Generalized Anxiety DisorderPhase 4NCT06218030
Adjunctive Treatment With L-methylfolate for Treatment-Resistant Generalized Anxiety Disorder: a Pilot Study
A Phase 4 study testing L-methylfolate in people with Generalized Anxiety Disorder, run by Queen's University at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Generalized Anxiety Disorder
- What is being tested?
- L-methylfolate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteCanada
- Study dates
- 22 Oct 2024to 1 May 2026
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
Kingston Health Sciences Centre
Kingston, Ontario, K7L 2V7
Yan Deng, +1-613-548-7839, yan.deng@queensu.ca
Rafael Freire, MD PhD
About this study
Official title: PSIY-744-23: Adjunctive Treatment With L-methylfolate for Treatment-Resistant Generalized Anxiety Disorder: a Pilot Study
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.
Read the 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.
- Conditions
- Generalized Anxiety Disorder
- Being tested
- L-methylfolate
- Keywords
- generalized anxiety disorder, anxiety disorder
- Medical subject headings
- Generalized Anxiety Disorder, Anxiety Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-methylfolateDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| L-methylfolate arm | Experimental | Oral administration of L-methylfolate 15 mg per day for 8 weeks. Receives: Drug: L-methylfolate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of treatment-emergent adverse events
Monitor participants for treatment-emergent adverse events and serious adverse events.
Measured: 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).
Measured: 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.
Measured: 4-week visit and 8-week visit.
Secondary outcomes (11)
Remission defined by CGI-S score below 3
Remission will be defined as a score of 1 or 2 on the Clinical Global Impression - Severity (CGI-S) scale.
CGI-S is a clinician administered one-item clinical scale rated from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Not assessed would confer score 0.
Measured: 4-week visit and 8-week visit.
Change in anxiety severity measured by CGI-S
Changes in scores for CGI-S by comparing the scores in each visit. CGI-S is a clinician administered one-item clinical scale rated from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). Not assessed would confer score 0.
Measured: Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with GAD-7
Changes in scores for Generalized Anxiety Disorder 7-item scale (GAD-7) by comparing the scores in each visit.
GAD-7 is a self-rated 7-item scale, each item is rated from 0 (not at all) to 3 (nearly every day).
Measured: Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with PSWQ
Changes in scores for Penn State Worry Questionnaire (PSWQ) by comparing the scores in each visit.
PSWQ is a self-rated 16-item scale, each item is rated from 1 (not at all typical of me) to 5 (very typical of me).
Measured: Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with BAI
Changes in scores for Beck Anxiety Inventory (BAI) by comparing the scores in each visit.
BAI is a self-rated 21-item scale, each item is rated from 0 (not at all) to 3 (severely - it bothered me a lot).
Measured: Baseline visit, 4-week visit and 8-week visit.
Concentration of CRP in serum
Collection of blood sample and measurement of the concentration of C-Reactive Protein (CRP) in serum.
Measured: Baseline visit and 8-week visit.
Concentration of homocysteine in serum
Collection of blood sample and measurement of the concentration of homocysteine in serum.
Measured: Baseline visit and 8-week visit.
Concentration of vitamin B12 in serum
Collection of blood sample and measurement of the concentration of vitamin B12 in serum.
Measured: Baseline visit and 8-week visit.
Concentration of folate in serum
Collection of blood sample and measurement of the concentration of folate in serum.
Measured: Baseline visit and 8-week visit.
Concentration of tumor necrosis factor alpha in serum
Collection of blood sample and measurement of the concentration of tumor necrosis factor alpha in serum.
Measured: Baseline visit and 8-week visit.
Concentration of interleukin 6 in serum
Collection of blood sample and measurement of the concentration of interleukin 6 in serum.
Measured: Baseline visit and 8-week visit.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jan 2024
- Study start22 Oct 2024
- Primary completion1 Apr 2026 (estimated)
- Study completion1 May 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Generalized Anxiety DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Queen's University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Dr. Rafael Freire, Queen's University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06218030
- Sponsor's protocol ID
- 6038351
- Status last verified
- May 2025
- First submitted
- 19 Dec 2023
- Last updated
- 25 May 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26.
