High Doses of Second-Generation Long-Acting Antipsychotics in the Treatment of Patients with Severe Resistant Schizophrenia: A Six-Year Mirror-Image Study

Background: This study explores whether high-dose treatment with second-generation antipsychotic long-acting injectable (SGA LAI) may benefit patients with schizophrenia that are inadequately controlled on a standard dose. The objectives of this study have been to evaluate the retention, effectiveness and tolerability of high doses of formulations SGA LAI in the treatment of patients with severe resistant schizophrenia.

Methods: A 72-month observational, mirror-image study of patients with severe (Clinical Global Impression-Severity, CGI-S ≥ 5) resistant schizophrenia receiving treatment with ≥75 mg of risperidone long-acting injectable (RLAI) (N = 60), ≥175 mg of monthly paliperidone palmitate (PP) (N = 60), and ≥600 mg of aripiprazole once-monthly (AOM) (N = 30). All of the patients were previously treated with at least two different APs, with poor outcomes. Patients were eligible if deemed likely to benefit from treatment with SGA LAIs: at risk of medication non-compliance, with a lack of effectiveness, or adverse effects with previous APs. Assessment included the CGI-S, the WHO Disability Assessment Schedule (WHO-DAS), the Medication Adherence Rating Scale (MARS), laboratory tests, weight, adverse effects reported, reasons for treatment discontinuation, hospital admissions and suicide attempts.

Results: The average antipsychotic doses were: RLAI = 111.2 (9.1 SD) mg/14 days; PP = 231.2 (12.3 SD) mg eq./28 days; and AM = 780 (120 SD) mg/28 days.Tolerability was good for all LAIs, reducing the side effects reported and the changes in biological parameters compared to previous treatments, especially in the AOM group. Weight and prolactin levels decreased in all LAI treatments; the reduction was statistically significant only among patients treated with AOM (p < 0.05). Two patients discontinued treatment due to side effects with AOM, five with PP and nine with RLAI. There were four discontinuations with RLAI, two with PP, and one with AOM due to a lack of effectiveness (severe symptoms or hospital admission). After three years, the scores decreased in CGI-S (p < 0.01) and in WHO-DAS in the four areas with all injectables. MARS increased with all LAIs (p < 0.01), especially with PP and AOM. We have reported a statistically significant decrease in both hospital admissions (p <0.001) and suicide attempts (p < 0.001) at the end of 36-month treatments, compared to the previous three years, without any difference across the three LAIs. In the previous three years, 60 patients discontinued their AP treatment, and 11 during the three-year follow-up (p < 0.0001).

Conclusions: Our study indicates the good effectiveness and tolerability of RLAI, PP and AM at high doses. These SGA LAI treatments improved treatment adherence and outcomes (hospitalizations, suicide attempts, clinical severity, disability) of the patients, with good tolerability, helping them to achieve clinical stabilization and better functioning. Therefore, we suggest that, in some illness critical conditions, high doses of SGA LAIs could represent an alternative to clozapine, to date the only therapy for resistant schizophrenia.

To cite this article: Fernández-Miranda JJ, Díaz-Fernández S, López-Muñoz F. High Doses of Second-Generation Long-Acting Antipsychotics in The Treatment of Patients with Severe Resistant Schizophrenia: A Six-Year Mirror-Image Study. Psychiatry and Clinical Psychopharmacology 2020;30(4):335-345