Psychiatry and Clinical Neurosciences 2015; 69: 497–503
doi:10.1111/pcn.12294
Regular Article
Risperidone long-acting injection and 1-year rehospitalization rate of schizophrenia patients: A retrospective cohort study Hsue-Wei Chan, MD,1,3 Chin-Yu Huang, Yung-Chieh Yen, MD, MSc, PhD1,4*
RN,1
Wen-Jui Feng,
MS2,5
and
Departments of 1Psychiatry, 2Quality and Safety, E-Da Hospital, 3Graduate Institute of Health Care Administration, 4 School of Medicine, I-Shou University, and 5Department of Business Administration, National Sun Yat-Sen University, Kaohsiung, Taiwan
Aims: We wanted to present a picture of patients with schizophrenia receiving risperidone long-acting injection (RLAI) treatment in a real-world setting. Methods: This was a retrospective cohort study; 379 patients with schizophrenia were enrolled and treated with different kinds of antipsychotic agents at E-Da Hospital, and received a 12-month follow up. The patients were distributed into three groups: the all-oral antipsychotic, oral risperidone and RLAI groups. The antipsychotic agents and dosages they used were recorded. The rate of rehospitalization, length of hospital stay, emergency room visits and medical expenditures were assessed. Results: The RLAI group had a significantly higher rate of hospitalization before enrolment (the all-oral antipsychotic group was 32.1%, the oral risperidone
CHIZOPHRENIA IS A severe psychiatric disorder in which patients’ mental function deteriorates. Its lifetime prevalence was estimated at 4.0 per 1000, and lifetime morbidity risk was 7.2 per 1000.1 The severe comorbidities, such as acute psychosis with chaotic appearance or violence, which might require psychiatric ward hospitalization, post-psychotic depression with high suicidality, and chronic long-
S
*Correspondence: Yung-Chieh Yen, MD, MSc, PhD, Department of Psychiatry, E-Da Hospital, 1 Yi-Da Road, Yan-Chau District, Kaohsiung 824, Taiwan. Email: [email protected] Received 8 May 2014; revised 25 January 2015; accepted 13 March 2015.
group, 35.9%, and the RLAI group, 88.4%, P < 0.0001). After a 1-year follow up, all three groups were similar in rehospitalization rates (the all-oral antipsychotic group was 28.9%, the oral risperidone group, 30.1%, and the RLAI group, 30.2%, P > 0.999), length of hospital stay and number of emergency room visits during follow up. The most commonly used oral antipsychotics were risperidone (0.5–7 mg/day), quetiapine (65–1200 mg/day), and olanzapine (2–25 mg/day).
Conclusions: Using RLAI reduces the severity of disease in more difficult patients. Key words: antipsychotic agents, hospital emergency service, patient readmission, risperidone, schizophrenia.
term disability, all lead to the suffering of the patients and their caregivers, and have a major social and economic impact.2–4 Many medications have been developed for the treatment of schizophrenia. Compared with traditional antipsychotics, atypical antipsychotics are reported to have fewer adverse effects5,6 and a lower risk of relapse.7 Poor medication or pharmacological adherence has been recognized as an important issue in the treatment of schizophrenia.8–11 Patients with schizophrenia discontinue their medication, often in spite of their doctor’s suggestion. The Clinical Antipsychotic Trials of Intervention study revealed that 74% of schizophrenia patients discontinued their treatment after 18
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
497
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Psychiatry and Clinical Neurosciences 2015; 69: 497–503
months.12 The European First Episode Schizophrenia Trial also found that 33–72% of patients discontinued their treatment within 12 months for any cause.13 The result of non-adherence may be the relapse of psychosis. In addition to the suffering of the patients, a relapse of psychosis may also lead to re-admission, which brings about greater expenditures and a reduced level of daily functioning of the patients, which then requires further training or rehabilitation programs.8 Long-acting injection of antipsychotic was developed for the purpose of improving the medication or pharmacological adherence of patients. Previous studies revealed that long-acting antipsychotics had improved efficacy in symptom control and relapse prevention, and in increasing adherence.10,14–18 Risperidone long-acting injection (RLAI) is the first of its kind for second-generation antipsychotics. Previous studies examining the safety and efficacy of risperidone in treating patients with schizophrenia included case–control studies, randomizedcontrolled trials, and observational studies.19–27 In the case–control studies and randomized-controlled trials, the patients were selected and grouped before being enrolled in the studies. Although these are the studies with the highest methodological quality, they may also have a lower external validity. In this study, we wanted to present patients with schizophrenia under treatment with RLAI in a real-world setting. We recruited patients with schizophrenia who were being treated with either oral antipsychotic or RLAI, and compared the rate of emergency room visits, re-hospitalizations and expenditures during treatment.
relation with different pharmacological treatment options during a 1-year follow up.
