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02 Executive summary
Compared to SSRIs alone, combining L-methylfolate with SSRIs is shown to reduce symptoms up to1
84%
No additional SSRI specific side effects
Adjunct L-methylfolate in clinical trials was comparable to placebo (sugar pill) in tolerability and side effect portfolio.2
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L-methylfolate augmentation to SSRI treatment is recommended by the two most widely used psychiatric guidelines in the world, CANMAT, and CARLAT Psychiatry report.3,4
1 .Papakostas G, et al. Am J Psychiatry. 2012;169:1267-1274.
2. Zajecka JM, et al. Journal of Clinical Psychiatry. 2016;77(5):654-660.
3. Sarris J, et al. World J BIol Psychiatry. 2022; 424-455
4. Carlat Report. https://www.thecarlatreport.com/blogs/2-the-carlat-psychiatry-podcast/post/5361-folate-and-depression
03 Mechanism
L-methylfolate serves as the critical precursor in monoamine neurotransmitter synthesis.
L-methylfolate augmentation drives the production of presynaptic serotonin synthesis. In contrast, SSRI dose blocks additional reuptake transporters, allowing existing serotonin to remain in the synaptic cleft longer. Together these mechansims work complementarily.
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SSRI alone
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SSRI + L-methylfolate
04 Library
Clinical trials and meta-analyses of clinical trials of L-methylfolate augmentation of SSRI.
Shelton, R. C., Sloan Manning, J., et al.
Assessing Effects ofl-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial
Ginsberg, L. D., Oubre, et al.
This study followed 554 adults with self-reported major depressive disorder taking prescription l-methylfolate (Deplin) 7.5–15 mg/day for ~3 months, usually as an antidepressant add-on. PHQ-9 scores fell by 8.5 points (58%), with 67.9% responding and 45.7% remitting, alongside improved functioning and treatment satisfaction.
Clinical trial (n = 554)
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Zajecka, J. M., Fava, et al.
Long-term Efficacy, Safety, and Tolerability of L-Methylfolate Calcium 15 mg as Adjunctive Therapy in Major Depressive Disorder: A 12-Month, Open-Label Study Following a Placebo-Controlled Trial
Ginsberg, L. D., Oubre, et al.
This 12-month open-label extension followed n=68 adults with MDD continuing l-methylfolate 15 mg/day adjunctive to antidepressants to assess long-term outcomes. 38% (n=26) achieved full recovery with no MDD recurrences.
12 month follow-up extension to clinical trial (n=68)
Ginsberg, L. D., Oubre, et al.
L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode
Ginsberg, L. D., Oubre, et al.
This study (N=242) compared starting an SSRI/SNRI + L-methylfolate (7.5–15 mg) vs SSRI/SNRI alone. At 60 days, major improvement was seen in 40% of L-methylfolate + SSRI/SNRI patients vs. 16.3% in monotherapy, with faster median time to major improvement (177 vs 231 days, p=.03)
Clinical trial (n=242)
Papakostas, G. I., Shelton, et al.
L-methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials
Papakostas, G. I., Shelton, et al.
Two multicenter RCTs in SSRI-resistant MDD compared SSRI + l-methylfolate vs SSRI + placebo (Trial 1: n=148; Trial 2: n=75). In Trial 2 (15 mg/day), response was 32% with l-methylfolate vs 15% with placebo (p≈0.05) and symptom reduction favored l-methylfolate (e.g., HAM-D change ~−5.6 vs −3.7).
Multi-center clinical trial (n=223)
Maruf, A. A., Poweleit, et al.
Comparative assessment of adherence and resource use: Second generation antipsychiotics vs L-methylfolate augmentation in SSRI/SNRI-treated depression
Maruf, A. A., Poweleit, et al.
This retrospective study with propensity matching compared SGA augmentation (n=4,053) vs L-methylfolate augmentation (n=1,351) over 231 days. L-methylfolate showed higher antidepressant adherence (acute 78.7% vs 68.7%; continuation 62.1% vs 50.3%).
Retrospective comparitive study (n = 5,404)
Maruf, A. A., Poweleit, E. A., et al.
Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders.
Maruf, A. A., Poweleit, E. A., et al.
This systematic review/meta-analysis (through Dec 31, 2020) evaluated adjunctive l-methylfolate with antidepressants in depressive disorders (9 studies; N=6,707). l-methylfolate provided modest benefit vs antidepressant alone, improving HAM-D-17 response (RR 1.25; 95% CI 1.08–1.46) and lowering symptom severity (SMD −0.38; 95% CI −0.59 to −0.17).
