Clozapine Treatment and Predictors of Response in Patients with Schizophrenia

Transcription

1 KISEP Original Article Clinical Psychopharmacology and Neuroscience 2003; 1: 22-6 Clozapine Treatment and Predictors of Response in Patients with Schizophrenia Chul Eung Kim, Sang Eun Shin, Min Hee Kang KEY WORDS: INTRODUCTION The introduction of the atypical antipsychotic agent, clozapine, was one of the most revolutionary events to occur since antipsychotic agents were first introduced for the treatment of schizophrenic patients in the 1950 s. Clozapine does not induce the extrapyramidal side effects known to be the most serious issue involved with typical antipsychotic agents, is effective in the treatment of not only the positive symptoms but also the negative symptoms of schizophrenia, and is the most effective antipsychotic agent available for treatment-resistant patients or for patients who develop intolerable side effects when treated with conventional antipsychotics. 1 Address for correspondence: Thus, clozapine is also used as a model in the development of new antipsychotic agents. However, clozapine is not effective in all patients with treatment-resistant schizophrenia and different effectiveness rates, varying from 30 to 60%, have been reported by different researchers. 2,3 Moreover careful attention should be paid when prescribing clozapine, due to its potential serious side effects, such as agranulocytosis, lowering of the seizure threshold, and the burdensome and costly blood tests that need to be done every week for 18 weeks. From the same perspective, the clinical significance lies in finding clinical predictors of the likely response to clozapine in those patients with refractory schizophrenia. Nonetheless, although some studies reported that some patients show good response to clozapine, there are still no clear predictive factors which can be used to anticipate a patient s response to clozapine. As for studies on the relationship between the response to clozapine and clinical variables, Stern, et al. 4 reported that schizophrenics with severe symptoms prior to using clozapine would likely respond well to clozapine. Lieberman, et al. 5 reported that schizophrenics, who were resistant to 22

2 23 typical antipsychotic agents, would likely respond well and rapidly to clozapine. Other studies reported that schizophrenics with paranoid type or affective symptoms would probably respond well to clozapine. 5-7 Two studies on the clinical predictors of responses to clozapine has been performed in Korea. One study 8 was followed up for only 6 weeks, which was not long enough to evaluate the clinical effectiveness of clozapine. However, the other study 9 was a well planned prospective controlled study that was done for more than one year. Even though these studies could offer good information on the clinical effects of a drug in a controlled environment, it would be quiet different from those in a real clinical setting since compliance could have been forced during the period of the controlled clinical drug study. In this study, we attempted to find clinical predictors, which would enable us to identify those schizophrenics who would be likely to respond well to clozapine treatment in a more realistic clinical environment, through a retrospective analysis of schizophrenics, who underwent clozapine treatment for more than 6 months during hospitalization or through the outpatient clinic and in which the treatment environment was not controlled. SUBJECTS AND METHODS Subjects The subjects of the present study were chosen from those schizophrenic patients treated, who were satisfied the diagnostic criteria of DSM-IV 10 and were treated in the department of psychiatry at Inha University Hospital, either by hospitalization or on an outpatient basis. All the patients were indicated clozapine treatment in the psychopharmacologic review of the past history, and agreed to be included in the study after the side effects of clozapine and the need for long-term blood tests were explained both to the patients and to their guardians. We excluded those patients who showed abnormal findings during routine blood tests and liver function tests, which were performed prior to treatment with clozapine. Furthermore, we also excluded those patients who were on clozapine for less than 6 months, who showed side effects and who refused to undergo blood tests in the final analysis. Among a total of 41 patients initially selected for the study, only 28 patients, who were under clozapine for more than 6 months, were included in the final analysis. There were 10 men and 18 women. Their average age was years range: 1555 years. The subtypes of schizophrenia according to DSM-IV were paranoid type in 12 patients, disorganized type in 4 patients and undifferentiated type in 12 patients. Seven of these subjects had a family history of mental illness in their first-degree relatives. Table 1 shows other clinical variables. Methods Clinical variables were examined by reviewing the medical records compiled during hospitalization or through the outpatient clinic and by interviewing the patients and their guardians. The Clinical Global Impression Scale CGI 11 was used by each attending physician to investigate the degree of response to clozapine. Various clinical variables were compared and analyzed by dividing the patients into the responding group, including those patients who had a CGI score of either 1 or 2, as evaluated by the attending physician, after using clozapine, and the non-responding group, including those Table 1. Some demographic background characteristics of the responsive and non-responsive schizophrenic patient meansd Resoponsive n=15 Non-responsive n=13 p-value Age at admission year Gender female/male 7/8 11/ Education level year Age at first admission year Number of hospitalization time Duration of illness year Occupation present/absent 6/09 3/ Family history of psychotic present/absent 4/11 2/ Number of positive symtoms Number of negative symtoms Maximum dosage of cloazpine mg/day Duration of clozapine treatment month Subtype disorganized/paranoid/undifferentiated type 2/10/3 2/2/9 0.02

