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Effectiveness of a psychosocial intervention for relapse prevention in patients with schizophrenia receiving risperidone via long-acting injection
Psychiatry Research 175 (2010) 195–199
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Effectiveness of a psychosocial intervention for relapse prevention in patients with schizophrenia receiving risperidone via long-acting injection Sang-Hyuk Lee, Tae Kyou Choi ⁎, ShinYoung Suh, Yong Woo Kim, Borah Kim, EunHee Lee, Ki Hwan Yook Department of Psychiatry, Pochon CHA University College of Medicine, 351 Yatap-Dong, Bundang-Gu, Seongnam-Si, Kyounggi-Do 135-720, Republic of Korea
a r t i c l e
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Article history: Received 13 March 2008 Received in revised form 9 May 2008 Accepted 12 June 2008 Keywords: Long-term outcome Relapse rate Medication compliance Combined therapy
a b s t r a c t Schizophrenia is a chronic disorder that is usually characterized by relapses alternating with periods of full or partial remission. We examined whether combined therapy with a psychosocial intervention for relapse prevention (PIRP) and risperidone administered by long-acting injection (RLAI) would be more effective in reducing relapses than RLAI with treatment-as-usual (TAU) among outpatients with schizophrenia. We conducted a prospective, controlled study over 2 years in 46 patients with schizophrenia receiving RLAI, of which 21 and 25 patients were assigned to the PIRP and TAU control groups, respectively. The 1- and 2-year relapse rates were lower and medication compliance was higher in the PIRP group than in the TAU group. Cox proportional analysis revealed that time from baseline to relapse was associated with RLAI discontinuation. These results indicate that PIRP can be effective in maintaining medication compliance, and that discontinuation of long-acting atypical antipsychotics might be predictive of the next relapse. However, these results need to be replicated in studies with larger samples. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Schizophrenia is a chronic disorder that is usually characterized by relapses alternating with periods of full or partial remission. Although antipsychotic medication is effective in reducing relapse rates, 30% to 40% of patients relapse within 1 year after hospitalization discharge even when they are receiving maintenance medication (Davis, 1975; Hogarty et al., 1979). Relapse or recurrence is strongly associated with partial medication compliance or noncompliance (Kane, 2006). Kane (2003) suggested that none of the interventions for improving compliance have been completely reliable, but several strategies such as long-acting injectable antipsychotics, second-generation oral antipsychotics, and psychosocial approaches can improve medication adherence in schizophrenic patients. Second generation atypical antipsychotics may have an advantage over typical antipsychotics in enhancing compliance rates because of their comparatively low extrapyramidal side effects (Kane et al., 2003). Reviews (Kane et al., 2003; Keith et al., 2004) have suggested that a recently developed form of risperidone administered by longacting injection (RLAI) is efficacious, safe, and well-tolerated, and that every patient should be evaluated for suitability for treatment with long-acting atypical antipsychotics. Patients may experience fewer
⁎ Corresponding author. Tel.: +82 31 780 5864; fax: +82 31 780 5862. E-mail address: [email protected] (T.K. Choi). 0165-1781/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2008.06.043
side effects from RLAI than the oral form of risperidone because RLAI enables a lower peak plasma concentration and smaller variations between peak and trough plasma concentrations (Lasser et al., 2005a). Moreover, many clinically stable but nonremitted patients achieve symptom remission after RLAI treatment, with significant improvements in multiple symptom domains and self-rated health status (Lasser et al., 2005b). Therefore, among the many antipsychotic drugs, long-acting injectable atypical antipsychotics offer considerable promise for improving compliance and preventing relapse or recurrence in patients with schizophrenia. However, long-acting injectable antipsychotics have several limitations. First, patients with schizophrenia sometimes fail to go to the hospital or community clinic for the injection. Second, the most effective relapse prevention cannot be expected from new long-acting antipsychotics in the absence of psychosocial treatment such as cognitive behavior therapy, social skills training, psychoeducation, and crisis intervention in the case of relapse. In general, combining maintenance antipsychotic medication therapy with psychosocial approaches has been found to be more effective than pharmacotherapy alone in delaying or preventing relapse and in reducing the duration of hospitalization (Zygmunt, 2002). Of many psychosocial strategies, the relapse prevention program developed by Herz et al. (2000) was one of the most effective for detecting warning symptoms of relapse early in an episode and for reducing relapse and hospitalization rates. We developed a program based on the concepts of Herz et al. that was focused on relapse prevention for schizophrenic patients receiving new long-acting antipsychotics; we termed the program psychosocial intervention for relapse prevention (PIRP). The PIRP program consists of psychoeducation
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S.-H. Lee et al. / Psychiatry Research 175 (2010) 195–199 hospital biweekly. The daily dose of RLAI was maintained to within 50 mg in both groups. Drug compliance and relapse were evaluated in all patients at every visit to the outpatient clinic. The PANSS, the GAF, and the Clinical Global Impression (CGI) were administered every 3 months and at each prodromal episode by a board-certified psychiatrist without knowledge of group assignment (T.K. Choi or S.Y. Suh). 2.2. Outcome measures The primary outcome measures were as follows:
Fig. 1. Design of this study.
