Prefrontal glutamatergic modulation by N-acetylcysteine and mindfulness-based cognitive therapy for mild depression in youth - PROJECT SUMMARY Mood disorders, including major depressive disorder and bipolar disorder, usually start during adolescence and early adulthood. Depressed youth are frequently treated with selective serotonin reuptake inhibitors but are particularly vulnerable to antidepressant-induced adverse reactions, such as manic switching, increased irritability, agitation, and suicidality. Therefore, it is crucial to find safer and effective alternatives to treat depression in youth. N-acetylcysteine (NAC), a dietary supplement, is a glutamate and glutathione modulator and has antioxidant and anti-inflammatory properties. Mindfulness-based cognitive therapy (MBCT) has been found to increase functional integration between prefrontal cortex and limbic system. Both interventions are safe and well-tolerated options to treat mild depression in youth, without causing significant side effects. Our preliminary data demonstrate that NAC is safe, well tolerated, and improves depressive symptoms in youth at familial risk for bipolar disorder (high-risk youth). We have also shown that MBCT increases integration of cortical-subcortical networks and improves mood dysregulation in high-risk youth. To extend these promising findings, we propose to conduct an 8-week, double-blind, placebo-controlled, multi-arm, parallel-group, randomized clinical trial of MBCT and NAC for the treatment of mild depression in youth, with integrated proton spectroscopy and resting state functional magnetic imaging examinations and blood biomarker assessments at baseline and endpoint. A total of 160 medication-free subjects, 15-24 years of age, experiencing mild depression will be randomized to receive either MBCT plus NAC, MBCT plus placebo, NAC plus sham-MBCT, or placebo plus sham-MBCT. Our central hypothesis is that modulating the glutamatergic output in the prefrontal cortex and improving the functional connectivity within prefrontal cortical-subcortical circuits, and within large scale emotion and attention regulation networks, underlie treatment response in mild depression. Our 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 depressed youth. Aim 2: To determine to what extent functional connectivity within the prefrontal cortex-limbic circuits and within large-scale brain networks change in response to treatment with NAC and/or MBCT in depressed youth. Exploratory Aim 3: To investigate the role of central and peripheral biomarkers of oxidative stress and inflammation in predicting treatment response to NAC and/or MBCT for mild depression in youth. The results of this study are anticipated to provide novel evidence that NAC and MBCT have neurobiological effects that are additive or potentially synergistic, neurophysiology substrates underlying treatment response, and will explore the potential role of oxidative stress and inflammation in treatment response. Together, such results would provide a strong empirical foundation in support of future trials to further evaluate these interventions as early treatment alternatives for depression in youth.
