Two studies suggest long-term value of Deplin in treating MDD

Two studies presented this week at the 164^th Annual Meeting of the American Psychiatric Association suggest the long-term value of Deplin^® (L-methylfolate 15mg) in treating major depressive disorder (MDD) and describe subsets of patients who may benefit more robustly from this medical food.

Deplin^® is classified as a medical food for the nutritional management of metabolic imbalance in MDD when used in addition to an antidepressant medicine.

The first study, authored by John Zajecka, MD, Associate Professor of Psychiatry and Director of the Depression Treatment and Research Center at Rush University Medical Center in Chicago, described the long term benefits of Deplin^®. The data demonstrated no relapse with adjunctive dietary management with Deplin^® over 12-months. This open-label, maintenance phase included patients who successfully achieved remission in 30 days during an acute phase of a larger double-blind trial.

Thirteen remitters from the acute phase elected to enter the maintenance phase and continued to receive Deplin^® with an SSRI. Follow-up visits to detect relapse (defined as Hamilton Depression Rating Scale-17 scores >15), sustained remission (defined as Hamilton Depression Rating Scale-17 scores ≤ 7), and safety and tolerability occurred every 12 weeks during the 12- month follow-up phase.

None of the thirteen remitters experienced relapse at any time point, and 54 percent of subjects (7 of 13 patients) maintained full remission at 12 months. There were no discontinuations due to adverse events reported during the 12-month open-label treatment.

"The implications of this follow-up phase are important since the optimal goal of therapy in major depressive disorder is prevention of relapse. Patients who relapse are vulnerable to recurrent bouts of depression," said Richard Shelton, MD, Charles Byron Ireland Professor of Psychiatry, and Vice-Chair of Research Department of Psychiatry and Behavioral Neurobiology at University of Alabama at Birmingham.

Biomarkers and Personalized Medicine:

The second study, authored by George Papakostas, MD, Associate Professor of Psychiatry at Harvard Medical School and Director of Treatment-Resistant Depression Studies in the Department of Psychiatry of Massachusetts General Hospital in Boston, was an analysis of secondary endpoints in the multi-center double-blind, randomized trial of Deplin^® in addition to an SSRI presented in 2011 at APA. The secondary endpoints evaluated the effects of specific metabolic biomarkers including inflammation, body mass index (BMI) and methlentetrahydrofolate reductase (MTHFR), a genetic defect.

In the double-blind phase, 75 patients with SSRI-resistant MDD were enrolled in a 60-day study, divided into two, 30-day evaluation periods. Patients were randomized to receive one of three treatments: (1) Deplin^® (L-methylfolate 15mg) in addition to an antidepressant for 60 days; (2) placebo in addition to a SSRI for 30 days followed by Deplin^® 15 mg. in addition to an antidepressant for 30 days; or (3) placebo in addition to an antidepressant for 60 days. The SSRI doses remained constant during the double-blind phase of the study.

Increased efficacy was observed with adjunctive Deplin® 15 mg versus SSRI therapy plus placebo. Pooled differences in mean changes on HDRS-17 and HDRS-28 (an expanded version of the Hamilton scale) were significantly different (p = 0.05 and 0.02, respectively).

Compared to patients given adjunctive placebo, a numerically greater treatment effect was observed in patients given Deplin 15mg in addition to their SSRI who had an allelic variant in the MTHFR (methylentetrahydrofolate reductase) C677T genotype. Differences in mean changes in HDRS-28 were -3.75 for patients with a “T” allele (homozygote and heterozygote alleles combined) versus -1.99 for the patients with a “CC” allele (considered the “normal” allele) and marginally significant (p=0.087). An allele is an alternative form of a gene (one of a pair) that is located at a specific position on a specific chromosome. They determine genetic traits.

Obesity as a Biomarker

Obese patients, defined as having a BMI greater than or equal to 30, receiving Deplin^® 15mg and an antidepressant experienced a significantly greater reduction in HDRS-28 scores compared to those receiving adjunctive placebo. Differences in mean changes in HDRS-28 was +0.99 for BMI < 30 and -4.66 for BMI ≥ 30. The difference for depressed individuals with BMI ≥ 30 was strongly significant ( p= 0.001). No difference in side effects was reported between the groups administered Deplin^® in addition to an antidepressant compared to placebo in addition to an antidepressant.

Significance of Findings

Obesity is known to increase the risk of MDD and decrease the response to antidepressants. As many as 40 percent of MDD patients have a BMI ≥30, meaning millions of patients are both significantly overweight and suffer from depression.

It is estimated that up to seventy percent of MDD patients have a "T" allele, which means they have a compromised ability to convert dietary folate into L-methylfolate which is needed for synthesis of serotonin, norepinephrine and dopamine.

"These findings suggest that there are subsets of depression patients, such as those with the MTHFR genetic variant or with a BMI ≥ 30, for whom Deplin^® may be most effective," says Dr. Shelton, who was an investigator in this study. "Personalizing therapies, that is being able to identify the patients who are most likely to optimally respond to treatment, is both medically and economically beneficial."

Folate Deficiency & L-methylfolate

Scientists have long suspected an association between a deficiency in the bioactive form of folate and depression, and studies have been conducted to determine if the active form of folate can improve depression symptoms.

L-methylfolate has been categorized as a Trimonoamine Modulator (TMM) because it is the only form of folate that can cross the blood-brain barrier to help regulate serotonin, norepinephrine and dopamine, the neurotransmitters associated with mood. In these studies Deplin^® (L-methylfolate) was chosen because of its ability to cross the blood brain barrier, its bioavailability and safety profile.