METHODS
Inclusion and exclusion criteria Patients were both male and female and at least 18 years of age, and were recruited at the same regional hospital, E-Da Hospital, where they received their psychiatric treatment. All of them were diagnosed as having schizophrenia according to DSM-IV-TR criteria. The exclusion criteria were serious medical conditions, women who were pregnant or breast-feeding, and those who did not receive follow up regularly.
Clinical outcomes We retrospectively collected the patients’ demographic data, previous history of treatment for schizophrenia, and pharmacological treatment from the hospital medical records. During the 12-month follow up, we recorded the antipsychotic agent(s) they took and the dosage and intervals of each drug. We also explored the rehospitalization rate, lengths of hospital stay, and emergency room visits.
Treatment options The patients recruited received their treatment mostly through ambulatory care. The selection and dose of antipsychotic agents were determined by psychiatrists, according to their evaluation and the patient’s clinical condition. If the patient received RLAI, their injection would be given when they came back to the outpatient department for follow up.
Study design The data presented were derived from a retrospective cohort study. This study included 379 patients with schizophrenia treated with different kinds of antipsychotic agents. Among the patients, 43 were treated with RLAI, while the others used oral-form antipsychotic agents. This was an observational study in the setting of a regional hospital, in which patients received psychiatric treatment in the outpatient department, but emergency room treatment and psychiatric ward hospitalization were available when necessary. We aimed to determine the clinical outcomes of the patients with schizophrenia and their
Statistical analysis Patients were categorized by the antipsychotic agents they took. Demographic data, baseline characteristics, and clinical outcomes were compared between groups, respectively. We performed the t-test to compare means of continuous variables between groups; Fisher’s exact test was used to compare distributions of categorical variables between groups. Within each group, the change between the hospitalization rate before recruitment and the rehospitalization rate after enrolment were examined by Fisher’s exact test.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 497–503
RLAI and schizophrenia rehospitalization 499
RESULTS Characteristics of the patients A total of 806 patients with schizophrenia received treatment at E-Da Hospital from 4 April 2011 to 30 September 2012; 60 of the patients used RLAI. Among the 806 patients, 379 had regular follow up for at least 3 months, and 43 of the 379 used RLAI. We continued following these 379 patients for another year (until 31 August 2013). The 379 patients were divided into three groups according to the antipsychotic treatment they received. The ‘all-oral antipsychotics’ group included patients with schizophrenia receiving any oral antipsychotic; the ‘oral risperidone’ group was part of the ‘all-oral antipsychotics’ group but included only those patients with schizophrenia receiving oral risperidone treatment only; ‘the RLAI’ group included patients with schizophrenia receiving RLAI. The all-
oral antipsychotic group was composed of 178 men and 158 women with a mean age of 39.4 years; the oral risperidone group included 48 men and 55 women with a mean age of 39 years; and the RLAI group comprised 23 men and 20 women with a mean age of 33.8 years. There was no significant difference in mean age (P = 0.031) or sex (P = 0.473) between the groups. The most commonly used oral antipsychotics were risperidone (103 patients with a dosage around 0.5–7 mg/day), quetiapine (61 patients with a dosage around 65–1200 mg/day), and olanzapine (58 patients with a dosage around 2–15 mg/day) (Table 1). Acute ward admission before enrolment was measured and compared in all groups. The RLAI group had the highest rate of acute ward admission before enrolment (the all-oral antipsychotic group was 32.1%, the oral risperidone group, 35.9%, and the RLAI group, 88.4%, P < 0.0001) (Fig. 1).
