L-methylfolate Augmentation to Antidepressants for Adolescents with Treatment-Resistant Depression: A Case Series

Abstract

Despite antidepressant treatment, some patients continue to experience significant symptoms of depression. Literature has demonstrated modest benefit of folate supplementation in treatment-resistant depression among adults, though evidence is lacking in the pediatric population. This case series describes 10 adolescents (mean age 14.4 ± 2.8 years) with treatment-resistant depression prescribed adjunctive l-methylfolate (LM). The patient population was predominantly female (80%), Caucasian (90%), with an average of three comorbid psychiatric diagnoses, and failures of three psychotropic medications before starting LM. The majority of patients (80%) had a single mutation among the two methylene tetrahydrofolate reductase (MTHFR) gene variants evaluated (50% A1298 AC; 30% C677 CT), indicating reduced MTHFR activity. Eighty percent of patients demonstrated improvement in depression, anxiety, and irritability. Overall, LM was well tolerated. These cases suggest that LM as an adjunct to antidepressant treatment may be a safe and effective strategy for managing treatment-resistant depression in pediatric patients.

Introduction

Major depressive disorder (MDD) among youth is common and if left untreated, significantly increases their risk for suicide (CDC 2016). In 2016, suicide was the second leading cause of death among individuals 10–24 years old (Heron 2018). MDD is typically treated with a combination of individual and family therapy, school-based behavioral interventions, and in some instances antidepressant medications. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed class of antidepressants in pediatric patients, although many patients continue to experience symptoms of depression despite ongoing pharmacologic treatment.

Treatment-resistant depression is difficult to manage, particularly given the lack of alternative treatment strategies in youth. When patients fail to fully respond to an antidepressant, practitioners must decide whether to prescribe concomitant medications to target depressive symptoms. However, the usage of additional psychotropic medications may increase the risk for long-term side effects, the potential for drug interactions, and reduce the likelihood of daily medication adherence.

Adult literature has identified a relationship between low folate levels and a reduced response to antidepressants, namely SSRIs (Papakostas et al. 2012). This evidence suggests that folate supplementation could be considered for the treatment of depression in adults, both as monotherapy and as an adjunct to antidepressants.

In light of this evidence, several studies have examined using l-methylfolate (LM), available commercially as Deplin^®, both as monotherapy and as augment to antidepressants. Randomized, controlled trials have demonstrated benefit of LM in adults with treatment-resistant depression and a partial response to antidepressants. In particular, those with reduced conversion of LM due to genetic variation of methylene tetrahydrofolate reductase (MTHFR) may benefit from supplemental LM therapy.

Currently, there is no evidence to support the use of LM in children or adolescents. We present a case series of 10 adolescents treated with adjunctive LM for treatment-resistant depression. In accordance with local institution approval (Colorado Multiple Institutional Review Board), medical charts of all patients prescribed LM for treatment-resistant depression in an outpatient child psychiatry clinic (Children's Hospital Colorado Pediatric Mental Health Institute) between January 2016 and December 2017 were reviewed. Charts were excluded in this review if there was a comorbid diagnosis of a substance use disorder or if they did not fall within the review period. Baseline characteristics, psychotropic medication history, and MTHFR genotype can be found in Table 1.

Table 1.