PubMed 18950248Saraswathy 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.
PubMed 30904222Taylor 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.
PubMed 15260915
Study at a glance
From the registry record, last updated by the sponsor on 25 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- PSIY-744-23: Adjunctive Treatment With L-methylfolate for Treatment-Resistant Generalized Anxiety Disorder: a Pilot Study
- ClinicalTrials.gov ID
- NCT06218030
- Acronym / sponsor ID
- 6038351
- Conditions
- Generalized Anxiety Disorder
- Keywords
- generalized anxiety disorder, anxiety disorder
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 10 participants (estimated)
- Lead sponsor
- Queen's UniversityUniversity, hospital or other
- Study start
- 22 Oct 2024 (actual)
- Primary completion
- 1 Apr 2026 (estimated)
- Study completion
- 1 May 2026 (estimated)
- First posted
- 23 Jan 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| L-methylfolate arm | Experimental | Drug: L-methylfolateOral administration of L-methylfolate 15 mg per day for 8 weeks. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-methylfolateOral 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. | Drug | L-methylfolate arm |
Primary outcome
Incidence of treatment-emergent adverse events
Time frame: Throughout the study, 8 weeks
Monitor participants for treatment-emergent adverse events and serious adverse events.
Incidence of treatment-emergent side effects measured with the ASEC
Time frame: Baseline visit, 4-week visit and 8-week visit.
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).
Response to treatment defined by CGI-I score below 3
Time frame: 4-week visit and 8-week visit.
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.
11 secondary outcomes
Remission defined by CGI-S score below 3
Time frame: 4-week visit and 8-week visit.
Change in anxiety severity measured by CGI-S
Time frame: Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with GAD-7
Time frame: Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with PSWQ
Time frame: Baseline visit, 4-week visit and 8-week visit.
Change of anxiety symptoms measured with BAI
Time frame: Baseline visit, 4-week visit and 8-week visit.
Concentration of CRP in serum
Time frame: Baseline visit and 8-week visit.
Concentration of homocysteine in serum
Time frame: Baseline visit and 8-week visit.
Concentration of vitamin B12 in serum
Time frame: Baseline visit and 8-week visit.
Concentration of folate in serum
Time frame: Baseline visit and 8-week visit.
Concentration of tumor necrosis factor alpha in serum
Time frame: Baseline visit and 8-week visit.
Concentration of interleukin 6 in serum
Time frame: Baseline visit and 8-week visit.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 May 2025.
- Background: PubMed 18950248Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. Altern Med Rev. 2008 Sep;13(3):216-26.
- Background: PubMed 30904222Saraswathy 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.
- Background: PubMed 15260915Taylor 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.
- Queen's University Anxiety Research LabLink provided by the sponsor.
- Individual participant dataSharing planned: No
Related trials for Generalized Anxiety Disorder
Active, not recruitingObservational study
BreathinG-induced Myocardial and Cerebral Perfusion in Anxiety Disorders
Generalized Anxiety Disorder, Oxygenation Sensitive CMR
RecruitingPhase 2
Study of ITI-1284 as an Adjunctive Treatment in Patients With Generalized Anxiety Disorder
Generalized Anxiety Disorder
RecruitingPhase 2
Study of ITI-1284 as Monotherapy Treatment in Patients With Generalized Anxiety Disorder
Generalized Anxiety Disorder
RecruitingPhase 3
A Study to Asses Safety and Tolerability of ITI-1284 Given Alone or as an Additional Treatment in Participants With Generalized Anxiety Disorder (GAD)
Generalized Anxiety Disorder
RecruitingPhase 3
A Study of JNJ-99245354 (ITI-1284) as an Adjunctive Treatment in Participants With Generalized Anxiety Disorder (GAD) Who Have an Inadequate Response to GAD Treatment
Generalized Anxiety Disorder
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing L-methylfolate in people with Generalized Anxiety Disorder, run by Queen's University at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 25 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Each site lists its own contact: choose the nearest one under Trial locations. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of treatment-emergent adverse events (time frame: Throughout the study, 8 weeks). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06218030, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 May 2025; AzTrials last refreshed its copy on 6 Nov 2026.