for long-acting injections, early detection of warning symptoms, relapse prevention, regular family education with biweekly intervention, crisis intervention including an increase of medication during the prodromal phase, and encouragement to patients to adhere to a biweekly schedule of hospital visits over a 1-year period. The purpose of our study was to examine whether combined therapy with PIRP and RLAI would be more effective for maintaining medication compliance and reducing relapse rates than RLAI with treatment-as-usual (TAU) among patients with schizophrenia. 2. Methods 2.1. Subjects and procedures We enrolled 57 patients with schizophrenia in this prospective study. Initially 24 patients with schizophrenia were assigned to the PIRP group and 33 patients were assigned to the TAU control group. RLAI (Risperdal Consta®) was used since it was the only long-acting injectable atypical antipsychotic drug available in Korea at the time of this study. We conducted the study at the Department of Psychiatry, Bundang CHA General Hospital, South Korea, between December 2004 and July 2007 in accordance with the Declaration of Helsinki and principles of good clinical practice. The Bundang CHA Institutional Review Board approved this research. The research outline was explained to potential participants, and only patients and their families who signed an informed consent document were chosen to participate in the study. The participants also had to (1) be between 17 and 60 years of age; (2) be diagnosed with schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV; (3) have an IQ above 80, as assessed by the Korean version of the Wechsler Adult Intelligence Scale at baseline; and (4) receive treatment with long-acting injectable risperidone as outpatients. In addition, the subjects had to have been stable for at least 4 weeks in an outpatient setting immediately before the baseline assessment. Exclusion criteria were (1) evidence of organic mental disorder or mental retardation and (2) severe drug or alcohol dependence that required inpatient treatment and/or detoxification. Five patients were excluded from this study because of low IQ (b 80), and 11 patients (3 and 8 in the PIRP and TAU groups, respectively) were also excluded after the termination of this study because they had not visited the hospital regularly within 3 months from baseline. At the final analysis, 21 and 25 patients with schizophrenia remained in the PIRP and TAU groups, respectively. Patients assigned in the PIRP group were expected to have poor compliance as well as a deficient awareness of their disorder as indicated by the fact they thought that they were mentally well or did not need medication (Drake et al., 2007). The PIRP program consisted of (1) 1 year of 2 × 12 60-min sessions of psychoeducation (see Appendix A), (2) active monitoring for early warning symptoms or signs such as by a psychiatrist based on patient reports on the Early Signs Questionnaire (Lamberti, 2001), and (3) crisis intervention or outreach available to patients assigned to PIRP and conducted by psychiatrists (S.H. Lee, Y.W. Kim, and B. Kim) and a specialized master's level social worker (E.H. Lee). Psychiatrists were instructed to notify the research interviewers as soon as they noted that a patient was demonstrating early signs of relapse so that the interviewers could rate patients on the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). Psychoeducation and active monitoring for symptoms were applied during each visit of patients for injection. Thus, patients assigned to the PIRP group received combined therapy of 1 year of the PIRP program with RLAI. To determine whether the effect of the 1-year PIRP program was maintained, we observed the PIRP group after termination of the PIRP program in the second year of the study period (Fig. 1). Before the appointed day of the program, patients who had been allocated to the PIRP group were contacted by text messages and telephone calls. Oral risperidone or haloperidol was given when an early warning symptom or sign was detected in a patient from the PIRP group. The dose of oral antipsychotics and benztropine was titrated according to the clinical needs of the patient, and reduced to the original maintenance dose 3 to 4 weeks after the return of symptoms to baseline. TAU consisted of individual supportive psychotherapy administered for less than 15 min during the injection period. Early warning signs of patients in the TAU group were detected only by patients complaining of their warning symptoms without an early sign questionnaire. Patients in both groups were instructed to visit the
2.2.1. Medication compliance Medication noncompliance was defined as a 1-week injection-free state after the day appointed for patients to receive RLAI. Medication compliance was defined as the number of actual visits for injections divided by the number of days when patients were scheduled to visit during the study period. 2.2.2. Relapse Operational criteria for relapse were an increase to a moderately severe or higher score (N 5) for any of the positive symptoms on the Psychosis subscale of the PANSS, and a GAF score of 30 or less (Herz et al., 2000). A 2-year relapse was considered to have occurred within the period from the baseline to the end of the second year. Owing to the high dropout rate, if a patient who was enrolled in the study no longer visited the outpatient clinic at the time of the second year evaluation, we contacted that person or his or her family by telephone to evaluate his or her inclusion as a 2-year-relapse case. 2.2.3. PANSS The interrater reliability (0.75–0.85 among raters) of the PANSS (Kay et al., 1987) was maintained by holding rater training sessions before each evaluation. 2.2.4. GAF Interrater reliability for the GAF (American Psychiatric Association, 1994) was 0.81. 2.2.5. CGI. (Guy, 1976) The secondary outcome measures were treatment discontinuation, injection discontinuation, and adverse events, defined as follows: 2.2.6. Treatment discontinuation Treatment discontinuation was defined when a patient in either group no longer visted the hospital for treatment. 2.2.7. Injection discontinuation Injection discontinuation was defined when a patient receiving long-acting atypical antipsychotics declined to take further injections and preferred to take oral medication, or when the patient no longer visited the hospital. 2.2.8. Adverse event All adverse events that occurred from the first dose of RLAI until the endpoint were recorded and defined as a treatment emergency, together with any serious adverse events between the first injection and 30 days after the last injection. Movement disorders were assessed with the Extrapyramidal Symptom Rating Scale (Chouinard et al., 1980) at baseline and every 3 months thereafter. 2.3. Statistical analysis Independent t-tests were used to compare age, education, duration of illness, frequency of recurrence, and initial PANSS and GAF scores between the PIRP and TAU groups. Chi-square analyses and Fisher's exact test were used to assess associations
Table 1 Sociodemographic characteristics of PIRP group and TAU group in schizophrenic patients receiving risperidone via long-acting injection (RLAI). PIRP (n = 21) TAU (n = 25) t or χ2 Age (years) (Mean ± S.D.) Sex [n (%)] Male Female Education (years) (mean ± S.D.) Duration of illness (years) (mean ± S.D.) Number of recurrences (mean ± S.D.) Initial PANSS score (mean ± S.D.) Initial GAF score (Mean ± S.D.) Initial CGI score (Mean ± S.D.)
df
P
46
0.46
31.9 ± 7.7
34.1 ± 12.1
t = − 0.5
8 (38) 13 (62) 13.7 ± 1.5 4.1 ± 3.9
8 (32) 17 (68) 13.2 ± 2.1 5.0 ± 5.0
χ2 = 0.04 1
0.83
t = 0.9 t = − 0.4
45 44
0.33 0.48
1.3 ± 6.2
2.1 ± 2.2
t = − 1.2
46
0.14
61.1 ± 11.0 46.4 ± 9.8 4.1 ± 0.5
58.7 ± 7.7 45.8 ± 14.3 4.0 ± 1.2
t = 0.72 t = 0.89 t = 0.19
38.3 0.47 45 0.37 45 0.85
t: Student's t test; χ2:Pearson's chi-square test. S.D.: standard deviation; PANSS: Positive and Negative Syndrome Scale; GAF: General Assessment of Functioning; CGI: Clinical Global Impression.
S.-H. Lee et al. / Psychiatry Research 175 (2010) 195–199 Table 2 Comparison of medication compliance, 1-year relapse, 2-year relapse and between PIRP group and TAU group in schizophrenic patients receiving RLAI. PIRP (n = 21)
TAU (n = 25)
t or χ2
df
P
1-year medication compliance (%) (mean ± S.D.) 2-year medication compliance (%) (mean ± S.D.) 1-year relapse [n (%)]
94.6 ± 12.2
75.9 ± 22.2
t = 3.5
45
0.00⁎⁎
92.1 ± 16.5
74.2 ± 26.6
t = 2.7
45
0.00⁎⁎
2 (9)
10 (45)
2-year relapse [n (%)]
5 (24)
12 (48)
Fisher's exact test χ2 = 4.2 1
0.00⁎⁎ 0.04⁎
t; Student's t test; χ2; Pearson's chi-square test; ⁎⁎P b 0.01, ⁎P b 0.05.
between sex, relapse rate, and group. To evaluate the efficacy of long-acting risperidone over time, an intent-to-treat analysis (last observation carried forward) was used, and the effects of both programs were analyzed using repeated measures analysis of variance (ANOVA) in which two factors were considered when comparing the performance between the two groups. These factors were a main effect of time (which indicated whether changes in an outcome variable occurred as a function of time, irrespective of the treatment received) and a time × treatment interaction (which indicated whether changes in subjects over time differed between the two treatment groups). Logistic regression analysis was used to examine the predictors of 1-year relapse. A Cox proportional survival regression analysis was performed to examine the relationship between medication compliance and time from baseline to relapse (SPSSWIN, version 11, Chicago, USA).
