Clinical trial NCT06218030: Adjunctive Treatment With L-methylfolate for Treatment-Resistant Generalized Anxiety Disorder: a Pilot Study
Official title: PSIY-744-23: Adjunctive Treatment With L-methylfolate for Treatment-Resistant Generalized Anxiety Disorder: a Pilot Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Generalized Anxiety Disorder
Keywords: generalized anxiety disorder
anxiety disorder
Lead sponsor: Queen's University
Sponsor class: OTHER
First posted: 2024-01-23
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

Detailed description: Background: Up to 33.7% of the population are affected by an anxiety disorder during their lifetime according to large populationbased surveys. Generalized anxiety disorder (GAD) has a lifetime prevalence of 2.8% to 6.2% in these studies. GAD is associated with functional, occupational, and quality of life impairments. Certain types of medications and psychotherapies are established treatments for GAD, but only 50% of the patients respond to the first treatment trial. Deficiency of folates and neuroinflammation are two hypothesis that could explain why some patients with anxiety disorders do not respond to the usual treatments. Supplementation with folates could correct these deficiencies and reduce inflammation, thus increasing the success rates for treatments. In studies with major depressive disorder, adjunctive folates were associated to higher remission rates. Other studies indicate that folate supplementation lowers homocysteine levels and inflammation. Objectives: Ascertain if adjunctive treatment with Lmethylfolate can produce improvement in treatment-resistant GAD subjects. Methods: This is a proof-of-concept pilot study, an open-label trial of adjunctive treatment with L-methylfolate in patients with treatment-resistant GAD. Ten adult patients with treatment-resistant GAD who have been on a stable dose of an SSRI or SNRI for at least 12 weeks will receive 15 mg doses of L-methylfolate daily for 8 weeks. Patients with moderate to severe major depressive disorder or suicide risk will not be included. Serum levels of folate, vitamin B12, C-reactive protein, homocysteine, tumor necrosis factor alpha and interleukin 6will be measured before and after the trial.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events
timeFrame: Throughout the study, 8 weeks
measure: Incidence of treatment-emergent side effects measured with the ASEC
timeFrame: Baseline visit, 4-week visit and 8-week visit.
measure: Response to treatment defined by CGI-I score below 3
timeFrame: 4-week visit and 8-week visit.
Secondary outcomes:
measure: Remission defined by CGI-S score below 3
timeFrame: 4-week visit and 8-week visit.
measure: Change in anxiety severity measured by CGI-S
timeFrame: Baseline visit, 4-week visit and 8-week visit.
measure: Change of anxiety symptoms measured with GAD-7
timeFrame: Baseline visit, 4-week visit and 8-week visit.
measure: Change of anxiety symptoms measured with PSWQ
timeFrame: Baseline visit, 4-week visit and 8-week visit.
measure: Change of anxiety symptoms measured with BAI
timeFrame: Baseline visit, 4-week visit and 8-week visit.
measure: Concentration of CRP in serum
timeFrame: Baseline visit and 8-week visit.
measure: Concentration of homocysteine in serum
timeFrame: Baseline visit and 8-week visit.
measure: Concentration of vitamin B12 in serum
timeFrame: Baseline visit and 8-week visit.
measure: Concentration of folate in serum
timeFrame: Baseline visit and 8-week visit.
measure: Concentration of tumor necrosis factor alpha in serum
timeFrame: Baseline visit and 8-week visit.
measure: Concentration of interleukin 6 in serum
timeFrame: Baseline visit and 8-week visit.
Other outcomes:
Locations:
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
Study officials:
References:
citation: Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26.
citation: 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.
citation: 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.