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 Atypical antipsychotics are considered first-line medications for schizophrenia (1). They are better tolerated and are superior to typical antipsychotics in terms of persistence (2,3) and efficacy (4), especially with regard to treatment of negative symptoms such as apathy and flat affect (5,6). Olanzapine and risperidone are the most widely prescribed antipsychotics (7). Persistence with treatment is an important factor in determining the success of long-term therapy. It is associated with symptom remission, relapse prevention, and tolerability. Clinical practice guidelines for schizophrenia suggest a treatment duration of 1 year or more for a first episode (1). A major problem with the use of antipsychotics is the high rate of treatment discontinuation. Proportions of patients discontinuing their treatment have been shown to vary between 27% and 57% (2,3,8). In addition, as many as 78% of patients will experience an exacerbation or relapse within 1 year of antipsychotic discontinuation (9). From US data on national expenditures for inpatient mental health care during 1986, Weiden and Olfson estimated that the aggregate cost of readmission due to noncompliance and antipsychotic loss of efficacy approached US$2 billion (1993 dollars) within 2 years of hospital discharge (10). Although monotherapy is the standard recognized treatment for psychosis, Procyshyn and others estimated that 27.5% of schizophrenia patients are discharged from hospital with an antipsychotic polypharmacy regimen (11). No evidence based data exist to determine whether patients benefit from concomitant treatment (11,12). Therefore, concomitant use of other antipsychotics may be considered to be a potential marker of a particular drug’s lack of effectiveness. As discontinuation of atypical antipsychotics has thus far been studied mostly in RCTs or by pooling data from controlled trials (2,3,8), the primary aim of our study was to compare discontinuation rates among first-time users of olanzapine with those among first-time users of risperidone in a large heterogeneous population of outpatients suffering from schizophrenia. We also compared the risks of receiving a concomitant antipsychotic drug among patients persisting with their initial treatment. MethodsWe carried out a population-based cohort study, using the Quebec health insurance databases maintained by the RAMQ and the Quebec database for hospitalizations administered by the Quebec Ministry of Health and Social Services. Data on patients and on their use of prescription drugs came from the RAMQ drug benefit plan database. This plan covers all Quebec residents who do not have a private drug insurance plan, who are welfare recipients, and who are aged 65 years and over. This database is known to be accurate for prescription claims (13). Diagnoses were obtained from the RAMQ database of physician services and from the database for hospitalizations. We asked RAMQ to identify all drug plan beneficiaries for whom were found at least one claim for an atypical antipsychotic (clozapine, olanzapine, quetiapine, or risperidone) between 1 January 1997 and 31 August 1999. The date of the first claim for any atypical antipsychotic in this time period was the index date. For each antipsychotic user, RAMQ sent us data on all drugs claimed for the entire period between 1 July 1996 and 31 August 2000, as well as eligibility periods and beneficiary type, age, and sex. We then excluded patients who were not eligible for the drug plan for the entire 180-day period prior to the index date. We also excluded patients who had received any atypical antipsychotic in the preceding 180-day period, who had received 2 atypical antipsychotics at the index date, or who had only claims of a 0-day supply in the database. Because they were few, we then excluded patients who had received clozapine or quetiapine as the first atypical antipsychotic. We excluded patients for whom we did not find a diagnosis of schizophrenia (diagnosed according to ICD-9, codes 295.0 to 295.9) in the 180-day period prior to the index date. Each remaining patient was then put into either the olanzapine treatment group or the risperidone treatment group. Person-time of follow-up was assessed as the time from the index date to 1 of the 5 following dates, whichever occurred first: 365 days of follow-up, discontinuation of index drug, ineligibility for the drug insurance plan, moving out of the province, or death. This research was approved by the Commission d’accès à l’information du Québec. To ensure anonymity, RAMQ scrambled beneficiaries’ health insurance numbers. Variables A unique encrypted health number was used to link 4 administrative databases at the patient level. The RAMQ beneficiary demographic database provided data on patients’ age, sex, region (rural or urban, as defined by Canada Post according to the national postal code), and drug plan eligibility. The physician claims database provided data on