Table 1. Characteristics of participants and antipsychotic options All oral antipsychotics (n = 336)
Oral risperidone (n = 103)
RLAI (n = 43)
Mean age (SD), years Sex, n (%) Male Female Hospitalization 1 year before enrolment Emergency room visit 1 year before enrolment, n (%)
39.4 (12.5)
39.0 (14.2)
33.8 (12.5)
0.031
178 (53.0) 158 (47.0) 108 (32.1) 57 (17.0)
48 (46.6) 55 (53.4) 37 (35.9) 19 (18.4)
23 (53.5) 20 (46.5) 29 (87.9) 23 (53.5)
0.473
Oral antipsychotics
Number
Mean dose (SD) (mg/day)
Range (mg/day)
Risperidone Quetiapine Olanzapine Amisulpride Ziprasidone Paliperidone Flupentixol Clozapine Chlorpromazine Sulpiride Zotepine Haloperidol
103 61 58 42 30 18 6 5 5 3 3 2
3 (1) 509 (274) 13 (6) 538 (207) 132 (44) 8 (3) 18 (6) 140 (64) 180 (40) 333 (47) 100 (41) 2 (0)
0.5–7 65–1200 2–25 100–1000 40–240 3–12 9–24 50–225 50–250 200–400 25–150 2
P†
0.999 0.621 0.029 0.021
†
The t-test was performed to compare means of continuous variables between the RLAI group and the oral risperidone group; Fisher’s exact test was used to compare distributions of categorical variables between the RLAI group and the oral risperidone group. RLAI, risperidone long-acting injection.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 497–503
RLAI and schizophrenia rehospitalization 501
RLAI in our study had a significantly higher rate of admission before enrolment than the group using oral antipsychotics implied that clinical psychiatrists tended to use RLAI as the treatment for severer patients, which was similar to the conclusion of previous observational studies. It was interesting that after a 1-year observation, the group using RLAI as treatment had similar readmission rates, lengths of hospital stay, rates of emergency room visits, and average time of emergency room visits to the groups using oral risperidone or oral antipsychotics, which means the severity of disease in these three groups became rather similar during this 1-year observation compared to 1 year before, when the RLAI group had significantly severer disease. Thus, we might conclude that using RLAI treatment reduces the severity of disease more significantly than oral antipsychotics. Poor insight and poor awareness of illness are often observed in patients with schizophrenia. The lack of insight is related to poor medication or pharmacological adherence, which leads to the consequences of relapse of the psychotic disorder, re-hospitalization, longer duration to remission, or even suicide, all of which bring about patient suffering, even greater health-care costs, and poor outcomes.8,32 Long-acting injection of antipsychotics helps improve medical adherence, and the use of this modality has been proved to be advantageous in achieving and maintaining remission, lowering the risk of relapse and lowering hospitalization rates.15,16 A previous study carried out in Hong Kong that examined the cost-effectiveness of using RLAI in the treatment of schizophrenia and schizoaffective disorder revealed that the cost of hospitalization had been reduced significantly after the use of RLAI.33 In Finland, the use of RLAI with schizophrenia patients led to a reduction in mean annual hospital costs and days of admission, and a lower hospitalization rate.34 Another national cohort study in Finland comparing the effect of oral and depot antipsychotics also revealed that the use of RLAI was associated with a lower re-hospitalization rate than use of oral risperidone.26 In our study, the re-hospitalization rate, number of emergency room visits, and the average days of hospital stay of the RLAI group were similar to that of the other two groups, even though the RLAI group had much more frequent hospitalizations prior to the study, which meant much greater medical costs. While the pharmacy expenditures would probably be higher among the RLAI subjects,
the reduction of medical expenditures should be related to lowered rates of admission and hospital visits. Another retrospective cohort study in the USA found that the use of long-acting injection of atypical antipsychotics (paliperidone palmitate and RLAI) was associated with a lower re-hospitalization rate and emergency room visit rate than the use of oral antipsychotics,35 which was also similar to the result of our study. The results of our study and of previous studies revealed that the use of RLAI significantly lessened the severity of schizophrenia. However, the reason why RLAI has a better effect in lowering disease severity than oral antipsychotics remains uncertain. One possible explanation is that patients taking RLAI need to receive a regular injection every 2 weeks. This means those patients visit the outpatient department more often than patients taking oral risperidone. Frequent visits provide psychiatrists with more opportunities to detect signs of disease deterioration, recent psychosocial stressors, and other factors that may contribute to disease relapse. With more contact with psychiatrists, patients may also be more likely to receive proper psycho-education and psychosocial interventions for promoting adherence and managing psychiatric symptoms. Another possible explanation is that adherence to oral risperidone is less secure than with its depot form. Hence, the use of RLAI seems to be more advantageous to maintaining disease stability than taking oral risperidone. In this study, we did not compare RLAI with all oral medications because if we had, we might not be able to explain whether the change in hospitalization rates was related to the use of long-acting injectable antipsychotics or the effectiveness of different antipsychotics. Some limitations of this study also need to be considered. One is the methodological limitations of the study design – as a retrospective cohort study, no contact or direct information was gathered from the patients. The information was gathered from medical records. Also, the groups might differ in terms of some important, yet unknown prognostic variables, as they were not randomized. The result could have greater interest if we were able to compare the medication history, the possibility of substance exposure and illness duration among the groups that used the different antipsychotics. However, this was an archive study. It is unfortunate that we could not interview each of the patients to acquire these data or check their previous medication
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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Psychiatry and Clinical Neurosciences 2015; 69: 497–503
history. We used the rate of hospitalization to present the severity of disease in each group. Therefore, we may conclude that in our study, the use of RLAI successfully reduced medical expenditures in the treatment of patients with schizophrenia, corresponding to the results of previous studies.
