L-Methylfolate as a Monotherapy for Treatment-Resistant Depression: A Case Study (2024)

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L-Methylfolate as a Monotherapy for Treatment-Resistant Depression: A Case Study (1)

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Integr Med (Encinitas). 2020 Aug; 19(4): 14–18.

PMCID: PMC7572139

PMID: 33132780

Angela Hardin, ND and Carrie Baldwin-Sayre, ND

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This case study examines a 49-year-old Asian American female patient with long-standing fatigue and depression (20 years or more), for which pharmaceutical antidepressant therapies have been ineffective. History, physical examination, laboratory tests, and Genomind Genecept Assay genetic testing were used to determine symptom severity, investigate the presence of organic causes of fatigue, and provide a potential novel monotherapy for depression. Therapeutic intervention included a slow titration of L-methylfolate to an eventual therapeutic daily dose of 15 mg.


Treatment-resistant depression has a somewhat broad and nonstandardized definition, but is generally characterized by two unsuccessful trials of two different classes of antidepressant pharmaceutical therapies in the treatment of major depressive episodes.1 An adequate antidepressant therapy trial is considered to last a minimum of 6-8 weeks, with one initial pharmaceutical at therapeutic dose.2,3 However, if no improvements are observed within 4-6 weeks, medication modification in the form of either augmentation or class switch may be considered sooner.1

Most commonly, the pharmaceutical approach to treating patients with depression begins with a trial of selective serotonin reuptake inhibitors (SSRIs), such as citalopram HBr, as they are considered to be the best-tolerated class of antidepressant medications.4,5 The next best-tolerated class is the selective norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine; followed by atypical antidepressants, such as bupropion HCl; tricyclic antidepressants (TCAs) such as amitriptyline HCl; and finally, monoamine oxidase inhibitors (MAOIs), such as isocarboxazid.4,5 Other drug classes that are considered, albeit less commonly, for depression, include second generation antipsychotics, lithium, and triiodothyronine.4

There is evidence that both pharmaceutical augmentation with a second antidepressant, or medication switch within the same class or to a different class, is effective as the second step of treatment when the initial treatment has not been sufficient. Typically, patients who experienced adverse effects from initial treatment prefer a medication switch, whereas patients who noticed little effect from initial treatment may be comfortable with augmentation.5

It is significant to note that nonpharmaceutical interventions, such as exercise and psychotherapy, should be employed as supportive therapies, regardless of the pharmaceutical algorithm for antidepressant initiation and augmentation. Aerobic exercise twice weekly for 60 minutes per day has been recognized as an effective add-on therapy in patients with depression who are unresponsive to pharmaceutical intervention within 6 weeks.3 Similarly, 20 minutes per day, 3 times per week of moderate intensity exercise may also be beneficial in reducing depressive symptoms.3 Compliance with all therapies should be assessed in patients whenever possible as a potential contributor to treatment failure.6

Presenting Concerns

This case study examines a 49-year-old Asian American female whose presenting complaint at the National University of Natural Medicine (NUNM) Lair Hill Health Center was long-standing fatigue. She first began to notice a decrease in her energy around the time she relocated from Taiwan to the U.S. (in her 20s). She described her fatigue as a “lack of interest and motivation.” In 2010, she began to notice sleep difficulty, which contributed to daytime sleepiness and the need for daily afternoon naps. At night, she endorsed proper sleep hygiene before bed. She reported that she occasionally awoke from naps due to an inability to breathe, which triggered immediate anxiety and heart palpitations. She believed that she occasionally snored, and had not had a sleep study.

Additionally, the patient endorsed an equally longstanding history of depression without mania, suicidal ideation, nor psychosis, which she related to undivulged childhood trauma and “poor parenting.” She explained that it is considered inappropriate in Taiwanese culture to discuss feelings of depression, and consequently her symptoms went untreated for many years. Eventually, she was prescribed multiple antidepressant medications from various drug classes in an effort to treat her depressive symptoms. The exact timeline, dosage, and duration of the treatments were unknown, but the patient was able to recall separate trials of sertraline HCl, bupropion HCl, and venlafaxine, all of which were ineffective in successfully managing her mood. Access to the patient’s past medical records was lacking, so medical decisions were based solely on the patient’s reporting.

