Novel approaches in schizophrenia-from risk factors and hypotheses to novel drug targets

Abstract

Schizophrenia is a severe psychiatric disorder characterized by emotional, behavioral and cognitive disturbances, and the treatment of schizophrenia is often complicated by noncompliance and pharmacoresistance. The search for the pathophysiological mechanisms underlying schizophrenia has resulted in the proposal of several hypotheses to explain the impacts of environmental, genetic, neurodevelopmental, immune and inflammatory factors on disease onset and progression. This review discusses the newest insights into the pathophysiology of and risk factors for schizophrenia and notes novel approaches in antipsychotic treatment and potential diagnostic and theranostic biomarkers. The current hypotheses focusing on neuromediators (dopamine, glutamate, and serotonin), neuroinflammation, the cannabinoid hypothesis, the gut-brain axis model, and oxidative stress are summarized. Key genetic features, including small nucleotide polymorphisms, copy number variations, microdeletions, mutations and epigenetic changes, are highlighted. Current pharmacotherapy of schizophrenia relies mostly on dopaminergic and serotonergic antagonists/partial agonists, but new findings in the pathophysiology of schizophrenia have allowed the expansion of novel approaches in pharmacotherapy and the establishment of more reliable biomarkers. Substances with promising results in preclinical and clinical studies include lumateperone, pimavanserin, xanomeline, roluperidone, agonists of trace amine-associated receptor 1, inhibitors of glycine transporters, AMPA allosteric modulators, mGLUR 2-3 agonists, D-amino acid oxidase inhibitors and cannabidiol. The use of anti-inflammatory agents as an add-on therapy is mentioned.

Neuroinflammation in Schizophrenia: The Key Role of the WNT/β-Catenin Pathway

“…Cytokines represent a wide range of molecules generated by cells, such as B and T immune cells, lymphocytes, macrophages, endothelial cells, and fibroblasts. In the first psychotic episode of schizophrenia, a decrease in anti-inflammatory markers, such as interleukins IL-10 and IL-4, has been observed, while pro-inflammatory factors, such as IL-6, are increased [ 1 ]. The oversecretion of cytokines has also been observed in peripheral blood mononuclear cells, with the stimulation of the expression of IL-6, IL-8, and tumor necrosis factor α (TNF-α) and a decreased expression of IL-2mRNA [ 21 ].…”

“…The oxidative stress observed in schizophrenia is associated with the secretion of pro-inflammatory cytokines, leading to a chronic neuroinflammatory process and genetic damage that in turn promotes chronic inflammation, surrounding oxidative stress impacting cells, and immune impairment [ 1 ]. A vulnerability–stress–inflammation interaction model operates in schizophrenia.…”

“…A strong relationship between oxidative stress and the immune system has been shown to be involved in schizophrenia [ 1 ]. Glutathione (GSH), an antioxidant that is essential for the myelination and maturation of white matter, is stimulated by the amino acid precursor N-acetyl cysteine (NAC).…”

“…Schizophrenia is a neurodevelopmental and mental illness affecting nearly 1% of the world’s population, and the age of onset age is between 23 and 34 years in women and close to 30 years in men [ 1 ]. Schizophrenia is characterized by generalized brain multi-dysconnectivity and marked by abnormal brain development, deregulated neuronal migration, impaired spatial neural arrangement, and the absence of gliosis [ 2 ].…”

Use of Psychoeducation for Psychotic Disorder Patients Treated With Modern, Long-Acting, Injected Antipsychotics

“…Changes in clinical, anthropometric and physiological measures over six months of treatment exposure were measured. Clinicians preferred risperidone and paliperidone antipsychotics for the long-term treatment of patient-subjects diagnosed with schizophrenia or other non-affective psychoses, possibly due to their relatively high affinity at dopamine D 2 -receptors and their reported benefits on both positive and negative psychotic symptoms (21). Olanzapine and aripiprazole were preferred with affective psychoses since they may have mood-stabilizing effects (22).…”