A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia

A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia
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  See discussions, stats, and author profiles for this publication at: A Nationwide Cohort Study of Oral and DepotAntipsychotics After First Hospitalization forSchizophrenia  ARTICLE   in  AMERICAN JOURNAL OF PSYCHIATRY · MARCH 2011 Impact Factor: 12.3 · DOI: 10.1176/appi.ajp.2011.10081224 · Source: PubMed CITATIONS 195 READS 288 6 AUTHORS , INCLUDING:Jari Kalevi HaukkaUniversity of Helsinki 243   PUBLICATIONS   7,347   CITATIONS   SEE PROFILE Mark TaylorRoyal Edinburgh Hospital; Universities of … 102   PUBLICATIONS   1,187   CITATIONS   SEE PROFILE Maxine PatelKing's College London 38   PUBLICATIONS   853   CITATIONS   SEE PROFILE Pasi Korhonen 49   PUBLICATIONS   1,842   CITATIONS   SEE PROFILE Available from: Mark TaylorRetrieved on: 14 January 2016  Article  AJP in Advance 1 (Am J Psychiatry Tiihonen et al.; 1–7) of first-episode patients experience only a single episode of psychosis (1).Medication nonadherence rates are high in schizo-phrenia, as they are in many chronic medical conditions. Three systematic reviews on adherence to antipsychotic medication for psychosis noted that patients took an av-erage of 58% of the recommended amount of medication (7), that 41.2% of patients did not regularly take medica-tion as prescribed (8), that prescription completion rates ranged from 28% to 85% (9), and that irregular medication use rates ranged from 31% to 62% (9). Many of the stud-ies were based on interviews or questionnaires, so patients not willing to participate were not included. Thus, nonad-herence rates are probably higher in unselected patient populations. Current guidelines for schizophrenia include long-acting injections of antipsychotics as an option for maintenance treatment, particularly for overcoming es-tablished nonadherence (1, 2, 10). Two earlier systematic A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia  Jari Tiihonen, M.D., Ph.D. Jari Haukka, Ph.D.Mark Taylor, F.R.C.Psych.Peter M. Haddad, M.D., F.R.C.Psych.Maxine X. Patel, M.D., M.R.C.Psych.Pasi Korhonen, Ph.D. Objective:  Data on the effectiveness of antipsychotics in the early phase of schizo-phrenia are limited. The authors exam-ined the risk of rehospitalization and drug discontinuation in a nationwide cohort of 2,588 consecutive patients hospitalized for the first time with a diagnosis of schizophre-nia between 2000 and 2007 in Finland. Method:  The authors linked national databases of hospitalization, mortality, and antipsychotic prescriptions and com-puted hazard ratios, adjusting for the ef-fects of sociodemographic and clinical variables, the temporal sequence of the antipsychotics used, and the choice of the initial antipsychotic for each patient. Results:  Of 2,588 patients, 1,507 (58.2%) collected a prescription for an antipsy-chotic during the first 30 days after hospi-tal discharge, and 1,182 (45.7%, 95% con-fidence interval [CI]=43.7–47.6) continued their initial treatment for 30 days or lon-ger. In a pairwise comparison between depot injections and their equivalent oral formulations, the risk of rehospitalization for patients receiving depot medications was about one-third of that for patients re-ceiving oral medications (adjusted hazard ratio=0.36, 95% CI=0.17–0.75). Compared with oral risperidone, clozapine (adjusted hazard ratio=0.48, 95% CI=0.31–0.76) and olanzapine (adjusted hazard ratio=0.54, 95% CI=0.40–0.73) were each associated with a significantly lower rehospitaliza-tion risk. Use of any antipsychotic com-pared with no antipsychotic was associat-ed with lower mortality (adjusted hazard ratio=0.45, 95% CI=0.31–0.67). Conclusions:  In Finland, only a minority of patients adhere to their initial antipsy-chotic during the first 60 days after dis-charge from their first hospitalization for schizophrenia. Use of depot antipsychot-ics was associated with a significantly low-er risk of rehospitalization than use of oral formulations of the same compounds. Among oral antipsychotics, clozapine and olanzapine were associated with more fa-vorable outcomes. Use of any antipsychot-ic was associated with lower mortality.  