Peripheral biomarkers of treatment-resistant schizophrenia: Genetic, inflammation and stress perspectives

Abstract

Treatment-resistant schizophrenia (TRS) often results in severe disability and functional impairment. Currently, the diagnosis of TRS is largely exclusionary and emphasizes the improvement of symptoms that may not be detected early and treated according to TRS guideline. As the gold standard, clozapine is the most prescribed selection for TRS. Therefore, how to predict TRS in advance is critical for forming subsequent treatment strategy especially clozapine is used during the early stage of TRS. Although mounting studies have identified certain clinical factors and neuroimaging characteristics associated with treatment response in schizophrenia, the predictors for TRS remain to be explored. Biomarkers, particularly for peripheral biomarkers, show great potential in predicting TRS in view of their predictive validity, noninvasiveness, ease of testing and low cost that would enable their widespread use. Recent evidence supports that the pathogenesis of TRS may be involved in abnormal neurotransmitter systems, inflammation and stress. Due to the heterogeneity of TRS and the lack of consensus in diagnostic criteria, it is difficult to compare extensive results among different studies. Based on the reported neurobiological mechanisms that may be associated with TRS, this paper narratively reviews the updates of peripheral biomarkers of TRS, from genetic and other related perspectives. Although current evidence regarding biomarkers in TRS remains fragmentary, when taken together, it can help to better understand the neurobiological interface of clinical phenotypes and psychiatric symptoms, which will enable individualized prediction and therapy for TRS in the long run.

Keywords: gene; inflammation; neurobiology; peripheral biomarkers; stress; treatment resistant schizophrenia (TRS).

FIGURE 1

Flowchart of study selection.

FIGURE 2

From peripheral biomarkers to neurobiology of treatment-resistant schizophrenia (TRS). To begin with, the lipid peroxidation product 4-hydroxynonenal (HNE) created by oxidative stress can alter the blood-brain barrier, and peroxidation also causes aberrant fatty acid levels in the synaptic membrane, leading to an altered neuronal microenvironment. Second, oxidative stress is a key mediator of carbonyl stress, as glucose and lipids are transformed to reactive carbonyl compounds (RCOs), and excess RCOs are converted to advanced glycation end products (AGEs). Glyoxalase converts RCOs to glutathione (GSH), which is an antioxidant. Vitamin B6 detoxifies RCOs and AGEs, and its deficiency can impact the metabolism of many neurotransmitters, resulting in various neurotransmission deficits in brain function. Third, AGEs interact with the AGE receptor (RAGE), causing inflammation to rise. Increased neurotoxic metabolites as a result of inflammatory damage mediated by the Kynurenine pathway. Microglia are also activated, releasing inflammatory cytokines that cause dysregulation of neuronal circuits and neurodegeneration. Therefore, TRS, a neurological disorder, is caused by the combination of mentioned mechanisms. ROSs, reactive oxygen species; GLO, glyoxalase.