OBJECTIVE: In this report, we aimed to evaluate the effect of add-on N-acetylcysteine (NAC) on depressive symptoms and functional outcomes in bipolar disorder. To that end, we conducted a secondary analysis of all patients meeting full criteria for a depressive episode in a placebo controlled trial of adjunctive NAC for bipolar disorder.
METHOD: Twenty-four week randomised clinical trial comparing adjunctive NAC and placebo in individuals with bipolar disorder experiencing major depressive episodes. Symptomatic and functional outcome data were collected over the study period.
RESULTS: Seventeen participants were available for this report. Very large effect sizes in favor of NAC were found for depressive symptoms and functional outcomes at endpoint. Eight of the ten participants on NAC had a treatment response at endpoint; the same was true for only one of the seven participants allocated to placebo.
DISCUSSION: These results indicate that adjunctive NAC may be useful for major depressive episodes in bipolar disorder. Further studies designed to confirm this hypothesis are necessary.
Dose was a modest 500 mg b.i.d. N-acetylcysteine is available OTC, and cheap. See also N-acetylcysteine as a mitochondrial enhancer: a new class of psychoactive drugs?
Among its known mechanisms of action, NAC-induced brain glutathione (GSH) replenishment is the most studied. Glutathione is the primary endogenous antioxidant of the cell, and has the ability to scavenge oxygen and nitrogen species, therefore maintaining the oxidative balance. In addition to restoring GSH levels, NAC modulates inflammation by exerting anti-inflammatory actions, and presents direct effects on glutamatergic and dopaminergic neurotransmission. The inflammatory-modulating effects of NAC may be important for its mood stabilizing efficacy, mainly due to the recently described relevance of systemic inflammation in bipolar disorder pathophysiology (Kapczinski et al.2). More specifically, its usefulness on depressive episodes may be linked to innovative mechanisms of action, which we speculate to be taking part throughout its treatment. Among them, modulation of cellular signaling pathways by NAC may ultimately increase mitochondrial resilience, as supported below.