3 24 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1: 22-6 patients who had CGI scores other than 1 or 2. The attending physicians decided on the degree of response to clozapine treatment, taking into consideration the seriousness of the current psychotic symptoms, compliance to social life, and the patient s ability to return to his or her job. The attending physicians conferred with each other, in order to adjust any severe interrater differences. The CPMS criteria defined by Norvatis were used to evaluate blood tests performed while taking clozapine and the reasons for dropping out of the study were recorded. Statistical analysis was done using the SAS program Version 6.12with t-test, 2 -test and regression analysis. The significance level was set to p0.05. RESULTS The number of patients exhibiting a CGI score of 1 or 2 after 6 months of the clozapine treatment was 15, showing an improvement rate of 53.6% 15/28. The responding group included 8 men and 7 women and the non-responding group included 2 men and 11 women, with no significant gender difference being shown according to Fisher s Exact test p=0.25. The average age of the patients was years for the responders and was years for the non-responders, showing no statistically significant difference p=0.25. Furthermore, no significant differences were seen in either the education level or the mode of onset of the disease. The averege onset age was years in the responding group and years in the nonresponding group, showing a higher age in the responding group but with no statistically significant difference p=0.19. Other factors, such as the number of hospitalizations, duration of hospitalization, duration of illness, and occupational and family history showed no significant difference between the two groups. When schizophrenic patients in the responding and non-responding groups were analyzed according to their past history of violent behavior, depressive symptoms, positive symptoms and negative symptoms, the rate of improvement was lower in those patients with more negative symptoms p=0.05, but no significant relationship was observed for the other symptoms. The maximum daily dose of clozapine was mg/day in the responding group and mg/day in the non-responding group, showing a slightly higher dose in the non-responding group, but with no statistically significant difference. The average duration of clozapine treatment at the time of investigation was months in the responding group and months in the non-responding group, showing no significant difference between the two groups. When the variables were turned into dummy variables, in order to examine the odds ratio of each subtype of schizophrenia, a significant rate of improvement was seen in the paranoid type compared with the disorganized type p=0.01, and the odds ratio between the two types was % CI= However, no significant difference was found between the disorganized type and undifferentiated type p=0.20table 1. DISCUSSION In this open retrospective study, which included 28 schizophrenic patients who displayed resistance to other treatments and who took clozapine for more than 6 months, the overall rate of improvement was 53.6%. A good response to treatment was observed in the case of fewer negative symptoms. And those patients with the paranoid subtype of schizophrenia responded better than those with the disorganized or undifferentiated subtypes. Considering that one study 12 performed outside of Korea reported that improvement could still be seen up to 1 year after clozapine treatment was started, 12 and that another study 13 performed in Korea reported that increased clinical improvement was seen when clozapine was administered for more than 10 months, we consider that the treatment period of 6 months employed in the present study was too short for the clinical effect of clozapine to be seen in its entirety. In spite of this short treatment period, the overall rate of response was 53.6%, which is higher than the 46% reported by Lee, et al. 9 who conducted their study in a well-controlled environment for a period of more than 1 year, probably because the patients included in the present study were not patients with strictly defined refractory schizophrenia, and were either patients who showed no response to typical antipsychotic agents or who experienced intolerable side effects. According to a study by Lieberman, et al. 5 in which clozapine was administered for 1 year, patients with chronic schizophrenia showed a higher response rate to clozapine of 76% and responded faster to clozapine, compared with a response rate of only 50% in patients with refractory schizophrenia. The side effects of clozapine reported by our patients were drowsiness, hypersalivation, dizziness, and weight gain. The particular side effect to be noted in the present study was enuresis which occurred in 5 patients 17.9%. Among the side effects of clozapine, enuresis occurred dose-dependently 15,16 and at a relatively low rate of 0.23%. 14 Thus, it was an interesting finding that enuresis did not develop when these patients were subjected to