3. Results
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Table 4 Significant variables included in the regression equation for predicting 1-year relapse. β
PIRP 3.7 1-year medication compliance − 0.12 Injection discontinuation 0.3 Constant 3.1
SE
Wald
df P
Exp (β)
95% confidence limits
2.0 0.05 1.5 4.4
3.5 5.4 0.048 0.49
1 1 1 1
44.5 0.8 1.3 22
0.85 2321 0.78 0.98 0.07 27
0.06 0.02⁎ 0.83 0.48
− 2 log likelihood = 18.6, Cox and Snell R2 = 0.54, Nagelkerke R2 = 0.78. Classification accuracy = 88.9; ⁎P b 0.05. SE; standard error.
in the three scales between the two groups. The frequencies of extrapyramidal symptoms [hyperkinesia (11% vs 13%), extrapyramidal disorder (8% vs 10%), and tremor (5% vs 3%)] and a prolactin-related adverse event (8% vs. 10%) also did not differ significantly between the PIRP and TAU groups. One schizophrenic patient in the PIRP group committed suicide. Tardive–dyskinesia-like movement was observed in one patient in the TAU group. 3.5. Identification of the predictive factors of 1-year relapse in schizophrenia patients receiving RLAI
Age, sex, education, duration of illness, number of recurrences, and initial PANSS and GAF scores did not differ significantly between the PIRP and TAU groups (Table 1).
Multivariate logistic regression analysis with long-term relapse as the dependent variable and variables that differed significantly between the PIRP and TAU groups as the independent variables showed that 1-year medication compliance was significantly associated with 1year relapse (Table 4). Logistic regression analysis showed that 1-year medication compliance could be a significant predictor of 1-year relapse, and that there was a marginal association between PIRP and 1-year relapse (P = 0.06).
3.2. Comparison of medication compliance and relapse rates between schizophrenic patients in the PIRP and TAU groups receiving RLAI
3.6. Time from baseline to relapse: Cox proportional survival regression analysis
We compared medication compliance and relapse rates between the PIRP and TAU groups. Scores of medication compliance were significantly higher, and the 1- and 2-year relapse rates were significantly lower, in the PIRP group than in the TAU group (Table 2).
A proportional survival regression model according to Cox was performed with the time between enrollment in the study and relapse as the endpoint (Table 5). The time from baseline to relapse was the dependent variable, and variables that differed significantly between the PIRP and TAU groups in the previous statistical analysis were the independent variables. This analysis revealed that injection discontinuation had a significant effect on the time from baseline to relapse (Fig. 2).
3.1. Comparison of sociodemographic characteristics between schizophrenic patients in the PIRP and TAU groups receiving RLAI
3.3. Comparison of treatment discontinuation and injection discontinuation between schizophrenic patients in the PIRP and TAU groups receiving RLAI We compared treatment discontinuation and injection discontinuation between the PIRP and TAU groups. The frequency of treatment discontinuation during the program differed significantly between the two groups, and the occurrence of injection discontinuation was significantly lower in the PIRP group than in the TAU group (Table 3). 3.4. Comparison of efficacy and safety between schizophrenic patients in the PIRP and TAU groups receiving RLAI Both groups showed statistically significant decreases over time in PANSS, CGI, and GAF scores (all P = 0.00). These results and the time × treatment interaction indicated the absence of significant differences
4. Discussion To our knowledge, this is the first study to examination whether combined therapy with PIRP (as a psychosocial approach) and RLAI (as a pharmacotherapeutic approach with a second-generation longacting antipsychotic drug) could be more effective in reducing the relapse rate than RLAI with TAU. We found that the 1- and 2-year relapse rates were lower in the PIRP group than in the TAU group.
Table 5 Time from baseline to relapse: Cox proportional survival regression analysis. Table 3 Comparison of treatment discontinuation and injection discontinuation between schizophrenic patients in the PIRP and TAU groups receiving RLAI. PIRP (n = 21) Treatment discontinuation [n (%)] 3 (14) Injection discontinuation [n (%)] 5 (23)
TAU (n = 25) 11 (28) 18 (68)
t or χ2 2
df P
χ = 6.0 1 χ2 = 13.0 1
t: Student's t test; χ2; Pearson's chi-square test; ⁎⁎P b 0.01, ⁎P b 0.05.
0.01⁎ 0.00⁎⁎
PIRP Medication compliance Injection discontinuation
β
SE
Wald
df
P
Exp(β)
95% confidence limits
0.5 − 0.01
0.57 0.01
0.8 1.7
1 1
0.36 0.18
1.7 0.9
0.55 0.9
1.5
6.9
1
0.01⁎
21.1
2.1
3.0
− 2 log likelihood = 107.3, ⁎P b 0.05.
5.1 1.0 203.3
198
S.-H. Lee et al. / Psychiatry Research 175 (2010) 195–199
Fig. 2. Cox survival regression analysis showing the relationship between injection discontinuation and time from baseline to relapse.
These results are consistent with a previous study (Herz et al., 2000) that suggested the efficacy of a program for relapse prevention. We found that 2 (21%) and 5 (24%) of 21 patients relapsed during 1and 2-year follow-ups, respectively, in the PIRP group, suggesting that combined therapy with long-acting atypical antipsychotics and a relapse prevention program reduces relapse rates more than the interventions considered in previous studies (Davis, 1975; Feldmann et al., 2002; Hogarty et al., 1979). The previously reported 1-year relapse rate for schizophrenic patients with long-acting depot medication was 27% compared with 42% for patients treated with oral medication (Feldmann et al., 2002; Kane, 2003), and the 2-year relapse rate for long-acting depot medication was 40% compared with 65% for oral medication (Hogarty et al., 1979). Therefore, long-acting atypical antipsychotic treatment combined with a relapse prevention program might be one of the most effective strategies to reduce relapse or recurrence in schizophrenia. However, there may also be other possible reasons for the low relapse rate in this study. First, it might have been due not only to the effect of PIRP but also to differences in subject characteristics from the previous studies. Second, although the sociodemographic data did not differ significantly between our two groups, our study design did not include a randomization process or a double-blind control method, so schizophrenia patients who wanted to participate in the PIRP program may have been preferentially assigned to the PIRP group, with their correspondingly high motivation possibly biasing the study results. Third, the small sample in our study may limit the generalizability of the results. Logistic regression analysis showed a trend toward effectiveness in preventing 1-year relapse in the PIRP group. Assuming that a 1-year period is long enough to reveal differences in relapse rates between two groups receiving long-acting atypical antipsychotics, we could deduce that RLAI alone does not substantially prevent relapse without also using another psychosocial approach. The compliance with schizophrenia medication was higher in the PIRP group than in the TAU group. Since biweekly injection with RLAI has been recommended for schizophrenic patients in Korean hospitals, this might facilitate the monitoring of relapse warning symptoms of individual schizophrenic patients. However, it might also be a disadvantage because it requires patients to make frequent hospital visits. Psychoeducation that addresses the relationship between partial compliance and relapse and usefulness of long-acting atypical antipsychotics in reducing relapse might encourage patients to make the necessary hospital visits.