A  fter the acute phase of treatment for a first episode of psychotic illness, guidelines usually indicate that sub-sequent maintenance antipsychotic medication treat-ment should continue for at least 1 year, but consensus is lacking regarding the total duration of treatment if the patient remains asymptomatic (1, 2). A 5-year observa-tional study of patients with first-episode psychosis indi-cated that stopping antipsychotic medication increased the rate of relapse nearly fivefold compared with contin-ued treatment (3). Discontinuation rates for oral antipsy-chotics have been shown to be high: 74% at 18 months for chronic schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) (4) and 42% at 12 months for first-episode schizophrenia in the European First Episode Schizophrenia Trial (EUFEST) (5). However, the risk of relapse needs to be weighed against the like-lihood and severity of adverse effects caused by antipsy-chotic medication (6) and the fact that approximately 20% AJP in Advance. Published March 1, 2011 (doi: 10.1176/appi.ajp.2011.10081224) Copyright 2011 American Psychiatric Association. All rights reserved.  ORAL AND DEPOT ANTIPSYCHOTICS AFTER FIRST HOSPITALIZATION FOR SCHIZOPHRENIA 2 AJP in Advance Method This was a register-based case linkage study of all people in Finland 16–65 years of age who had their first hospitalization in  which schizophrenia was diagnosed (ICD-10 code F20) during the period of 2000–2007 and who had not collected (i.e., pur-chased) any antipsychotic prescription (Anatomic Therapeutic Chemical [ATC] code N05A) within 6 months before admission.The study cohort was identified from the Finnish National Hospital Discharge Register, which is administrated by the Na-tional Institute for Health and Welfare. A total of 33,318 patients had at least one hospitalization due to schizophrenia-related ill-ness (ICD-10 codes F20–F25) during the study period. Of these, 7,434 experienced their first hospitalization during that period, and 2,588 had a strictly defined schizophrenia diagnosis (F20) during their first hospitalization. Detailed information about the prescription database and the procedure for calculating the dura-tion of antipsychotic use is presented in the data supplement that accompanies the online edition of this article. Statistical Analysis The outcome measures of interest were 1) the risk of all-cause discontinuation of the initial antipsychotic medication; 2) the risk of rehospitalization for schizophrenia; and 3) the risk of death. Only those patients who had received any antipsychotic medi-cation within the first 30 days after discharge were included in the analysis of all-cause discontinuation. The follow-up for each patient started at the end of the first hospitalization period. The end of follow-up for the whole study was December 31, 2007. For the analysis of all-cause discontinuation (N=1,507), patients’ follow-up ended at the time their initial treatment changed for any reason, at death, or at the end of the study period, whichever occurred first. For the analysis of rehospitalization (N=2,588), fol-low-up ended at the time of the first rehospitalization, at death, or at the end of the study period. For the mortality analysis, follow-up ended at death or at the end of the study period. Detailed in-formation about the statistical analysis is presented in the online data supplement. Results The mean age of the study population was 37.8 years (SD=13.7), and 62% were male. Of 2,588 patients with a first hospitalization, 1,507 (58.2%) used an antipsychot-ic medication during the first 30 days after discharge, and 1,182 (45.7% of the total, 95% confidence interval [CI]=43.7–47.6) continued the initial antipsychotic medi-cation (started within 30 days after hospital discharge) for 30 days or longer. Alternatively, 54.3% of our cohort either did not collect an antipsychotic prescription within 30 days of hospital discharge or used their initial antipsy-chotic medication for less than 30 days.The association between clinical and sociodemograph-ic variables and the risk of all-cause antipsychotic discon-tinuation over a mean follow-up period of 2 years (5,221 person-years) is summarized in Table S1 in the online data supplement. During the follow-up period, 1,394 patients discontinued their initial antipsychotic medication (start-ed not only during the first 30 days but at any time during follow-up) for the following reasons: 50.6% (705 patients) because of a change in antipsychotic prescription, 34.3% (478 patients) because of discontinuation, 14.8% (207 pa-reviews on depot injections (11, 12) suggested a nonadher-ence rate of only 24% (range=0%–54%), and more recently Shi et al. (13) calculated the mean medication possession ratio (cumulative number of days covered by depot divid-ed by 365 days) to be 91% for patients receiving depot first-generation antipsychotics.Studies comparing clinical outcomes for depot and oral antipsychotics vary in study design and methodological rigor as well as in their primary findings. A meta-analysis (14) showed no