Patient Characteristics

Patient	Age/sex/race	DSM-5 diagnoses	Psychotropic medication history	ADs at start of LM therapy (dose in mg/day)	MTHFR mutation	Initial/current dose of LM (mg/day)	Duration of LM treatment (weeks)	Current AD therapy (mg/day)
1	17/F/C	MDD, GAD, SAD	Bupropion, fluoxetine	Sertraline 25	C677 CT	7.5/7.5	73	Sertraline 150
2	11/M/C	DMDD, GAD, ADHD, ASD, MDD	Fluoxetine, fluvoxamine, risperidone, aripiprazole, escitalopram, venlafaxine	Quetiapine IR 200	A1298 AC	3.75/3.75	29	Quetiapine IR 200
3	17/F/A	MDD, GAD	Bupropion, sertraline, venlafaxine	Fluoxetine 40	C677 CT	3.75/15	34	Fluoxetine 60
4	17/F/C	GAD, PD, ADHD, SAD	Venlafaxine, lamotrigine, fluoxetine, citalopram, sertraline	Bupropion SR 200, aripiprazole 1	A1298 AC	3.75/15	33	Bupropion SR 200, venlafaxine XR 112.5, lamotrigine 50, trazodone 75
5	13/F/C	MDD, GAD	Fluoxetine, escitalopram, sertraline	Citalopram 10	A1298 AC	5/7.5	50	Citalopram 40
6	16/M/C	MDD, GAD	Fluoxetine	Mirtazapine 15, sertraline 100	C677 CT	7.5/7.5	16	Duloxetine 40, mirtazapine 45
7	9/F/C	GAD, unspecified depressive disorder	Fluoxetine	Sertraline 50	A1298 AC	∼2 (1/4 tab)/3.75	29	Escitalopram 7.5
8	13/F/C	MDD, GAD, pica	Venlafaxine, escitalopram, aripiprazole	Sertraline 150	C677 CT	∼2/15	29	Duloxetine 20 + duloxetine 30 (alternate days)
8	13/F/C	MDD, GAD, pica	Venlafaxine, escitalopram, aripiprazole	Sertraline 150	A1298 AC	∼2/15	29	Duloxetine 20 + duloxetine 30 (alternate days)
9	15/F/C	MDD, PTSD, GAD	Fluoxetine	Aripiprazole 10, sertraline 200	A1298 AC	7.5/7.5	57	Venlafaxine XR 112.5
10	16/F/C	MDD, gender dysphoria disorder, GAD	Venlafaxine, sertraline, fluoxetine, bupropion, lamotrigine	Escitalopram 10	C677 CT	7.5/15	29	Citalopram 40
10	16/F/C	MDD, gender dysphoria disorder, GAD	Venlafaxine, sertraline, fluoxetine, bupropion, lamotrigine	Escitalopram 10	A1298 AC	7.5/15	29	Citalopram 40

DSM-5, Diagnostic and Statistical Manual 5th Edition; AD(s), antidepressant(s); LM, l-methylfolate; F, female; M, male; C, Caucasian; A, Asian; MDD, major depressive disorder; GAD, general anxiety disorder; SAD, social anxiety disorder; DMDD, disruptive mood dysregulation disorder; ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; PD, panic disorder; PTSD, posttraumatic stress disorder; MTHFR, methylene tetrahydrofolate reductase.

Case 1

A 17-year-old female presented with ongoing complaints of anxiety and depression accompanied by significant nausea, vomiting, and frequent school absences. Past medication trials were mostly ineffective or associated with adverse or paradoxical effects.

Genetic testing revealed an MTHFR gene mutation, so she was started on LM 7.5 mg daily. At this time, sertraline was also started. Overall, the patient reported doing “much better” since the start of sertraline and LM. She continued to have difficulty getting out of bed in the morning, but endorsed improved energy, fewer anxious episodes, improved appetite, increased interest in activities, and she was no longer missing school. The provider noted that her anxiety and depression had nearly resolved after ∼1 year of LM and sertraline therapy.

Case 2

An 11-year-old male with ongoing mood dysregulation (i.e., irritability, aggression, and depressive symptoms) presented with a history of several psychotropic medication trials. He failed multiple antidepressants and tried various stimulants with minimal symptom relief. He was also trialed on risperidone, but it was discontinued due to adverse effects.

As a result of persistent depressive symptoms, MTHFR gene testing was ordered, and he was subsequently started on LM 3.75 mg daily to be taken as an adjunct with clonidine and quetiapine. About 1 month later, he appeared remarkably improved with a brighter affect and improved social engagement. Per patient report he was “generally happy now” and had increased interaction with peers.

