Therapeutic efficacy of atypical antipsychotic drugs by targeting multiple stress-related metabolic pathways

Abstract

Schizophrenia (SZ) is considered to be a multifactorial brain disorder with defects involving many biochemical pathways. Patients with SZ show variable responses to current pharmacological treatments of SZ because of the heterogeneity of this disorder. Stress has a significant role in the pathophysiological pathways and therapeutic responses of SZ. Atypical antipsychotic drugs (AAPDs) can modulate the stress response of the hypothalamic-pituitary-adrenal (HPA) axis and exert therapeutic effects on stress by targeting the prefrontal cortex (PFC) and hippocampus. To evaluate the effects of AAPDs (such as clozapine, risperidone and aripiprazole) on stress, we compared neurochemical profile variations in the PFC and hippocampus between rat models of chronic unpredictable mild stress (CUMS) for HPA axis activation and of long-term dexamethasone exposure (LTDE) for HPA axis inhibition, using an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS/MS)-based metabolomic approach and a multicriteria assessment. We identified a number of stress-induced biomarkers comprising creatine, choline, inosine, hypoxanthine, uric acid, allantoic acid, lysophosphatidylcholines (LysoPCs), phosphatidylethanolamines (PEs), corticosterone and progesterone. Specifically, pathway enrichment and correlation analyses suggested that stress induces oxidative damage by disturbing the creatine-phosphocreatine circuit and purine pathway, leading to excessive membrane breakdown. Moreover, our data suggested that the AAPDs tested partially restore stress-induced deficits by increasing the levels of creatine, progesterone and PEs. Thus, the present findings provide a theoretical basis for the hypothesis that a combined therapy using adenosine triphosphate fuel, antioxidants and omega-3 fatty acids as supplements may have synergistic effects on the therapeutic outcome following AAPD treatment.

Figure 1

Partial least square-discriminant analysis (PLS-DA) modeling of ultraperformance liquid chromatography–mass spectrometry (UPLC–MS/MS) spectral data derived from aqueous extracts of prefrontal cortex samples in the positive ion mode. (a) All seven groups; (b) atypical antipsychotic drug (AAPD) groups versus normal control (NC). ARI, aripiprazole; CLO, clozapine; CUMS, chronic unpredictable mild stress; LTDE, long-term dexamethasone exposure; RIS, risperidone.

Figure 2

Multicriteria strategy for the selection of stress-induced biomarkers. (a) Value of importance (VIP) plot, (b) S-plot and (c–e) loading plots with the jack-knife confidence interval (CIJF_jk). Specifically, creatine is labeled with a red arrow in these plots. For further interpretation, please see the Results section. AAPD, atypical antipsychotic drugs; CUMS, chronic unpredictable mild stress; LTDE, long-term dexamethasone exposure.

Figure 3

Spearman rank correlations between different categories of biomarkers in the prefrontal cortex (PFC). (a) The sum of purines (inosine and hypoxanthine) was positively correlated with uric acid in the PFC. (b) The sum of purines was negatively associated with the sum of lysophosphatidylcholines (LysoPCs 16:0, 18:0 and 18:1). (c) There was a negative correlation between uric acid and the sum of LysoPCs. (d) There was a positive association between progesterone and the sum of phosphatidylethanolamines (PEs).

Figure 4

The perturbed stress-related metabolic pathways and responses to AAPD treatment. (a) An imbalanced creatine–phosphocreatine circuit results in an inability to satisfy the demand for ATP; (b) insufficient ATP leads to abnormal purine metabolism and oxidative stress; (c) peroxidation and biosynthetic dysfunction of membrane phospholipids, and (d) altered steroidogenesis by stress and subsequent changes in multiple arrays of physiological function. AAPD, atypical antipsychotic drug; ADP, adenosine diphosphate; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CUMS, chronic unpredictable mild stress; LTDE, long-term dexamethasone exposure; LysoPC, lysophosphatidylcholine; PC, phosphatidylcholine; PE, phosphatidylethanolamine; ROS, reactive oxidative species.