difference in the risk of relapse for depot first-generation antipsychotics compared with oral medi-cations, although global improvement was more likely in the depot cohort. However, patients for whom depot medication is most indicated—those who are nonadherent  with oral formulations—are likely to be underrepresented in randomized controlled trials. Observational studies are generally more supportive of depot medication; mirror-im-age (before-after) studies show a consistent benefit for de-pot medication over prior medication in terms of reducing total number of days in hospital, but a major problem in these studies is that, by definition, the initial (oral) medica-tion has failed (15, 16), and the temporal order of medica-tions (first oral, then depot injection) may have a substan-tial effect on the medications’ comparative effectiveness.Depot antipsychotics are not widely prescribed after a first episode of psychosis (17), even though nonadherence rates in first-episode patients are high and are strongly linked to relapse (18). Relapse at this crucial period in ear-ly adulthood can have marked psychosocial consequenc-es in terms of education or work opportunities. The low use of depot antipsychotics at this point in the illness pro-cess may reflect a presumed dislike of injectable medica-tion among first-episode patients and negative attitudes associated with use of depot injections (19, 20). However, several studies have suggested that depot medications are effective and acceptable in patients with first-episode psy-chotic illness (17, 21). Unfortunately, there is a dearth of long-term data comparing the use of depot and oral anti-psychotics after first-episode psychosis (22).Using case linkage of the comprehensive national data-bases available in Finland, we analyzed data from a large nationwide cohort of patients discharged after a first hospi-talization in which schizophrenia was diagnosed to assess risk of rehospitalization, all-cause discontinuation, and to-tal mortality for patients using any antipsychotic or no an-tipsychotic and for patients receiving depot formulations or the equivalent oral formulations. We also compared commonly used depot antipsychotics with the most com-monly used oral second-generation antipsychotics that are not available in depot formulation to further answer the question of which are the most effective antipsychotics in the maintenance phase after a first hospitalization for schizophrenia, as assessed by risk of rehospitalization. We hypothesized that there would be no differences between different antipsychotic drugs, irrespective of whether they  were administered orally or as a depot injection.  TIIHONEN, HAUKKA, TAYLOR, ET AL.  AJP in Advance 3 olanzapine (hazard ratio=0.54, 95% CI=0.40–0.73) were associated with a significantly lower risk of rehospitaliza-tion than oral risperidone. In the pairwise comparisons between depot agents and their equivalent oral formula-tions, no significant differences in rehospitalization risk  were observed between pairs, but in the pooled analysis, depot agents were associated with a significantly lower risk of rehospitalization (adjusted hazard ratio=0.36, 95% CI=0.17–0.75, p=0.007; weighted mean=0.53, 95% CI=0.32–0.88) (Table 1).There were 160 deaths during the follow-up period. Use of any antipsychotic (64 deaths/6,260 person-years) compared with no use of antipsychotic (96 deaths/4,509 person-years), when considered in terms of number of deaths per person-years, was associated with a lower risk of mortality (Cox model hazard ratio=0.49, 95% CI=0.34–0.72; marginal structural modeling hazard ratio=0.38, 95% CI=0.19–0.74). When the hospital episodes were excluded from the time at risk for death (16 deaths censored), the hazard ratio was reduced to 0.45 (95% CI=0.31–0.67). Be-cause of the low number of deaths, the confidence inter-vals were wide, and no statistically significant differences in mortality were observed between antipsychotic medi-cations. Discussion To our knowledge, this is the first study of the adherence and comparative effectiveness of specific antipsychotic treatments in a large unselected population of patients in a real-world setting after their   first hospitalization with tients) because of hospitalization, and 0.3% (four patients) because of death.The all-cause drug discontinuation risks and the me-dian dosages for each medication are listed in Figure S1 in the online data supplement. Table 1 lists the pairwise comparisons for all-cause discontinuation between depot antipsychotics (mean age, 46.4 years; mean duration of first hospitalization, 95.9 days) and their equivalent oral formulations (mean age, 39.8 years; mean duration of first hospitalization, 63.5 days). Of a total depot monotherapy of 298 person-years, 73 person-years (24.5%) consisted of treatment that was started within 30 days after discharge from the first hospitalization. For haloperidol, perphen-azine, and risperidone, the depot formulation was associ-ated with a significantly lower risk of discontinuation than  was the oral formulation. In the pooled analysis of depot and oral antipsychotics (haloperidol, perphenazine, ris-peridone, and zuclopenthixol), depot antipsychotics were associated with a 59% lower risk of discontinuation than oral antipsychotics (hazard ratio=0.41, 95% CI=0.27–0.61, p<0.0001).During a mean follow-up period of 2.0 years (5,221 person-years), 1,496 patients (57.8%) were rehospitalized because of a relapse of schizophrenia symptoms. Com-pared with no use of antipsychotics, use of any antipsy-chotic was associated with a lower risk of rehospitalization (Cox model hazard ratio=0.38, 95% CI=0.34–0.43; marginal structural model hazard ratio=0.48, 95% CI=0.42–0.56). The risk of rehospitalization for individual antipsychot-ics is summarized in Table 2 and Figure 1. Only clozapine (fully adjusted hazard ratio=0.48, 95% CI=0.31–0.76) and TABLE 1. Pairwise Comparisons for Risk of All-Cause Discontinuation of the Initial Antipsychotic Treatment and Risk of Rehospitalization After a First Hospitalization for Schizophrenia a All-Cause DiscontinuationRehospitalizationComparisonAdjusted Hazard Ratio b 95% CIpAdjusted Hazard Ratio b 95% CIpAny depot injection compared with equivalent oral formulation0.410.27–0.61<0.00010.360.17–0.750.007Haloperidol depot injection compared with oral haloperidol0.270.08–0.880.030.120.01–1.130.06Perphenazine depot injection compared with oral perphenazine0.320.19–0.53<0.00010.530.22–1.280.16Risperidone depot injection compared with oral risperidone0.440.31–0.62<0.00010.570.30–1.080.09Zuclopenthixol depot injection compared with oral zuclopenthixol0.750.29–1.890.540.490.11–2.140.35 a  All-cause discontinuation was analyzed among those patients who had started their initial antipsychotic treatment during the first 30 days after the index hospitalization (1,507 patients had started any antipsychotic, and 587 patients had started haloperidol, perphenazine, risperidone, or zuclopenthixol). In the analysis of risk of rehospitalization, those patients in the total cohort (N=2,588) who had used ha-loperidol, perphenazine, risperidone, or zuclopenthixol at any time during follow-up (967 person-years) were included in the analysis. b  The hazard ratios are adjusted by using the following as covariates: age at diagnosis, sex, duration of first hospital episode, and current and previous use of anxiolytics, hypnotics and sedatives, antidepressants, drugs used in addictive disorders, analgesics, antiparkinsonian drugs, blood glucose-lowering drugs, and lipid-modifying agents. For risk of rehospitalization, covariates also included previous use of anti-psychotics during the follow-up and the choice of initial antipsychotic (serving as a surrogate for the patient’s clinical status at baseline and thus reflecting the clinical correlates determining the selection of treatment). If pooled estimates were weighted using the person-years of each monotherapy category (for all-cause discontinuation: haloperidol 7/207, perphenazine 20/207, risperidone 167/207, and zuclopen-thixol 13/207 person-years; for risk of rehospitalization: haloperidol 31/967, perphenazine 172/967, risperidone 700/967, and zuclopen-thixol 64/967 person-years), the adjusted hazard ratios would have been 0.43 (95% CI=0.32–0.58, p<0.0001) for all-cause discontinuation and 0.53 (95% CI=0.32–0.88, p=0.0139) for rehospitalization.  ORAL AND DEPOT ANTIPSYCHOTICS AFTER FIRST HOSPITALIZATION FOR SCHIZOPHRENIA 4 AJP in Advance blind randomized controlled trials, but is generally cho-sen by the patient and clinician. Not all discontinuations in our study can be assumed to indicate nonadherence; some patients would have stopped medication between prescriptions because of other events, such as medication switch, rehospitalization, and death. However, approxi-mately one-third of discontinuations did not precede such an event, and it is reasonable to assume that most of these cases do represent nonadherence; it is unlikely that clinicians would deliberately stop medication early when the diagnosis is schizophrenia.The mean age of the patients was greater than 37 years. This relatively high age is probably due to delays in set-tling on a strictly defined diagnosis of schizophrenia, since 21% of the patients had a history of