Oxidation-reduction mechanisms in psychiatric disorders: A novel target for pharmacological intervention

Abstract

While neurotransmitter dysfunction represents a key component in mental illnesses, there is now a wide agreement for a central pathophysiological hub that includes hormones, neuroinflammation, redox mechanisms as well as oxidative stress. With respect to oxidation-reduction (redox) mechanisms, preclinical and clinical evidence suggests that an imbalance in the pro/anti-oxidative homeostasis toward the increased production of substances with oxidizing potential may contribute to the etiology and manifestation of different psychiatric disorders. The substantial and continous demand for energy renders the brain highly susceptible to disturbances in its energy supply, especially following exposure to stressful events, which may lead to overproduction of reactive oxygen and nitrogen species under conditions of perturbed antioxidant defenses. This will eventually induce different molecular alterations, including extensive protein and lipid peroxidation, increased blood-brain barrier permeability and neuroinflammation, which may contribute to the changes in brain function and morphology observed in mental illnesses. This view may also reconcile different key concepts for psychiatric disorders, such as the neurodevelopmental origin of these diseases, as well as the vulnerability of selective cellular populations that are critical for specific functional abnormalities. The possibility to pharmacologically modulate the redox system is receiving increasing interest as a novel therapeutic strategy to counteract the detrimental effects of the unbalance in brain oxidative mechanisms. This review will describe the main mechanisms and mediators of the redox system and will examine the alterations of oxidative stress found in animal models of psychiatric disorders as well as in patients suffering from mental illnesses, such as schizophrenia and major depressive disorder. In addition, it will discuss studies that examined the effects of psychotropic drugs, including antipsychotics and antidepressants, on the oxidative balance as well as studies that investigated the effectiveness of a direct modulation of oxidative mechanisms in counteracting the behavioral and functional alterations associated with psychiatric disorders, which supports the promising role of the redox system as a novel therapeutic target for the improved treatment of brain disorders.

Keywords: Animal models; Antidepressants; Antipsychotics; Major depressive disorder; Redox balance; Schizophrenia.