13. Kahn RS, Fleischhacker WW, Boter H et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: An open randomised clinical trial. Lancet 2008; 371: 1085–1097. 14. Ju PC, Chou FH, Lai TJ et al. Long-acting injectables and risk for rehospitalization among patients with schizophrenia in the home care program in Taiwan. J. Clin. Psychopharmacol. 2014; 34: 23–29. 15. Manchanda R, Chue P, Malla A et al. Long-acting injectable antipsychotics: Evidence of effectiveness and use. Can. J. Psychiatry 2013; 58: 5S–13S. 16. Kishimoto T, Nitta M, Borenstein M, Kane JM, Correll CU. Long-acting injectable versus oral antipsychotics in schizophrenia: A systematic review and meta-analysis of mirror-image studies. J. Clin. Psychiatry 2013; 74: 957– 965. 17. Leucht C, Heres S, Kane JM, Kissling W, Davis JM, Leucht S. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of randomised long-term trials. Schizophr. Res. 2011; 127: 83–92. 18. Kirk Morton N, Zubek D. Adherence challenges and longacting injectable antipsychotic treatment in patients with schizophrenia. J. Psychosoc. Nurs. Ment. Health Serv. 2013; 51: 13–18. 19. Williams R, Chandrasena R, Beauclair L, Luong D, Lam A. Risperidone long-acting injection in the treatment of schizophrenia: 24-month results from the electronic Schizophrenia Treatment Adherence Registry in Canada. Neuropsychiatr. Dis. Treat. 2014; 10: 417–425. 20. Barrio P, Batalla A, Castellví P et al. Effectiveness of longacting injectable risperidone versus oral antipsychotics in the treatment of recent-onset schizophrenia: A casecontrol study. Int. Clin. Psychopharmacol. 2013; 28: 164– 170. 21. Leatherman SM, Liang MH, Krystal JH et al. Differences in treatment effect among clinical subgroups in a randomized clinical trial of long-acting injectable risperidone and oral antipsychotics in unstable chronic schizophrenia. J. Nerv. Ment. Dis. 2014; 202: 13–17. 22. Barnett PG, Scott JY, Krystal JH, Rosenheck RA, CSP 555 Research Group. Cost and cost-effectiveness in a randomized trial of long-acting risperidone for schizophrenia. J. Clin. Psychiatry 2012; 73: 696–702. 23. Malla A, Chue P, Jordan G et al. An exploratory open-label randomized trial comparing risperidone long acting injectable (RLAI) with oral antipsychotic medication in the treatment of early psychosis. Neuropsychopharmacology 2011; 36: 548. 24. Gaebel W, Schreiner A, Bergmans P et al. Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: Results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology 2010; 35: 2367– 2377.
ACKNOWLEDGMENT This study is supported by grants from the E-Da Hospital (EDAHP102022 and EDAHT103021). There was no conflict of interest in the preparation of this article.
REFERENCES 1. McGrath J, Saha S, Chant D, Welham J. Schizophrenia: A concise overview of incidence, prevalence, and mortality. Epidemiol. Rev. 2008; 30: 67–76. 2. Hor K, Taylor M. Suicide and schizophrenia: A systematic review of rates and risk factors. J. Psychopharmacol. 2010; 24: 81–90. 3. Volavka J. Violence in schizophrenia and bipolar disorder. Psychiatr. Danub. 2013; 25: 24–33. 4. Caqueo-Urízar A, Gutiérrez-Maldonado J, MirandaCastillo C. Quality of life in caregivers of patients with schizophrenia: A literature review. Health Qual. Life Outcomes 2009; 7: 84. 5. Salimi K, Jarskog LF, Lieberman JA. Antipsychotic drugs for first-episode schizophrenia. CNS Drugs 2009; 23: 837– 855. 6. Caccia S. Safety and pharmacokinetics of atypical antipsychotics in children and adolescents. Paediatr. Drugs 2013; 15: 217–233. 7. Kishimoto T, Agarwal V, Kishi T, Leucht S, Kane JM, Correll CU. Relapse prevention in schizophrenia: A systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol. Psychiatry 2013; 18: 53–66. 8. Higashi K, Medic G, Littlewood KJ, Diez T, Granström O, De Hert M. Medication adherence in schizophrenia: Factors influencing adherence and consequences of nonadherence, a systematic literature review. Ther. Adv. Psychopharmacol. 2013; 3: 200–218. 9. Mueser KT, McGurk SR. Schizophrenia. Lancet 2004; 363: 2063–2072. 10. Osterberg L, Blaschke T. Adherence to medication. N. Engl. J. Med. 2005; 353: 487–497. 11. Cramer JA, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatr. Serv. 1998; 49: 196–201. 12. Lieberman JA, Stroup TS, McEvoy JP et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 2005; 353: 1209–1223.
