Adjunctive L-Methylfolate May Help in Treatment-Resistant Depression

Folate Deficiency Common in Major Depression

Jill Stein

March 18, 2011

March 18, 2011 (Vienna, Austria) — L-methylfolate is showing promise as an augmenting agent for depressed patients who are unresponsive to traditional antidepressants, new research suggested.

Presented here at EPA 2011: 19th European Congress of Psychiatry, the study results revealed L-methylfolate, 15 mg/d, was effective, safe, and relatively well tolerated as an adjunct treatment strategy for patients with major depressive disorder (MDD) who were partial responders or nonresponders to selective serotonin reuptake inhibitor (SSRI) therapy.

"According to the literature, only about 1 of every 3 patients with depression will achieve remission with standard antidepressant monotherapy," principal investigator George Papakostas, MD, who is director of treatment-resistant depression (TRD) studies, Psychiatry Division at Massachusetts General Hospital and associate professor of psychiatry at Harvard Medical School in Boston, told Medscape Medical News.

"So it's clear that we need better therapies for depression. We found that L-methylfolate, 15 mg/d, produced favorable results, but the data are preliminary and need to be replicated in a larger trial," he added.

For the roughly two-thirds of patients who are inadequate responders or nonresponders, augmentation strategies or switching strategies altogether are indicated, he added.

A variety of treatment options are available, including atypical agents, folates, or lithium, but the choice of therapy ultimately depends on the patient's individual profile and his/her personal preference.

Dr. Papakostas presented results from 2 multicenter, placebo-controlled trials of L-methylfolate used as an adjunct to SSRI therapy in patients with SSRI-resistant MDD who were 18 to 65 years of age. SSRI doses remained constant throughout the 2 TRD studies, which enrolled a total of 223 patients.

Folate Deficiency Common in MDD

Roughly 70% of patients with MDD have a specific genetic factor that causes L-methylfolate deficiency. Individuals with deficient L-methylfolate are more likely to experience a later onset of action, less improvement, a more severe depressive episode, and a higher chance of relapse when taking conventional antidepressants.

Several studies have examined the use of folic acid or various folic acid metabolites, such as folinic acid and methyltetrahydrofolate, as either monotherapy or adjunctive therapy for MDD.

L-methylfolate was selected as the augmenting agent in the 2 TRD studies because of evidence suggesting it may have advantages with respect to bioavailability over other folates. L-methylfolate is thought to work as an augmenting agent to antidepressants by acting as a trimonoamine modulator, enhancing the synthesis of the 3 monoamines, dopamine, norepinephrine, and serotonin, and thereby boosting the efficacy of antidepressants.

Significant Benefit

In the TRD-1 study, 148 patients were randomized in a 2:3:3 design to receive either L-methylfolate for 60 days (7.5 mg/d in phase 1 and 15 mg/d in phase 2), placebo for 30 days followed by L-methylfolate for 30 days (7.5 mg/d), or placebo for 60 days.

The 75-patient TRD-2 was identical in design to TRD-1 except for a target dose of 15 mg/d of L-methylfolate throughout both phases.

The coprimary endpoints for both studies were the differences in response rates and in degree of improvement in the Hamilton Depression Rating Scale (HDRS-17) between treatment groups. An HDRS-17 response was defined asa 50% or greater reduction in HDRS-17 scale scores during treatment or a final score of 7 or less.

The TRD-1 study found no difference in outcome between the treatment groups.

The TRD-2 study showed greater efficacy for adjunctive 15 mg/d of L-methylfolate administered for up to 30 days vs placebo when added to continued SSRI therapy plus placebo on both primary outcome measures (degree of change and response rates according to the HDRS, P = .05 and .04, respectively).

There was no difference in the rates of treatment withdrawal due to adverse events in the L-methylfolate 15 mg/d/antidepressant and the placebo/antidepressant groups.

Finally, the number of patients needed to treat (NNT) for a response in the TRD-2 study was between 5 and 6 patients in favor of adjunctive 15 mg/dof L-methylfolate vs placebo. "This is on a par with NNTs reported for other augmentation strategies in MDD," Dr. Papakostas said.

Funding for the study was provided by Pamlab LLC in Covington, Louisiana. Dr. Papakostas has served as a consultant for Abbott Laboratories, AstraZeneca PLC, Brainsway Ltd, Bristol-Myers Squibb Company, Cephalon Inc, Eli Lilly Co, GlaxoSmithKline, Evotec AG, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc, Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, and Wyeth Inc. He has received honoraria from Abbott Laboratories, Astra Zeneca PLC, Bristol-Myers Squibb Company, Brainsway Ltd, Cephalon Inc, Eli Lilly Co, Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Titan Pharmaceuticals, and Wyeth Inc. He has received research support from Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB LLC, Pfizer Inc, and Ridge Diagnostics (formerly known as Precision Human Biolaboratories). Finally, Dr. Papakostas has served (in the past but not currently) on the speaker's bureau for BristolMyersSquibb Co and Pfizer Inc.

EPA 2011: 19th European Congress of Psychiatry: P01-588. Presented March 13, 2011.


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