Inverse association between urbanicity and treatment resistance in schizophrenia

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Abstract

Background

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.

Methods

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.

Results

Among the 13,349 schizophrenia patients, 17.3% experienced TRS during follow-up (median follow-up: 7 years, inter-quartile range: 3–12 years). 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.

Conclusion

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.

Introduction

The association between urbanicity and schizophrenia has been extensively studied, and consistently an increased incidence of schizophrenia has been observed at higher levels of urbanicity (March et al., 2008, Pedersen and Mortensen, 2001b, Vassos et al., 2012, Vassos et al., 2015). This finding was invariant to the definition used for urban exposure (population size or density); whether urbanicity was determined at birth, upbringing, schizophrenia diagnosis, or interview; and whether based on cohort or cross-sectional study designs (March et al., 2008, Pedersen, 2006, Pedersen, 2015, Pedersen and Mortensen, 2001a, Torrey et al., 1997).

Treatment-resistant schizophrenia (TRS) is generally defined as not responding adequately to treatment despite at least two first-line antipsychotic treatments. It is a clinically relevant complication of the course of schizophrenia affecting approximately 30% of all persons with schizophrenia. TRS is burdened with heavy reductions in life quality and high costs of medication and health services (Barnes, 2011, Kennedy et al., 2013).

It is debated whether TRS merely constitutes the most severe end of spectrum of schizophrenia or if it defines a distinct subtype of schizophrenia. The latter may suggest a different aetiology of TRS than of schizophrenia; in that sense, urbanicity would be hypothesized to act differently in TRS. This hypothesis was supported by a recent study reporting an increased incidence of TRS at lower levels of urbanicity compared to higher levels of urbanicity (Wimberley et al., 2016). This association merits closer investigation in an aetiological setting adjusting for an appropriately chosen set of confounders and evaluating its temporal association. This could help elucidate the nature and course of schizophrenia and predict TRS. A better understanding of urban-rural differences in TRS may be helpful to optimize treatment for patients with TRS and thereby improve treatment outcomes. Utilizing the nationwide longitudinal information on all individuals with schizophrenia recorded in Danish registers, we therefore aim to assess the association between urbanicity and a treatment-based proxy for TRS. Moreover, we aim to evaluate the temporal association between urbanicity and TRS.

Section snippets

Study cohort

We conducted a population-based cohort study including all individuals born in Denmark after 1955 with a first diagnosis of schizophrenia (ICD-10: F20) between January 1, 1996 and July 1, 2013 and aged 18 years or older. We excluded individuals who received clozapine prior to their first recorded schizophrenia diagnosis, or died or emigrated during their first admission to a psychiatric hospital with a schizophrenia diagnosis. We followed individuals from their first diagnosis of schizophrenia

Results

Among the 13,349 individuals with their first schizophrenia diagnosis between January 1, 1996 and July 1, 2013, a total number of 2313 (17.3%) individuals fulfilled the proxy definition for TRS by meeting at least one of the two criteria for TRS during follow-up, whichever came first; 1210 (9.1%) due to a redemption of clozapine (criterion one) and 1103 (8.3%) due to a hospital admission after at least two periods of different antipsychotic monotherapy (criterion two). Median follow-up was 7 

Discussion

The present study demonstrates that the lower the degree of urbanicity the higher the risk of TRS, irrespective of which point in time urbanicity was measured. Based on the worldwide consistent finding that the higher the degree of urbanicity the higher the risk of schizophrenia, our finding was contrary to our expectations.

Our finding is in accordance with a Danish study showing that individuals treated at university hospitals, which are mainly located in the more urban areas of Denmark, are

Role of funding source

None.

Contributors

T Wimberley, C Gasse, CB Pedersen, H Støvring, JH MacCabe and HJ Sørensen designed the study and interpreted the results. T Wimberley did the datamanagement, dataanalyses, and wrote the first draft of the manuscript. A Astrup contributed to the datamanagement and dataanalysis. HT Horsdal and PB Mortensen contributed to the interpretation of the results. All authors contributed to and have approved the final manuscript.

Conflict of interest

Henrik Støvring has personally received fees for teaching or consulting from the Danish Association of Pharmaceutical Manufacturers, Astra Zeneca, UCB and AbbVie. Christiane Gasse has previously received unrestricted research grants funded by Eli-Lilly, Lundbeck A/S and Janssen. James H MacCabe is partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, UK.

Acknowledgement

The research leading to these results has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 279227.

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