Making Sense of Trial Eligibility for Schizophrenia Studies

Heidi Taipale, PhD

Randomized controlled trials (RCT) may not truly be representative of the patient population of individuals with schizophrenia, according to new research.

A team, led by Heidi Taipale, PhD, quantified the proportion of real-world individuals with schizophrenia spectrum disorders who would be ineligible to participate in randomized controlled trial and identified whether clinical outcomes differ between eligible and ineligible participants.

The majority of research on antipsychotics for patients with schizophrenia spectrum disorders generally rely on randomized clinical trials. However, this type of study design represents only a portion of the population and could result in an efficacy-effectiveness gap.

“RCT outcomes (efficacy) may differ from the utility of interventions in routine clinical practice (effectiveness), in what has been termed the efficacy-effectiveness gap,” the authors wrote. “Efficacy-effectiveness gaps have been identified in several health care areas, including pneumology, oncology, infectology, and internal medicine; nonpharmacological interventions in psychology; and antidepressants.”

How Eligibility Impacts Results

To better understand how patient eligibility impacts results, the investigators applied eligibility criteria that is typically used in trials for relapse prevention in patients with schizophrenia to real-world populations.

They identified patients with schizophrenia recorded in national patient registries in Finland and Sweden and selected patients who used antipsychotics continuously for 12 weeks in outpatient care.

Each participant was followed for up to 1 year while receiving maintenance therapy with any second-generation antipsychotic other than clozapine.

The investigators also censored follow-up at treatment discontinuation, initiation of add-on antipsychotics, death, and end of database linkage.

The team sought main outcomes of the proportion of randomized controlled trial ineligible individuals with schizophrenia owing to any and specific trial exclusion criteria. They also compared the risk of hospitalization because of psychosis within 1-year of follow-up in both cohorts of patients.

Overall, the mean age in the Finnish sample (n = 17,801) was 47.5 years and the mean age in the Swedish cohort (n = 7458) was 44.8 years.

Higher Rates of Hospitalization

The investigators found 79% ( n = 20,060) of potential participants with schizophrenia were deemed ineligible for randomized controlled trials. This included 14,221 individuals in the Finnish cohort and 5839 individuals in the Swedish cohort.

The most common explanation for exclusion was a serious somatic comorbidities and concomitant antidepressant/mood stabilizer use.

However, there was a higher risk of hospitalization because of psychosis among ineligible compared to eligible individuals (Finnish cohort: 18.4% vs 17.2%; HR, 1.14; 95% CI, 1.04-1.24; Swedish cohort: 20.1% vs 14.8%; HR, 1.47; 95% CI, 1.28-1.92).

The largest risks of hospitalization because of psychosis were found in ineligible individuals owing to treatment resistance, tardive dyskinesia, and history of suicide attempts.

The investigators also said with more ineligibility criteria met, larger risks of hospitalization due to psychosis were identified in both Sweden and Finland.

“RCTs may represent only about a fifth of real-world individuals with schizophrenia spectrum disorders,” the authors wrote. “Underrepresented (ineligible) patients with schizophrenia spectrum disorders have moderately higher risks of admission due to psychosis while receiving maintenance treatment than RCT-eligible patients.”

The investigators said the results should yield future studies targeting real-world populations currently not represented by randomized controlled trials.

The study, “Representation and Outcomes of Individuals With Schizophrenia Seen in Everyday Practice Who Are Ineligible for Randomized Clinical Trials,” was published online in JAMA Psychiatry.