Case 3

A 17-year-old female presented with ongoing daytime sedation and frequent school refusals. She tried multiple antidepressants, but most were discontinued due to side effects and lack of symptom improvement. Given a partial positive response to fluoxetine, she was tested for the MTHFR gene, which revealed a mutation. Fluoxetine was therefore restarted, and she was prescribed LM 3.75 mg daily as an adjunct to fluoxetine.

Her mood slowly improved over 7 months, with reports of increased participation in activities, in addition to improved sleep and appetite. During this time, her dose of LM was gradually increased to 15 mg daily. Overall, she endorsed continued tiredness, but her symptoms remained stable.

Case 4

A 17-year-old female continued to miss most days of school despite several trials of antidepressants. Hydroxyzine, lorazepam, and aripiprazole were also trialed to target ongoing depression and anxiety, all of which were ineffective. Due to continued symptoms, gene testing for MTHFR was ordered.

LM was initiated at 3.75 mg daily, which seemed to provide immediate symptom improvement, though symptoms gradually returned. After a few medication changes and gradually increasing LM to 15 mg daily, the patient reported lessened symptoms of anhedonia, poor energy, hypersomnia, and hopelessness. The patient also endorsed that she felt her “medication was working now.”

Case 5

A 13-year-old female initially presented with depressive symptoms for the past year, in addition to ongoing self-harm and suicidal ideation. She also struggled with social anxiety and complained of near constant stomach aches and pains that interfered with her ability to engage in activities. She trialed several antidepressants, all of which initially improved her symptoms, but none provided long-term relief.

Upon identification of a MTHFR gene mutation, LM was started at 3.75 mg daily. Over a period of 6 months, her depression improved. She reported less irritability, increased interest in activities, and better social interactions. She still struggled with sleep and thoughts of self-harm, but her suicidal thoughts were not nearly as severe or frequent.

Case 6

A 16-year-old male presented with chronic insomnia and ongoing symptoms of severe depression, including daily suicidal thoughts. After failing two antidepressant trials, MTHFR gene activity was measured. The test revealed a mutation, and LM was started at 7.5 mg daily.

One month after starting LM and increasing sertraline, he complained of nausea, vomiting, and diarrhea. In response to these symptoms, sertraline was changed to escitalopram, and LM was reduced to 5 mg daily. Despite these changes and a trial of aripiprazole, his depression continued to worsen. His insomnia mildly improved, but sleep remained erratic and his suicidal thoughts were constant.

Case 7

A 9-year-old female presented with persistent depression and anxiety, including episodes of mild self-harm, excessive worry, outbursts, and severe mood swings. Her past medical history was significant for delays in motor development and a family history of mental illness in both mother and sister. After failing two antidepressants, MTHFR activity was tested. Given reduced MTHFR activity, LM was started at 2 mg daily.

About 2 months after the initiation of LM, her depressive symptoms stabilized per mother's report. Her anxiety was less frequent, but with the same intensity. She also continued to display self-injurious behaviors. LM was increased to 3.75 mg daily, and sertraline was changed to escitalopram. A few months later, she still endorsed symptoms of anxiety, but her symptoms were stable.

Case 8

A 13-year-old female with an extensive history of multiple inpatient psychiatric hospitalizations (for suicidal ideation and/or foreign body ingestion) failed two antidepressants and aripiprazole. Given her lack of response to medications, parents became interested in an alternative treatment approach. She was then started on LM 2 mg daily as an adjunct to mirtazapine.

Despite initiation of LM, she continued to struggle with daily suicidal ideation, mood lability, irritability, disruptive sleep, and defiant/disruptive behaviors. Her mood and sleep mildly improved after starting mirtazapine, but she felt that her panic attacks and anxiety were worsening. Over the next 4–5 months, she continued to feel incredibly anxious, with reported dissociations and body spasms. Several medications were tapered and titrated during this time, eventually leading to cessation of all psychotropic medications. However, she remained on LM therapy, which was titrated to 15 mg. Discovering the appropriate medication for this patient remains a challenge, as she still endorses severe anxiety and mood lability.