physician services (date and diagnosis). The prescription claims database provided data on dispensed drugs (drug identification, dispensing date, number of days’ supply, and prescriber’s specialty). The hospitalizations database provided data on diagnoses (date, first diagnosis, and up to 16 secondary diagnoses). Using information from the above databases, we defined the subtype of schizophrenia, past hospitalization for mental illness, comorbidity, substance use disorder, and persistence with the index drug, as well as concomitant antipsychotic prescriptions. First, we determined the subtype of schizophrenia according to ICD-9 codes (295.0 to 295.9) entered in the 180-day period preceding the index date. Then, we classified each person as either having been hospitalized for a mental illness (first diagnosis: ICD-9 codes 290 to 319) or not in the 180-day period preceding the index date. We also assessed comorbid substance use disorders in the 180-day period preceding the start of treatment, since these disorders can play a role in the persistence of antipsychotic use. For this, we used ICD-9 codes 291 (alcoholic psychosis), 292 (drug psychosis), 303 (alcohol dependence syndrome), 304 (drug dependence), and 305 (nondependent abuse of drugs). To assess comorbidity, we used a chronic disease score with empirically derived weights based on age, sex, and prescription claims (14). To assess this score, we used claims for the 180-day period prior to the index date. This score is a modified version of a chronic disease score (15) often used in observational database studies. It is computed with prescription claims of drugs used to treat different chronic diseases or to relieve acute symptoms. Scores ranged from 252.3 to 55 168.0, and the higher the score, the higher the comorbidity level. We placed individuals in 3 equal categories according to their score: low comorbidity (scores less than 2777), medium comorbidity (scores between 2777 and 4668) and high comorbidity (scores above 4668). Outcome Variables Treatment discontinuation was defined as the failure to refill the index drug within twice the days’ supply of the preceding claim. For claims of 3 days or less, the permissible gap between the end date of the claim and the date of the next renewal was set at 7 days. Discontinuation date was the date of the last renewal plus the days’ supply. We assessed concomitant antipsychotic use among patients who persisted 365 days with the index drug. Those receiving at least one prescription of another antipsychotic (AHFS class 28:16.08) after the index date were considered to have concomitant antipsychotic use. To avoid assuming that a transition from one antipsychotic to another indicated concomitant use, the days’ supply of a claim for a concomitant antipsychotic had to end before the end of the subject’s follow-up. Statistical Analysis Baseline characteristics were described for the 2 treatment groups. Differences at baseline were assessed with the chi-square test for proportions. We used a Cox proportional hazards model to compute the HRs of treatment discontinuation and to obtain adjusted survival curves. We used a logistic regression model to compare the odds of receiving concomitant antipsychotic treatments. Using the interaction terms method in both models, we observed that age, sex, region, subtype of schizophrenia, comorbidity, prior mental illness hospitalization, beneficiary type, substance use disorder, and prescriber’s specialty did not cause an interaction in the association between the initial atypical antipsychotic and treatment discontinuation or concomitant antipsychotic use. We therefore adjusted all models for these same characteristics. All ratios are presented with their 95%CIs. Analyses were performed with SAS Version 8.1 (16). ResultsBetween 1 January 1997 and 31 August 1999, 38 048 patients were dispensed a prescription of olanzapine, risperidone, quetiapine, or clozapine. Of these, 4648 were not eligible for the drug plan in the 180-day period prior to the index date, and 2676 received an atypical antipsychotic during this same period. In addition, 55 received 2 atypical antipsychotics at the index date, and 8 had only claims of a 0-day supply. Of the 30 661 remaining patients, we excluded 268 clozapine users and 533 quetiapine users. Then, we excluded a further 23 455 patients who had not received a diagnosis of schizophrenia in the 180-day period prior to the index date. Thus 6405 patients were eligible for the analysis: 3687 olanzapine users and 2718 risperidone users. We compared baseline characteristics of study patients and observed some statistically significant differences between the 2 treatment groups in age, sex, beneficiary type, comorbidity, and prescriber specialty (Table 1).
Treatment Discontinuation There were 3877 (60.5%) patients who discontinued the index drug before the end of the 365-day study period. Median duration of follow-up was 233 days for olanzapine users and 142 days for risperidone users (Table 2).
