Retrospective examination of adjunctive L-methylfolate in children and adolescents with unipolar depression



Adjunctive l-methylfolate is commonly prescribed for children and adolescents with treatment-resistant mood disorders; however, the relationship between l-methylfolate augmentation across methylenetetrahydrofolate reductase (MTHFR) genotypes in youths with depressive symptoms is unclear.


We retrospectively examined the electronic health records of patients (N = 412) with depressive symptoms associated with unipolar depressive disorders and their MTHFR C677T genotypes from 2013 to 2019. Patients were ≤18 years of age at the time of MTHFR pharmacogenetic testing. Treatment response was assessed with Clinical Global Impression–Improvement (CGI-I) score reported in the medical record.


Patients with an MTHFR C677T C/T or T/T genotype were more likely to be prescribed l-methylfolate when the clinician knew their MTHFR genotype (p < 0.0001, OR: 15.1, 95 % CI: [5.1, 44.2]), but not when the clinician did not know their genotype (p = 0.4, OR: 2.1, 95 % CI: [0.4, 11.4]). Change in baseline and endpoint CGI-I scores between patients with an MTHFR C677T variant who were prescribed and not prescribed l-methylfolate did not significantly differ (p = 0.39). Response rate was not associated with l-methylfolate prescription (p = 0.17) or l-methylfolate dose (p = 0.69).


This was a retrospective study, which yielded a heterogeneous patient population and limited data availability (e.g., adherence). Patients are severely ill and may have a refractory illness that limits response to adjunctive l-methylfolate.


Clinicians prescribe l-methylfolate to children and adolescents with depressive symptoms associated with unipolar depressive disorders who have an MTHFR C677T variant, although augmentation may not be associated with treatment response, regardless of MTHFR genotype or dose.


Major depressive disorder (MDD) and other mood disorders are common in children and adolescents and are often associated with significant social and occupational impairment and poor long-term outcome (Culpepper, 2016; Heron, 2018). Nearly 1 in 10 youths will experience a depressive disorder by the age of 16, and MDD is the leading cause of morbidity in adolescents worldwide (Mullen, 2018; Neavin et al., 2018). Evidence-based treatments for depressed youths include psychotherapy (e.g., cognitive behavioral therapy, interpersonal therapy for adolescents) and pharmacotherapy with medications for depression, including serotonin and norepinephrine reuptake inhibitors (Neavin et al., 2018). Despite psychotherapeutic and pharmacologic interventions, 30–40 % of depressed youths continue to experience significant symptoms (Maalouf et al., 2011; Strawn et al., 2020).

Folate deficiency is associated with an increased risk for depression in children, adolescents, and adults, and folate-deficient individuals may be predisposed to reduced response to antidepressant treatment (Fava et al., 1997; Herbison et al., 2012; Papakostas et al., 2005; Reynolds et al., 1970; Stengler, 2021). Therefore, augmentation with folate or other relevant nutrient derivatives (e.g., l-methylfolate) are commonly utilized in patients with treatment-resistant depression (Nelson, 2012). Indeed, folate supplementation in clinical practice is based on the understanding that low folate concentrations have multiple downstream effects related to biochemical processes relevant to the pathophysiology of many disorders (Bender et al., 2017; Hoepner et al., 2021). Namely, reduced folate levels are associated with an increased risk for developing bipolar disorder, schizophrenia, autism spectrum disorder, and attention-deficit/hyperactivity disorder (Liew and Gupta, 2015; Wan et al., 2018; Yadav et al., 2016), and are also associated with vascular disease, psoriasis, pregnancy complications, diabetes, cancer, and others (Liew and Gupta, 2015; Yadav et al., 2016).

Folate is essential to numerous biological pathways, including homocysteine and monoamine synthesis (Tiemeier et al., 2002). Methylenetetrahydrofolate reductase, which is encoded by the MTHFR gene, is an enzyme responsible for folate metabolism into its biologically-active form known as l-methylfolate (Kandler and Lam, 2019; Stengler, 2021). L-methylfolate crosses the blood-brain barrier and facilitates tetrahydrobiopterin (BH4) formation, which is essential in synthesizing monoamines (Stahl, 2008). Due to higher bioavailability and CNS penetration, l-methylfolate provides greater benefit than folic acid supplementation in folic acid deficiency (Henderson et al., 2018; Lea et al., 2009; Shelton et al., 2013).