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25. Rosenheck RA, Krystal JH, Lew R et al. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N. Engl. J. Med. 2011; 364: 842–851. 26. Tiihonen J, Haukka J, Taylor M, Haddad PM, Patel MX, Korhonen P. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am. J. Psychiatry 2011; 168: 603–609. 27. Vehof J, Postma MJ, Bruggeman R et al. Predictors for starting depot administration of risperidone in chronic users of antipsychotics. J. Clin. Psychopharmacol. 2008; 28: 625–630. 28. Lambert T, Emmerson B, Hustig H, Resseler S, Jacobs A, Butcher B, e-STAR Research Group. Long acting risperidone in Australian patients with chronic schizophrenia: 24-month data from the e-STAR database. BMC Psychiatry 2012; 12: 25. 29. Patel MX, de Zoysa N, Bernadt M, David AS. A crosssectional study of patients’ perspectives on adherence to antipsychotic medication: Depot versus oral. J. Clin. Psychiatry 2008; 69: 1548–1556. 30. Shi L, Ascher-Svanum H, Zhu B, Faries D, Montgomery W, Marder SR. Characteristics and use patterns of patients taking first-generation depot antipsychotics or oral antipsychotics for schizophrenia. Psychiatr. Serv. 2007; 58: 482–488.
31. Bernardo M, San L, Olivares JM et al. Treatment patterns and health care resource utilization in a 1-year observational cohort study of outpatients with schizophrenia at risk of nonadherence treated with long-acting injectable antipsychotics. Patient Prefer. Adherence 2011; 5: 601– 610. 32. Acosta FJ, Hernández JL, Pereira J, Herrera J, Rodríguez CJ. Medication adherence in schizophrenia. World J. Psychiatry 2012; 2: 74–82. 33. Wu DB, Lee EH, Chung WS et al. Cost analysis of risperidone long-acting injection in the treatment of schizophrenia and schizoaffective disorders in Hong Kong: An approach using generalised estimating equations. Psychiatry Res. 2013; 210: 745–750. 34. Asseburg C, Willis M, Löthgren M, Seppälä N, Hakala M, Persson U. Hospitalisation utilisation and costs in schizophrenia patients in Finland before and after initiation of risperidone long-acting injection. Schizophr. Res. Treatment 2012; 2012: 791468. 35. Lafeuille MH, Laliberté-Auger F, Lefebvre P, Frois C, Fastenau J, Duh MS. Impact of atypical long-acting injectable versus oral antipsychotics on rehospitalization rates and emergency room visits among relapsed schizophrenia patients: A retrospective database analysis. BMC Psychiatry 2013; 13: 221.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
doi:10.1111/pcn.12294
Regular Article
Risperidone long-acting injection and 1-year rehospitalization rate of schizophrenia patients: A retrospective cohort study Hsue-Wei Chan, MD,1,3 Chin-Yu Huang, Yung-Chieh Yen, MD, MSc, PhD1,4*
RN,1
Wen-Jui Feng,
MS2,5
and
Departments of 1Psychiatry, 2Quality and Safety, E-Da Hospital, 3Graduate Institute of Health Care Administration, 4 School of Medicine, I-Shou University, and 5Department of Business Administration, National Sun Yat-Sen University, Kaohsiung, Taiwan
Aims: We wanted to present a picture of patients with schizophrenia receiving risperidone long-acting injection (RLAI) treatment in a real-world setting. Methods: This was a retrospective cohort study; 379 patients with schizophrenia were enrolled and treated with different kinds of antipsychotic agents at E-Da Hospital, and received a 12-month follow up. The patients were distributed into three groups: the all-oral antipsychotic, oral risperidone and RLAI groups. The antipsychotic agents and dosages they used were recorded. The rate of rehospitalization, length of hospital stay, emergency room visits and medical expenditures were assessed. Results: The RLAI group had a significantly higher rate of hospitalization before enrolment (the all-oral antipsychotic group was 32.1%, the oral risperidone
CHIZOPHRENIA IS A severe psychiatric disorder in which patients’ mental function deteriorates. Its lifetime prevalence was estimated at 4.0 per 1000, and lifetime morbidity risk was 7.2 per 1000.1 The severe comorbidities, such as acute psychosis with chaotic appearance or violence, which might require psychiatric ward hospitalization, post-psychotic depression with high suicidality, and chronic long-
S
*Correspondence: Yung-Chieh Yen, MD, MSc, PhD, Department of Psychiatry, E-Da Hospital, 1 Yi-Da Road, Yan-Chau District, Kaohsiung 824, Taiwan. Email: [email protected] Received 8 May 2014; revised 25 January 2015; accepted 13 March 2015.
group, 35.9%, and the RLAI group, 88.4%, P < 0.0001). After a 1-year follow up, all three groups were similar in rehospitalization rates (the all-oral antipsychotic group was 28.9%, the oral risperidone group, 30.1%, and the RLAI group, 30.2%, P > 0.999), length of hospital stay and number of emergency room visits during follow up. The most commonly used oral antipsychotics were risperidone (0.5–7 mg/day), quetiapine (65–1200 mg/day), and olanzapine (2–25 mg/day).
