Antipsychotics of a New Generation: Where Are We Now?

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Background

Schizophrenia is a chronic brain disorder that causes severe psychotic episodes leading to patient disability. The prevalence of schizophrenia remains consistently high, and according to the World Health Organization, 50 million people in the world suffer from this severe mental illness. The main treatments for schizophrenia are antipsychotic drugs (APDs), which are represented by two classes: typical (haloperidol, chlorpromazine, etc.), which are dopamine blockers D2 receptors (D2R) and atypical (clozapine, olanzapine, etc.), affecting D2R and other neurotransmitter receptors. About 60% of schizophrenics do not respond to APD therapy and develop therapeutic resistance. Moreover, currently used APDs, in addition to the main clinical actions, cause such side effects as extrapyramidal syndrome, weight gain, dyskinesia, diabetes and dysfunction of the reproductive system.

One of the most frequent combined conditions occurring in schizophrenia and complicating its treatment is metabolic syndrome (MS). Its incidence rate for schizophrenia is two times higher than in the general population and is observed in schizophrenic patients in up to 58.7% of cases. MS is associated with the risk of developing cardiac pathology and diabetes, and mortality among patients with schizophrenia is 2–3 times higher than in the general population. APDs leads to metabolic disorders in schizophrenia’ patients. For example, MS induced by APDs, is observed in 39% of patients taking haloperidol and 44% of clozapine. Hence, the problem of metabolic disorders and the side effects of APDs in schizophrenia comes to the fore.

D2R is the main target of APDs’ action and the clinical efficacy correlates with their binding ability with D2R. In order to create APDs without side effects, MS, a deep understanding of the D2R signaling pathways is necessary to identify new therapeutic targets. D2R mediates its action through intracellular Gi / Go-proteins that control adenylate cyclase activity, exchange of phosphatidylinositol, release of arachidonic acid, K+ and Ca2+ channel’ activity and protein kinases. D2R also acts independently of G-proteins, for example, through β-arrestin-2, which initiates the formation of a complex with protein phosphatase-2A (PP2A), protein kinase-B (Akt (PKB)), activation of glycogen synthase kinase type 3 (GSK-3). The main mechanism of regulation of D2R is kinase-dependent desensitization of D2R, endocytosis, and endosomal traffic, which then leads to the formation of a complex with β-arrestin-2, a protein-2 adapter and clathrin. We also showed the pathogenic role of enhanced interactions between D2R and DISC1 (Disrupted-In-Schizophrenia-1) in schizophrenia. The peptide uncoupling D2R and DISC1 protein-protein interactions, elicited APD capacities in pharmacological and genetic models of schizophrenia. Inhibition of the enzymatic activity of proteins related to the DISC1 interactive protein also produced APD-like effects, including GSK-3 and PDE4B. However, GSK-3 and PDE4B inhibitors cause side effects (e.g. the PDE4B blocker causes vomiting).

Notably, converging evidence suggests that GSK-3 plays an important role in schizophrenia. Atypical and typical APDs as well as some psychostimulants alter GSK-3 activity. In addition, several genes associated with schizophrenia regulate GSK-3 activity. It was suggested that GSK-3 regulation is crucial to schizophrenia, where insulin signaling pathways offer new targets for therapy. Moreover, there are some evidence for a possible link between bioenergetic dysfunction in patients with schizophrenia on transcriptomic, proteomic, metabolic levels, which is related to poor development and functioning of synapses in brain. Indeed, schizophrenia patients often suffer from the metabolic disorders before drug treatment, such as elevated lipid levels, decreased sensitivity to insulin, and type 2 diabetes. The metabolic problems could be further aggravated with typical and atypical neuroleptics. Further molecular studies revealed dysfunctions of other insulin related signaling besides increased GSK-3beta activity, like decreased insulin receptor and increased Akt activity, as demonstrated in post-mortem brains of schizophrenics. Furthermore, growth factor deficiency was proposed as a one of the etiological factors to the development of schizophrenia, mediated by synaptogenesis dysregulation. Insulin signaling as additional factor may be involved in this process, as well as amid in the pharmacological mechanism of traditional and atypical neuroleptic treatments. We suggest that insulin-related drugs for treatment of diabetes might be proposed as APDs of new generation following repurposing strategy to battle mental disorders.

However, the pathological dysregulation of metabolic biochemical mechanisms in schizophrenia’ brains was overlooked and only recently attracted attention of neuroscientists. Hence, in this current Research Topic in Frontiers in Pharmacology, we will be focusing on metabolic systems in neuronal and glial cells to potentially select new therapeutic targets in order to translate this knowledge for the better diagnostic and prevention and/or treatment of schizophrenia.

Keywords: Brain neuronal circuitries, bioenergetic balance, genes, animal models of schizophrenia

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