Aims: To investigate the mechanism of action of N‐acetylcysteine (NAC) in depressive symptoms in young individuals at familial risk for bipolar disorder. Methods: We conducted an 8‐week open label clinical trial of NAC 2400 mg/days in 15–24 years old depressed offspring of a bipolar I disorder parent, with baseline and endpoint proton magnetic resonance spectroscopy acquired within the left ventrolateral prefrontal cortex (VLPFC). Results: Nine participants were enrolled and finished the study. NAC significantly improved depressive and anxiety symptom scores, and clinical global impression (all p <.001). There was a non‐significant reduction in glutamate levels in the left VLPFC. Reduction in depressive symptom scores was positively associated with reduction in glutamate levels in the left VLPFC (p =.007). Conclusions: This pilot study suggests that NAC might be efficacious for depressive symptoms in at‐risk youth, and that its mechanism of action involves the modulation of glutamate in the left VLPFC. [ABSTRACT FROM AUTHOR]