Case 9

A 15-year-old female presented with a primary complaint of panic attacks that occurred up to three times a day, suicidal ideation, and self-harming behaviors. Due to persistent symptoms, MTHFR gene testing was obtained, which revealed reduced activity, prompting usage of LM 7.5 mg daily. Shortly after, she had increased anxiety and felt “jittery.” This was resolved by decreasing her sertraline dose and temporarily stopping LM. Although still symptomatic, her anxiety and suicidal ideation were improving, so LM was reinitiated at 3.75 mg daily.

Nearly 3 months later, the patient endorsed improvements in sleep, appetite, energy, and increased interest in activities. By month 7, she felt that her depression had resolved. She no longer required a benzodiazepine for panic attacks and she denied suicidal ideation, self-harm, anhedonia, and low energy. During this time, LM was increased to 7.5 mg daily. After experiencing a traumatic event 2 months later, her symptoms responded well to an increased dose of her antidepressant and ongoing LM treatment.

Case 10

A 16-year-old transgender male presented with daily suicidal ideation, self-injurious behavior, and mild anhedonia. After failing trials of several antidepressants and a mood stabilizer, gene testing was obtained to assess for folate deficiency. After a mutation in the MTHFR gene was detected, LM was started at 7.5 mg daily and escitalopram was restarted. Of note, the patient was also receiving exogenous testosterone for cross-sex hormone therapy during this time.

His mother reported moderate improvement after ∼2 weeks on LM, and the patient appeared noticeably brighter and engaged. After 1 month of therapy, his suicidal thoughts diminished, his sleep and appetite returned to normal, and he regained interest in activities. Over the next 5–6 months, his mood remained stable, despite intermittent self-injurious behavior in response to social stressors. LM was increased to 15 mg daily during this time. With further titration of his antidepressant and continued LM treatment, his symptoms remained stable despite ongoing difficulties at school.

Discussion

MDD is a common psychiatric condition that affects up to 8% of adolescents and 2.5% of children. Identification of MDD in pediatric populations is difficult, given variability of symptom presentation throughout each stage of development. In youth, untreated or inadequately treated depression also interferes with development; it impairs academic and social functioning, and increases the risk of suicide (Dopheide et al. 2006). First-line treatment options for pediatric patients include a combination of psychotherapy, psychosocial interventions, and/or pharmacologic treatment. Antidepressants, particularly SSRIs, have demonstrated efficacy in pediatric patients with MDD as well as anxiety disorders. Despite the availability of pharmacologic treatment strategies and treatment guidelines to support medication decisions, some pediatric patients do not achieve symptom remission.

It is difficult to manage treatment-resistant depression, typically defined as the failure of two or more antidepressants with different mechanisms of action, particularly given the lack of alternative treatment strategies in youth. Remission data for pediatric depression are highly variable, with estimates ranging from 23% to 63% (Kennard et al. 2009). This is similar to adult literature, which estimates that more than half of all adult patients treated with antidepressant monotherapy fail to reach remission (Papakostas et al. 2012). In cases of partial antidepressant response, providers must decide how to optimize medication treatment. Such strategies may include the addition of a dual-reuptake inhibitor antidepressant (e.g., bupropion), second-generation antipsychotic (SGA) (e.g., aripiprazole), or mood stabilizer (e.g., lithium). Complementary and alternative medications have also been evaluated as augment strategies in treatment-resistant MDD.

Literature has suggested that folate deficiency is associated with depressive disorders, reduced likelihood to respond to antidepressants, increased likelihood of symptom relapse, and longer duration of depressive episodes (Stahl 2007; Fava and Mischoulon 2009; Zhao et al. 2011; Papakostas et al. 2012). The link between folate and depressive symptoms has also been supported by observations that reduced conversion of folate to its centrally active form is more common in patients with MDD (Stahl 2007). This association may be explained by the presence of common genetic variants of MTHFR.

