title: Inverse association between urbanicity and treatment resistance in schizophrenia.
abstract: Living in a larger city is associated with increased risk of schizophrenia; and world-wide, consistent evidence shows that the higher the degree of urbanicity the higher the risk of schizophrenia. However, the association between urbanicity and treatment-resistant schizophrenia (TRS) as a more severe form of schizophrenia or separate entity of schizophrenia has not been fully explored yet. We aimed to investigate the association between urbanicity and incidence of TRS.
  
  
  
  A large Danish population-based cohort of all individuals with a first schizophrenia diagnosis after 1996 was followed until 2013 applying survival analysis techniques. TRS was assessed using a treatment-based proxy, defined as the earliest observed instance of either clozapine initiation or hospital admission due to schizophrenia after having received two prior antipsychotic monotherapy trials of adequate duration.
  
  
  
  Among the 13,349 schizophrenia patients, 17.3% experienced TRS during follow-up (median follow-up: 7years, inter-quartile range: 3-12years). The 5-year risk of TRS ranged from 10.5% in the capital area to 17.6% in the rural areas. Compared with individuals with schizophrenia residing in the capital area, hazard ratios were 1.44 (1.31-1.59) for provincial areas and 1.60 (1.43-1.79) for rural areas.
  
  
  
  Higher rates of TRS were found in less urbanized areas. The different direction of urban-rural differences regarding TRS and schizophrenia risk may indicate urban-rural systematic differences in treatment practices, or different urban-rural aetiologic types of schizophrenia.
authors.affiliation: National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Denmark. Electronic address: tw@econ.au.dk.
authors.forename: Theresa
authors.initials: T
authors.lastname: Wimberley
authors.affiliation: National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Denmark; Centre for Integrated Register-based Research, CIRRAU, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Pedersen
authors.affiliation: Department of Psychosis Studies, The Institute of Psychiatry Psychology and Neuroscience, King's College London, United Kingdom.
authors.forename: James H
authors.initials: JH
authors.lastname: MacCabe
authors.affiliation: Department of Public Health, Biostatistics, Aarhus University, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Støvring
authors.affiliation: National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Denmark.
authors.forename: Aske
authors.initials: A
authors.lastname: Astrup
authors.affiliation: Research unit , Mental Health Centre Copenhagen, Faculty of Health Sciences, University of Copenhagen, Denmark.
authors.forename: Holger J
authors.initials: HJ
authors.lastname: Sørensen
authors.affiliation: National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Denmark.
authors.forename: Henriette T
authors.initials: HT
authors.lastname: Horsdal
authors.affiliation: National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Denmark; Centre for Integrated Register-based Research, CIRRAU, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark.
authors.forename: Preben B
authors.initials: PB
authors.lastname: Mortensen
authors.affiliation: National Centre for Register-based Research, School of Business and Social Sciences, Aarhus University, Denmark.
authors.forename: Christiane
authors.initials: C
authors.lastname: Gasse
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D003024:Clozapine / Q000627:therapeutic use; D003718:Denmark; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D010343:Patient Admission; D016016:Proportional Hazards Models; D012307:Risk Factors; D012424:Rural Population; D012559:Schizophrenia / Q000453:epidemiology* / Q000628:therapy*; D012565:Schizophrenic Psychology; D016019:Survival Analysis; D016896:Treatment Outcome; D014505:Urban Population; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine
keywords: Antipsychotics; Clozapine; Schizophrenia; Treatment resistance; Urbanicity