Clozapine Clinical Use And It's Impacts On The Outcome Of Discharged Patients With Schizophrenia

BackgroundSchizophrenia is one of the most important public health issues. The incidence rate of schizophrenia ranges from 0.2%o to 0.6‰among adults, and the lifetime prevalence is approximately 1% all over the world. It was estimated that there are about 7.8 million patients suffering from schizophrenia in China in 1993. The characteristics of schizophrenia are chronic, high disability rates and poor prognosis, and it is one of the top ten diseases which lead to disability in labor age population. Since Chlorpromazine has been applied in the clinical treatment in 1951, antipsychotics have been playing important roles in improving the prognosis and the quality life of schizophrenia patients and becoming a main treatment. Clozapine is accredited as the most efficient antipsychotic to treat negative symptoms. It can be used in treatment refractory schizophrenia, in preventing suicide, in controlling violence behaviors of patients, as well as in decreasing hospitalization rates of patients and reducing costs of treatments. However, there were some reports that clozapine has severe side effects of agranulocytosis. In the United States, the use of clozapine has been restricted in clinical treatments, and it's use has been limited to the treatment of refractory schizophrenia since 1980s.In China, clozapine was approved by use in clinical treatment in 1978, and has been used as common antipsychotics because of its better effective and lower price. It had been used as first-line antipsychotics for schizophrenia for a long period in China. However, because of its side effects, and because the development of new atypical antipsychotics, such as Risperdal, in the 1990s gave psychiatrists more choices in the treatment of schizophrenia, The Chinese Medical Association published "China schizophrenia treatment guidelines" (the Guidelines) in 2003. The Guidelines state that clozapine can't be the first-line antipsychotic.Although to a high extend has the Guidelines restricted the usage of clozapine, it is still widely used in the treatment of schizophrenia in China. There are four reasons:(1) It may take some time for the guidelines to really influence the clinical decisions. (2) In current China, Costs of other atypical antipsychotics are too high to be accepted by many schizophrenia patients, while clozapine is preferred by many patients and psychiatrists in lower level hospitals because of its good effectiveness and much lower price. (3) It was reported that other atypical antipsychotics are not efficient for at least 30% of schizophrenia patients. So, it meets one of the criteria that clozapine can be used for the refractory schizophrenia. (4) clozapine is the only antipsychotics which can decrease the suicide rate among schizophrenia patients. Previous studies on clozapine were carried out in China before or just after the release of the Guidelines, and it may not reflect the real situation about the changes of clozapine use pattern. Furthermore, those studies were cross-sectional researches which implemented in different years or different areas, and there is lack of longitudinal comparability among those data. Until now, there has been no study either about the historic changes of the clozapine use in a specific area, or about the clinical features of patients who accept the clozapine treatment in China. Moreover, there is no systematic research on long-term outcomes or its associated factors among the schizophrenia patients who receive the clozapine treatment.ObjectivesThe study is to conduct a longitudinal observation about the situation of clozapine use among schizophrenia patients in Tangshan region, to evaluate the affects of clozapine use on the outcomes of schizophrenia, and then to provide scientific evidences to modify the Guidelines and to develop new policies for the prevention and treatment of schizophrenia.The specific objectives are as follow:(1) To describe the status of clozapine use and its changes among all schizophrenia inpatients in Tangshan from 1986 to 2006;(2) To explore the related factors of clozapine treatment among schizophrenia inpatients;(3) To follow up schizophrenia inpatients who used clozapine at the time of being discharged in 2 years, and to evaluate their clinical symptoms, subjective quality of life and general functions;(4) To explore related factors to the outcomes of schizophrenia inpatients in 2 years after being discharged.MethodsPart One:a survey on the changes of clozapine use rate among discharged schizophrenia patients in Tangshan from 1986 to 2006Medical records from six psychiatric hospitals (three county-level and three city-level hospitals) in 1986,1996,2001 and 2006 were all reviewed by trained interviewers