Clinical Findings

The patient’s medical history included chronic tension-type headaches, for which she had been receiving craniosacral therapy and acupuncture for years. She had a history of hemoglobin A1C (HbA1C) levels in the prediabetic range, and she avoided dietary sugars as a result. Her serum vitamin D3 level had recently been low, and her family health history was unknown.

The patient stated that she had quit her full-time job in 2014 and had since been working from home only part-time, though her stress remained high. She exercised 30 minutes each morning, and stretched each evening. She also danced and played soccer regularly. She received counseling every 3-4 weeks, and acupuncture regularly, which had only been somewhat effective for symptom relief. She had self-prescribed an extensive list of supplements in an effort to elevate mood and energy, but only small improvements resulted. Her daily supplements included, but were not limited to, vitamin D3 3000 IU, L-methylfolate 1 mg, vitamins B6 and B12, a multivitamin with iron, and many herbal formulations designed for support of adrenal gland function.

She primarily ate a diet high in fats and animal protein, and low in grains, starches, and simple carbohydrates. She did not consume caffeine, alcohol, tobacco products, nor drugs and was having regular menstrual periods. She did not have children, had never been married, and was currently living alone in Portland. She admitted to feelings of loneliness and the desire for more socialization.

Physical examination of the mouth revealed an enlarged tongue, which made visualization of the posterior pharynx difficult. The patient’s vital signs were unremarkable—there was no evidence of thyromegaly, lymphadenopathy, or pallor; heart and lung screening examinations were unremarkable.

The patient’s STOP-Bang questionnaire score in-office was 2, which suggested a low risk for obstructive sleep apnea (OSA); her Epworth Sleepiness Scale in-office score was 11, which was considered moderate excessive daytime sleepiness; her Patient Health Questionnaire 9-item (PHQ-9) score in-office was 17, which was suggestive of moderately severe depression and met the criteria for major depression (based on the presence of 5+ depressive symptoms).

Diagnostic Assessment

Adults with depression account for roughly 5%-10% of patients in a primary care setting.5 The term “depression” may refer to either a depressed mood state, which can be both normal or pathologic, or it might refer to unipolar depression/Major Depressive Disorder (MDD) which is considered to be a syndrome, or constellation of symptoms and signs that may also include a depressed mood.7 These depressive syndromes occur on a spectrum; the most common of those syndromes being major, minor, and persistent depression.7 Common symptoms of a depressed mood include feelings of sadness, lack of interest, fatigue, anxiety, despair, discouragement, hopelessness, having no feelings, and/or being tearful.7

The diagnosis of depressive disorders is largely clinical. Unipolar major depression includes at least 5 of the following symptoms, which cause significant distress or impairment, and must be present for 2 weeks or longer, for nearly every day of those 2 weeks—depressed mood which lasts most of the day; anhedonia related to activities that the patient previously found to be pleasurable; insomnia or hypersomnia; at least a 5% weight loss or gain within 1 month, or decreased or increased appetite; psychom*otor retardation or agitation that is observable by others; fatigue or low energy; difficulty in concentration and decision-making; thoughts of guilt or worthlessness; and/or recurrent thoughts of, or attempt of, suicide.7

As part of clinical assessment of patients with suspected depression, in addition to the patient’s mood symptoms, evaluation of current and past medical illnesses, family and social history, examination of mental status, and physical examinations and laboratory tests, which are pertinent or as part of investigation of underlying conditions, are warranted.7

The PHQ-9 is a standardized rating scale used in most clinics that is nondiagnostic for depression, but is a subjective measure of symptom severity, and may serve as a tool to monitor treatment efficacy. Scores ≥20 indicate severe depression, scores <5 indicate remission, and a decrease in score of 50% or greater indicates significant clinical response.8

It is important to refer patients whose diagnosis is uncertain, and depression is suspected. Also refer those whose depression is unresponsive to initial treatment; if the life of the patient or another is in danger as a result of the patient’s symptoms and behavior; if the patient exhibits severe, psychotic and catatonic depression; and/or if the patient has features suggestive of bipolar disorder, schizoaffective disorder, or schizophrenia.7

There are several depressive episode subtypes. These include anxious distress, atypical features, catatonia, melancholic features, mixed features, peripartum onset, psychotic features, and seasonal pattern, none of which will be discussed in detail here.7