LM, the biologically active form of folate, is derived from synthetic folic acid (through supplementation or folic-acid-enriched food) or dihydrofolate (found naturally in leafy green vegetables, legumes, beans, and citrus fruits), and is commercially available as a prescribed medical food (Deplin) in the United States. In the body, LM is converted from methylene tetrahydrofolate by MTHFR during the final step of the biosynthesis pathway. LM is thought to be the only form of folate that crosses the blood–brain barrier, playing a critical role in the regulation of the cofactor tetrahydrobiopterin (BH4), which is responsible for monoamine neurotransmitter synthesis (Stahl 2007, 2008; Miller 2008). For this reason, it is thought that LM deficiency may lead to reduced levels of monoamines, thereby increasing an individual's risk to develop depression or have an incomplete response to antidepressants (Stahl 2007, 2008).

Literature has sought to more clearly define the impact that genetic variations have on LM synthesis. It has been reported that up to 70% of adult patients with MDD have a genetic variant of the MTHFR gene, compromising their ability to convert dietary folate or synthetic folic acid to LM (Shelton et al. 2013). Two common variants of the MTHFR gene, primarily C677C>T and A1298A>C, have been shown to predict MTHFR activity (Stahl 2008; Nelson 2012). Studies examining C677T demonstrate that individuals who are homozygous for the T variant (C677 TT) express 30% of MTHFR enzyme activity compared to those with the wild-type variant (C677 CC). Heterozygous individuals (C677 CT) express 65% of MTHFR activity (Nelson 2012). Similarly, studies have demonstrated that A1298 CC carriers have a more pronounced decrease in MTHFR activity than heterozygous (A1298 AC) or wild-type individuals (A1298 AA). One study also found that the A1298C mutation is highly prevalent and similar in frequency to the C677T mutation, but the A1298C mutation reduced MTHFR enzyme activity to a lesser extent than those with the C677T mutation (Friedman et al. 1999).

An early evaluation of adjunctive methylfolate demonstrated positive results in adults with a diagnosis of MDD or schizophrenia and documented folate deficiency. Forty-one patients with folate deficiency were randomized to methylfolate 15 mg daily or placebo for 6 months as adjunct to psychotropic medications. Significant improvement in depressive symptoms (as measured by the 17-item Hamilton Depression Rating Scale [HAM-D]) was noted as early as month 3 in patients with depression and month 6 for those with schizophrenia. The authors did not evaluate tolerability of methylfolate but did describe increases in serum folate levels in those who received supplementation (Godfrey et al. 1990).

To formally evaluate the role of LM as adjunct to SSRIs and to determine a desirable LM dose in adults with MDD, Papkostas et al. conducted two multicenter, sequential parallel comparison trials. The first trial demonstrated that adjunctive 7.5 mg daily of LM was not superior to continued SSRI treatment plus placebo (n = 148) after 30 days. Patients who subsequently received 15 mg daily of LM for 30 days demonstrated a greater response rate than those who continued SSRI treatment plus placebo (25% vs. 9%, p = 0.1) as measured by the HAM-D. Similarly, the second trial demonstrated significantly greater response rates among adults who received LM 15 mg daily compared to placebo (32.3% vs. 14.6%, p = 0.04). LM was well tolerated, and rates of adverse events were no different than placebo (Papakostas et al. 2012).

In an effort to evaluate longer term efficacy, safety, and tolerability of LM 15 mg daily in combination with SSRI treatment, Zajecka, et al. enrolled the previously described patients in a 12-month, open-label study. Overall, 38% of patients achieved full recovery (defined as ≥6 months of remission from the start of the open-label phase); among those who achieved recovery, none experienced a recurrence of their MDD during the study period. Of note, 70% of patients who entered the open-label phase as nonresponders (<50% improvement in HAM-D score) achieved a response during the study period, with 92% reporting a response within the first 3–6 months. In addition, 60% of nonresponders achieved remission and 26% met recovery criteria during the open-label phase. Furthermore, LM appeared well tolerated. A total of 42 of 164 patients (∼26%) reported adverse effects, which were comparable with placebo during the double-blind phase. The most commonly reported were gastrointestinal, sleep, psychological, and somatic-related symptoms. To date, this is one of the longest studies available examining adjunctive LM to psychotropic treatment (Zajecka et al. 2016).

