Combining N-acetylcysteine and mindfulness-based cognitive therapy to target prefrontal glutamate in mildly depressed youth

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

This trial will test whether taking N-acetylcysteine (NAC) together with mindfulness-based cognitive therapy (MBCT) helps mildly depressed teens and young adults by changing prefrontal glutamate levels and brain connectivity.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 160 (estimated)
• Ages: 15 Years to 24 Years
• Sex: All
• Sponsor: University of Cincinnati (Academic / other)
• Locations: 1 site (Cincinnati, Ohio)
• Trial ID: NCT07464886 on ClinicalTrials.gov

What this trial studies

This randomized Phase 3 trial compares combined NAC plus MBCT versus NAC alone, MBCT alone, and placebo with a sham mindfulness intervention in mildly depressed participants aged 15 to 24. Treatment effects will be linked to neurobiological measures using proton magnetic resonance spectroscopy (1H-MRS) to quantify glutamate and glutathione in left VLPFC and ACC, and resting-state fMRI to measure cortical-subcortical functional connectivity. Participants are medication-naïve or medication-free (with specific exceptions for stable ADHD stimulants) and will attend in-person therapy and imaging visits at the study site. The study aims to determine whether changes in glutamatergic signaling and PFC-limbic connectivity underlie clinical improvement in this population.

Who should consider this trial

Good fit: Ideal candidates are 15 to 24 years old with DSM-5 mild major depressive episode or persistent/other specified depressive disorder, medication-naïve or off psychoactive meds (with allowed stimulant exceptions), Tanner stage ≥ III, and low suicidal risk.

Not a fit: Patients with moderate or severe depression, recent significant suicidal ideation or any lifetime suicide attempts, or other exclusionary conditions are unlikely to benefit from participation in this protocol.

Why it matters

Potential benefit: If successful, the approach could provide a well-tolerated combined medication-plus-therapy option that improves mood and targets brain glutamate and connectivity in mildly depressed youth.

How similar studies have performed: Smaller studies and preliminary data suggest NAC and MBCT each can improve mood and that MBCT can alter PFC-limbic connectivity, but combining NAC and MBCT with integrated MRS/fMRI in mildly depressed youth is novel.

Eligibility criteria

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

Where this trial is running

Cincinnati, Ohio

• University of Cincinnati, Department of Psychiatry and Behavioral Neuroscience — Cincinnati, Ohio, United States (Recruiting)

Study contacts

• Study coordinator: Fabiano Nery, MD, PhD

Conditions Mild Depression; Depression; adolescent; young adult; youth; mindfulness-based cognitive therapy; N-acetylcysteine; double-blind placebo controlled