The PIRP program was also effective at maintaining compliance with depot medication. If schizophrenic patients receiving long-acting depot medication do not understand the advantages of long-acting depot medication, depot medication is only useful for slightly prolonging the injection period. Actually, patients who dropped out of this study earlier relapsed earlier (r = 0.87, P = 0.00), despite receiving long-acting atypical antipsychotics. It is possible that psychoeducation could also have affected this result. Most previous relapse prevention programs have not contained depot-specific psychoeducation. Before the study began, we hypothesized that educating schizophrenic patients and their families about the importance of depot medication would reduce the rates of noncompliance, relapse, and rehospitalization. Patients in both groups received RLAI, and a within-group analysis showed that PANSS, CGI, and GAF scores decreased over time. However, repeated-measures ANOVA showed that there was no time× treatment interaction between the two groups. That might be due to the small number of subjects, which limited the power to show positive results, and it is possible that RLAI alone is sufficient to maintain a partial or full remission state without including another psychosocial approach. Cox proportional survival regression analysis showed that longacting risperidone (injection discontinuation) alone influences the time from baseline to relapse. Before the study began, we also hypothesized that PIRP might affect the time from baseline to relapse. However, we found that this was not the case, which might be due to the fact that the PIRP program lasted only 1 year. This result has the following clinical implications: (1) that RLAI could affect the longterm outcome of schizophrenia, (2) that combined therapy of PIRP and RLAI is better for preventing relapse and rehospitalization in schizophrenia, and (3) that if combined therapy is impossible, at least long-acting injection could be prescribed to reduce the longterm relapse rate. This study has the following limitations: First, the sample was small. Although we found that the PIRP program significantly reduced the relapse rate of schizophrenia, the small sample limits the ability to generalize this result to most patients with schizophrenia. Studies with larger samples are needed to examine whether these results can be applicable to other schizophrenic populations. Second, a randomization process was not used in the study design. To reduce the probability of the resulting type 1 errors, we used Cox proportional survival regression to analyze the relationship between medication compliance and time from baseline to relapse. To minimize the effect of nonrandomization, a subject-blinded boardcertified psychiatrist assessed the subjects on the various rating scales employed. Third, we excluded schizophrenic patients who had dropped out early from the treatment (within 3 months) in both groups (3 and 8 patients in the PIRP and TAU groups, respectively). This might have affected the results for the primary and secondary outcome measures. Note, however, that the percentage of patients who dropped out was similar in the two groups. Therefore, even if we had analyzed data including dropouts, the significant differences in 1- and 2-year relapse rates, medication compliance, and injection discontinuation between the two groups would have been maintained. Fourth, we assessed early warning symptoms of patients in the PIRP group biweekly, which might have been too long a period to detect such symptoms, since 1 week is long enough to progress from warning symptoms to relapse in some schizophrenic patients. One schizophrenic patient committed suicide in the PIRP group. Although the long study period prevented us from assessing patients weekly, we did detect early warning symptoms in three patients in the PIRP group, and successfully stabilized them. Finally, there is a possibility that this intervention can only be applied to eligible patients who have the ability (e.g. IQ N 80) to understand the cognitive, behavioral, and educational aspects of the intervention. Furthermore, there was a difference in treatment time between the groups, which might have affected the results.
S.-H. Lee et al. / Psychiatry Research 175 (2010) 195–199
In conclusion, the results presented here suggest that a PIRP program can maintain medication compliance and that RLAI can prevent relapse. The use of a large sample in a randomized controlled trial is needed to verify these results. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.psychres.2008.06.043. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. APA, Washington, DC. Chouinard, G., Ross-Chouinard, A., Annable, L., Jones, B., 1980. The extrapyramidal symptom rating scale [Abstract] Canadian Journal of Neurological Science 7 (3), 233. Davis, J.M., 1975. Overview: maintenance therapy in psychiatry: I. Schizophrenia. American Journal of Psychiatry 132, 1237–1245. Drake, R.J., Dunn, G., Tarrier, N., Bentall, R.P., Haddock, G., Lewis, S.W., 2007. Insight as a predictor of the outcome of first-episode nonaffective psychosis in a prospective cohort study in England. Journal of Clinical Psychiatry 68, 81–86. Feldmann, R., Hornung, W.P., Prein, B., Buchkremer, G., Arolt, V., 2002. Timing of psychoeducational psychotherapeutic interventions in schizophrenic patients. European Archives of Psychiatry and Clinical Neuroscience 252, 115–119. Guy, W., 1976. Clinical Global Impressions. National Institute of Mental Health, Rockville, MD. Herz, M.I., Lamberti, J.S., Mintz, J., Scott, R., O'Dell, S.P., McCartan, L., Nix, G., 2000. A program for relapse prevention in schizophrenia: a controlled study. Archives of General Psychiatry 57, 277–283.
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Hogarty, G.E., Schooler, N.R., Ulrich, R., Mussare, F., Ferro, P., Herron, E., 1979. Fluphenazine and social therapy in the aftercare of schizophrenic patients. Relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride. Archives of General Psychiatry 36, 1283–1294. Kane, J.M., 2003. Strategies for improving compliance in treatment of schizophrenia by using a long-acting formulation of an antipsychotic: clinical studies. Journal of Clinical Psychiatry 64, 34–40. Kane, J.M., 2006. Review of treatments that can ameliorate nonadherence in patients with schizophrenia. Journal of Clinical Psychiatry 67, 9–14. Kane, J.M., Eerdekens, M., Lindenmayer, J.P., Keith, S.J., Lesem, M., Karcher, K., 2003. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. American Journal of Psychiatry 160, 1125–1132. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276. Keith, S.J., Kane, J.M., Turner, M., Conley, R.R., Nasrallah, H.A., 2004. Academic highlights: guidelines for the use of long-acting injectable atypical antipsychotics. Journal of Clinical Psychiatry 65, 120–131. Lamberti, J.S., 2001. Seven keys to relapse prevention in schizophrenia. Journal of Psychiatric Practice 7 (4), 253–259. Lasser, R.A., Bossie, C.A., Gharabawi, G.M., Baldessarini, R.J., 2005a. Clinical improvement in 336 stable chronically psychotic patients changed from oral to long-acting risperidone: a 12-month open trial. International Journal of Neuropsychopharmacology 8, 427–438. Lasser, R.A., Bossie, C.A., Gharabawi, G.M., Kane, J.M., 2005b. Remission in schizophrenia: results from a 1-year study of long-acting risperidone injection. Schizophrenia Research 77, 215–227. Zygmunt, A., 2002. Interventions to improve medication adherence in schizophrenia. American Journal of Psychiatry 159, 1653–1664.
