---
title: "Effect of adjunctive L-methylfolate 15 mg among inadequate…"
description: "Certain biological and genetic markers may identify depressed patients who are more likely to respond to adjunctive L-methylfolate when SSRIs are…"
url: "https://magellanlongevity.com/study/d24813065.md"
canonical: "https://magellanlongevity.com/study/d24813065.html"
html: "https://magellanlongevity.com/study/d24813065.html"
type: "study"
study_key: "d24813065"
journal: "J Clin Psychiatry"
year: 2014
pmid: "24813065"
doi: "10.4088/JCP.13m08947"
citations: 1
updated: 2026-09-02
author: "Gabriel Radu, DO"
author_credentials: "Physiatrist (PM&R). NY medical license 275110. NPI 1376861765."
publisher: "Magellan Longevity"
content_format: "markdown"
---

# Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients

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## Citation

| Field | Value |
| --- | --- |
| Journal | J Clin Psychiatry |
| Year | 2014 |
| PMID | [24813065](https://pubmed.ncbi.nlm.nih.gov/24813065/) |
| DOI | [10.4088/JCP.13m08947](https://doi.org/10.4088/JCP.13m08947) |
| Study key | d24813065 |

## Takeaway

Certain biological and genetic markers may identify depressed patients who are more likely to respond to adjunctive L-methylfolate when SSRIs are insufficient.

## The question

Can specific biological and genetic markers predict the antidepressant efficacy of adjunctive L-methylfolate 15 mg in depressed patients who have not adequately responded to SSRIs?

## Hypothesis

The study hypothesized that specific biological and genetic markers would influence the antidepressant efficacy of adjunctive L-methylfolate 15 mg compared to placebo in patients with SSRI-resistant major depressive disorder.

## Methods

This was a double-blind, randomized, placebo-controlled trial using a sequential parallel comparison design. Outpatients with SSRI-resistant MDD received L-methylfolate 15 mg/d for 60 days, or placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days. The primary response measure was the 28-Item Hamilton Depression Rating Scale (HDRS-28), and the effects of baseline biological and genetic markers on treatment response were evaluated.

## Results

Seventy-five patients were enrolled. Patients with specific biological markers (BMI ">=" 30 kg/m², elevated high-sensitivity C-reactive protein or 4-hydroxy-2-nonenal, low S-adenosylmethionine/S-adenosylhomocysteine ratio) and genetic markers at baseline showed significantly greater pooled mean change from baseline on the HDRS-28 with L-methylfolate versus placebo. Most combinations of baseline biological and genetic markers also predicted significantly greater reductions in pooled mean change from baseline in HDRS-28 scores with L-methylfolate versus placebo.

## Conclusion

Biomarkers related to inflammation or metabolism and genomic markers associated with L-methylfolate synthesis and metabolism may help identify patients with SSRI-resistant depression who could benefit from adjunctive L-methylfolate 15 mg therapy.

## Limitations

This was a post hoc analysis, and confirmatory studies are needed to validate these findings.

## Verbatim from the abstract

> greater pooled mean change with L-methylfolate versus placebo

## Where this study is used on Magellan

This paper is one of the citations behind the evidence grade on the pages below. Grades are assigned from the published research and are independent of affiliate commissions.

| Compound or device | Evidence grade | Graded pages |
| --- | --- | --- |
| L-Methylfolate (5-MTHF) | Moderate evidence | [L-Methylfolate (5-MTHF)](https://magellanlongevity.com/p/130.md) |

## Reference

1. **Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients**
   J Clin Psychiatry 2014 · [PMID 24813065](https://pubmed.ncbi.nlm.nih.gov/24813065/) · [DOI 10.4088/JCP.13m08947](https://doi.org/10.4088/JCP.13m08947)

   > greater pooled mean change with L-methylfolate versus placebo

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## Related on Magellan Longevity

- [L-Methylfolate (5-MTHF)](https://magellanlongevity.com/p/130.md) — product graded on this and related evidence
- [Evidence: active folate, methylation cofactor](https://magellanlongevity.com/study/s130.md)
- [Longevity research map](https://magellanlongevity.com/longevity-research-map.html)
- [Evidence-based longevity supplements](https://magellanlongevity.com/longevity-supplements.md)

## Scope and disclosures

Educational information, not medical advice. Nothing here is intended to diagnose, treat, cure, or prevent any disease. Talk to your physician before starting any supplement or device, especially if you are pregnant, nursing, or taking medication.

Editorial firewall: evidence grades are assigned from the published research and are independent of any affiliate commission. As an Amazon Associate, Magellan Longevity earns from qualifying purchases.

Reviewed for accuracy by a board-certified physician (DO).