Meta-analysis
Lam, N. S. K., Long, X. X. et al.
The Potential Use of Folate and Its Derivatives in Treating Psychiatric Disorders: A Systematic Review
Lam, N. S. K., Long, X. X. et al.
This PRISMA systematic review (1974–Aug 16, 2021) synthesized 23 clinical trials of folate derivatives across psychiatric disorders (MDD n=9 studies; schizophrenia n=5; ASD n=6; bipolar n=2; ADHD n=1). Across included trials, oral levomefolic acid (5-methylfolate/L-methylfolate) was most consistently associated with improved clinical outcomes, particularly when used adjunctively, and was generally well tolerated.
Systematic Review
Papakostas, G. I., Shelton, et al.
Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial
Papakostas, G. I., Shelton, et al.
This double-blind, placebo-controlled trial (n=75) tested L-methylfolate 15 mg/day added to an SSRI vs placebo for 60 days (primary: HDRS-28). L-methylfolate showed greater symptom improvement vs placebo primarily in biomarker/genotype-defined subgroups (e.g., higher inflammatory/metabolic markers and select folate-pathway variants), suggesting these measures may help identify likely responders.
Clinical trial (n=75)
Siddique, A., Khokhar, et al.
Effect of Combination Therapy of Methylfolate With Antidepressants in Patients With Depressive Disorder
Siddique, A., Khokhar, et al.
This 4-week trial (n=44) compared antidepressant + methylfolate 800 µg/day vs antidepressant alone using PHQ-9. By day 28, combination therapy produced greater symptom improvement than antidepressant monotherapy (40.33% vs 26.43%, p<0.05).
Clinical trial (n=44)
Altaf, R., Gonzalez, I., Rubino, et al.
Folate (L-methylfolate or folic acid) adjunct to SSRI/SNRI vs monotherapy in major depression (systematic review/meta-analysis)
Altaf, R., Gonzalez, I., Rubino, et al.
This meta-analysis pooled 5 studies comparing SSRI/SNRI + folate (L-methylfolate or folic acid) vs SSRI/SNRI alone. Adjunct folate improved outcomes: HAM-D mean difference −2.16 (95% CI −3.62 to −0.69), higher response (RR 1.36, 95% CI 1.16–1.59) and remission (RR 1.39, 95% CI 1.00–1.92), with symptom-score benefits at 4 weeks (SMD −0.38), 6 weeks (SMD −0.94), and ≥8 weeks (SMD −0.57).
Meta-analysis
Maletic, V., Shelton, et al.
A Review of l-Methylfolate as Adjunctive Therapy in the Treatment of Major Depressive Disorder.
Maletic, V., Shelton, et al.
This narrative review (2000–Apr 2021) summarizes l-methylfolate augmentation for antidepressant-inadequate-response MDD. Benefits were most consistent with 15 mg/day, with stronger signals in patients with BMI ≥30 and elevated inflammatory markers.
Meta-analysis
Zajecka, J. M., Fava, et al.
Long-term Efficacy, Safety, and Tolerability of L-Methylfolate Calcium 15 mg as Adjunctive Therapy in Major Depressive Disorder: A 12-Month, Open-Label Study Following a Placebo-Controlled Trial
Zajecka, J. M., Fava, et al.
This 12-month open-label extension followed n=68 adults with MDD continuing l-methylfolate 15 mg/day adjunctive to antidepressants to assess long-term outcomes. 38% (n=26) achieved full recovery with no MDD recurrences.
12 month follow-up extension to clinical trial (n=68)
Ginsberg, L. D., Oubre, et al.
L-methylfolate Plus SSRI or SNRI from Treatment Initiation Compared to SSRI or SNRI Monotherapy in a Major Depressive Episode
Ginsberg, L. D., Oubre, et al.
This study (N=242) compared starting an SSRI/SNRI + L-methylfolate (7.5–15 mg) vs SSRI/SNRI alone. At 60 days, major improvement was seen in 40% of L-methylfolate + SSRI/SNRI patients vs. 16.3% in monotherapy, with faster median time to major improvement (177 vs 231 days, p=.03)
Clinical trial (n=242)
Papakostas, G. I., Shelton, et al.
L-methylfolate as Adjunctive Therapy for SSRI-Resistant Major Depression: Results of Two Randomized, Double-Blind, Parallel-Sequential Trials
Papakostas, G. I., Shelton, et al.
