L-Methylfolate For Bipolar I depressive episodes: An open trial proof-of-concept registry

J Affect Disord. 2017 Jan 1;207:429-433. doi: 10.1016/j.jad.2016.09.053. Epub 2016 Oct 1.


Background: L-methylfolate is a compelling candidate to treat bipolar I major depressive episodes. While approved as an adjunct for unipolar major depressive disorder, no studies have been done to assess the tolerability, safety, and efficacy of L-methylfolate for bipolar depression. As a first step, we developed a registry of bipolar patients treated with L-methylfolate to examine tolerability and outcomes.

Methods: Subjects (N=10) received treatment as usual plus daily L-methylfolate 15mg for 6 weeks in this open-label registry. Depressive symptoms were assessed with the Montgomery Asberg Depression Rating Scale (MADRS) and manic symptoms with the Young Mania Rating Scale (YMRS). Effect size was measured with Cohen's d to provide an estimate of potential efficacy.

Results: The pre-treatment mean (SD) MADRS score was 23.4 (4.34); the post-treatment score was 13.9 (8.24). Cohen's d was 1.19. At post-treatment, 6/10 patients had at least 50% MADRS improvement, and 4/10 patients exhibited remission with MADRS≤10. The pre-treatment YMRS score was 3.2 (3.0); the post-treatment score was 2.7 (5.2). Cohen's d was 0.17.

Limitations: This registry was a small open-label clinical trial for a fluctuating disorder. We cannot rule out that our results are due to regression to the mean. A controlled trial is warranted.

Conclusions: This first proof-of-concept open registry suggests that L-methylfolate in combination with treatment as usual has potential to treat bipolar depression.

Keywords: Bipolar disorder; Deplin; Depression; L-methylfolate.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Antidepressive Agents / therapeutic use*
  • Antipsychotic Agents / therapeutic use*
  • Bipolar Disorder / diagnosis*
  • Depressive Disorder, Major / drug therapy*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Registries
  • Tetrahydrofolates / administration & dosage*
  • Treatment Outcome


  • Antidepressive Agents
  • Antipsychotic Agents
  • Tetrahydrofolates
  • 5-methyltetrahydrofolate