Genomind Genecept Assay genetic testing revealed the following findings for the patient:

  1. decreased activity in the MTHFR (methylenetetrahydrofolate reductase) enzyme, which impairs the conversion of folic acid to methylfolate. Methylfolate crosses the blood brain barrier and is a cofactor required for the complete synthesis of serotonin, norepinephrine, and dopamine in the brain.10 Supplementation with L-methylfolate in addition to SSRIs or SNRIs shows symptom reduction in MDD, and may be an effective monotherapy in MDD.9

  2. decreased activity of brain-derived neurotrophic factor (BDNF), a protein which is involved in neuronal development and plasticity. Altered activity in BDNF suggests a potential risk for increased depressive symptoms, impaired memory, and altered stress response. Exercise has been linked to improvements in cognition, and if clinically indicated, patients with this mutation may benefit from increased physical exercise as this will stimulate the protein’s activity.9

  3. poor response to, or impaired metabolism of, many classes of antidepressants, excluding SNRIs and atypical antidepressants.

All of these findings may, in isolation or in combination, contribute to the patient’s symptoms of fatigue, depression, and resistance to multiple treatments.

Many other underlying organic causes of fatigue and depression have been ruled out with laboratory testing, including thyroid disease, vitamin D3 deficiency, anemias, and infections. Though it is unclear whether or not the patient has true treatment-resistant depression, as documentation of all attempted trials is lacking, symptoms of MDD in this patient were evident and warranted treatment and regular monitoring, and follow-up visits.

A sleep study remained indicated for this patient to rule out OSA and/or other sleep disorders which, in addition to depression, may have contributed to the patient’s excessive daytime sleepiness.

Therapeutic Intervention

Therapeutic options indicated by the Genomind Genecept Assay results included venlafaxine (SNRI), which was offered to the patient. Although the patient reported that she had tried this medication in the past, the exact timeline of the trial and whether or not the therapeutic dose was achieved is unclear. The patient declined initiation of venlafaxine, and instead opted for monotherapy of L-methylfolate at a much higher dosage than the standard RDA (400-800 mcg daily).

The patient stated that she had already been supplementing with L-methylfolate 1 mg for many weeks. She was instructed to increase her supplementation to 2 mg daily for 1 week, and increase by 1-2 mg per week until a total of 15 mg was achieved. A slow titration of the supplement was advised to avoid certain known side effects, including gastrointestinal distress, anxiety, and/or agitation. L-methylfolate has mostly been studied as an add-on therapy in higher doses (15 mg daily) with an SSRI or other antidepressant, but may also be an effective monotherapy for patients with MDD.10,11

The patient was encouraged to continue with regular moderate to vigorous exercise, as was reflected in her genetic test results, and because the patient endorsed improved mood and energy during exercise. She was also encouraged to continue regular visits with her counselor and acupuncturist if she noticed benefit.

Follow-up and Outcomes

The patient was compliant with the supplementation dosage adjustments of L-methylfolate, and continues to supplement with 15 mg daily. She has reported improvements in both mood and energy levels since initiating the higher dose (higher than 7 mg), and her PHQ-9 follow-up score within 3 months was 0.

Within a few weeks of the patient’s initial office visit, she completed a sleep study, which was negative for OSA.


Fatigue and depression often coexist, however, the presence of both is not always related. The main strength of this case is the drastic improvement in the patient’s mood and energy, which can likely be attributed to high-dose L-methylfolate therapy. In fact, the treatment was so effective in increasing her energy level, the patient had to decrease the dosage at one point to avoid sleep disturbance. Although she took multiple nutritional supplements daily, maintained a healthy diet, avoided alcohol and other substances, exercised regularly, and attended counseling and acupuncture appointments, her fatigue and depression remained until she increased her L-methylfolate dose to 10 mg.

Limitations in this patient’s case were that her family’s medical history was unclear, and there were no accessible medical records that provided a solid understanding of her course of disease and past treatments. Additionally, there is limited research on L-methylfolate as a monotherapy for MDD, and more research on this topic is needed to determine validity and reproducibility.

