title: Diurnal neurobiological alterations after exposure to clozapine in first-episode schizophrenia patients.
abstract: BACKGROUND
  Irregular circadian rhythm and some of its most characteristic symptoms are frequently observed in patients with schizophrenia. However, changes in the expression of clock genes or neuropeptides that are related to the regulation of circadian rhythm may influence the susceptibility to recurrence after antipsychotic treatment in schizophrenia, but this possibility has not been investigated.
  
  
  METHODS
  Blood samples were collected from 15 healthy male controls and 13 male schizophrenia patients at 4h intervals for 24h before and after treatment with clozapine for 8 weeks. The outcome measures included the relative expression of clock gene mRNA PERIOD1 (PER1), PERIOD2 (PER2), PERIOD3 (PER3) and the levels of plasma cortisol, orexin, and insulin.
  
  
  RESULTS
  Compared with healthy controls, schizophrenia patients presented disruptions in diurnal rhythms of the expression of PER1, PER3, and NPAS2 and the release of orexin, accompanied by a delayed phase in the expression of PER2, decreases in PER3 and NPAS2 expression, and an increase in cortisol levels at baseline. Several of these disruptions (i.e., in PER1 and PER3 expression) persisted after 8 weeks of clozapine treatment, similar to the decreases in the 24-h expression of PER3 and NPAS2. Clozapine treatment for 8 weeks significantly decreased the 24-h levels of PER2 and increased the 24-h levels of insulin.
  
  
  CONCLUSIONS
  These persistent neurobiological changes that occur after 8 weeks of clozapine treatment may contribute to the vulnerability to recurrence and efficacy of long-term maintenance treatment in schizophrenia.
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing 100191, China.
authors.forename: Hong-Qiang
authors.initials: HQ
authors.lastname: Sun
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Su-Xia
authors.initials: SX
authors.lastname: Li
authors.affiliation: 102 Military Hospital of China, Changzhou 213000, China.
authors.forename: Fang-Bin
authors.initials: FB
authors.lastname: Chen
authors.affiliation: 102 Military Hospital of China, Changzhou 213000, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing 100191, China; 102 Military Hospital of China, Changzhou 213000, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: 102 Military Hospital of China, Changzhou 213000, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Jin
authors.affiliation: National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Beijing Hui-Long-Guan Hospital, Peking University, Beijing 100096, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing 100191, China.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Mi
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing 100191, China; National Institute on Drug Dependence, Peking University, Beijing 100191, China.
authors.forename: Le
authors.initials: L
authors.lastname: Shi
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing 100191, China.
authors.forename: Jing-Li
authors.initials: JL
authors.lastname: Yue
authors.affiliation: Beijing Hui-Long-Guan Hospital, Peking University, Beijing 100096, China.
authors.forename: Fu-De
authors.initials: FD
authors.lastname: Yang
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health and Key Laboratory of Mental Health, Ministry of Health, Peking University, Beijing 100191, China; National Clinical Research Center for Mental Disorder, Peking University, Beijing 100191, China. Electronic address: linlu@bjmu.edu.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
mesh_terms: D000293:Adolescent; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000097:blood; D016022:Case-Control Studies; D002940:Circadian Rhythm / Q000187:drug effects*; D003024:Clozapine / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000097:blood; D000068797:Orexins / Q000097:blood; D056950:Period Circadian Proteins / Q000096:biosynthesis* / Q000097:blood; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy*; D013997:Time Factors; D055815:Young Adult
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003024:Clozapine; D006854:Hydrocortisone; D007328:Insulin; D009419:Nerve Tissue Proteins; D000068797:Orexins; D056950:Period Circadian Proteins; C104264:NPAS2 protein, human
keywords: Circadian rhythm; Clock genes; Clozapine; Hormones; Peptides; Schizophrenia