Figure 1 shows survival curves of treatment discontinuation adjusted for age, sex, region, schizophrenia subtype, comorbidity, prior mental illness hospitalization, beneficiary type, substance use disorder, and prescriber specialty. We observed a high discontinuation rate in the first 30 days of treatment, indicating that many patients had filled one prescription only. The adjusted risk of discontinuing the index drug was lower for olanzapine users, compared with risperidone users (HR = 0.79; 95%CI, 0.74 to 0.84). Concomitant Antipsychotic Use Among the 1560 olanzapine users and the 897 risperidone users who persisted with the drug, 738 (47.3%) and 435 (48.5%) patients, respectively, received at least one concomitant antipsychotic prescription. When comparing olanzapine to risperidone users, we found that the adjusted OR of receiving at least one concomitant antipsychotic prescription was not statistically significant (OR 0.85; 95%CI, 0.71 to 1.01).
 DiscussionAmong all patients who began taking olanzapine or risperidone, 60.5% discontinued their initial treatment during the first year. In previous studies, the proportion of patients discontinuing their treatment had been shown to vary between 27% and 57% (2,3,8). Two factors may explain the high proportion of discontinuation observed in our study. First, since patients in RCTs are closely monitored, one might expect higher discontinuation proportions in outpatient settings. Second, most studies of atypical antipsychotics measured discontinuation over a period of less than 1 year (3,8), whereas our study measured it for a complete year. Moreover, in other chronic disease areas such as hypertension, discontinuation has been shown to increase over time (17). The results of a metaanalysis of RCTs comparing risperidone, olanzapine, and quetiapine users with those using a placebo (8) and the results of a randomized clinical study comparing clozapine, olanzapine, risperidone, and haloperidol users (18) showed no significant differences in treatment persistence among atypical antipsychotic users. The strict inclusion criteria, short trial duration, and strict monitoring of RCTs when compared with a real-life setting may explain why these studies had failed to show any differences in persistence. Our results indicate that discontinuation rate was lower for patients using olanzapine, compared with those using risperidone. Reasons for our study’s difference in favour of olanzapine are unclear. Indeed, there is no evidence of the superior efficacy of olanzapine over risperidone (4,8). There may be some advantage to olanzapine over risperidone concerning dosage-related extrapyramidal reactions (19), but the current low dosages used with risperidone (Table 2) give this statement little import (20,21). Conversely, it is possible that low dosages used with risperidone, particularly when initiating treatment, may be suboptimal. Random variation within the 2 groups may also confound the difference observed between them. As stated earlier, monotherapy is the standard recognized treatment for psychosis. However, concomitant use of 2 antipsychotics is considered appropriate when treatment response to an atypical antipsychotic is inadequate (22). In our study, olanzapine and risperidone users were at equal risk for having some antipsychotic drugs in combination therapy. Our results are concordant with those reported in the RODOS study, in which hospitalized risperidone and olanzapine users were compared and in which no difference was found in concomitant use of antipsychotic drugs (23). However, the RODOS study focused on hospitalized patients, in contrast to our ambulatory setting. Our study has some limitations. First, given that many patients were over age 45 years, it is likely that many had previous exposure to antipsychotics, because the onset of schizophrenia generally occurs prior to age 45 years. We therefore explored the effect of age on treatment discontinuation by conducting separate analyses for patients aged under 45 years and those aged 45 years or over. Age did not affect HRs (data not shown). Second, our study has limitations inherent in the analysis of administrative databases. Information on disease severity, reduction of symptoms, and side effects was not available. Also, because the database did not capture in-hospital use of medications