Treatment-Resistant Schizophrenia a Distinct Disease?

Nancy A. Melville

March 03, 2016

Key factors associated with treatment-resistant schizophrenia differ from known risk factors for treatment-responsive schizophrenia, raising the possibility that the two are separate disorders, new research shows.

"These findings are consistent with the possibility that, rather than representing a severe form of schizophrenia, the treatment-resistant subtype could have a fundamentally different cause than the treatment-responsive subtype," the authors, led by Theresa Wimberley, a doctoral candidate with the National Centre for Register-based Research at the School of Business and Social Sciences, Aarhus University, in Denmark, write.

The study was published online February 24 in Lancet Psychiatry.

Predictors of Resistance

The study included 8624 patients aged 18 years and older who had incident schizophrenia. The patients were identified in Danish national registry data; 1703 (21%) of cases met the definition of being treatment-resistant schizophrenia.

Treatment resistance was defined as either the need for early initiation of therapy with clozapine (multiple brands), a commonly used drug when other schizophrenia treatments fail, or hospital admission for schizophrenia after two unsuccessful attempts at treatment with different antipsychotic monotherapies.

The mean follow-up period was 9.1 years. The strongest factors linked to treatment resistance were younger age (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.95 - 0.97); living in less urban areas (HR for provincial residence, 1.38; 95% CI, 1.23 - 1.56; HR for rural residence, 1.44 95% CI, 1.25 - 1.65); higher education level (HR, 0.88, 95% CI, 0.79 - 0.98); more than 30 bed-days in a psychiatric hospital in the year before first schizophrenia diagnosis (HR, 1.54; 95% CI, 1.35 - 1.75); being an inpatient at first schizophrenia diagnosis (HR, 2.07; 95% CI, 1.87 - 2.29); paranoid subtype (HR, 1.24; 95% CI, 1.13 - 1.37); comorbid personality disorder (HR, 1.24; 95% CI, 1.11 0 1.39); psychotropic drug use (HR for use of antipsychotics, 1.51; 95% CI, 1.35 - 1.69; HR for use of antidepressants, 1.15; 95% CI, 1.03 - 1.29; HR for use of benzodiazepines, 1.22; 95% CI, 1.10 0 1.37); and previous suicide attempt (HR, 1.21; 95% CI, 1.07 0 1.39).

Factors commonly associated with schizophrenia, such as male sex, family history of schizophrenia, seasonality of birth, paternal age, early parental loss, and living in an urban area, were not found to be risk factors.

Although the findings support previous research showing that factors such as previous diagnosis of personality disorder, suicide attempt, and paranoid schizophrenia subtype are associated with increased rates of treatment resistance, the finding that residing in a nonurban area was linked to treatment resistance is new and is contrary to the known schizophrenia risk factor of living in an urban area.

"This finding of increased treatment-resistant schizophrenia in less urban areas might partly be explained by different treatment practices across regions, supported by different rates of clozapine prescribing based on region or type of hospital," the authors note.

The study expands on previous research by including patients who were eligible for clozapine therapy as well as those who were treated with the drug.

"We extended the proxy definition to include patients eligible for clozapine, as clozapine is considered to be underprescribed," Wimberley told Medscape Medical News. "We found similar results regardless of definition used."

She noted, however, that in general, it is not uncommon to find different associations and risk factors when restricting study participants to those having a specific disease, as was done in the current study, vs comparing patients with the general population.

That said, the findings have important clinical implications and provide predictors of potential treatment resistance that can be obtained at the first diagnosis of schizophrenia.

"It is important that the practitioner can use characteristics of the patients already at first diagnosis of schizophrenia to predict their treatment response in order to optimize treatment as early as possible after diagnosis," Wimberley said. "More focus regarding optimized treatment ― for example, early consideration of clozapine treatment ― should then be given to high-risk patients.

"Previous studies have shown that a longer duration of untreated psychosis is associated with worse response to treatment," she noted.


In an accompanying editorial, Mathias Zink, MD, and Susanne Englisch, MD, of the Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany, write that the study underscores the problem of treatment resistance.

"Despite multifaceted treatment approaches, fewer than 20% of patients with schizophrenia achieve sufficient recovery," they write.

However, they question the study authors' suggestion that treatment-resistant schizophrenia is distinct from non-treatment-resistant schizophrenia.

"This assumption by far exceeds what can be concluded from the presented data, and more research involving comprehensive psychopathological examinations, neurogenetic profiling, and functional magnetic resonance imaging will be necessary to provide a sound basis for this hypothesis," the authors write.

Nevertheless, they add, the study is important in shedding light on the factors associated with treatment resistance.

"Although this study might not disentangle the underlying pathological changes in patients with treatment-resistant schizophrenia, it contributes by defining obstacles between health-care providers and patients in need.

"All hurdles that prevent patients from gaining access to treatment should be removed. To do this, early detection and intervention services have to be provided not only in cities, but also in more rural areas," they conclude.

The study received funding from the European Community's Seventh Framework Programme. The authors of the study have disclosed no relevant financial relationships. Dr Zink and Dr Englisch have disclosed numerous ties to industry, which are listed in the original article.

Lancet Psychiatry. Published online February 24, 2016. Abstract, Editorial


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