From the Journals

B vitamin may help boost antidepressant efficacy



The B vitamin, L-methylfolate (LMF) can be an effective adjunctive treatment for patients with major depressive disorder (MDD) with an inadequate response to antidepressants, new research suggests.

The investigators analyzed six studies and found support for adjunctive use of LMF with patients with MDD not responding to antidepressant monotherapy. Treatment response was highest in those with obesity and inflammatory biomarkers.

psychiatry and behavioral science, University of South Carolina School of Medicine, Greenville Vladimir Maletic

Dr. Vladimir Maletic

“If clinicians try LMF on their patients with treatment-resistant depression, the treatment is very robust in patients who have high BMI [body mass index] or inflammatory biomarkers, and it’s worth a try even in patients who don’t have these indicators, since it’s safe and well tolerated, with no downside,” study investigator Vladimir Maletic, MD, MS, clinical professor of psychiatry and behavioral science, University of South Carolina, Greenville, said in an interview.

The study was published online in the Journal of Clinical Psychiatry.

‘Shortcut’ to the brain

A considerable percentage of patients with MDD fail to achieve an adequate response to treatment, the authors wrote.

Previous research shows benefits of folate (vitamin B9) and other B vitamins in the pathophysiology and treatment of depression.

Folate is available in several forms, including LMF, which differs from dietary folate and synthetic folic acid supplements because it’s a reduced metabolite that readily crosses the blood-brain barrier.

“This is a ‘shortcut’ that gets directly to the brain, especially in those with higher BMI or inflammatory indicators, allowing their antidepressant to work better,” Dr. Maletic said.

LMF is available as a prescription medical food and approved for the clinical dietary management of patients with MDD.

The authors wanted to understand the potential role of LMF in treating patients with MDD with insufficient response to current antidepressant therapy.

They analyzed six studies:

  • Two multicenter, randomized, double-blind, placebo-controlled sequential parallel trials for patients with SSRI-resistant MDD (n = 148 and n = 75).
  • A 12-month open-label extension trial of the two randomized, controlled trials (n = 68).
  • A retrospective cohort study evaluating patients previously prescribed LMF (n = 554).
  • Two post hoc exploratory analyses of the second randomized, controlled trial, stratifying patients by specific biological and genetic markers (n = 74) and evaluating the effect of biomarkers on treatment effect (n = 74).

The primary endpoints were improvement on the 17-item Hamilton Depression Rating Scale (HDRS-17) or the Patient Health Questionnaire (PHQ-9).

Patients in all trials were treated with either 7.5 mg or 15 mg of LMF.

Both RCTs were divided into two 30-day phases, with patients assessed every 10 days. Response was defined as at least a 50% reduction in HDRS-17 score during treatment or a final score of 7 or less.

‘Salvage pathway’

In the RCTs, patients who received 7.5 mg of LMF did not achieve efficacy superior to placebo, while those receiving 15 mg/day of LMF for 30 days showed significantly greater reduction in HDRS-17 scores (–5.6 vs. –3.0; P = .05, respectively) and higher response rates (32.3% vs. 14.6%; P = .05, respectively).

The 12-month open extension trial showed that among patients who received the 15-mg dose, 61% achieved remission at any point, and 38% achieved recovery. Among initial nonresponders, 60% eventually achieved remission, with no serious adverse events.

“These results indicate that patients who respond well to shorter-term treatment are likely to maintain that response over the subsequent year and shows that those not adequately responding within the first 8 weeks of therapy may benefit from longer-term LMF treatments,” the investigators noted.

In the prospective observational study, the pooled mean change in PHQ-9 was –8.5, with response and remission rates of 67.9% and 45.7%, respectively.

“These outcomes suggest that the results seen in the controlled trial are likely to extend to patients in real-world practice,” the researchers wrote.

The post hoc analyses focusing on the findings of the two RCTs explored the differences in response to LMF, based on biomarker, BMI, and genotype.

Individuals with BMI less than 30 did not have a significant change from baseline with LMF treatment, in contrast to those with BMI of 30 or higher (pooled treatment effect, –4.66;95% CI, –7.22 to –1.98) – a difference the authors call “striking.”

Levels of inflammatory markers (tumor necrosis factor–alpha, interleukin-8, heart-specific C-reactive protein, and leptin) above the median value were associated with significantly greater treatment effect – a finding that remained significant even after adjustment for BMI.

Although BMI and cytokines all showed significant main effects, the “synergy” between them “suggests that these risk factors may interact with each other to influence response to LMF,” the authors wrote.

The mechanism by which LMF augments antidepressant treatment is tied to monoamine synthesis, since LMF promotes the synthesis of key monoamine neurotransmitters associated with MDD (serotonin, norepinephrine, and dopamine), Dr. Maletic explained.

High levels of inflammation (often tied to obesity) cause oxidative stress, which inhibits the synthesis of these neurotransmitters and depletes them more rapidly. LMF provides a “salvage pathway” that may prevent this from happening, thus increasing the antidepressant response of the monoamines, he said.

A ‘good addition’

In a comment, David Mischoulon, MD, PhD, Joyce R. Tedlow Professor of Psychiatry at Harvard Medical School and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston, said the paper “does a good job of synthesizing what we know about LMF as an adjunctive treatment in major depression.”

David Mischoulon, MD, PhD, professor of psychiatry, Harvard Medical School, and director of the depression clinical and research program at Massachusetts General Hospital, both in Boston

Dr. David Mischoulon

However, he recommended “caution” when interpreting the findings, since “relatively few” studies were reviewed.

Dr. Mischoulon, who was not involved with the study, said that a “particularly interesting finding from these studies is individuals who are overweight and/or have elevation in inflammatory activity ... seemed to respond better to the addition of LMF.” This finding is similar to what his research team observed when investigating the potential role of fish oils in treating depression.

“These findings overall are not surprising, in view of the well-established multidirectional relationship between depression, inflammation, and overweight status,” he said.

LMF “seems like a good addition to the pharmacological armamentarium for depression; and because it is safe and has minimal side effects, it can be added to the treatment regimen of patients who are depressed and not responding adequately to standard antidepressants,” he said.

This work was funded by Alfasigma USA. The authors did not receive payment for their participation. Dr. Maletic has received writing support from Alfasigma USA; consulting/advisory fees from AbbVie/Allergan, Acadia, Alfasigma USA, Alkermes, Eisai-Purdue, Intra-Cellular Therapies, Janssen, Lundbeck, Jazz, Noven, Otsuka America, Sage, Sunovion, Supernus, and Takeda; and honoraria for lectures from AbbVie, Acadia, Alkermes, Allergan, Eisai, Ironshore, Intra-Cellular, Janssen, Lundbeck, Otsuka America, Sunovion, Supernus, and Takeda. Dr. Mischoulon has received research support from Nordic Naturals and Heckel Medizintechnik. He has received honoraria for speaking from the Massachusetts General Hospital Psychiatry Academy, PeerPoint Medical Education Institute, and Harvard blog.

A version of this article first appeared on

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