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Effectiveness of a psychosocial intervention for relapse prevention in patients with schizophrenia receiving risperidone via long-acting injection Sang-Hyuk Lee, Tae Kyou Choi ⁎, ShinYoung Suh, Yong Woo Kim, Borah Kim, EunHee Lee, Ki Hwan Yook Department of Psychiatry, Pochon CHA University College of Medicine, 351 Yatap-Dong, Bundang-Gu, Seongnam-Si, Kyounggi-Do 135-720, Republic of Korea
a r t i c l e
i n f o
Article history: Received 13 March 2008 Received in revised form 9 May 2008 Accepted 12 June 2008 Keywords: Long-term outcome Relapse rate Medication compliance Combined therapy
a b s t r a c t Schizophrenia is a chronic disorder that is usually characterized by relapses alternating with periods of full or partial remission. We examined whether combined therapy with a psychosocial intervention for relapse prevention (PIRP) and risperidone administered by long-acting injection (RLAI) would be more effective in reducing relapses than RLAI with treatment-as-usual (TAU) among outpatients with schizophrenia. We conducted a prospective, controlled study over 2 years in 46 patients with schizophrenia receiving RLAI, of which 21 and 25 patients were assigned to the PIRP and TAU control groups, respectively. The 1- and 2-year relapse rates were lower and medication compliance was higher in the PIRP group than in the TAU group. Cox proportional analysis revealed that time from baseline to relapse was associated with RLAI discontinuation. These results indicate that PIRP can be effective in maintaining medication compliance, and that discontinuation of long-acting atypical antipsychotics might be predictive of the next relapse. However, these results need to be replicated in studies with larger samples. © 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Schizophrenia is a chronic disorder that is usually characterized by relapses alternating with periods of full or partial remission. Although antipsychotic medication is effective in reducing relapse rates, 30% to 40% of patients relapse within 1 year after hospitalization discharge even when they are receiving maintenance medication (Davis, 1975; Hogarty et al., 1979). Relapse or recurrence is strongly associated with partial medication compliance or noncompliance (Kane, 2006). Kane (2003) suggested that none of the interventions for improving compliance have been completely reliable, but several strategies such as long-acting injectable antipsychotics, second-generation oral antipsychotics, and psychosocial approaches can improve medication adherence in schizophrenic patients. Second generation atypical antipsychotics may have an advantage over typical antipsychotics in enhancing compliance rates because of their comparatively low extrapyramidal side effects (Kane et al., 2003). Reviews (Kane et al., 2003; Keith et al., 2004) have suggested that a recently developed form of risperidone administered by longacting injection (RLAI) is efficacious, safe, and well-tolerated, and that every patient should be evaluated for suitability for treatment with long-acting atypical antipsychotics. Patients may experience fewer
⁎ Corresponding author. Tel.: +82 31 780 5864; fax: +82 31 780 5862. E-mail address: [email protected] (T.K. Choi). 0165-1781/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2008.06.043
side effects from RLAI than the oral form of risperidone because RLAI enables a lower peak plasma concentration and smaller variations between peak and trough plasma concentrations (Lasser et al., 2005a). Moreover, many clinically stable but nonremitted patients achieve symptom remission after RLAI treatment, with significant improvements in multiple symptom domains and self-rated health status (Lasser et al., 2005b). Therefore, among the many antipsychotic drugs, long-acting injectable atypical antipsychotics offer considerable promise for improving compliance and preventing relapse or recurrence in patients with schizophrenia. However, long-acting injectable antipsychotics have several limitations. First, patients with schizophrenia sometimes fail to go to the hospital or community clinic for the injection. Second, the most effective relapse prevention cannot be expected from new long-acting antipsychotics in the absence of psychosocial treatment such as cognitive behavior therapy, social skills training, psychoeducation, and crisis intervention in the case of relapse. In general, combining maintenance antipsychotic medication therapy with psychosocial approaches has been found to be more effective than pharmacotherapy alone in delaying or preventing relapse and in reducing the duration of hospitalization (Zygmunt, 2002). Of many psychosocial strategies, the relapse prevention program developed by Herz et al. (2000) was one of the most effective for detecting warning symptoms of relapse early in an episode and for reducing relapse and hospitalization rates. We developed a program based on the concepts of Herz et al. that was focused on relapse prevention for schizophrenic patients receiving new long-acting antipsychotics; we termed the program psychosocial intervention for relapse prevention (PIRP). The PIRP program consists of psychoeducation
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S.-H. Lee et al. / Psychiatry Research 175 (2010) 195–199 hospital biweekly. The daily dose of RLAI was maintained to within 50 mg in both groups. Drug compliance and relapse were evaluated in all patients at every visit to the outpatient clinic. The PANSS, the GAF, and the Clinical Global Impression (CGI) were administered every 3 months and at each prodromal episode by a board-certified psychiatrist without knowledge of group assignment (T.K. Choi or S.Y. Suh). 2.2. Outcome measures The primary outcome measures were as follows:
Fig. 1. Design of this study.