using self-designed Medical Information Questionnaire. The information included the admission date, discharged date, reference number of hospitalization, socio-demographic data, health insurance status, duration of the disease, admission times, antipsychotics prescription at the time of discharge, family history of mental disorders, and the history of suicide behaviors. The definition of clozapine treatment is that patients used clozapine when being discharged, either only with clozapine, or combining with other antipsychotics. The evidences of schizophrenia diagnoses were from their medical records directly. Psychiatrists in this region have been using the Chinese Classification of Mental Disorders (CCMD) since CCMD-Ⅰwas published in 1981. Part Two:a study about the effectiveness of clozapine use during hospitalization on the outcomes of schizophrenia patients two years after dischargeSchizophrenia patients who met the criteria of DSM-IV, and were residents in Tangshan, as well as being discharged from January 1st to December 31st 2006 from the six psychiatric hospitals with only clozapine or one of any other antipsychotics treatments were recruited to the study. Patients in the clozapine group were selected from those with clozapine treatments by stratified cluster random sampling. Patients with one of any other antipsychotics treatments were consisted of the control groups matched with the patients on clozapine by the same hospital, same gender and similar admission dates (±2 days). Information was collected by face to face interviews using certain questionnaires, which included DSM-Ⅳ-TR disorders diagnosis by Structured Clinical Interview for-axisⅠ-research version (SCID-Ⅰ), social-demographic data and rehabilitation information after being discharged from hospitals by self-designed follow-up questionnaire, social supports and family environments of the patients by Family Adaptability and Cohesion Scale, Second Edition- Chinese Version (FACESⅡ-CV) and Social Support Scale, as well as clinical symptoms, quality of life and general functions by Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Quality of Life Scale and Global Assessment Function (GAF).Results:Part One:Changes of clozapine use rates in discharged patients with Schizophrenia in Tangshan from 1986 to 2006There were 6550 discharged patients and 7920 men-times from the six psychiatric hospitals in the four index years in total. The number of discharged schizophrenia patients was 2717 which was 41.48% to all the discharged patients, and the discharged schizophrenia men-times were 3195 which was 40.34% to all the men-times.Clozapine use rate in schizophrenia patients at discharge was 6.2%, which is the seventh drug use rate of schizophrenia in 1986. The use rate increased to 45.2% in 1996 and kept increasing to 59.9% till 2001. It was the most frequently used antipsychotics in the two years. However, the rate fell down to 35.7% in 2006, and clozapine was the second most frequently used antipsychotics following risperdal.Clozapine was the most frequently antipsychotic drug used in poly-antipsychotic drug therapy except 1986, combining with sulpiride and risperidal.Average prescription doses of single clozapine use at time of discharge rose from (263±106) mg/d to (310±139) mg/d from 1986 to 2006. The doses of combined clozapine use fluctuated between (173±131) mg/d and (207±120) mg/d.There are different characteristics between patients who used clozapine and other antipscychotics when they were being discharged in the four years. Onset age of patients treated by clozapine was significantly lower than the patients treated by other antipsychotics (25±8 vs 27±9 years,t=7.076, P<0.001). The percentage of low economic level among patients treated by clozapine was significantly higher than that among patients treated by other antipsychotics (22.53% vs 16.51%, x2=18.215, P<0.001). The percentage of patients with family history of mental disorders in clozapine use group was significantly higher than that in other drugs group (32.02% vs 26.43%,c2=11.286, P<0.001). Rate of past suicidal behavior in clozapine use patients group was significantly higher than that in other antipsychotics use group (19% vs 15%, x2=9.049, P=0.003). The rehospitalization rate in patients treated by clozapine was significantly higher than that in other antipsychotics use group (39.6% vs 37%,x2=97.88, P<0.001). The rate of patients with clozapine treatment in county level hospitals was significantly higher than the rate in city level hospitals (15.71% vs 10.31%,x2=20.48, P<0.001). Based on the results above, we could find that patients with clozaphine treatment surrounded by more predictors of adverse outcome and lived in poorer economical condition compared with patients treated by other antipsychotics. Logistic