Multiple Risk Factors May Predict Treatment-Resistant Schizophrenia

Poorly managed treatment-resistant schizophrenia has a significant personal and economic impact, with unfavorable long-term outcomes.

The strongest predictors of treatment-resistant schizophrenia in a patient include taking antipsychotics, being an inpatient at the time of diagnosis, or spending more than 30 days in a psychiatric hospital before a schizophrenia diagnosis, according to new research reported in Lancet Psychiatry. An estimated 30% of patients with schizophrenia demonstrate resistance to treatment — not responding to sufficient dosages of at least 2 antipsychotic medications — and therefore require clozapine.

“The social and economic costs of poorly managed treatment-resistant schizophrenia are high, and duration of insufficiently treated or untreated psychosis is strongly associated with unfavorable long-term outcomes,” wrote Theresa Wimberley, MSc, of Aarhus University in Denmark, and her colleagues. “Identification of patients at high risk for treatment resistance at the time of schizophrenia diagnosis would be of clinical benefit in minimizing the delay to clozapine treatment.”

The researchers followed all Danish adults diagnosed with schizophrenia between 1996 and 2006 from the time of diagnosis until the end of 2010. Primary treatment-resistant schizophrenia criteria included a clozapine prescription or hospitalization for schizophrenia within 18 months of trying at least 2 different monotherapy antipsychotics for at least 6 weeks each. A secondary proxy included taking at least 2 different antipsychotics together for at least 90 days.

Among the 8624 patients followed for a median of 9 years, 13% were eventually prescribed clozapine, 11% were admitted for schizophrenia, and 44% of patients received polypharmacy treatment for at least 90 days. Of the 8044 patients for whom the researchers had all data, 21% met the primary criteria, and the researchers assessed the strength of 16 possible risk factors.

Those with treatment-resistant schizophrenia were slightly more likely to be younger at diagnosis, to take antidepressants, and to have a lower primary education level. Further, those with a paranoid subtype or a comorbid personality disorder were 24% more likely to have treatment-resistant schizophrenia, those taking benzodiazepines were 22% more likely, and those with a previous suicide attempt were 21% more likely.

Patients first diagnosed while an inpatient were twice as likely to have treatment-resistant schizophrenia, and they were 54% more likely to demonstrate resistance to first-line treatment if they spent more than 30 days in a psychiatric hospital during the year before diagnosis. Prior antipsychotic use additionally indicated a 51% higher likelihood of treatment-resistant schizophrenia. Living in an urban area appeared to have a protective effect: living in a provincial or rural area increased the risk of treatment-resistant schizophrenia by 38% and 44%, respectively.


  1. Wimberley T, Stovring H, Sorensen HJ, Horsdal HT, MacCabe JH, Gasse C. Predictors of treatment resistance in patients with schizophrenia: a population-based cohort study. Lancet Psychiatry. 2016;3:358-366.