for long-acting injections, early detection of warning symptoms, relapse prevention, regular family education with biweekly intervention, crisis intervention including an increase of medication during the prodromal phase, and encouragement to patients to adhere to a biweekly schedule of hospital visits over a 1-year period. The purpose of our study was to examine whether combined therapy with PIRP and RLAI would be more effective for maintaining medication compliance and reducing relapse rates than RLAI with treatment-as-usual (TAU) among patients with schizophrenia. 2. Methods 2.1. Subjects and procedures We enrolled 57 patients with schizophrenia in this prospective study. Initially 24 patients with schizophrenia were assigned to the PIRP group and 33 patients were assigned to the TAU control group. RLAI (Risperdal Consta®) was used since it was the only long-acting injectable atypical antipsychotic drug available in Korea at the time of this study. We conducted the study at the Department of Psychiatry, Bundang CHA General Hospital, South Korea, between December 2004 and July 2007 in accordance with the Declaration of Helsinki and principles of good clinical practice. The Bundang CHA Institutional Review Board approved this research. The research outline was explained to potential participants, and only patients and their families who signed an informed consent document were chosen to participate in the study. The participants also had to (1) be between 17 and 60 years of age; (2) be diagnosed with schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV; (3) have an IQ above 80, as assessed by the Korean version of the Wechsler Adult Intelligence Scale at baseline; and (4) receive treatment with long-acting injectable risperidone as outpatients. In addition, the subjects had to have been stable for at least 4 weeks in an outpatient setting immediately before the baseline assessment. Exclusion criteria were (1) evidence of organic mental disorder or mental retardation and (2) severe drug or alcohol dependence that required inpatient treatment and/or detoxification. Five patients were excluded from this study because of low IQ (b 80), and 11 patients (3 and 8 in the PIRP and TAU groups, respectively) were also excluded after the termination of this study because they had not visited the hospital regularly within 3 months from baseline. At the final analysis, 21 and 25 patients with schizophrenia remained in the PIRP and TAU groups, respectively. Patients assigned in the PIRP group were expected to have poor compliance as well as a deficient awareness of their disorder as indicated by the fact they thought that they were mentally well or did not need medication (Drake et al., 2007). The PIRP program consisted of (1) 1 year of 2 × 12 60-min sessions of psychoeducation (see Appendix A), (2) active monitoring for early warning symptoms or signs such as by a psychiatrist based on patient reports on the Early Signs Questionnaire (Lamberti, 2001), and (3) crisis intervention or outreach available to patients assigned to PIRP and conducted by psychiatrists (S.H. Lee, Y.W. Kim, and B. Kim) and a specialized master's level social worker (E.H. Lee). Psychiatrists were instructed to notify the research interviewers as soon as they noted that a patient was demonstrating early signs of relapse so that the interviewers could rate patients on the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF). Psychoeducation and active monitoring for symptoms were applied during each visit of patients for injection. Thus, patients assigned to the PIRP group received combined therapy of 1 year of the PIRP program with RLAI. To determine whether the effect of the 1-year PIRP program was maintained, we observed the PIRP group after termination of the PIRP program in the second year of the study period (Fig. 1). Before the appointed day of the program, patients who had been allocated to the PIRP group were contacted by text messages and telephone calls. Oral risperidone or haloperidol was given when an early warning symptom or sign was detected in a patient from the PIRP group. The dose of oral antipsychotics and benztropine was titrated according to the clinical needs of the patient, and reduced to the original maintenance dose 3 to 4 weeks after the return of symptoms to baseline. TAU consisted of individual supportive psychotherapy administered for less than 15 min during the injection period. Early warning signs of patients in the TAU group were detected only by patients complaining of their warning symptoms without an early sign questionnaire. Patients in both groups were instructed to visit the
2.2.1. Medication compliance Medication noncompliance was defined as a 1-week injection-free state after the day appointed for patients to receive RLAI. Medication compliance was defined as the number of actual visits for injections divided by the number of days when patients were scheduled to visit during the study period. 2.2.2. Relapse Operational criteria for relapse were an increase to a moderately severe or higher score (N 5) for any of the positive symptoms on the Psychosis subscale of the PANSS, and a GAF score of 30 or less (Herz et al., 2000). A 2-year relapse was considered to have occurred within the period from the baseline to the end of the second year. Owing to the high dropout rate, if a patient who was enrolled in the study no longer visited the outpatient clinic at the time of the second year evaluation, we contacted that person or his or her family by telephone to evaluate his or her inclusion as a 2-year-relapse case. 2.2.3. PANSS The interrater reliability (0.75–0.85 among raters) of the PANSS (Kay et al., 1987) was maintained by holding rater training sessions before each evaluation. 2.2.4. GAF Interrater reliability for the GAF (American Psychiatric Association, 1994) was 0.81. 2.2.5. CGI. (Guy, 1976) The secondary outcome measures were treatment discontinuation, injection discontinuation, and adverse events, defined as follows: 2.2.6. Treatment discontinuation Treatment discontinuation was defined when a patient in either group no longer visted the hospital for treatment. 2.2.7. Injection discontinuation Injection discontinuation was defined when a patient receiving long-acting atypical antipsychotics declined to take further injections and preferred to take oral medication, or when the patient no longer visited the hospital. 2.2.8. Adverse event All adverse events that occurred from the first dose of RLAI until the endpoint were recorded and defined as a treatment emergency, together with any serious adverse events between the first injection and 30 days after the last injection. Movement disorders were assessed with the Extrapyramidal Symptom Rating Scale (Chouinard et al., 1980) at baseline and every 3 months thereafter. 2.3. Statistical analysis Independent t-tests were used to compare age, education, duration of illness, frequency of recurrence, and initial PANSS and GAF scores between the PIRP and TAU groups. Chi-square analyses and Fisher's exact test were used to assess associations
Table 1 Sociodemographic characteristics of PIRP group and TAU group in schizophrenic patients receiving risperidone via long-acting injection (RLAI). PIRP (n = 21) TAU (n = 25) t or χ2 Age (years) (Mean ± S.D.) Sex [n (%)] Male Female Education (years) (mean ± S.D.) Duration of illness (years) (mean ± S.D.) Number of recurrences (mean ± S.D.) Initial PANSS score (mean ± S.D.) Initial GAF score (Mean ± S.D.) Initial CGI score (Mean ± S.D.)
df
P
46
0.46
31.9 ± 7.7
34.1 ± 12.1
t = − 0.5
8 (38) 13 (62) 13.7 ± 1.5 4.1 ± 3.9
8 (32) 17 (68) 13.2 ± 2.1 5.0 ± 5.0
χ2 = 0.04 1
0.83
t = 0.9 t = − 0.4
45 44
0.33 0.48
1.3 ± 6.2
2.1 ± 2.2
t = − 1.2
46
0.14
61.1 ± 11.0 46.4 ± 9.8 4.1 ± 0.5
58.7 ± 7.7 45.8 ± 14.3 4.0 ± 1.2
t = 0.72 t = 0.89 t = 0.19
38.3 0.47 45 0.37 45 0.85
t: Student's t test; χ2:Pearson's chi-square test. S.D.: standard deviation; PANSS: Positive and Negative Syndrome Scale; GAF: General Assessment of Functioning; CGI: Clinical Global Impression.
S.-H. Lee et al. / Psychiatry Research 175 (2010) 195–199 Table 2 Comparison of medication compliance, 1-year relapse, 2-year relapse and between PIRP group and TAU group in schizophrenic patients receiving RLAI. PIRP (n = 21)
TAU (n = 25)
t or χ2
df
P
1-year medication compliance (%) (mean ± S.D.) 2-year medication compliance (%) (mean ± S.D.) 1-year relapse [n (%)]
94.6 ± 12.2
75.9 ± 22.2
t = 3.5
45
0.00⁎⁎
92.1 ± 16.5
74.2 ± 26.6
t = 2.7
45
0.00⁎⁎
2 (9)
10 (45)
2-year relapse [n (%)]
5 (24)
12 (48)
Fisher's exact test χ2 = 4.2 1
0.00⁎⁎ 0.04⁎
t; Student's t test; χ2; Pearson's chi-square test; ⁎⁎P b 0.01, ⁎P b 0.05.
between sex, relapse rate, and group. To evaluate the efficacy of long-acting risperidone over time, an intent-to-treat analysis (last observation carried forward) was used, and the effects of both programs were analyzed using repeated measures analysis of variance (ANOVA) in which two factors were considered when comparing the performance between the two groups. These factors were a main effect of time (which indicated whether changes in an outcome variable occurred as a function of time, irrespective of the treatment received) and a time × treatment interaction (which indicated whether changes in subjects over time differed between the two treatment groups). Logistic regression analysis was used to examine the predictors of 1-year relapse. A Cox proportional survival regression analysis was performed to examine the relationship between medication compliance and time from baseline to relapse (SPSSWIN, version 11, Chicago, USA).