Finally, Shelton et al. sought to prospectively assess the impact of LM on depression severity, quality of life, and medication satisfaction in a naturalistic setting. Overall, 554 adult patients with MDD prescribed LM as augment to their existing antidepressant regimen (∼91%) or as monotherapy (∼5%) were surveyed. Participants reported a significant (p < 0.0001) mean reduction of 8.5 points in their Patient Health Questionnaire (PHQ-9) score after ∼3 months of treatment. Significant improvements in depressive symptoms and functioning were demonstrated, with 67.9% of patients responding to LM treatment (defined as a ≥50% reduction in baseline PHQ-9 score) and 45.7% achieving remission (PHQ-9 score <5 after 90 days of treatment) over 12 weeks. Quality of life also significantly improved, as the proportion of patients who reported “depressive symptoms made it very or extremely difficult to function” decreased from 50% to 13% (p < 0.0001). This study also showed high patient medication satisfaction and compliance, with >90% of patients reporting that they took every dose or nearly every dose of LM (Shelton et al. 2013).

To our knowledge, this case series is the first description of LM use in adolescents with treatment-resistant MDD. Our patient population (mean age 14.4 ± 2.8 years) was predominantly female (80%) and Caucasian (90%), with an average of three comorbid psychiatric diagnoses. Most common psychiatric diagnoses included generalized anxiety disorder (100%), MDD (80%), and social anxiety disorder (20%). On average, patients failed three psychotropic medications before starting LM. SSRIs (fluoxetine >sertraline >escitalopram) and serotonin norepinephrine reuptake inhibitors (venlafaxine) were the most common classes of antidepressants prescribed.

The addition of LM was considered after a minimum of two failed antidepressant trials, after evaluation of MTHFR genotype, and in some cases in an effort to avoid or reduce doses of augment SGAs. All patients were found to have some genetic variation of C677C>T and/or A1298A>C; specifically, 30% expressed C677 CT (reduced activity), 50% expressed A1298 AC (reduced activity), and 20% expressed both C677 CT and A1298 AC (significantly reduced activity). Upon LM initiation, most patients were treated with SSRI monotherapy (60%). A small number were treated with a concomitant SGA (30%). Several medication changes were made throughout LM treatment, and many patients (40%) were transitioned from an SSRI to an SNRI. Of note, two patients treated with aripiprazole before LM initiation were tapered off the SGA after a few weeks of LM.

Patients were typically started on a dose of 3.75–7.5 mg and titrated to a maximum dose of 15 mg. The mean final dose was 9.4 mg per day. Of note, dosing was generally based on available capsule sizes of Deplin (7.5 and 15 mg). In addition, some families purchased over-the-counter (OTC) tablet formulations allowing for significant dose variation. The average duration of therapy was ∼38 weeks (range 16–73 weeks) and to our knowledge, patients took LM during the entire stated time period.

As this was a retrospective review, efficacy measures were not consistently documented across our patient population. Efficacy was assessed through subjective reports from the patient, family, and provider. In general, LM was noted to be modestly effective, with 8 of 10 patients noting a subjective improvement in symptoms of depression, anxiety, and irritability. For most patients, symptom improvement was described by the first or second follow-up visit after starting LM (e.g., 1–2 months). Two patients continued to experience severe depression despite the addition of LM.

LM was generally well tolerated. One patient experienced gastrointestinal discomfort, which improved with a dose decrease. A second patient reported increased anxiety and jitteriness shortly after starting LM, which was managed by temporarily discontinuing LM and later resuming at a lower dose. Of note, these effects could have been explained by concomitant antidepressant changes.

