Evidence for anterior cingulate cortex glutathione levels as a biomarker of oxidative stress and antioxidant response in people with bipolar disorder

Glutathione (GSH), the brain’s primary antioxidant, confers a critical first line of defense against oxidative-stress-induced cellular damage, with some evidence supporting compensatory upregulation of anterior cingulate cortex (ACC) GSH in bipolar disorder (BD). N-acetylcysteine (NAC), which increases GSH by providing cells with the rate-limiting substrate of GSH synthesis (i.e., cysteine), has been investigated as an adjunctive treatment for BD and has been found to reduce residual depressive symptoms, though no studies have evaluated whether NAC affects brain GSH levels in these patients. To further evaluate brain GSH levels as a candidate oxidative-stress biomarker and interventional target for adjunctive treatment for BD, we present data from two independent proton MR spectroscopy ( 1 H-MRS) investigations; a cross-sectional comparison of dorsal ACC (dACC) GSH levels in BD (n = 29) vs HC (n = 26) individuals, followed by a pilot (n = 12), randomized, placebo-controlled, double-blind, crossover study of 3 g/day of NAC versus placebo on dACC GSH levels. We demonstrate that BD individuals have significantly elevated dACC GSH levels (Cohen’s d = 0.56, p = 0.046), which are associated with a greater number of past-year depressive episodes ( r = 0.39, p = 0.041), relative to HC individuals, and that NAC treatment is associated with significantly higher dACC GSH (Cohen’s d = 0.45, p = 0.040) but not glutamate (p = 0.325) levels, relative to placebo, in people with BD. These preliminary results, which should be interpreted with caution given the small sample sizes therein, further pave the way for ACC GSH levels to serve as a primary mechanistic target for novel antioxidant treatments for BD that overcome the bioavailability limitations of NAC.