and the use of physician samples, this may have translated into an overestimation of discontinuation rates and an underestimation of concomitant antipsychotic prescriptions. As well, a pharmacy claim for dispensing a drug does not confirm the actual use of the drug. The RAMQ database, on the other hand, is accurate for prescription claims (13). Another problem with administrative database analysis is that patients are not randomly assigned to their treatment group, which may introduce confounding factors. As mentioned before, we selected only diagnosed schizophrenia patients who were new users of olanzapine or risperidone to minimize this potential bias. We also adjusted our models for age, sex, subtype of schizophrenia, region, comorbidity, prior mental illness hospitalization, beneficiary type, substance use disorder, and prescriber specialty. That being said, we were able to perform a population-based head-to-head comparison of 2 atypical antipsychotics in terms of persistence and use patterns; as well, our assessment was based on a large population. Moreover, our 365-day follow-up period was long enough to provide a comprehensive assessment of the patterns of use of atypical antipsychotics, given that most clinical guidelines suggest at least 1 year of treatment after a first psychotic episode (1). To conclude, our results suggest certain clinical implications. First, the high rate of discontinuation in the first month of treatment highlights the need for strict monitoring and for greater support of patients initiating treatment using atypical antipsychotics. Second, persistence with treatment is an important factor in the long-term success of therapy. Olanzapine users seem less likely to discontinue their treatment in the first year. However, this advantage must be balanced against the importance of potential adverse events such as weight gain, diabetes, or dyslipidemia. In fact, increasing evidence suggests that olanzapine users are more at risk for developing diabetes (24–26) or dyslipidemia (26–28) than are risperidone users. Finally, a high proportion of persistent users of risperidone or olanzapine use concomitant antipsychotic drugs. The complex drug regimens followed by these patients may increase adverse drug reactions and may lessen treatment adherence. These important factors should be considered in the initial choice of treatment. Further studies comparing use patterns are needed to investigate the relative economic implications of these drugs in head-to-head cost-effectiveness analysis. Funding and SupportThe research presented here was supported by an unrestricted grant from Janssen-Ortho Canada. The whole process of the study was conducted independently of influence on the part of the sponsor. References1. Bhanji NH, Tempier R. Managing schizophrenia during the stable phase: is there consensus among practice guidelines? Can J Psychiatry 2002;47:76–80. 2. Wahlbeck K, Tuunainen A, Ahokas A, Leucht S. Dropout rates in randomised antipsychotic drug trials. Psychopharmacology 2001;155:230–3. 3. Glick ID, Berg PH. Time to study discontinuation, relapse, and compliance with atypical or conventional antipsychotics in schizophrenia and related disorders. Int Clin Psychopharmacol 2002;17:65–8. 4. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003;60:553–64. 5. Remington G, Kapur S. Atypical antipsychotics: are some more atypical than others? Psychopharmacology 2000;148:3–15. 6. Ho BC, Miller D, Nopoulos P, Andreasen NC. A comparative effectiveness study of risperidone and olanzapine in the treatment of schizophrenia. J Clin Psychiatry 1999;60:658–63. 7. Hermann RC, Yang D, Ettner SL, Marcus SC, Yoon C, Abraham M. Prescription of antipsychotic drugs by office-based physicians in the United States, 1989–1997. Psychiatr Serv 2002;53:425–30. 8. Srisurapanont M, Maneeton N. Comparison of the efficacy and acceptability of atypical antipsychotic drugs: a meta-analysis of randomized, placebo-controlled trials. J Med Assoc Thai 1999;82:341–6. 9. Gitlin M, Nuechterlein K, Subotnik KL, Ventura J, Mintz J, Fogelson DL, and others. Clinical outcome following neuroleptic discontinuation in patients with remitted recent-onset schizophrenia. Am J Psychiatry 2001;158:1835–42. 10. Weiden PJ, Olfson M. Cost of relapse in schizophrenia. Schizophr Bull 1995;21:419–29. 