MTHFR activity was primarily evaluated through Mayo Laboratories. Two primary variants, C677C>T and A1298A>C, were measured and evaluated by the prescribing clinician. At this time, the Clinical Pharmacogenomics Implementation Consortium does not have specific guideline recommendations for measuring MTHFR activity, though evidence-based guidelines for interpretation of specific gene drug pairs are available for certain classes of psychotropic medications (e.g., antidepressants). In our experience, patients with treatment-resistant depression were only started on LM after a deficiency in MTHFR activity was identified. Further evaluations are needed to determine (1) the most appropriate timing of MTHFR genetic testing, (2) standardized interpretation of results (e.g., what dose and duration of treatment should be recommended based on the individual's phenotype), and (3) specific products that should be recommended (e.g., Deplin vs. OTC products). In addition, cost of MTHFR genetic testing may vary widely based on the method of measurement (e.g., individual MTHFR panel as a send-out laboratory vs. bundled with a pharmacogenomic proprietary test).

The variety of commercially available methylfolate products warrants close evaluation. LM is available in the United States as a prescription medical food (Deplin). A medical food is defined as “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition” (Office of Nutrition and Food Labeling 2016). While medical foods are not regulated by the FDA, manufacturers must comply with all applicable FDA requirements for food. OTC LM products are available, though none with a United States Pharmacopeia designation, making it difficult to assess quality and safety. In our experience, Deplin is not covered by most insurance companies and may not be a cost-effective option for many patients (estimated cost $60 U.S. dollars/month). While OTC products are likely cheaper, quality concerns and lack of systematic studies make them less desirable products.

Given the retrospective nature of this case series, it is difficult to make strong conclusions regarding the efficacy of LM. It was impossible to control for confounding variables, particularly concurrent psychotropic medication changes. Half of the patients described were on different antidepressants than at the start of LM therapy, making it difficult to assess whether a response to LM was solely due to the initiation of the supplement. Other limitations of this retrospective analysis include lack of standardized assessment of medication adherence and efficacy, inconsistent timing of follow-up assessments, and significant product variability. Due to the expense of obtaining the commercially available product, Deplin, most patients used a variety of OTC methylfolate formulations.

Despite these limitations, this case series provides clinicians with a real-world description of the safe and effective use of LM in pediatric patients with a variety of psychiatric conditions. Further studies are warranted in pediatric patients to validate the positive response we observed. Long-term safety and efficacy of LM in youth should be assessed, in addition to remission, recovery, and sustained remission data in pediatric patients taking LM.

Conclusions

Treatment-resistant depression can be debilitating and challenging to manage, making LM an appealing option. In this group of patients, 80% had mild-to-significant improvement in symptoms of depression after the addition of LM to antidepressant therapy. In our experience, LM was well tolerated when initiated at 3.75–7.5 mg and is a potential option for treatment-resistant depression in patients with an MTHFR gene mutation. While LM may be efficacious, the cost of testing for MTHFR deficiencies and daily supplementation may be a barrier for many families. In addition, there is a lack of data comparing LM to alternative augmentation strategies in MDD (e.g., vitamin D and thyroid hormone supplementation).

In this retrospective review, LM was well tolerated and appeared effective in improving depressive symptoms among pediatric patients with MDD. Controlled studies are needed to more closely evaluate the role of LM in pediatric patients to validate this observation and to answer important clinical questions: (1) What is the most appropriate timing and method of MTHFR genotype testing? (2) What specific gene-drug recommendations should be made based on these results? (3) What is the most effective product and dose? and (4) What is the most appropriate duration of treatment?.

Clinical Significance

LM represents a novel treatment option for pediatric patients with treatment-resistant depression. Many pediatric patients fail to fully respond to an antidepressant, and the addition of a second medication may increase the risk for adverse effects, long-term side effects, and the potential for drug interactions. As a result, LM supplementation is an appealing therapeutic option. These cases suggest that LM as an adjunct to antidepressant treatment may be a safe and effective strategy for managing treatment-resistant depression in pediatric patients.

Footnotes

Disclosures

No competing financial interests exist.

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