3. Results
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Table 4 Significant variables included in the regression equation for predicting 1-year relapse. β
PIRP 3.7 1-year medication compliance − 0.12 Injection discontinuation 0.3 Constant 3.1
SE
Wald
df P
Exp (β)
95% confidence limits
2.0 0.05 1.5 4.4
3.5 5.4 0.048 0.49
1 1 1 1
44.5 0.8 1.3 22
0.85 2321 0.78 0.98 0.07 27
0.06 0.02⁎ 0.83 0.48
− 2 log likelihood = 18.6, Cox and Snell R2 = 0.54, Nagelkerke R2 = 0.78. Classification accuracy = 88.9; ⁎P b 0.05. SE; standard error.
in the three scales between the two groups. The frequencies of extrapyramidal symptoms [hyperkinesia (11% vs 13%), extrapyramidal disorder (8% vs 10%), and tremor (5% vs 3%)] and a prolactin-related adverse event (8% vs. 10%) also did not differ significantly between the PIRP and TAU groups. One schizophrenic patient in the PIRP group committed suicide. Tardive–dyskinesia-like movement was observed in one patient in the TAU group. 3.5. Identification of the predictive factors of 1-year relapse in schizophrenia patients receiving RLAI
Age, sex, education, duration of illness, number of recurrences, and initial PANSS and GAF scores did not differ significantly between the PIRP and TAU groups (Table 1).
Multivariate logistic regression analysis with long-term relapse as the dependent variable and variables that differed significantly between the PIRP and TAU groups as the independent variables showed that 1-year medication compliance was significantly associated with 1year relapse (Table 4). Logistic regression analysis showed that 1-year medication compliance could be a significant predictor of 1-year relapse, and that there was a marginal association between PIRP and 1-year relapse (P = 0.06).
3.2. Comparison of medication compliance and relapse rates between schizophrenic patients in the PIRP and TAU groups receiving RLAI
3.6. Time from baseline to relapse: Cox proportional survival regression analysis
We compared medication compliance and relapse rates between the PIRP and TAU groups. Scores of medication compliance were significantly higher, and the 1- and 2-year relapse rates were significantly lower, in the PIRP group than in the TAU group (Table 2).
A proportional survival regression model according to Cox was performed with the time between enrollment in the study and relapse as the endpoint (Table 5). The time from baseline to relapse was the dependent variable, and variables that differed significantly between the PIRP and TAU groups in the previous statistical analysis were the independent variables. This analysis revealed that injection discontinuation had a significant effect on the time from baseline to relapse (Fig. 2).
3.1. Comparison of sociodemographic characteristics between schizophrenic patients in the PIRP and TAU groups receiving RLAI
3.3. Comparison of treatment discontinuation and injection discontinuation between schizophrenic patients in the PIRP and TAU groups receiving RLAI We compared treatment discontinuation and injection discontinuation between the PIRP and TAU groups. The frequency of treatment discontinuation during the program differed significantly between the two groups, and the occurrence of injection discontinuation was significantly lower in the PIRP group than in the TAU group (Table 3). 3.4. Comparison of efficacy and safety between schizophrenic patients in the PIRP and TAU groups receiving RLAI Both groups showed statistically significant decreases over time in PANSS, CGI, and GAF scores (all P = 0.00). These results and the time × treatment interaction indicated the absence of significant differences
4. Discussion To our knowledge, this is the first study to examination whether combined therapy with PIRP (as a psychosocial approach) and RLAI (as a pharmacotherapeutic approach with a second-generation longacting antipsychotic drug) could be more effective in reducing the relapse rate than RLAI with TAU. We found that the 1- and 2-year relapse rates were lower in the PIRP group than in the TAU group.
Table 5 Time from baseline to relapse: Cox proportional survival regression analysis. Table 3 Comparison of treatment discontinuation and injection discontinuation between schizophrenic patients in the PIRP and TAU groups receiving RLAI. PIRP (n = 21) Treatment discontinuation [n (%)] 3 (14) Injection discontinuation [n (%)] 5 (23)
TAU (n = 25) 11 (28) 18 (68)
t or χ2 2
df P
χ = 6.0 1 χ2 = 13.0 1
t: Student's t test; χ2; Pearson's chi-square test; ⁎⁎P b 0.01, ⁎P b 0.05.
0.01⁎ 0.00⁎⁎
PIRP Medication compliance Injection discontinuation
β
SE
Wald
df
P
Exp(β)
95% confidence limits
0.5 − 0.01
0.57 0.01
0.8 1.7
1 1
0.36 0.18
1.7 0.9
0.55 0.9
1.5
6.9
1
0.01⁎
21.1
2.1
3.0
− 2 log likelihood = 107.3, ⁎P b 0.05.
5.1 1.0 203.3
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S.-H. Lee et al. / Psychiatry Research 175 (2010) 195–199
Fig. 2. Cox survival regression analysis showing the relationship between injection discontinuation and time from baseline to relapse.
These results are consistent with a previous study (Herz et al., 2000) that suggested the efficacy of a program for relapse prevention. We found that 2 (21%) and 5 (24%) of 21 patients relapsed during 1and 2-year follow-ups, respectively, in the PIRP group, suggesting that combined therapy with long-acting atypical antipsychotics and a relapse prevention program reduces relapse rates more than the interventions considered in previous studies (Davis, 1975; Feldmann et al., 2002; Hogarty et al., 1979). The previously reported 1-year relapse rate for schizophrenic patients with long-acting depot medication was 27% compared with 42% for patients treated with oral medication (Feldmann et al., 2002; Kane, 2003), and the 2-year relapse rate for long-acting depot medication was 40% compared with 65% for oral medication (Hogarty et al., 1979). Therefore, long-acting atypical antipsychotic treatment combined with a relapse prevention program might be one of the most effective strategies to reduce relapse or recurrence in schizophrenia. However, there may also be other possible reasons for the low relapse rate in this study. First, it might have been due not only to the effect of PIRP but also to differences in subject characteristics from the previous studies. Second, although the sociodemographic data did not differ significantly between our two groups, our study design did not include a randomization process or a double-blind control method, so schizophrenia patients who wanted to participate in the PIRP program may have been preferentially assigned to the PIRP group, with their correspondingly high motivation possibly biasing the study results. Third, the small sample in our study may limit the generalizability of the results. Logistic regression analysis showed a trend toward effectiveness in preventing 1-year relapse in the PIRP group. Assuming that a 1-year period is long enough to reveal differences in relapse rates between two groups receiving long-acting atypical antipsychotics, we could deduce that RLAI alone does not substantially prevent relapse without also using another psychosocial approach. The compliance with schizophrenia medication was higher in the PIRP group than in the TAU group. Since biweekly injection with RLAI has been recommended for schizophrenic patients in Korean hospitals, this might facilitate the monitoring of relapse warning symptoms of individual schizophrenic patients. However, it might also be a disadvantage because it requires patients to make frequent hospital visits. Psychoeducation that addresses the relationship between partial compliance and relapse and usefulness of long-acting atypical antipsychotics in reducing relapse might encourage patients to make the necessary hospital visits.