antipsychotic use in outpatient care (earlier than 6 months before the index hospitalization). A 1966 birth cohort study (N=11,017) in northern Finland (24) showed that until age 27, all 37 co-hort members who were listed in the national treatment register as being hospitalized with a schizophrenia diag-nosis were in fact found to have schizophrenia when re-searchers applied DSM-III-R criteria to the information in available hospital records (0% false positive)—but the study authors found an additional 34 patients hospitalized  with other diagnoses of psychotic illness who also fulfilled DSM criteria for schizophrenia (48% false negatives). Thus, it is likely that many patients had symptoms and transient antipsychotic treatment before their first hospitalization  with a schizophrenia diagnosis (although those patients  who used antipsychotics in outpatient care during the 6 months preceding our study period were excluded).a diagnosis of schizophrenia. The results showed that in Finland, a high-income country where the cost of antipsy-chotic medication is fully reimbursed, more than half of patients either did not collect an antipsychotic prescrip-tion within 30 days after discharge from their first hospi-talization or discontinued their initial antipsychotic med-ication within 30 days. This finding was not attributable to selection bias, since the study population included all patients in Finland with a first hospitalization for schizo-phrenia. No information was available on the medication used in the hospital, but it can be assumed that virtually all patients had received some kind of antipsychotic treat-ment (23). Because there is no compulsory outpatient treatment in Finland, our results on the comparative ef-fectiveness of specific antipsychotics can be generalized only to those patients who are willing to use antipsychotic treatment in outpatient care.In two previous large randomized controlled trials, the all-cause discontinuation rates were 74% for all patients at 18 months (in the CATIE study [4]) and 42% at 12 months (in the EUFEST study [5 at 2 months, the all-cause dis-continuation rates in those studies were substantially lower than 50%. This may be explained by selection and follow-up of the patients: in a real-world setting, patients may be less motivated or less cooperative, and routine clinical care and follow-up are less intensive than in ran-domized controlled trials. Also, the participants in CATIE  were patients with a previously established pattern of an-tipsychotic treatment. On the other hand, one might have expected that continuation would be favored in clinical practice, since medication is not blinded, as it is in double- TABLE 2. Risk of Rehospitalization After a First Hospitalization for Schizophrenia, by Antipsychotic Treatment Pattern (N=2,588) TreatmentN a Person- YearsCrude Relative Risk95% CIAdjusted Hazard Ratio b 95% CIFully Adjusted Hazard Ratio c 95% CIpHaloperidol, depot1180.290.04–––1.600.13Clozapine584120.720.53–0.990.510.37–0.720.480.31–0.760.001Olanzapine1349040.760.59–0.980.710.55–0.910.540.40–0.73<0.0001Other antipsychotics10820.630.33–1.200.690.36–1.330.560.29–1.100.09Risperidone, depot 151190.650.38–1.110.940.55–1.630.570.30–1.080.09Perphenazine, depot 131090.610.34–1.090.660.37–1.180.590.31–1.120.11Polypharmacy803211.280.96–1.711.250.92–1.690.920.66–1.280.62Zuclopenthixol, depot 6520.590.26–1.350.660.29–1.520.950.37–2.440.92Risperidone, oral1135811.001.001.00Perphenazine, oral11630.900.48–1.671.250.67–2.341.110.57–2.180.76Quetiapine542171.280.93–1.771.581.14––1.640.60No treatment9932,3182.201.81–2.682.271.86–2.781.631.30–2.04<0.0001Haloperidol, oral5131.980.81–4.841.770.71–4.361.790.63–5.090.28Zuclopenthixol, oral3121.290.41–4.051.880.60–5.961.930.57–6.580.29 a  N=number of rehospitalizations. b  The hazard ratios are adjusted by using the following as covariates: age at diagnosis, sex, duration of first hospital episode, previous use of antipsychotics during follow-up, and current and previous use of anxiolytics, hypnotics and sedatives, antidepressants, drugs used in addic-tive disorders, analgesics, antiparkinsonian drugs, blood glucose-lowering drugs, and lipid-modifying agents. c  The fully adjusted hazard ratios (illustrated in Figure 1) were adjusted using the same covariates as the adjusted ratios but also included the choice of the initial antipsychotic for each patient (reflecting the clinical correlates determining the selection of treatment). The Bonferroni-corrected p value corresponding to a statistical significance level of 0.05 with 13 multiple comparisons is 0.05/13=0.0038.
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