Patient Perspective

The patient was pleased that after years of searching for an effective treatment and “doing everything right” without a significant change in her mood and energy, a genetic test was able to determine the presence of an MTHFR enzyme alteration that may explain both her symptoms and the lack of efficacy of several attempted treatments. She was encouraged by the additional knowledge from her test results, and the novel recommendation of higher dose L-methylfolate. She expressed satisfaction with the new treatment plan, and reported adherence at several follow-up visits. The patient expressed improvement in both energy and mood since the initiation of higher doses of L-methylfolate. This outcome provides some reassurance that a similar high-dose treatment may be appropriate and help in the enhancement of mood and energy in certain patients, if tolerated.

Table 1.

DatesRelevant Past Medical History and Interventions
Prior to 10/2018Patient’s long-standing history of depression and daytime sleepiness were reported to be resistant to several antidepressant medication trials and counseling.

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Table 2.

DateSummaries from Initial and Follow-up VisitsDiagnostic TestingInterventions
10/1/18Initial visit:
  • CC: daytime sleepiness and depression

  • PE revealed enlarged tongue

  • Stop-Bang score: 2 (low)

  • Epworth Scale: 11 (moderate excessive)

  • PHQ-9 score: 17 (moderately severe)

  • CBC

  • Ferritin

  • Hcy

  • MMA

  • CMP

  • TSH

  • Exercise, 150 minutes weekly

  • Happy Light use, 30 min, qam

  • Omega-3 fish oil, 2 g/d

  • Sleep study ordered

  • Pt reports no change in sxs

  • Lab review (WNL)

  • Genomind Genecept buccal swab genetic testing

  • Continue with prior recommendations

  • Sleep study pending

  • Reports no change in sxs

  • Genetic testing revealed decreased enzymatic activity of MTHFR

  • Initiated 2 mg L-methylfolate for 1 week; increased by 1-2 mg/week until 15 mg daily dosage qas achieved

  • Continue with prior recommendations

  • Sleep study pending

11/29/18Phone call:
  • Pt reported sx improvement with supplementation and requested Rx for 10 mg strength of L-methylfolate

  • Rx provided for higher dose L-methylfolate

  • Continue with prior recommendations

  • Sleep study pending

  • Pt reached dose of 10 mg L-methylfolate and reported improvement in symptoms PHQ-9: 12 (moderate)

  • GAD-7: 11 (moderate)

  • Sleep study scheduled for 2/2019

  • Continue with prior recommendations

  • Pt reported continued sx improvement with 15 mg daily L-methylfolate

  • PHQ-9 score: 0

  • Continue with prior recommendations

  • Pt reported mild insomnia and anxiety with 15 mg daily dosage

  • Alternate dosing of 15 mg with 10 mg qod

  • Well-woman exam

  • Pt reported fatigue with lower dose of supplementation

  • Reported anxiety and insomnia related to potential home relocation to Mexico for Peace Corps

  • Cervical cytology with HPV co-testing (WNL)

  • Return to 15 mg daily dosage of L-methylfolate

  • Initiate PS for sleep support: 250 mg qhs for 3 nights; increase to 500 mg qhs thereafter

  • Pt reported improved sleep and decreased anxiety with PS 375 mg qhs and denied depression

  • Continue with prior recommendations

  • Patient continued 15 mg daily supplementation with L-methylfolate and reported stable mood and energy with treatment. Sleep study was negative for OSA.

  • Continue with prior recommendations

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Abbreviations: CC, chief complaint, PE, physical examination, PHQ, patient health questionnaire, CBC, complete blood count, Hcy, hom*ocysteine, MMA, methylmalonic acid, CMP, comprehensive metabolic panel, TSH, thyroid stimulating hormone, min/wk, minutes per week, g/d, grams per day, qam, every morning, pt, patient, sxs, symptoms, WNL, within normal limits, phosphatidylserine, PS, MTHFR, methylenetetrahydrofolate reductase, N/A, not applicable, mg, milligrams, Rx, prescription, GAD, generalized anxiety disorder questionnaire, qod, every other day, HPV, human papilloma virus, qhs, every night at bedtime, OSA, obstructive sleep apnea.


Ethical Considerations

The authors declare no conflicts of interest in this case. HIPAA Privacy Rule [45 CFR 164.501, 164.508, 164.512(i)]


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