Second-Generation Long-Acting Injectables Significantly Improve Long-Term Severe Schizophrenia Outcomes


A 6-year mirror analysis of risperidone, once-monthly paliperidone palmitate or once-monthly aripiprazole concludes suggesting the regimens may serve as an alternative to clozapine.

Second-Generation Long-Acting Injectables Significantly Improve Long-Term Severe Schizophrenia Outcomes

High-dose regimens of long-acting injectable (LAI) risperidone, once-monthly paliperidone palmitate or once-monthly aripiprazole provided improved disease severity, hospitalization and disability outcomes among treated patients with severe, resistant schizophrenia, according to new findings.

In data presented at the American Psychiatric Association (APA) 2022 Annual Meeting in New Orleans this weekend, a team of international investigators observed not only improved severe outcomes with second-generation LAI therapy, but a notable rate of treatment adherence and tolerability among more in-need patients with schizophrenia.

Led by Juan J. Fernández-Miranda, MD, PhD, senior psychiatrist with the Registration in the Central Services of the Health Service of the Principality of Asturias (SESPA) in Spain, the team sought to assess the associated retention, efficacy and tolerability of risperidone, paliperidone palmitate and aripiprazole in patients with severe, resistant schizophrenia. Their observational, mirror-image analysis was conducted over 72 months.

Eligible patients were diagnosed with severe, treatment-resistant schizophrenia—defined as CGI-S ≥5—and deemed likely to benefit from second-generation LAI regimens based on their risk of treatment non-compliance, as well as a lack of observed efficacy or greater incidence of adverse events with prior antipsychotic drug treatment. All included patients were previously treated with ≥2 different antipsychotics.

The patients were administered either 75 mg risperidone (n = 60), 175 mg monthly paliperidone palmitate (n = 60) or 600 mg aripiprazole (n = 30). Fernández-Miranda and colleagues sought outcomes for improvement in CGI-S and WHO-DAS, Medication Adherence Rating Scale (MARS), adverse events, laboratory test results, weight change, hospital admissions and suicide attempts.

Mean antipsychotic treatment doses for each arm were as follows:

  • Risperidone LAI, 111.2 mg/14 days
  • Paliperidone palmitate, 231.2/mg 28 days
  • Aripiprazole, 780 mg/28 days

Investigators observed decreased mean patient CGI-S (P <.01) and WHO-DAS scores across the indices’ 4 areas after 3 years. MARS increased with all LAIs (P <.01), particularly with paliperidone palmitate and aripiprazole.

Statistically significant decreases in hospital admissions (P <.001) and suicide attempts (P <.001) were observed among patients at the end of 36-month LAI regimens, compared to the previous 3 years; the treatment arms did not significantly differ in these outcomes.

The team also observed 11 patient LAI treatment discontinuations over 3 years, versus 60 antipsychotic medications among the same population in the previous 3 years (P <.0001). Treatment tolerability was favorable for all 3 LAIs, as the rate of reported adverse events decreased—as did measures including weight gain and prolactin levels.

Fernández-Miranda and colleagues reported 9 treatment discontinuations among patients treated with risperidone due to adverse events, and 4 due to a lack of efficacy. Among patients treated with paliperidone palmitate, discontinuation counts were 5 due to adverse events and 2 due to lack of efficacy; among patients treated with aripiprazole, discontinuation counts were 2 and 1, respectively.

The team concluded that the 6-year analysis showed benefit of high-dose risperidone, paliperidone palmitate and aripiprazole in key severe, resistant schizophrenia outcomes including hospitalizations, suicide attempts and measures of tolerability. The findings would suggest an opportunity for such patients to achieve “clinical stabilization and better function” with such agents.

“Therefore, we suggest that, in some illness critical conditions, high doses of second-generation LAIs could represent an alternative to clozapine,” they wrote.

The study, “High Doses of Second-Generation Long-Acting Antipsychotics in Patients With Severe Resistant Schizophrenia. a Six-Year Mirror-Image Study,” was presented at APA 2022

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