Conclusions: Using RLAI reduces the severity of disease in more difficult patients. Key words: antipsychotic agents, hospital emergency service, patient readmission, risperidone, schizophrenia.
term disability, all lead to the suffering of the patients and their caregivers, and have a major social and economic impact.2–4 Many medications have been developed for the treatment of schizophrenia. Compared with traditional antipsychotics, atypical antipsychotics are reported to have fewer adverse effects5,6 and a lower risk of relapse.7 Poor medication or pharmacological adherence has been recognized as an important issue in the treatment of schizophrenia.8–11 Patients with schizophrenia discontinue their medication, often in spite of their doctor’s suggestion. The Clinical Antipsychotic Trials of Intervention study revealed that 74% of schizophrenia patients discontinued their treatment after 18
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
497
498 H-W. Chan et al.
Psychiatry and Clinical Neurosciences 2015; 69: 497–503
months.12 The European First Episode Schizophrenia Trial also found that 33–72% of patients discontinued their treatment within 12 months for any cause.13 The result of non-adherence may be the relapse of psychosis. In addition to the suffering of the patients, a relapse of psychosis may also lead to re-admission, which brings about greater expenditures and a reduced level of daily functioning of the patients, which then requires further training or rehabilitation programs.8 Long-acting injection of antipsychotic was developed for the purpose of improving the medication or pharmacological adherence of patients. Previous studies revealed that long-acting antipsychotics had improved efficacy in symptom control and relapse prevention, and in increasing adherence.10,14–18 Risperidone long-acting injection (RLAI) is the first of its kind for second-generation antipsychotics. Previous studies examining the safety and efficacy of risperidone in treating patients with schizophrenia included case–control studies, randomizedcontrolled trials, and observational studies.19–27 In the case–control studies and randomized-controlled trials, the patients were selected and grouped before being enrolled in the studies. Although these are the studies with the highest methodological quality, they may also have a lower external validity. In this study, we wanted to present patients with schizophrenia under treatment with RLAI in a real-world setting. We recruited patients with schizophrenia who were being treated with either oral antipsychotic or RLAI, and compared the rate of emergency room visits, re-hospitalizations and expenditures during treatment.
relation with different pharmacological treatment options during a 1-year follow up.
METHODS
Inclusion and exclusion criteria Patients were both male and female and at least 18 years of age, and were recruited at the same regional hospital, E-Da Hospital, where they received their psychiatric treatment. All of them were diagnosed as having schizophrenia according to DSM-IV-TR criteria. The exclusion criteria were serious medical conditions, women who were pregnant or breast-feeding, and those who did not receive follow up regularly.
Clinical outcomes We retrospectively collected the patients’ demographic data, previous history of treatment for schizophrenia, and pharmacological treatment from the hospital medical records. During the 12-month follow up, we recorded the antipsychotic agent(s) they took and the dosage and intervals of each drug. We also explored the rehospitalization rate, lengths of hospital stay, and emergency room visits.
Treatment options The patients recruited received their treatment mostly through ambulatory care. The selection and dose of antipsychotic agents were determined by psychiatrists, according to their evaluation and the patient’s clinical condition. If the patient received RLAI, their injection would be given when they came back to the outpatient department for follow up.
Study design The data presented were derived from a retrospective cohort study. This study included 379 patients with schizophrenia treated with different kinds of antipsychotic agents. Among the patients, 43 were treated with RLAI, while the others used oral-form antipsychotic agents. This was an observational study in the setting of a regional hospital, in which patients received psychiatric treatment in the outpatient department, but emergency room treatment and psychiatric ward hospitalization were available when necessary. We aimed to determine the clinical outcomes of the patients with schizophrenia and their
Statistical analysis Patients were categorized by the antipsychotic agents they took. Demographic data, baseline characteristics, and clinical outcomes were compared between groups, respectively. We performed the t-test to compare means of continuous variables between groups; Fisher’s exact test was used to compare distributions of categorical variables between groups. Within each group, the change between the hospitalization rate before recruitment and the rehospitalization rate after enrolment were examined by Fisher’s exact test.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
Psychiatry and Clinical Neurosciences 2015; 69: 497–503
RLAI and schizophrenia rehospitalization 499
RESULTS Characteristics of the patients A total of 806 patients with schizophrenia received treatment at E-Da Hospital from 4 April 2011 to 30 September 2012; 60 of the patients used RLAI. Among the 806 patients, 379 had regular follow up for at least 3 months, and 43 of the 379 used RLAI. We continued following these 379 patients for another year (until 31 August 2013). The 379 patients were divided into three groups according to the antipsychotic treatment they received. The ‘all-oral antipsychotics’ group included patients with schizophrenia receiving any oral antipsychotic; the ‘oral risperidone’ group was part of the ‘all-oral antipsychotics’ group but included only those patients with schizophrenia receiving oral risperidone treatment only; ‘the RLAI’ group included patients with schizophrenia receiving RLAI. The all-
oral antipsychotic group was composed of 178 men and 158 women with a mean age of 39.4 years; the oral risperidone group included 48 men and 55 women with a mean age of 39 years; and the RLAI group comprised 23 men and 20 women with a mean age of 33.8 years. There was no significant difference in mean age (P = 0.031) or sex (P = 0.473) between the groups. The most commonly used oral antipsychotics were risperidone (103 patients with a dosage around 0.5–7 mg/day), quetiapine (61 patients with a dosage around 65–1200 mg/day), and olanzapine (58 patients with a dosage around 2–15 mg/day) (Table 1). Acute ward admission before enrolment was measured and compared in all groups. The RLAI group had the highest rate of acute ward admission before enrolment (the all-oral antipsychotic group was 32.1%, the oral risperidone group, 35.9%, and the RLAI group, 88.4%, P < 0.0001) (Fig. 1).