Polymorphisms of the MTHFR gene, which are common in the general population, reduce methylenetetrahydrofolate reductase activity (Kevere et al., 2014). Among these polymorphisms, two are commonly evaluated in clinical settings: C677T and A1298C. Heterozygotes (C/T) at the C677T locus of the MTHFR gene have a 35 % reduction in enzyme activity, while homozygotes (T/T) have a 70 % reduction (Chango et al., 2000; Frosst et al., 1995). The MTHFR A1298C polymorphism also reduces MTHFR enzyme activity, but to a lesser extent than the C677T polymorphism (Chango et al., 2000; van der Put et al., 1998; Weisberg et al., 1998).

Several studies support the benefits of adjunctive l-methylfolate for MDD (Ginsberg et al., 2011; Jain et al., 2020) and bipolar depression (Nierenberg et al., 2017), including several randomized, controlled trials, which demonstrate the benefit of l-methylfolate as an adjunct to medications for depression in adults with treatment-resistant depression (Godfrey et al., 1990; Kakar et al., 2017; Papakostas et al., 2012). However, none of these studies assessed the impact of MTHFR polymorphisms on response, with the exception of an exploratory, post-hoc study, which found no difference in response rates for both MTHFR C677T and A1298C genotypes (Papakostas et al., 2014). Further, few studies have examined this relationship in children and adolescents. A recent, small retrospective analysis found that l-methylfolate was well-tolerated in children and adolescents with various neuropsychiatric disorders who were treated with other medications (Rainka et al., 2019). Similarly, a recent case series suggested that adjunctive l-methylfolate is well-tolerated and effective for children and adolescents with treatment-resistant MDD and an MTHFR variant (Dartois et al., 2019).

With these considerations in mind, we retrospectively analyzed the electronic health record (EHR) of children and adolescents with depression symptoms associated with unipolar depressive disorders to determine if MTHFR genotype and adjunctive l-methylfolate are associated with treatment response. Based on pharmacogenetic studies in adults, we hypothesized that pediatric patients receiving l-methylfolate supplementation will have improved response. We also hypothesized that polymorphisms in MTHFR C677T influence treatment response, with the supplementation being more effective in those with MTHFR variants associated with reduced enzyme activity.

Section snippets


Following Institutional Review Board approval, data were identified and extracted from the EHR of eligible patients from Cincinnati Children’s Hospital Medical Center (CCHMC) who had MTHFR genotyping. Eligible patients participated in inpatient psychiatric hospitalization and returned for follow-up in the outpatient clinic. Genetic testing occurred between September 2013 and December 2019. Patients were excluded if they met any of the following criteria: the presence of a tricyclic


A total of 412 patients with available MTHFR C677T genotypes were included in this retrospective examination (Table 1). This patient sample was predominantly female and white, with a majority of patients having at least one MTHFR C677T variant (n = 226, 55 %). Only 63 patients (15.3 %) were prescribed l-methylfolate, with 6 (9.5 %) having a C/C genotype, 42 (66.7 %) having a C/T genotype, and 15 (23.8 %) having a T/T genotype. All patients were prescribed l-methylfolate adjunctively, with the


In this retrospective examination, we assessed the effectiveness of adjunctive l-methylfolate in youths with unipolar depressive disorders. Overall, the findings of this study did not reveal significant differences in treatment response in children and adolescents prescribed l-methylfolate adjunctively to psychotropic medications. Notably, neither MTHFR genotype nor l-methylfolate dose influenced response or improvement.

Source: Author links open overlay panelEmily A. Bopp a 1, Ethan A. Poweleit b c d e 1, Marley O. Cox a, Jenni E. Farrow a, Jeffrey R. Strawn a d f, Luis R. Patino Duran a f, Cynthia A. Prows e g, Melissa P. DelBello a f, Laura B. Ramsey d e f

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