Prefrontal Glutamatergic Modulation by NAC and MBCT for Depression in Youth

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.

Inclusion criteria

• age between 15 years, 0 months to 24 years, 11 months old;
• 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);
• 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;
• if on ADHD stimulant medication over 2 months prior to screening, willing to maintain stimulant dose constant during the study participation;
• Tanner stage greater than or equal to III;

Exclusion criteria

• 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;
• current major depressive episode, moderate or severe
• current or lifetime history of manic or hypomanic episodes, and/or diagnosis of bipolar disorder;
• current or lifetime history of psychotic disorders, and/or prior diagnosis of schizophrenia spectrum disorders;
• active or current substance use disorders in the last 3 months, except cannabis or alcohol use disorder, mild;
• diagnosis of autism spectrum disorder, pervasive developmental disorder, obsessive-compulsive disorder, post-traumatic stress disorders, Tourette's syndrome
• any contraindication to MRI scanning;
• pregnancy;
• history of major neurological disorder (e.g, epilepsy), or head trauma with > 10 minutes loss of consciousness;
• intellectual disability (IQ less than or equal to 70), as determined by the Weschler Abbreviated Scale of Intelligence (WASI);
• previous participation in any mindfulness-based treatment;
• 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;
• no current diagnosis of asthma
• history of allergic reaction to N-acetylcysteine