Abstract Schizophrenia is a chronic and often severe psychotic disorder. Its causes include imbalances in mediators involved in neuroplasticity, apoptosis, cell resilience and dendritic arborization. Among these mediators, oxidative species are particularly relevant for the pathophysiology of the disease, and this is the rationale for experimental use of antioxidant medications, such as N-acetylcysteine (NAC). Onset of schizophrenia is usually preceded by a period of subtle and unspecific symptoms, the prodrome, in which preventive interventions could delay or even stop the progression to full-blown psychosis. In this article, we propose that NAC could be a useful medication to prevent evolution of schizophrenia in individuals at risk for psychosis.
Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due to an imbalance between pro-oxidants and antioxidant defense mechanisms has been proposed as risk factor contributing to their pathophysiology. Altered antioxidant systems and signs of increased oxidative stress are observed in peripheral tissues and brains of SZ and BD patients including abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological and neurochemical alterations analogous to pathologies observed in patients. Mice with GSH deficit display phenotypical changes including increased stress reactivity, altered social behavior, impaired prepulse inhibition and exaggerated locomotor responses to psychostimulant injection. These behavioral changes are accompanied by NMDA receptor hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons and abnormal neuronal synchronization, as well as altered dopamine neurotransmission and deficient myelination. Such effects of GSH deficit are prevalent in the anterior cortex and the ventral hippocampus. Treatment with the GSH precursor and antioxidant N-acetylcysteine (NAC) normalizes some of those deficits. Given as adjunct to antipsychotic medication, NAC also improves SZ and BD symptoms. Together these data emphasize the contributing role of redox imbalance to the development of SZ and BD pathophysiologies and demonstrate the usefulness of GSH deficient rodent models to identify their underlying biological mechanisms.