regression analyses were conducted to analyze the associated factors to clozapine use in discharged schizophrenia patients in the 3 investigated years,1996,2001, and 2006 (αenter=0.05,αexcluded=0.10, P<0.05). In 1996,2 predictors, rehospitalization (OR=1.100,95%CI:1.016～1.190) and onset age (OR=0.945,95%CI:0.926～0.964) entered the model (R2=0.09). It indicates readmitted and earlier onset patients were more likely to be treated by clozapine. In 2001, the same 2 predictors consisted of the model as in the 1996's model (R2=0.121, first rehospitalizationβ=0.541,P=0.005, OR=1.717,OR 95%CI:1.177～2.505 and onset ageβ=-0.031,P=0.008,OR=0.970, OR 95%CI:0.955～0.984). However, a different model was found in 2006, and five predictors consisted of the model (R2=0.227). They were suicidal behavior (OR=1.440, 95%CI:1.025～2.021), classification of hospital (OR=0.291,95%CI: 0.201～0.422), economic status (OR=1.341,95%CI:1.003～11.972), positive family history with mental disorders (OR=1.476,95%CI: 1.104～1.972), onset age (OR=0.968,95%CI:0.953～0.983), and first rehospitalization (OR=2.264,95%CI:1.561～3.283). Patients who had previously attempted suicide, were admitted in county level hospital, had worse economic condition, had positive family history, had younger onset age, and were rehospitalized were more likely to be treated by clozapine.Part Two:The affection of clozapine use on outcomes among discharged schizophrenia patientsAmong the 95 schizophrenic patients who were discharged with mono-clozapine treatment, one patient died of physical disease,1 died by suicide,5 were failed to be contacted because of incorrect address or phone number, and 13 refused to participate. Therefore, there were 78 patients were followed up. According to the examination with SCID for DSM-IV-TR at follow-up,76 patients met the inclusion criteria and consisted of clozapine group.Among the 127 control patients,1 patient died by suicide,5 were failed to be contacted because of incorrect address or phone number and 30 refused to participate. So, ninety-one patients were followed up. According to the examination with SCID for DSM-IV-TR at follow-up, 85 patients met the inclusion criteria and consisted of the control group.Onset age in the study group (M21, QL18, QU26) was significantly lower than that in the control group (M24, QL19, QU31), (Z=1.341 P =0.031). The number of admissions in the study group (M5, QL3, QU8) was significantly higher than that in the control group(M3, QL2, QU5), (Z =2.772 P=0.000). Course of disease in the study group(M13, QL8, QU20) was significantly longer than that in the control group(M6, QL4, QU14), (Z=4.512 P=0.000). Moreover, length of hospitalization when investigated in the study group (M45, QL26, QU158) was significantly longer than in the control group (M35,QL21, QU78), (Z=2.262 P=0.021). Additionally, rates of positive mental disorders family history and suicidal behavior in the study group were significantly higher than in the control group. At the follow-up, there were 53 patients (74.6%) in the study group still used clozapine as what they used when being discharged, but only 33 patients (38.8%) in the control group still had the same treatment as what they had when being discharged. There were 2 patients in the study group treated by other antipsychotic drug combining with clozapine, and 21 patients (24.7%) in the control group treated by other combined antipsychotic drugs. The differences of drug use status between the two groups had statistic significance during the follow-up (x2=12.6, P<0.001).During the time after discharge and follow-up,23 patients (30.3%) in the study group had been readmitted, which was significantly lower than the control group with 40 patients (47.1%) were readmitted (x2=3.27 P=0.032).Cox Proportional-Hazards Regression was conducted to analyze the related factors of rehospitalization:whether treated with clozapine when discharged or not(β=-0.74, P=0.01, HR=0.48), onset age (β=-0.21, P<0.001, HR=0.812), location of inhabitation (county vs villageβ=-0.60, P=0.082, HR=0.553, city vs villageβ=-0.78, P=0.022, HR=0.462), and course of disease (β=0.25, P<0.001, HR=1.281) composed of model. Patients who were treated by clozapine, had lower onset age, lived in village, and had longer course of disease were more likely to be readmitted.Multiple regression was conducted to analyze the related factors to social support:total score of PANSS (β=-0.324, t=-4.382, P<0.001) and course of schizophrenia (β=-0.177, t=-2.390 P=0.018) consisted into the model. It referred that the severe level of schizophrenia symptoms and course of disease negatively related to social support.There was no significant difference of FACESⅡ-CV (Chinese version of the Family Adaptability and Cohesion Scale) scores between the clozapine group and