Inverse association between urbanicity and treatment resistance in schizophrenia

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.