Good, better, best: clinical scenarios for the use of L-methylfolate in patients with MDD

Introduction

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Depression is one of the most prevalent mental disorders in the United States; more than 16% of individuals suffer from depression in the course of their lifetime.Reference Kessler and Wang 1 Globally, it is the leading cause of disability and impacts more than 300 million people. 2 Despite the prevalence and severity of the disease, its precise pathophysiology remains unclear. Because of considerable heterogeneity in the neurobiology and genetics of depression, there is a need for a variety of options in order to individualize treatment. Unfortunately, there are no clinically useful biomarkers to guide selection of optimal treatment.Reference McGrath, Kelley and Holtzheimer 3 The monoaminergic theory of depression, centered around insufficient levels of or abnormal neurotransmission of serotonin (5-hydroxytryptamine [5-HT]), was the most widely accepted explanation for the symptoms of depression for the latter part of the 20th century, and has evolved to encompass the tri-monoamine theory, which also implicates abnormalities of dopamine and norepinephrine.Reference Belmaker and Agam 4 , Reference Delgado 5 Indeed, research in recent decades has determined that specific monoaminergic neurotransmitters modulate various aspects of mood and behavior.Reference Nutt 6 For instance, norepinephrine plays a role in alertness, energy, and attention, and low levels may contribute to feelings of anhedonia, a lack of interest in taking pleasure from life. Dopamine, the hallmark neurotransmitter in the reward pathway, is implicated in attention, motivation, and pleasure, while serotonin is implicated in depressed mood, anxiety, and obsessive thoughts.Reference Nutt 6 More recently, folate deficiency has been identified as having a role in the pathology of depression.Reference Bottiglieri 7 L-methylfolate is thought to be the only form of folate that is able to pass through the blood-brain barrier and is involved in the regeneration of tetrahydrobiopterin (BH4; a critical cofactor for neurotransmitter synthesis), the levels of which are depleted with inflammation or oxidative stress.Reference Stahl 8 – Reference Subramaniapillai, Carmona, Rong and McIntyre 11 In major depressive disorder (MDD) patients who are unresponsive to antidepressants, L-methylfolate may be a viable treatment option.

This article highlights new advancements in our understanding of the heterogeneous pathogenesis of MDD, particularly those regarding the role of folate inflammation, stress, obesity, and related biomarkers. It also reviews the efficacy and safety data on a prescription form of L-methylfolate that support its clinical use in MDD.

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