Table 1. Characteristics of participants and antipsychotic options All oral antipsychotics (n = 336)
Oral risperidone (n = 103)
RLAI (n = 43)
Mean age (SD), years Sex, n (%) Male Female Hospitalization 1 year before enrolment Emergency room visit 1 year before enrolment, n (%)
39.4 (12.5)
39.0 (14.2)
33.8 (12.5)
0.031
178 (53.0) 158 (47.0) 108 (32.1) 57 (17.0)
48 (46.6) 55 (53.4) 37 (35.9) 19 (18.4)
23 (53.5) 20 (46.5) 29 (87.9) 23 (53.5)
0.473
Oral antipsychotics
Number
Mean dose (SD) (mg/day)
Range (mg/day)
Risperidone Quetiapine Olanzapine Amisulpride Ziprasidone Paliperidone Flupentixol Clozapine Chlorpromazine Sulpiride Zotepine Haloperidol
103 61 58 42 30 18 6 5 5 3 3 2
3 (1) 509 (274) 13 (6) 538 (207) 132 (44) 8 (3) 18 (6) 140 (64) 180 (40) 333 (47) 100 (41) 2 (0)
0.5–7 65–1200 2–25 100–1000 40–240 3–12 9–24 50–225 50–250 200–400 25–150 2
P†
0.999 0.621 0.029 0.021
†
The t-test was performed to compare means of continuous variables between the RLAI group and the oral risperidone group; Fisher’s exact test was used to compare distributions of categorical variables between the RLAI group and the oral risperidone group. RLAI, risperidone long-acting injection.
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
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RLAI in our study had a significantly higher rate of admission before enrolment than the group using oral antipsychotics implied that clinical psychiatrists tended to use RLAI as the treatment for severer patients, which was similar to the conclusion of previous observational studies. It was interesting that after a 1-year observation, the group using RLAI as treatment had similar readmission rates, lengths of hospital stay, rates of emergency room visits, and average time of emergency room visits to the groups using oral risperidone or oral antipsychotics, which means the severity of disease in these three groups became rather similar during this 1-year observation compared to 1 year before, when the RLAI group had significantly severer disease. Thus, we might conclude that using RLAI treatment reduces the severity of disease more significantly than oral antipsychotics. Poor insight and poor awareness of illness are often observed in patients with schizophrenia. The lack of insight is related to poor medication or pharmacological adherence, which leads to the consequences of relapse of the psychotic disorder, re-hospitalization, longer duration to remission, or even suicide, all of which bring about patient suffering, even greater health-care costs, and poor outcomes.8,32 Long-acting injection of antipsychotics helps improve medical adherence, and the use of this modality has been proved to be advantageous in achieving and maintaining remission, lowering the risk of relapse and lowering hospitalization rates.15,16 A previous study carried out in Hong Kong that examined the cost-effectiveness of using RLAI in the treatment of schizophrenia and schizoaffective disorder revealed that the cost of hospitalization had been reduced significantly after the use of RLAI.33 In Finland, the use of RLAI with schizophrenia patients led to a reduction in mean annual hospital costs and days of admission, and a lower hospitalization rate.34 Another national cohort study in Finland comparing the effect of oral and depot antipsychotics also revealed that the use of RLAI was associated with a lower re-hospitalization rate than use of oral risperidone.26 In our study, the re-hospitalization rate, number of emergency room visits, and the average days of hospital stay of the RLAI group were similar to that of the other two groups, even though the RLAI group had much more frequent hospitalizations prior to the study, which meant much greater medical costs. While the pharmacy expenditures would probably be higher among the RLAI subjects,
the reduction of medical expenditures should be related to lowered rates of admission and hospital visits. Another retrospective cohort study in the USA found that the use of long-acting injection of atypical antipsychotics (paliperidone palmitate and RLAI) was associated with a lower re-hospitalization rate and emergency room visit rate than the use of oral antipsychotics,35 which was also similar to the result of our study. The results of our study and of previous studies revealed that the use of RLAI significantly lessened the severity of schizophrenia. However, the reason why RLAI has a better effect in lowering disease severity than oral antipsychotics remains uncertain. One possible explanation is that patients taking RLAI need to receive a regular injection every 2 weeks. This means those patients visit the outpatient department more often than patients taking oral risperidone. Frequent visits provide psychiatrists with