2012
DOI: 10.1176/appi.ajp.2012.11071114
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l-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials

Abstract: Adjunctive L-methylfolate at 15 mg/day may constitute an effective, safe, and relatively well tolerated treatment strategy for patients with major depressive disorder who have a partial response or no response to SSRIs.

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Cited by 227 publications
(190 citation statements)
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“…Adjunctive L-methyl folate has recently been shown to be helpful in adults with treatmentresistant depression (Papakostas et al 2012). Participant serum concentrations of folate in our study were either deficient or close to deficient at baseline, an unexpected finding, given that grain product fortification with folic acid was mandated in the United States effective January 1, 1998 (Oakley et al 1996).…”
Section: Folic Acid (Vitamin B9)mentioning
confidence: 56%
“…Adjunctive L-methyl folate has recently been shown to be helpful in adults with treatmentresistant depression (Papakostas et al 2012). Participant serum concentrations of folate in our study were either deficient or close to deficient at baseline, an unexpected finding, given that grain product fortification with folic acid was mandated in the United States effective January 1, 1998 (Oakley et al 1996).…”
Section: Folic Acid (Vitamin B9)mentioning
confidence: 56%
“…Relevant pharmacologic agents include dopamine agonists, stimulants, bupropion, monoamine oxidase-B inhibitors, adenosine A2A receptor antagonists, and drugs that support dopamine synthesis through supplementation of BH4 including saproterin and folic acid, L-methylfolate, and Sadenosylmethionine (SAMe) that help convert the inactive BH2 to BH4. Clinical trials have been conducted using Lmethylfolate and SAMe in depression with mixed results (Papakostas et al, 2012;Sarris et al, 2015). Interestingly, however, a recent study using L-methylfolate in patients with an inadequate response to antidepressants demonstrated in a post hoc analysis that combinations of elevated CRP, TNF, IL-6, and IL-8 along with BMI predicted an improved antidepressant response to L-methylfolate treatment (Shelton et al, 2015).…”
Section: Reviewmentioning
confidence: 99%
“…Unfortunately, we lack animal behaviors or other pharmacodynamic biomarkers that predict antidepressant action in humans with sufficient fidelity (Insel, 2012). However, multipronged clinical pharmacology data converge on that 5-HT Ext elevation beyond the SSRI effect equals enhanced antidepressant effect (Ebert et al, 1995;Nardini et al, 1983;Papakostas et al, 2012;van Praag, 1982;Walinder et al, 1976;Whale et al, 2010). For this explicit reason, we optimized our experimental design to specifically address our primary end point-whether adjunct 5-HTP SR can safely elevate 5-HT Ext beyond the SSRI effect.…”
Section: Advantages and Limitations Of Our Experimental Approachmentioning
confidence: 99%
“…But chronic SSRI downregulates 5-HT 1A autoreceptors (Hensler, 2003), which likely explains why adjunct pindolol is little effective in TRD (Whale et al, 2010). Further, adjunct methylfolate to SSRIs is reported to be effective in TRD (Papakostas et al, 2012), via a mechanism believed to involve augmented 5-HT synthesis and neurotransmission (Stahl, 2008). Thus, our overall therapeutic hypothesis is that an adjunct drug that safely and in a sustained manner elevates 5-HT Ext beyond the SSRI effect will be effective in TRD.…”
Section: Introductionmentioning
confidence: 98%