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Randomized Study Combining L-Methylfolate with Antidepressant Shows Significant Boost in Patient Response

Higher Remission Rates Seen with Combination Therapy

BOCA RATON, Fla.--(BUSINESS WIRE)--Jun 13, 2011 - New findings from a multi-center, randomized, placebo-controlled clinical study of Deplin® 15mg (L-methylfolate) added to commonly prescribed antidepressants known as selective serotonin reuptake inhibitors (SSRIs) showed that all patients who achieved remission at 30 days using Deplin® 15mg adjuvant therapy, and who chose to enter a 12 month maintenance phase, maintained their remission after a year of treatment.

The 223 patient study was presented today at NCDEU, a scientific congress sponsored by the American Society of Psychopharmacology, meeting in Boca Raton this week. This study supports the growing the body of evidence for the metabolic management of major depressive disorder with Deplin® (L-methylfolate), a medical food, administered in combination with antidepressants.1

Outcomes

As previously reported at the American Psychiatric Association 2011 Annual Meeting, two primary outcome measures were used in the study: Rates of response (50 percent reduction) in the 17-question Hamilton Depression Rating Scale (HDRS-17) and degree of improvement (mean change) in HDRS-17. Both primary outcome measures used in the study achieved statistical significance.

The data showed that 32.3 percent of patients who received adjunctive therapy with 15 mg of Deplin® combined with an SSRI responded after 30 days of treatment compared to 14.6 percent of patients who received SSRI with placebo (p=0.04).

A greater reduction in depressive symptoms using the mean change in HDRS-17 was found in the adjuvant Deplin® arm compared to the adjuvant placebo arm--5.58 points versus 3.04 points (p=0.05).

“Adjunctive Deplin® 15mg helped patients with major depressive disorder experiencing an inadequate response to an SSRI achieve the benefits of their antidepressant therapy during the double-blind trial and maintain the benefits of antidepressant therapy after continuation in a 12 month open label phase,” said Dr. John Zajecka, Associate Professor of Psychiatry and Clinical Director of the Depression Treatment and Research Center at Rush University Medical Center in Chicago.

A secondary outcomes measure was remission status using the HDRS-17 (a final score of 7 or less).

On remission, there was a numerically important difference in favor of Deplin® + SSRI compared to placebo + SSRI in the double-blind phase. Although not statistically significant after the 30-day evaluation period, of patients who achieved remission during the double-blind phase and entered into the 12 month, open label maintenance phase, none relapsed.2

Personalized Medicine: Genetic Findings

Four genetic inborn errors of folate metabolism, including methyltetrahydrofolate reductase (MTHFR) enzyme were evaluated. A significant treatment effect with adjuvant Deplin® compared to adjuvant placebo was found after adjusting for genotypes in the double blind 30-day trial (p<.05).

These polymorphisms create poor folate metabolizers who are at greater risk of depression3,4 and lack of response to antidepressants.5 These errors limit their ability to convert folate from food or synthetic folic acid, found in vitamin supplements, to L-methylfolate, the only form of folate the brain can use immediately to regulate neurotransmitters.

“In patients with inadequate response to SSRI monotherapy for depression, the addition of L-methylfolate 15mg (Deplin®) may offer a personalized approach to improve responses to antidepressant therapy in genetic errors of folate metabolism such as the MTHFR polymorphism,” said Dr Zajecka. “Although this study is speculative, it represents promise in a genotypically defined subgroup of patients and an option for personalized medicine in major depression.”

About the Study

The two trials in this study used a novel sequential parallel comparison design (or SPCD). Results from the first of two trials (n = 148) were used to inform the dosing of the second trial (n = 75). The first trial found 7.5 mg dosing of L-methylfolate and an SSRI was not significantly different in efficacy compared to placebo and SSRI. The second trial found 15 mg dosing L-methylfolate and an SSRI was significantly superior on response rates and degree of improvement in depressive symptoms compared to placebo and SSRI.

Before beginning the study, all patients had to demonstrate inadequate response to one or two SSRIs. Antidepressants included in the randomized trial were therapeutic doses of fluoxetine, citalopram, paroxetine, escitalopram, and sertraline. Once the patients entered into the study, the SSRI doses remained constant. There was no significant difference in side effects reported with adjunctive L-methylfolate 15 mg. Rates of discontinuation due to adverse events were no different in the L-methylfolate 15 mg and SSRI group compared to the placebo and SSRI group.1

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.2

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.6 In this randomized, placebo controlled study, Deplin® or L-methylfolate was chosen because of its ability to cross the blood brain barrier, its bioavailability and safety benefits compared to folic acid and other synthetic folates.

About Deplin®

Deplin® is a medical food dispensed by prescription for the clinical dietary management of the metabolic imbalances associated with depression. Use under medical supervision.7

For more information visit http://www.deplin.com or see full prescribing information.

1 Papakostas, George. NCDEU 51st Annual Meeting. Honolulu, HI. 13 June 2011. Scientific and Clinical Report Presentation. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

2 Papakostas, George. American Psychiatric Association 2011 Annual Meeting. Honolulu, HI. 18 May 2011. Scientific and Clinical Report Presentation. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

3 Arinami T. Methylenetetrahydrofolate Reductase Variant and Schizophrenia/Depression. Am. J. Med. Genet. 1997;74:526-238.

4 Papakostas GI et al. Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part II). Psychiatry Research: Neuroimaging 2005;140:301-307 Guaraldi et al. An Open Trial of Methyltetrahydrofolate in Elderly Depressed Patients. Annals Clin Psych.

5 Procopciuc LM et al. C677T MTHFR Polymorphism and Psychiatric Diseases Schizophrenia-like Psychosis and Depression in Romanian Patients. Poster Presentation 5. P86 presented at Biol Psych. 2005.

6 Stahl SM. Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant Augmenting Agent. CNS Spectrums. 2007;12(10):739-44.

7 Deplin® Package Insert. Pamlab, L.L.C. 04/2011.

Contact: For Pamlab, L.L.C.
Michael Durand, 917-856-5373
deplinpr@pamlab.com

 

 

Posted: June 2011

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