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Transl Psychiatry. 2017 May 16;7(5):e1130. doi: 10.1038/tp.2017.94.

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

Cai HL1,2, Jiang P3, Tan QY4, Dang RL3, Tang MM1,2, Xue Y1,2, Deng Y1,2, Zhang BK1,2, Fang PF1,2, Xu P1,2, Xiang DX1,2, Li HD1,2, Yao JK5,6,7.

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Department of Pharmacy, Second Xiangya Hospital of Central South University, Changsha, China.
The Institute of Clinical Pharmacy, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Jining First People's Hospital, Jining Medical University, Jining, China.
School of Pharmacy, Guilin Medical University, Guilin, China.
Medical Research Service, VA Pittsburgh Healthcare System, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.


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.

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