more opportunities to detect signs of disease deterioration, recent psychosocial stressors, and other factors that may contribute to disease relapse. With more contact with psychiatrists, patients may also be more likely to receive proper psycho-education and psychosocial interventions for promoting adherence and managing psychiatric symptoms. Another possible explanation is that adherence to oral risperidone is less secure than with its depot form. Hence, the use of RLAI seems to be more advantageous to maintaining disease stability than taking oral risperidone. In this study, we did not compare RLAI with all oral medications because if we had, we might not be able to explain whether the change in hospitalization rates was related to the use of long-acting injectable antipsychotics or the effectiveness of different antipsychotics. Some limitations of this study also need to be considered. One is the methodological limitations of the study design – as a retrospective cohort study, no contact or direct information was gathered from the patients. The information was gathered from medical records. Also, the groups might differ in terms of some important, yet unknown prognostic variables, as they were not randomized. The result could have greater interest if we were able to compare the medication history, the possibility of substance exposure and illness duration among the groups that used the different antipsychotics. However, this was an archive study. It is unfortunate that we could not interview each of the patients to acquire these data or check their previous medication
© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology
502 H-W. Chan et al.
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history. We used the rate of hospitalization to present the severity of disease in each group. Therefore, we may conclude that in our study, the use of RLAI successfully reduced medical expenditures in the treatment of patients with schizophrenia, corresponding to the results of previous studies.
13. Kahn RS, Fleischhacker WW, Boter H et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: An open randomised clinical trial. Lancet 2008; 371: 1085–1097. 14. Ju PC, Chou FH, Lai TJ et al. Long-acting injectables and risk for rehospitalization among patients with schizophrenia in the home care program in Taiwan. J. Clin. Psychopharmacol. 2014; 34: 23–29. 15. Manchanda R, Chue P, Malla A et al. Long-acting injectable antipsychotics: Evidence of effectiveness and use. Can. J. Psychiatry 2013; 58: 5S–13S. 16. Kishimoto T, Nitta M, Borenstein M, Kane JM, Correll CU. Long-acting injectable versus oral antipsychotics in schizophrenia: A systematic review and meta-analysis of mirror-image studies. J. Clin. Psychiatry 2013; 74: 957– 965. 17. Leucht C, Heres S, Kane JM, Kissling W, Davis JM, Leucht S. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of randomised long-term trials. Schizophr. Res. 2011; 127: 83–92. 18. Kirk Morton N, Zubek D. Adherence challenges and longacting injectable antipsychotic treatment in patients with schizophrenia. J. Psychosoc. Nurs. Ment. Health Serv. 2013; 51: 13–18. 19. Williams R, Chandrasena R, Beauclair L, Luong D, Lam A. Risperidone long-acting injection in the treatment of schizophrenia: 24-month results from the electronic Schizophrenia Treatment Adherence Registry in Canada. Neuropsychiatr. Dis. Treat. 2014; 10: 417–425. 20. Barrio P, Batalla A, Castellví P et al. Effectiveness of longacting injectable risperidone versus oral antipsychotics in the treatment of recent-onset schizophrenia: A casecontrol study. Int. Clin. Psychopharmacol. 2013; 28: 164– 170. 21. Leatherman SM, Liang MH, Krystal JH et al. Differences in treatment effect among clinical subgroups in a randomized clinical trial of long-acting injectable risperidone and oral antipsychotics in unstable chronic schizophrenia. J. Nerv. Ment. Dis. 2014; 202: 13–17. 22. Barnett PG, Scott JY, Krystal JH, Rosenheck RA, CSP 555 Research Group. Cost and cost-effectiveness in a randomized trial of long-acting risperidone for schizophrenia. J. Clin. Psychiatry 2012; 73: 696–702. 23. Malla A, Chue P, Jordan G et al. An exploratory open-label randomized trial comparing risperidone long acting injectable (RLAI) with oral antipsychotic medication in the treatment of early psychosis. Neuropsychopharmacology 2011; 36: 548. 24. Gaebel W, Schreiner A, Bergmans P et al. Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: Results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology 2010; 35: 2367– 2377.
ACKNOWLEDGMENT This study is supported by grants from the E-Da Hospital (EDAHP102022 and EDAHT103021). There was no conflict of interest in the preparation of this article.
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