Research Article: Comparative effectiveness of second generation long-acting injectable antipsychotics based on nationwide database research in Hungary

Date Published: June 13, 2019

Publisher: Public Library of Science

Author(s): P. Takács, P. Czobor, L. Fehér, J. Gimesi-Országh, P. Fadgyas-Freyler, M. Bacskai, P. Rakonczai, A. Borsi, R. Hegyi, T. Németh, J. Sermon, I. Bitter, Vincenzo De Luca.


Schizophrenia is a severe condition that affects approximately 1% of the population. Certain elements of antipsychotic treatment can only be examined in large population, thus the need for population-based real-world analyses has been increasing.

Hungarian National Health Fund database includes all healthcare data of the population of Hungary. All patients diagnosed with schizophrenia between 01.01.2006 and 31.12.2015 were included in the study. We analyzed all patients with newly initiated second-generation antipsychotic during the inclusion period (01.01.2012–31.12.2013). Patients were followed for 2 years. All-cause treatment discontinuation served as the primary outcome of the study. Patients with newly initiated long-acting injectable treatments were further investigated in stratified analyses based on their previous treatment.

106,624 patients had schizophrenia diagnosis during the study period. 12,232 patients met the inclusion criteria for newly initiating second-generation antipsychotic during the inclusion period. The proportion of patients still on treatment after 1 year for oral treatments varied between 17% (oral risperidone) and 31% (oral olanzapine) while the analogous data for long acting injectables were between 32% (risperidone long acting) and 64% (paliperidone long acting one monthly). The 2-year data were similarly in favor of long-actings. Median time to discontinuation in the oral group varied between 57 days (clozapine) and 121 days (olanzapine). The median time to discontinuation for long-actings was significantly longer: between 176 and 287 days; in case of paliperidone long acting, median was not reached during the observation period. Patients receiving long-acting treatment switched from another long-acting remained on the newly initiated treatment significantly longer than those switched from orals.

Our results indicate the superiority of second generation long-acting antipsychotics with regard to rates of treatment discontinuation and periods of persistence to the assigned medication.

Partial Text

Schizophrenia is a chronic and severe condition that has a significant and long-lasting impact on the individual patients, their caregivers, and society. Numerous clinical trials and meta-analyses [1,2,3] have evaluated and compared the effects of oral, first generation (FGA) long acting injectable (LAI) and second generation (SGA) LAI. The contradicting outcomes of the clinical trials may result from the varying study designs but more so from the more controlled nature of the randomized clinical trials that can result in a lower than real life discontinuation rate of oral antipsychotics in clinical trial settings [1,4]. While discontinuation of treatment has been accepted as a proxy for treatment failure [5] as it is widely perceived as the main reason behind relapse, recently questions were raised whether certain patient population may benefit from a no-treatment period. [6,7]

During the inclusion period between 01.01.2012 and 31.12.2013 a total of 126,463 patients were prescribed antipsychotic treatment, including both first and second-generation antipsychotics. Out of these, 12,232 patients met the inclusion criteria for newly started monotherapy with SGA treatment as specified above.

The uniqueness of the current study is based on its full-population scale, the large number of patients (more than 12,000 newly treated schizophrenia patients in the study period), the long-term retrospective follow-up period (data available for 10 years), the prospective follow-up of the different treatment arms (2 years) and the information about treatments prior to the inclusion in the study. The primary endpoint of the current analysis was 1- and 2-year discontinuation rates of oral and LAI SGA treatments in both raw and matched estimates between the different treatment arms, with the statistical endpoint of the hazard ratio of discontinuation. Significant superiority of LAIs versus oral treatments was observed in the majority of cases, although a few treatment arms did not obtain statistical significance, as shown in the Results section.

Due to the increasing utilization of SGA LAI treatments, the evidence supporting the importance of adherence in the relapse prevention of schizophrenia is also increasing and the superiority of LAI formulations versus oral treatment in the real world is well documented. Our study provides further evidence from a full populational study for this superiority and demonstrates a strong association between the time to treatment discontinuation of the current/last treatment and the drug formulation (oral versus LAI) of the previous treatment. Our findings also suggest that better relapse prevention and clinical stability could be achieved by switching from one LAI to another LAI if switching is deemed necessary. Further analyses, such as long-term patient pathways including more than one LAI treatment period are needed to reveal the impact of LAI treatment on further outcomes, including death, hospitalization, co-medication or suicide.




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