Treatment-Resistant Schizophrenia in Urban Environments

In a Danish cohort, researchers found data that showed treatment-resistant schizophrenia was a liability of residing in an urban area at birth.

People with schizophrenia who are born in urban areas are more likely to be resistant to treatment, according to study results published in Schizophrenia Research.

The reasons for treatment-resistant schizophrenia (TRS) remain unknown, and specific genetic factors related to TRS have not yet been identified. Results from previous studies show that patients with schizophrenia born in rural areas may be at increased risk for TRS. However, results from a separate Danish study show that people with a higher polygenic risk score for schizophrenia (PRS-SZ) are more likely to be born and live in urban areas. The objective of this study was to find a more precise association between a PRS-SZ and urbanicity and TRS, and to determine whether levels of PRS-SZ vary in people with and without TRS across different geographical areas.

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In this prospective cohort study, researchers linked several Danish administrative registries to identify people born in Denmark after May 1, 1981, who were diagnosed with schizophrenia between 1996 and 2012. TRS was defined as the first occurrence of either clozapine initiation or hospitalization due to schizophrenia during antipsychotic treatment within 18 months. PRS-SZ was calculated using summary statistics from a Psychiatric Genomics Consortium meta-analysis. Geographical areas at birth were categorized into 3 levels: capital, provincial, and rural areas. 

Researchers performed Cox regression analysis for TRS in relation to PRS-SZ and urbanicity. Of the people with schizophrenia (n=4475), there were 593 individuals with TRS who were followed for 17,558 person years. 

Results revealed that the adjusted hazard ratio (HR) of the association between a 1 standard deviation increase in the PRS-SZ and TRS was 1.11 (95% CI, 1.00-1.24). The adjusted HRs for TRS across the levels of urbanicity at birth were 1.20 (95% CI, 0.98-1.47) for provincial areas and 1.19 (95% CI, 0.96–1.47) for rural areas compared with the capital area. In the adjusted model, 1 standard deviation increase in the PRS-SZ increased the risk for TRS by an HR of 1.39 (95% CI, 1.14-1.70) in the capital area, 0.99 (95% CI, 0.84-1.17) in provincial areas, and 1.03 (95% CI, 0.86-1.25) in rural areas. 

This study had several limitations. First, the collider-stratification bias may have applied to this study to complicate comparisons between results in this study and those obtained from studies not conditioning on schizophrenia status in those with TRS. Second, other genetic markers of TRS may be needed because the predictive value of PRS-SZ based on markers in this study may be too unspecific to be useful. Third, TRS was defined using register information only, without clinical information on negative symptoms. Fourth, the definition of TRS in this study may be too culturally sensitive to apply to other health care practices. Lastly, the main analysis did not exclude genetic outliers that indicated ethnicities outside of Danish origin.

The study researchers concluded there is a weak genetic liability for schizophrenia and birthplace in association with TRS, and that people with schizophrenia born in urban areas may have a higher PRS-SZ and risk for TRS.


Gasse C, Wimberley T, Wang Y, et al. Schizophrenia polygenic risk scores, urbanicity and treatment-resistant schizophrenia [published online August 22, 2019]. Schizophr Res. doi: 10.1016/j.schres.2019.08.008