Two multicenter RCTs in SSRI-resistant MDD compared SSRI + l-methylfolate vs SSRI + placebo (Trial 1: n=148; Trial 2: n=75). In Trial 2 (15 mg/day), response was 32% with l-methylfolate vs 15% with placebo (p≈0.05) and symptom reduction favored l-methylfolate (e.g., HAM-D change ~−5.6 vs −3.7).
Multi-center clinical trial (n=223)
Maruf, A. A., Poweleit, et al.
Comparative assessment of adherence and resource use: Second generation antipsychiotics vs L-methylfolate augmentation in SSRI/SNRI-treated depression
Maruf, A. A., Poweleit, et al.
This retrospective study with propensity matching compared SGA augmentation (n=4,053) vs L-methylfolate augmentation (n=1,351) over 231 days. L-methylfolate showed higher antidepressant adherence (acute 78.7% vs 68.7%; continuation 62.1% vs 50.3%).
Retrospective comparitive study (n = 5,404)
Maruf, A. A., Poweleit, E. A., et al.
Systematic Review and Meta-Analysis of L-Methylfolate Augmentation in Depressive Disorders.
Maruf, A. A., Poweleit, E. A., et al.
This systematic review/meta-analysis (through Dec 31, 2020) evaluated adjunctive l-methylfolate with antidepressants in depressive disorders (9 studies; N=6,707). l-methylfolate provided modest benefit vs antidepressant alone, improving HAM-D-17 response (RR 1.25; 95% CI 1.08–1.46) and lowering symptom severity (SMD −0.38; 95% CI −0.59 to −0.17).
Meta-analysis
Lam, N. S. K., Long, X. X. et al.
The Potential Use of Folate and Its Derivatives in Treating Psychiatric Disorders: A Systematic Review
Lam, N. S. K., Long, X. X. et al.
This PRISMA systematic review (1974–Aug 16, 2021) synthesized 23 clinical trials of folate derivatives across psychiatric disorders (MDD n=9 studies; schizophrenia n=5; ASD n=6; bipolar n=2; ADHD n=1). Across included trials, oral levomefolic acid (5-methylfolate/L-methylfolate) was most consistently associated with improved clinical outcomes, particularly when used adjunctively, and was generally well tolerated.
Systematic Review
Papakostas, G. I., Shelton, et al.
Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial
Papakostas, G. I., Shelton, et al.
This double-blind, placebo-controlled trial (n=75) tested L-methylfolate 15 mg/day added to an SSRI vs placebo for 60 days (primary: HDRS-28). L-methylfolate showed greater symptom improvement vs placebo primarily in biomarker/genotype-defined subgroups (e.g., higher inflammatory/metabolic markers and select folate-pathway variants), suggesting these measures may help identify likely responders.
Clinical trial (n=75)
Siddique, A., Khokhar, et al.
Effect of Combination Therapy of Methylfolate With Antidepressants in Patients With Depressive Disorder
Siddique, A., Khokhar, et al.
This 4-week trial (n=44) compared antidepressant + methylfolate 800 µg/day vs antidepressant alone using PHQ-9. By day 28, combination therapy produced greater symptom improvement than antidepressant monotherapy (40.33% vs 26.43%, p<0.05).
Clinical trial (n=44)
Altaf, R., Gonzalez, I., Rubino, et al.
Folate (L-methylfolate or folic acid) adjunct to SSRI/SNRI vs monotherapy in major depression (systematic review/meta-analysis)
Altaf, R., Gonzalez, I., Rubino, et al.
This meta-analysis pooled 5 studies comparing SSRI/SNRI + folate (L-methylfolate or folic acid) vs SSRI/SNRI alone. Adjunct folate improved outcomes: HAM-D mean difference −2.16 (95% CI −3.62 to −0.69), higher response (RR 1.36, 95% CI 1.16–1.59) and remission (RR 1.39, 95% CI 1.00–1.92), with symptom-score benefits at 4 weeks (SMD −0.38), 6 weeks (SMD −0.94), and ≥8 weeks (SMD −0.57).
Meta-analysis
Maletic, V., Shelton, et al.
A Review of l-Methylfolate as Adjunctive Therapy in the Treatment of Major Depressive Disorder.
Maletic, V., Shelton, et al.
This narrative review (2000–Apr 2021) summarizes l-methylfolate augmentation for antidepressant-inadequate-response MDD. Benefits were most consistent with 15 mg/day, with stronger signals in patients with BMI ≥30 and elevated inflammatory markers.
Meta-analysis
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