11. Procyshyn RM, Kennedy NB, Tse G, Thompson B. Antipsychotic polypharmacy: a survey of discharge prescriptions from a tertiary care psychiatric institution. Can J Psychiatry 2001;46:334–9. 12. Stahl SM. Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 1999;60(Suppl 10):31–41. 13. Tamblyn R, Lavoie G, Petrella L, Monette J. The use of prescription claims databases in pharmacoepidemiological research: the accuracy and comprehensiveness of the prescription claims database in Québec. J Clin Epidemiol 1995;48:999–1009. 14. Clark DO, Von Korff M, Saunders K, Baluch WM, Simon GE. A chronic disease score with empirically derived weights. Med Care 1995;33:783–95. 15. Von Korff M, Wagner EH, Saunders K. A chronic disease score from automated pharmacy data. J Clin Epidemiol 1992;45:197–203. 16. SAS Institute, Inc. SASOnlineDoc. Version 8; 1999. Available: http://gsbwww.uchicago.edu/computing/research/ SASManual/main.htm. Accessed 2005 Oct 27. 17. Caro JJ, Salas M, Speckman JL, Raggio G, Jackson JD. Persistence with treatment for hypertension in actual practice. CMAJ 1999;160:31–7. 18. Volavka J, Czobor P, Sheitman B, Lindenmayer JP, Citrome L, McEvoy JP, and others. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 2002;159:255–62. 19. Brown CS, Markowitz JS, Moore TR, Parker NG. Atypical antipsychotics: Part II: Adverse effects, drug interactions, and costs. Ann Pharmacother 1999;33:210–7. 20. Procyshyn RM, Zerjav S. Drug utilization patterns and outcomes associated with in-hospital treatment with risperidone or olanzapine. Clin Ther 1998;20:1203–17. 21. Moisan J, Grégoire J-P, Chabot I. Risperidone and olanzapine use at a psychiatric hospital: comparison of clinical use and acquisition costs. Can J Hosp Pharm 2001;54:278–83. 22. Stahl SM. Antipsychotic polypharmacy, Part 1: Therapeutic option or dirty little secret? J Clin Psychiatry 1999;60:425–6. 23. Kasper S, Jones M, Duchesne I. Risperidone olanzapine drug outcomes studies in schizophrenia (RODOS): health economic results of an international naturalistic study. Int Clin Psychopharmacol 2001;16:189–96. 24. Koro CE, Fedder DO, L’Italien GJ, Weiss SS, Magder LS, Kreyenbuhl J, and others. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case–control study. BMJ 2002;325:243. 25. Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 2004;161:1709–11. 26. Moisan J, Grégoire JP, Gaudet M, Cooper D. Exploring the risk of diabetes mellitus and dyslipidemia among ambulatory users of atypical antipsychotics: a population-based comparison of risperidone and olanzapine. Pharmacoepidemiol Drug Saf 2005;14:427–36. 27. Koro CE, Fedder DO, L’Italien GJ, Weiss S, Magder LS, Kreyenbuhl J, and others. An assessment of the independent effects of olanzapine and risperidone exposure on the risk of hyperlipidemia in schizophrenic patients. Arch Gen Psychiatry 2002;59:1021–6. 28. Meyer JM, Koro CE. The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res 2004;70:1–17. Author(s)Manuscript received January 2005, revised, and accepted April 2005. Previously presented in part at the 19th International Conference on Pharmacoepidemiology; 2003 Aug 21–24; Philadelphia (PA). 1. PhD Candidate, Faculté de pharmacie, Université Laval, Quebec City, Quebec; PhD Candidate, Unité de recherche en santé des populations, Centre hospitalier affilié universitaire de Québec, Quebec City, Quebec. 2. Professor, Faculté de pharmacie, Université Laval, Quebec City, Quebec; Scientist, Unité de recherche en santé des populations, Centre hospitalier affilié universitaire de Québec, Quebec City, Quebec. 3. Statistician, Unité de recherche en santé des populations, Centre hospitalier affilié universitaire de Québec, Quebec City, Quebec. 4. Professor, Département de médecine sociale et préventive, Centre hospitalier affilié universitaire de Québec; Scientist, Unité de recherche en santé des populations, Université Laval, Quebec City, Quebec. 5. Professor, Faculté de pharmacie, Université Laval, Quebec City, Quebec; Director, Unité de recherche en santé des populations, Centre hospitalier affilié universitaire de Québec, Quebec City, Quebec. Address for correspondence: Dr J Moisan, Unité de recherche en santé des populations, Centre hospitalier affilié universitaire de Québec, 1050, chemin Ste-Foy, Quebec, QC G1S 4L8 e-mail: Jocelyne.Moisan@pha.ulaval.ca
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