<scp>l</scp>-Methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials

Papakostas, George I.; Shelton, Richard C.; Zajecka, John; Etemad, Bijan; Rickels, Karl; Clain, Alisabet; Baer, Lee; Dalton, Elizabeth D.; Sacco, Garret R.; Schoenfeld, David; Pencina, Michael J.; Meisner, Allison; Bottiglieri, Teodoro; Nelson, Erik; Mischoulon, David; Alpert, Jonathan E.; Barbee, James G.; Zisook, Sidney; Fava, Maurizio

doi:10.1176/appi.ajp.2012.11071114

Cited by 227 publications

(190 citation statements)

References 36 publications

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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%

Nutritional and Safety Outcomes from an Open-Label Micronutrient Intervention for Pediatric Bipolar Spectrum Disorders

Frazier

Gracious²,

Arnold³

et al. 2013

Journal of Child and Adolescent Psychopharmacology

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Objective: The purpose of this study was to report the safety, tolerability, and serum micronutrient concentrations and their correlations with mood changes from an 8 week pilot feasibility study of a 36 ingredient multinutrient supplement, EMPowerplus (EMP+), for pediatric bipolar spectrum disorders (BPSD). Methods: Ten children ages 6-12 received EMP + escalating from one to four capsules t.i.d., with four children increased to the maximum suggested dose, five capsules t.i.d. Outcome measures were micronutrient concentrations in serum and red blood cells, vital signs, body mass index (BMI), dietary intake (Food Frequency Questionnaire and 24 hour dietary recall interview), and mood and global functioning ratings. Results: Seven children (70%) completed the study. Three (30%) terminated early for tolerability and compliance issues. Adverse effects were mild and transient, and chiefly consisted of initial insomnia or gastrointestinal (GI) upset. No differences occurred in BMI ( p = 0.310) or waist-hip ratio (WHR; p = 0.674) pre-to postsupplementation. Four of the tested serum vitamin concentrations increased from pre-to postsupplementation: vitamin A-retinol, vitamin B6, vitamin E-a-tocopherol; and folate (all p < 0.05). The increase in serum 25-OH vitamin D approached significance ( p = 0.063). No differences were found in dietary intake pre-to postsupplementation, suggesting that blood nutrient level increases were caused by EMP + . Conclusions:In this open prospective study, short-term use of EMP + in children with BPSD appeared safe and welltolerated, with a side effect profile preferable to first-line psychotropic drugs for pediatric bipolar spectrum disorders. A double-blind, randomized clinical trial is feasible, appears safe, and is warranted by open-label clinical outcomes and plausible mechanisms of action, combined with documentation of increased serum concentrations of specific micronutrients.

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Section: Folic Acid (Vitamin B9)mentioning

confidence: 56%

Nutritional and Safety Outcomes from an Open-Label Micronutrient Intervention for Pediatric Bipolar Spectrum Disorders

Frazier

Gracious²,

Arnold³

et al. 2013

Journal of Child and Adolescent Psychopharmacology

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“…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%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

118

124

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A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

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“…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%

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

Jacobsen

Rudder

Roberts

et al. 2016

Neuropsychopharmacol

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Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HT Ext ) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HT Ext beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) elevates 5-HT Ext beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment-resistant depression (TRD). However, sustained, stable 5-HT Ext elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HT Ext elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5-HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HT Ext beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HT Ext spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HT Ext beyond the SSRI effect and represent a novel treatment for TRD.

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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.

Cited by 227 publications

References 36 publications

Nutritional and Safety Outcomes from an Open-Label Micronutrient Intervention for Pediatric Bipolar Spectrum Disorders

Nutritional and Safety Outcomes from an Open-Label Micronutrient Intervention for Pediatric Bipolar Spectrum Disorders

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

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