSRI.The two  trials differ in dosing. This was a 60 day multi centre,randomized, double-blind, sequential parallel comparison  in adult patients with major depression who has been on an adequate dose of SSRI for at least 8 weeks, with a stable dose in the previous 4 weeks, currently scoring more than 12 on QIDS-SR ie insufficient response to an SSRI. Those with psychotic symptoms , those who has substance use disorders, and hose who have failed to respond to have sufficient improvement after more than 2 antidepressant trails were excluded.


Trial 1. 148 patients .80% completed study. Two phased design. 7.5 mg/day of adjunctive l-methylfolate did not appear to result in a treatment efficacy superior to continued SSRI therapy plus placebo in either phase of the study. However, patients who underwent an increase in dosage to 15 mg/day in phase 2 had a greater response rate than those who continued on SSRI therapy plus adjunctive placebo (24.0% compared with 9%).  The difference fell short of statistical significance (p=0.1). No difference in side effects between groups observed.

Trial 2. 75 patients. 81% completed study. 15 mg/day of adjunctive l-methylfolate  resulted  in  superior  treatment outcome  to continued SSRI therapy plus placebo in  the difference in response rates (32 % compared with 15%, p=0.04) . No difference in side effects were observed.

No difference in remission rates observed. The 30 day observation is insufficient for remission to be studied.

Results suggest that 15 mg/day of l-methylfolate can be a useful adjunctive treatment strategy for patients with major depression who have not responded enough to SSRIs. NNT of 6 for folate is simiar to other augmentig agents. The medication is well tolerated.The results are applicable to augmenting SSRIs only and the exclusion criteria may limit generalisability of the findings.



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