The PIRP program was also effective at maintaining compliance with depot medication. If schizophrenic patients receiving long-acting depot medication do not understand the advantages of long-acting depot medication, depot medication is only useful for slightly prolonging the injection period. Actually, patients who dropped out of this study earlier relapsed earlier (r = 0.87, P = 0.00), despite receiving long-acting atypical antipsychotics. It is possible that psychoeducation could also have affected this result. Most previous relapse prevention programs have not contained depot-specific psychoeducation. Before the study began, we hypothesized that educating schizophrenic patients and their families about the importance of depot medication would reduce the rates of noncompliance, relapse, and rehospitalization. Patients in both groups received RLAI, and a within-group analysis showed that PANSS, CGI, and GAF scores decreased over time. However, repeated-measures ANOVA showed that there was no time× treatment interaction between the two groups. That might be due to the small number of subjects, which limited the power to show positive results, and it is possible that RLAI alone is sufficient to maintain a partial or full remission state without including another psychosocial approach. Cox proportional survival regression analysis showed that longacting risperidone (injection discontinuation) alone influences the time from baseline to relapse. Before the study began, we also hypothesized that PIRP might affect the time from baseline to relapse. However, we found that this was not the case, which might be due to the fact that the PIRP program lasted only 1 year. This result has the following clinical implications: (1) that RLAI could affect the longterm outcome of schizophrenia, (2) that combined therapy of PIRP and RLAI is better for preventing relapse and rehospitalization in schizophrenia, and (3) that if combined therapy is impossible, at least long-acting injection could be prescribed to reduce the longterm relapse rate. This study has the following limitations: First, the sample was small. Although we found that the PIRP program significantly reduced the relapse rate of schizophrenia, the small sample limits the ability to generalize this result to most patients with schizophrenia. Studies with larger samples are needed to examine whether these results can be applicable to other schizophrenic populations. Second, a randomization process was not used in the study design. To reduce the probability of the resulting type 1 errors, we used Cox proportional survival regression to analyze the relationship between medication compliance and time from baseline to relapse. To minimize the effect of nonrandomization, a subject-blinded boardcertified psychiatrist assessed the subjects on the various rating scales employed. Third, we excluded schizophrenic patients who had dropped out early from the treatment (within 3 months) in both groups (3 and 8 patients in the PIRP and TAU groups, respectively). This might have affected the results for the primary and secondary outcome measures. Note, however, that the percentage of patients who dropped out was similar in the two groups. Therefore, even if we had analyzed data including dropouts, the significant differences in 1- and 2-year relapse rates, medication compliance, and injection discontinuation between the two groups would have been maintained. Fourth, we assessed early warning symptoms of patients in the PIRP group biweekly, which might have been too long a period to detect such symptoms, since 1 week is long enough to progress from warning symptoms to relapse in some schizophrenic patients. One schizophrenic patient committed suicide in the PIRP group. Although the long study period prevented us from assessing patients weekly, we did detect early warning symptoms in three patients in the PIRP group, and successfully stabilized them. Finally, there is a possibility that this intervention can only be applied to eligible patients who have the ability (e.g. IQ N 80) to understand the cognitive, behavioral, and educational aspects of the intervention. Furthermore, there was a difference in treatment time between the groups, which might have affected the results.
S.-H. Lee et al. / Psychiatry Research 175 (2010) 195–199
In conclusion, the results presented here suggest that a PIRP program can maintain medication compliance and that RLAI can prevent relapse. The use of a large sample in a randomized controlled trial is needed to verify these results. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.psychres.2008.06.043. References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. APA, Washington, DC. Chouinard, G., Ross-Chouinard, A., Annable, L., Jones, B., 1980. The extrapyramidal symptom rating scale [Abstract] Canadian Journal of Neurological Science 7 (3), 233. Davis, J.M., 1975. Overview: maintenance therapy in psychiatry: I. Schizophrenia. American Journal of Psychiatry 132, 1237–1245. Drake, R.J., Dunn, G., Tarrier, N., Bentall, R.P., Haddock, G., Lewis, S.W., 2007. Insight as a predictor of the outcome of first-episode nonaffective psychosis in a prospective cohort study in England. Journal of Clinical Psychiatry 68, 81–86. Feldmann, R., Hornung, W.P., Prein, B., Buchkremer, G., Arolt, V., 2002. Timing of psychoeducational psychotherapeutic interventions in schizophrenic patients. European Archives of Psychiatry and Clinical Neuroscience 252, 115–119. Guy, W., 1976. Clinical Global Impressions. National Institute of Mental Health, Rockville, MD. Herz, M.I., Lamberti, J.S., Mintz, J., Scott, R., O'Dell, S.P., McCartan, L., Nix, G., 2000. A program for relapse prevention in schizophrenia: a controlled study. Archives of General Psychiatry 57, 277–283.
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Hogarty, G.E., Schooler, N.R., Ulrich, R., Mussare, F., Ferro, P., Herron, E., 1979. Fluphenazine and social therapy in the aftercare of schizophrenic patients. Relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride. Archives of General Psychiatry 36, 1283–1294. Kane, J.M., 2003. Strategies for improving compliance in treatment of schizophrenia by using a long-acting formulation of an antipsychotic: clinical studies. Journal of Clinical Psychiatry 64, 34–40. Kane, J.M., 2006. Review of treatments that can ameliorate nonadherence in patients with schizophrenia. Journal of Clinical Psychiatry 67, 9–14. Kane, J.M., Eerdekens, M., Lindenmayer, J.P., Keith, S.J., Lesem, M., Karcher, K., 2003. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. American Journal of Psychiatry 160, 1125–1132. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13, 261–276. Keith, S.J., Kane, J.M., Turner, M., Conley, R.R., Nasrallah, H.A., 2004. Academic highlights: guidelines for the use of long-acting injectable atypical antipsychotics. Journal of Clinical Psychiatry 65, 120–131. Lamberti, J.S., 2001. Seven keys to relapse prevention in schizophrenia. Journal of Psychiatric Practice 7 (4), 253–259. Lasser, R.A., Bossie, C.A., Gharabawi, G.M., Baldessarini, R.J., 2005a. Clinical improvement in 336 stable chronically psychotic patients changed from oral to long-acting risperidone: a 12-month open trial. International Journal of Neuropsychopharmacology 8, 427–438. Lasser, R.A., Bossie, C.A., Gharabawi, G.M., Kane, J.M., 2005b. Remission in schizophrenia: results from a 1-year study of long-acting risperidone injection. Schizophrenia Research 77, 215–227. Zygmunt, A., 2002. Interventions to improve medication adherence in schizophrenia. American Journal of Psychiatry 159, 1653–1664.