Prefrontal Glutamatergic Modulation by NAC and MBCT for Depression in Youth (NAC+MIND)

Prefrontal Glutamatergic Modulation by N-acetylcysteine and Mindfulness-based Cognitive Therapy for Mild Depression in Youth

The primary goal is to investigate to what extent changes in glutamate and glutathione modulation and functional integration between brain networks associated with emotion and attention regulation are associated with treatment response in mildly depressed youth.

Study Overview

• Status: Recruiting
• Conditions: Mild Depression
• Intervention / Treatment: Drug: Placebo; Drug: N-acetylcysteine; Behavioral: Mindfulness-based cognitive therapy; Behavioral: Sham mindfulness-based intervention

Detailed Description

The specific goals are to determine whether treatment with a combination of mindfulness-based cognitive therapy (MBCT) and N-acetylcysteine (NAC) enhances changes in left ventrolateral prefrontal cortex (VLPFC) and anterior cingulate cortex (ACC) glutamate and glutathione levels, and cortical-subcortical functional connectivity (Fc) compared with MBCT alone or NAC alone. The central hypothesis is that modulating glutamatergic output in the prefrontal cortex (PFC) and improving the cortical-subcortical functional connectivity (Fc) underlie treatment response in this population. The rationale for testing this hypothesis with a randomized controlled trial of NAC and MBCT, integrated with imaging, is that NAC is a glutamate modulator, MBCT has evidence for improving PFC-limbic Fc, both interventions have preliminary evidence for treating depression or mood symptoms have a benign safety profile. The investigators have a well-established record of conducting intervention studies integrating magnetic resonance spectroscopy (1H-MRS) and resting state functional magnetic resonance imaging (rs-fMRI) to study the neurophysiology of mood disorders. The university health center associated clinics provide the investigators access to the target population of this study. Therefore, the investigators are well positioned to investigate the neurobiological mechanisms associated with treatment response to glutamatergic modulation in mildly depressed youth. In this study, the specific aims are:

Aim 1: To determine to what extent glutamate levels in the left VLPFC change in response to treatment with NAC and/or MBCT in mildly depressed youth. The investigators will utilize 1H-MRS to measure changes in the left VLPFC glutamate following eight-week treatment with NAC and/or MBCT. The investigators predict that MBCT combined with NAC will lead to greater increases in left VLPFC glutamate levels compared with either MBCT or NAC alone.

Aim 2: To determine to what extent Fc within PFC-limbic circuits and within large-scale brain networks change in response to treatment with NAC and/or MBCT in mildly depressed youth. The investigators will utilize rs-fMRI to identify changes in Fc between the PFC (VLPFC, ACC) and subcortical regions, and within large scale brain networks associated with emotion and attention regulation (cingulo-opercular, fronto-parietal, and default mode networks). The investigators predict that MBCT combined with NAC will lead to greater increases in Fc compared with either MBCT or NAC alone.

Exploratory Aim 3: To investigate the role of central and peripheral biomarkers of oxidative stress and inflammation in predicting response to treatment to NAC and/or MBCT for mild depression in youth. The investigators will explore the role of central glutathione and peripheral thiobarbituric acid reactive substances (TBARS), malondialdehyde (MDA), high-sensitivity C-reactive protein (hs-CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in predicting response to treatment to NAC and/or MBCT.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Fabiano Nery, MD, PhD; Phone Number: 513 558-5035; Email: neryfo@ucmail.uc.edu

Study Locations

• United States
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Recruiting
      • University of Cincinnati, Department of Psychiatry and Behavioral Neuroscience
      • Contact: Casey Moore, CCRP; Phone Number: 513 558-6307; Email: casey.moore@uc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. age between 15 years, 0 months to 24 years, 11 months old;
2. presenting with mild depression, defined by meeting DSM-5 criteria for a current major depressive episode, mild severity, or persistent depressive disorder, or other specified depressive disorder (depressive episode with insufficient symptoms to meet criteria for a major depressive episode);
3. medication-naïve or medication free for at least 5 half-lives since the last use of a psychoactive medication, with the exception of stimulants for ADHD;
4. if on ADHD stimulant medication over 2 months prior to screening, willing to maintain stimulant dose constant during the study participation;
5. Tanner stage greater than or equal to III;

Exclusion Criteria:

