brain sciences Review Regulation of Reactive Oxygen Species-Mediated Damage in the Pathogenesis of Schizophrenia Samskruthi Madireddy 1,* and Sahithi Madireddy 2 1 Independent Researcher, 1353 Tanaka Drive, San Jose, CA 95131, USA 2 Massachusetts Institute of Technology, 77 Massachusetts Ave, Cambridge, MA 02139, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-408-9214162 Received: 4 September 2020; Accepted: 15 October 2020; Published: 16 October 2020 Abstract: The biochemical integrity of the brain is paramount to the function of the central nervous system, and oxidative stress is a key contributor to cerebral biochemical impairment. Oxidative stress, which occurs when an imbalance arises between the production of reactive oxygen species (ROS) and the efficacy of the antioxidant defense mechanism, is believed to play a role in the pathophysiology of various brain disorders. One such disorder, schizophrenia, not only causes lifelong disability but also induces severe emotional distress; however, because of its onset in early adolescence or adulthood and its progressive development, consuming natural antioxidant products may help regulate the pathogenesis of schizophrenia. Therefore, elucidating the functions of ROS and dietary antioxidants in the pathogenesis of schizophrenia could help formulate improved therapeutic strategies for its prevention and treatment. This review focuses specifically on the roles of ROS and oxidative damage in the pathophysiology of schizophrenia, as well as the effects of nutrition, antipsychotic use, cognitive therapies, and quality of life on patients with schizophrenia. By improving our understanding of the effects of various nutrients on schizophrenia, it may become possible to develop nutritional strategies and supplements to treat the disorder, alleviate its symptoms, and facilitate long-term recovery. Keywords: schizophrenia; oxidative stress; reactive oxygen species; nutrients; antioxidants; antipsychotics 1. Introduction As the most metabolically active part of the human body, the brain generates many reactive oxygen species (ROS), which can cause oxidative stress (OS) when excessively produced or inadequately removed [1–3]. This, in turn, can lead to neural cell damage [4,5]. Given that high oxidation activity must be balanced with antioxidant activity in the brain, it is an organ prone to oxidation-related damage [6–8]. Such OS is a potential factor in brain deterioration and loss of gray matter, which lead to issues with cognition and daily functioning [9–12]; furthermore, OS has been associated with a plethora of psychiatric disorders [13–17]. One such disorder, schizophrenia is characterized by emotional, cognitive, and behavioral disturbances, as well as inaccurate perceptions of reality and high mortality and morbidity [18–22]. Understanding the etiology and pathophysiology of schizophrenia is a prerequisite for developing more effective treatments. To date, the factors implicated in the development of schizophrenia include excessive free radicals and impaired antioxidant defense [5,23]. As such, a diet rich in antioxidants has been suggested as a promising strategy for slowing the progression of the disorder [24,25]. This review specifically focuses on the role of ROS-mediated oxidative damage in the pathophysiology of schizophrenia. In addition, current knowledge on treating schizophrenia with antioxidants is presented, along with information on how antioxidant levels in patients with schizophrenia may be regulated by nutritional, pharmacological, and lifestyle factors. Because Brain Sci. 2020, 10, 742; doi:10.3390/brainsci10100742 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, x FOR PEER REVIEW 2 of 24 antioxidants is presented, along with information on how antioxidant levels in patients with Brain Sci. 2020, 10, 742 2 of 24 schizophrenia may be regulated by nutritional, pharmacological, and lifestyle factors. Because schizophrenia is a progressive disorder from its onset in adolescence or early adulthood [10,26–28], schizophreniathe intake of natural is a progressive antioxidants disorder may help from regulate its onset its in development adolescence [29] or early. adulthood [10,26–28], the intake of natural antioxidants may help regulate its development [29]. 2. Schizophrenia 2. Schizophrenia Schizophrenia is a severe mental disorder characterized by frequent relapses, cognitive impairmentSchizophrenia [30–32], isand a emotional severe mental and functional disorder disability characterized [33–35] by. 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Brain parietal abnormalities lobule, medial in thetemporal amygdala, lobe, cerebellum,superior temporal basal ganglia, gyrus, prefrontal corpus callosum, cortical inferiorareas, and parietal thalamus lobule, have medial also been temporal found lobe, in postmortem superior temporal studies of gyrus, individuals prefrontal with cortical the dis areas,order and[38,39] thalamus. The symptoms have also beenof schizophrenia found in postmortem are classified studies as of positive, individuals such with as thehallucinations disorder [38 ,and39]. Thedelusions, symptoms and ofnegative, schizophrenia such areas social classified withdrawal as positive, and such flat as affect hallucinations [40–45]. andCognitive delusions, deficits, and negative,including such the asimpairment social withdrawal of attention, and flat memory, affect [40 –and45]. Cognitiveexecutive deficits,function, including are also the hallmarks impairment of ofschizophrenia; attention, memory, they present and executive from the function, prodromal are also phase hallmarks of the ofdisorder schizophrenia; before psychotic they present symptoms from the prodromalfully intensify phase [28,46,47] of the disorder. Such beforecognitive psychotic decline symptoms can present fully at intensify an early [28 age,46 ,47among]. Such those cognitive with declineschizophrenia, can present eventually at an early leadin ageg to among self-care those issues with and schizophrenia, impaired social eventually and occupational leading to self-carefunction issues[28,48,49] and. impairedMoreover, social patients and occupational with schizophrenia function [28 often,48,49 ].report Moreover, anxiety, patients depression, with schizophrenia obsessive oftenbehavior, report substance anxiety, abuse, depression, and suicidal obsessive ideation. behavior, Given substance these symptoms, abuse, and schizophrenia suicidal ideation. has a Given high thesesocial symptoms,impact [26] schizophrenia. has a high social impact [26]. 3. 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