the control group. Multiple linear regression model was conducted to analyze the related factors to FACESII-CV scores. It stated that severe level of schizophrenia symptoms and course of disease negatively related to family adaptability and cohesion.There was no significant difference of PANSS scores between the study group and the control group. Generalized Linear Model was conducted to analyze the related factors to PANSS score:duration of onset to the first treatment(month,β=3.044, Z=3.430, P=0.001), total scores of social support scale (β=-0.793, Z=-4.150, P=0.000), the family per-capital income (β=-0.91, Z=-3.290, P=0.001), and total scores of CDSS (Calgary Depression Scale for Schizophrenia) composed of the model. It indicated that duration of onset to the first treatment and severity of depression were positively related to schizophrenia symptoms; on the contrary, total scores of social support scale and family economical status were negatively related to schizophrenia symptoms.There was no significant difference in scores of life quality between clozapine group and the control group. Ggeneralized Linear Model was conducted to analyze the related factors to life quality: duration of onset to the first treatment (month,β=-0.403, Z=-2.83 P=0.005), total scores of social support scale (β=0.192, Z=6.27, P<0.001), total scores of CDSS (β=-0.231, Z=-3.92, P<0.001) entered the model. It meant the duration of untreated psychosis and the severity of depression were negatively related to the level of subjective life quality, and the scores of social support was positively related to the level subjective life quality.There was no significant difference of global assessment function (GAF) score between the two groups. GLM was applied to analyze the related factors to the GAF score:living area (county vs urbanβ=-4.94, Z=-2.29, P=0.021; village vs urbanβ=-3.70, Z=-1.92, P=0.048), onset age (β=0.19, Z=2.192, P=0.029), total score of social support (β=0.37, Z=3.261, P=0.001), family per capital income (β=0.17, Z=2.311, P=0.022), regularity of medication(regular vs irregular:β=7.35, Z =4.632, P<0.001) enter the model. It implicated that onset age and social support score were positively related to the GAF, the GAF level was better among city patients than county and rural patients, and the patients who had medicine regularly were better.ConclusionsFirst series/cluster of the conclusions(1) The use rate of clozapine among discharged patients in Tangshan increased until 2002, and then decreased in 2006.(2) Clozapine was one of the antipsychotics with higher use rate among schizophrenia inpatients in 2006.(3) There were several changes of clozapine use from 1986 to 2006. The daily dose and the weight of combination use with other antipsychotics has been increased.(4) Clozapine use was affected by the different clinical characteristics of the disease and their economic status. Second series/cluster of the conclusions(1) At the follow-up, the proportion of patients still on the antipsychotic drug prescribed at the time of discharge in clozapine group was higher than that in the control group.(2) During the two-year follow-up, the rate of re-hospitalization among patients with clozapine treatment when being discharged was lower, and the time between discharged and the next admission was longer than those with other treatments. (3) Although the patients with clozapine treatment when being discharged had more adverse clinical features (previous) to the prognosis than those with other treatments, the two groups had no statistical difference in their clinical symptoms, subjective quality of life and general functions by the end of follow up.SignificanceClozapine has been a widely used antipsychotic agent in China since 1970s which is prominent both in efficacy and in side effects. This has been the first investigation on changing use pattern of clozapine and on factors that influnce this course in a municipal region with population of 7 million over the period 1986～2006 in China. In addition, patients taking clozapine at the time of discharge were followed up two years after their discharge. This preliminary naturalistic observation indicates that clozapine use can promote positive outcomes of schizophrenia patients after their discharge in community. The study provided the new evidences for further revising China Schizophrenia Treatment Guidelines, especially for the principles of rational clozapine use. The results also suggested that the systematically cost-effectiveness and risk-benefits analysis of clozapine should be carried out in Chinese context and antipsychotics use principles suited to the present conditions of our country should be formulated on the basis of such researches, thereby to utilize the mental health resources properly and effectively.