Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

Abstract

Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants’ mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.

Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging

“…F2-isoprostanes are ROS-mediated products of arachidonic acids and are very sensitive markers of the lipid peroxidation process (Dietrich-Muszalska and Kontek 2010 ). Increased levels of isoprostanes, and predominantly 8-iso-prostaglandin (8-iso-PGF2α) have been detected in the urine of patients, making analysis of isoprostanes a valuable and reliable marker of the level of oxidative damage in schizophrenia patients (De Simone et al 2023 ).…”

Protective Effect of Hyperprolactinemia on Oxidative Stress in Patients with Psychotic Disorder on Atypical Antipsychotics Risperidone and Paliperidone: A Cross-Sectional Study

“…On the one hand, it has been shown that subjects with schizophrenia experience endogenous oxidative stress, which can trigger the initiation of symptoms [8]. On the other hand, antipsychotic treatment may trigger oxidative imbalance; however, both typical and atypical antipsychotics vary significantly in their effects on redox balance [36].…”

Phenols and GABAA receptors: from structure and molecular mechanisms action to neuropsychiatric sequelae

“…Regulating GABA A R desensitization is an essential process that is controlled at the signaling pathway and receptor levels; however, modulating receptor function at the level of the energy processes plays a key role in understanding withdrawal in neurological and psychiatric disorders ( Rezin et al, 2009 ). Mitochondrial dysfunction is a key factor in epilepsy, Parkinson’s disorder, schizophrenia, and other synaptic and extra-synaptic pathologies ( De Simone et al, 2023 ). However, the relationship between GABA A R activity, impaired energy balance, and manifestations of NPDs remains poorly understood.…”