Adjunctive Treatment With L-methylfolate for Treatment-Resistant Generalized Anxiety Disorder: a Pilot Study

NCT06218030 | Recruiting Phase 4 FDA Drug

• 1 other identifier: 6038351
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this feasibility study is to determine the tolerability and safety of add on treatment with L-methylfolate in patients with treatment-resistant generalized anxiety disorder (GAD). The primary objective is to monitor for side effects and other risks associated with the treatment. Secondary objectives are to compare the severity of symptoms, serum levels of folate, vitamin B12, C-reactive protein, homocysteine, tumor necrosis factor alpha and interleukin 6 before and after treatment. Participants will continue with their usual treatment for GAD and receive add on treatment with L-methylfolate 15 mg per day for 8 weeks. All participants will receive the same intervention.

Conditions

Generalized Anxiety Disorder

Keywords

generalized anxiety disorder; anxiety disorder

Outcome Measures

Primary Outcomes (3)

• Incidence of treatment-emergent adverse events

  Monitor participants for treatment-emergent adverse events and serious adverse events.

  Throughout the study, 8 weeks

• Incidence of treatment-emergent side effects measured with the ASEC

  Monitor participants for minor treatment-emergent side effects measured with the Antidepressant Side-Effect Checklist (ASEC). ASEC is a list of 21 possible side effects from antidepressants. Each item is rated from 0 (absent) to 3 (severe).

  Baseline visit, 4-week visit and 8-week visit.

• Response to treatment defined by CGI-I score below 3

  Response to treatment, which will be defined as a score of 1 or 2 on the Clinical Global Impression - Improvement (CGI-I) scale. CGI-I is a clinician administered one-item clinical scale rated from 1 (very much improved) to 7 (very much worse). Not assessed would confer score 0.

  4-week visit and 8-week visit.

Secondary Outcomes (11)

• Remission defined by CGI-S score below 3

  4-week visit and 8-week visit.

• Change in anxiety severity measured by CGI-S

  Baseline visit, 4-week visit and 8-week visit.

• Change of anxiety symptoms measured with GAD-7

  Baseline visit, 4-week visit and 8-week visit.

• Change of anxiety symptoms measured with PSWQ

  Baseline visit, 4-week visit and 8-week visit.

• Change of anxiety symptoms measured with BAI

  Baseline visit, 4-week visit and 8-week visit.

Study Arms (1)

L-methylfolate arm

EXPERIMENTAL

Oral administration of L-methylfolate 15 mg per day for 8 weeks.

Drug: L-methylfolate

Interventions

L-methylfolate DRUG

Oral administration of L-methylfolate 15 mg per day for 8 weeks. The study drug will be given in addition to the standard of care (SOC) for GAD.

L-methylfolate arm

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults.
• Patients on a stable dose of an selective serotonin uptake inhibitors (SSRI) or serotonin and noradrenaline reuptake inhibitors (SNRI) for at least 8 weeks.
• Treatment-resistant GAD, defined by lack of response to at least two drugs, from two different classes of drugs considered first-line or second-line for GAD according to the Canadian Clinical Practice Guidelines for the Management of Anxiety, Posttraumatic Stress and Obsessive-Compulsive Disorders (Katzman et al., 2014). Only trials lasting at least 8 weeks and with at least the minimum effective dose of the given medication will be considered failed trials.

You may not qualify if:

• Patients with moderate to severe major depressive disorder based on the Patient Health Questionnaire - Nine Item (PHQ-9) scale (score of 15 or above) at baseline.
• Mini International Neuropsychiatric Interview version (MINI) 7.0 indicates moderate to high current suicidality or "suicide likely in near future" or current suicidal behavior disorder.
• Patients diagnosed with obsessive-compulsive disorder (OCD), bipolar disorder, schizophrenia, schizoaffective disorder, personality disorders, substance use disorders, intellectual disabilities, dementia, epilepsy or other severe neurological diseases.
• Patients with cardiovascular diseases, infections, inflammatory diseases, recent surgeries, recent physical trauma and other medical issues that could produce elevation of c-reactive protein (CRP) or homocysteine.
• Consumption of cannabis, any cannabis by-products, illicit drugs, or alcohol above 3 drinks per week.
• Supplementation of diet with vitamins or consumption of natural health products that may affect anxiety or depression symptoms.
• Reading competence below Grade 5.
• Participants who do not have capacity to conduct consent process.

Sponsors & Collaborators

• Queen's University: lead

Study Sites (1)

Kingston Health Sciences Centre

Kingston, Ontario, K7L 2V7, Canada

RECRUITING

Related Publications (3)

• Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26.

  PMID: 18950248 BACKGROUND

• Saraswathy KN, Ansari SN, Kaur G, Joshi PC, Chandel S. Association of vitamin B12 mediated hyperhomocysteinemia with depression and anxiety disorder: A cross-sectional study among Bhil indigenous population of India. Clin Nutr ESPEN. 2019 Apr;30:199-203. doi: 10.1016/j.clnesp.2019.01.009. Epub 2019 Feb 12.

  PMID: 30904222 BACKGROUND

• Taylor MJ, Carney SM, Goodwin GM, Geddes JR. Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials. J Psychopharmacol. 2004 Jun;18(2):251-6. doi: 10.1177/0269881104042630.

  PMID: 15260915 BACKGROUND

Related Links

• Queen's University Anxiety Research Lab

MeSH Terms

Conditions

Generalized Anxiety Disorder; Anxiety Disorders

Interventions

5-methyltetrahydrofolate

Condition Hierarchy (Ancestors)

Mental Disorders

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: December 19, 2023
• First Posted: January 23, 2024
• Study Start: October 22, 2024
• Primary Completion: April 1, 2026
• Study Completion: May 1, 2026
• Last Updated: May 25, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)