1. significant suicidal risk, defined by suicidal ideation of type 3, 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) in the past 3 months, or any lifetime suicidal attempts;
2. current major depressive episode, moderate or severe
3. current or lifetime history of manic or hypomanic episodes, and/or diagnosis of bipolar disorder;
4. current or lifetime history of psychotic disorders, and/or prior diagnosis of schizophrenia spectrum disorders;
5. active or current substance use disorders in the last 3 months, except cannabis or alcohol use disorder, mild;
6. diagnosis of autism spectrum disorder, pervasive developmental disorder, obsessive-compulsive disorder, post-traumatic stress disorders, Tourette's syndrome
7. any contraindication to MRI scanning;
8. pregnancy;
9. history of major neurological disorder (e.g, epilepsy), or head trauma with > 10 minutes loss of consciousness;
10. intellectual disability (IQ less than or equal to 70), as determined by the Weschler Abbreviated Scale of Intelligence (WASI);
11. previous participation in any mindfulness-based treatment;
12. initiating psychotherapy within 2 months prior to screening, or planning to initiate psychotherapy during study participation; if on therapy, frequency and type should remain stable for 2 months prior to enrollment and during study participation;
13. no current diagnosis of asthma
14. history of allergic reaction to N-acetylcysteine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: NAC plus MBCT; N-acetylcysteine 2400 mg daily and mindfulness-based cognitive therapy over 8 weeks	Drug: N-acetylcysteine; N-acetylcysteine 2400 mg/d; Other Names: NAC; Acetylcysteine; N-acetyl-cysteine; N-acetyl-L-cysteine; Behavioral: Mindfulness-based cognitive therapy; Mindfulness-based cognitive therapy
Placebo Comparator: Placebo plus MBCT; Placebo capsules and mindfulness-based cognitive therapy over 8 weeks	Drug: Placebo; Placebo capsules; Other Names: placebo oral capsules; placebo comparator; control; Behavioral: Mindfulness-based cognitive therapy; Mindfulness-based cognitive therapy
Sham Comparator: NAC plus sham MBCT; N-acetylcysteine 2400 mg daily and sham mindfulness-based intervention over 8 weeks	Drug: N-acetylcysteine; N-acetylcysteine 2400 mg/d; Other Names: NAC; Acetylcysteine; N-acetyl-cysteine; N-acetyl-L-cysteine; Behavioral: Sham mindfulness-based intervention; Sham mindfulness-based intervention
Other: Placebo plus sham MBCT; Placebo capsules daily and sham mindfulness-based intervention over 8 weeks	Drug: Placebo; Placebo capsules; Other Names: placebo oral capsules; placebo comparator; control; Behavioral: Sham mindfulness-based intervention; Sham mindfulness-based intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glutamate levels in the left ventrolateral prefrontal cortex (VLPFC)	Changes in glutamate levels, measured by proton spectroscopy, in the left VLPFC following 8-week treatment with NAC and/or MBCT.	From baseline to week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional connectivity (Fc) within prefrontal cortex-limbic circuits and within large-scale brain networks	Changes in Fc in the prefrontal cortex (VLPFC, ACC) and subcortical regions, and within large scale brain networks associated with emotion and attention regulation (cingulo-opercular, fronto-parietal, and default mode networks) following treatment with NAC and/or MBCT.	From baseline to week 8

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glutathione levels in the prefrontal cortex	Changes in central biomarker of oxidative stress (glutathione levels in the left VLPFC and in the anterior cingulate cortex) following treatment with NAC and/or MBCT. Exploratory.	From baseline to week 8
Thiobarbituric acid reactive substances (TBARS) serum levels	Changes in peripheral biomarker of oxidative stress (TBARS serum levels) following treatment with NAC and/or MBCT	From baseline to week 8
Malondialdehyde (MDA) serum levels	Changes in peripheral marker of oxidative stress (MDA serum levels) following treatment with NAC and/or MBCT	From baseline to week 8
High-sensitivity C-reactive protein (hs-CRP) serum levels	Changes in peripheral biomarker of inflammation (hs-CRP serum levels) following treatment with NAC and/or MBCT	From baseline to week 8
Interleukin-6 (IL-6) serum levels	Changes in peripheral biomarker of inflammation (IL-6) following treatment with NAC and/or MBCT	From baseline to week 8
Tumor necrosis factor alpha (TNF-alpha) serum levels	Changes in peripheral biomarker of inflammation (TNF-alpha serum levels) following treatment with NAC and/or MBCT	From baseline to week 8

Collaborators and Investigators

• Sponsor: University of Cincinnati
• Collaborators: National Center for Complementary and Integrative Health (NCCIH)

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2026
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: July 28, 2025
• First Submitted That Met QC Criteria: March 6, 2026
• First Posted (Actual): March 11, 2026

Study Record Updates

• Last Update Posted (Actual): March 11, 2026
• Last Update Submitted That Met QC Criteria: March 6, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Depression; adolescent; young adult; youth; N-acetylcysteine; mindfulness-based cognitive therapy; double-blind placebo controlled
• Additional Relevant MeSH Terms: Behavioral Symptoms; Behavior; Depression; Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Amino Acids; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities; Cognitive Behavioral Therapy; Cysteine; Amino Acids, Sulfur; Mindfulness; Acetylcysteine; Mindfulness-Based Cognitive Therapy
• Other Study ID Numbers: NAC+MIND - 2024-0981; 1R01AT013115 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No