4 25 high doses of clozapine while being hospitalized, but rather when clozapine was maintained at stable doses mg/days at a time when the patients symptoms were stabilized. Following the multi-centered study performed by Kane, et al., 2 which reported that clozapine was more effective than the typical antipsychotic agent, chlorpromazine, in the case of schizophrenia exhibiting resistance to treatment, many researchers have confirmed the effectiveness of clozapine for refractory schizophrenia. However, the benefits and risks of using clozapine should be weighed carefully in patients with refractory schizophrenia, due to the possibility of their experiencing serious side effects, such as agranulocytosis. 17 Moreover, determining the factors predicting the likely response to clozapine would constitute an important step forward in the furthering our understanding of the pathophysiology of refractory schizophrenia, since clozapine is an atypical antipsychotic agent that has different pharmacologic and clinical properties than typical antipsychotic agents. One consistent finding s predicting the likely response to clozapine 5,18 was the presence of severe extrapyramidal symptoms resulting from poor tolerance to typical antipsychotic agents. 5,18 Moreover, a previous study 5 reported that patients with the paranoid subtype of schizophrenia responded better to clozapine than those with the nonparanoid subtype, as observed in the present study. Other factors predicting a probable lack of response to clozapine were early onset and long duration of illness 5 ; however, in the present study, no significant difference was observed between patients with a higher or lower age of onset in the responding group, which corresponds well with the results of Honer, et al. 19 who reported no differences in significant clinical variables between the responding and non-responding groups. There is known to be a gender difference in the treatment response to antipsychotic agents, and women would be expected to show a better overall prognosis compared with men in the case of schizophrenia. 20,21 Nevertheless, no gender difference was observed in the treatment response to clozapine in the present study. However, poor prognosis was reported in women after using clozapine in the case of refractory schizophrenia. 5,22 This finding could be an important clue to understanding the pathophysiology of refractory schizophrenia, and we expect that this pathophysiology will be able to be revealed in well-designed studies to be performed in the future using a larger number of patients. The results of the present retrospective open study have some methodological shortcomings. Firstly, we did not apply strict criteria to the issue of treatment resistance and the degree of response was evaluated retrospectively. Secondly, the overall number of patients was small, so that the statistical power of our study was somewhat limited, despite the fact that several significant results were obtained in this study. However, the results of the present study were particularly significant, in spite of the above limitations, since the observation of the natural progress of the treatment, rather than that observed in an artificially controlled environment, is more likely to reflect the actual treatment situation. We hope that the pathophysiology and factors predicting the likely response to clozapine in patients with refractory schizophrenia will be revealed in the future through further well-designed prospective studies using a larger number of patients. REFERENCES 1. Baldessarini R, Frankenburg F. Clozapine: a novel antipsychotic agent. New Engl J Med 1991; 324: Kane JM, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic: A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45: Naber D, Holzbach R, Perro C, Hippius H. Clinical management of clozapine patients in relation to efficacy and side effects. Br J Psychiatry 1992; 160suppl 17: Stern RG, Kahn RS, Davidson M, Nora RM, Davis KL. Early response to clozapine in schizophrenia. Am J Psychiatry 1994; 151: Lieberman JA, Safferman AZ, Pollack S, Szymanski S, Johns C, Howard A, Kronig M, Bookstein P, Kane JM. Clinical effects of clozapine in chronic schizophrenia: Response to treatment and predictors of outcome, Am J Psychiatry 1994; 151: Owen RR Jr, Beake BJ, Marby D, Dessaain EC, Cole JO. Response to clozapine in chronic psychotic patients. Psychopharmacol Bull 1989; 25: Zarate CA Jr, Tohen M, Baldessarini RJ. Clozapine in severe mood disorders. J Clin Psychiatry 1995; 56: Jae Hyung Kim, Young Dae Suh, Sung Hwa Park, Young In Chung. Clinical predictors of clozapine response in schizophrenics. J Korean Neuropsychiatr Assoc 1998; 37: Hong Shik Lee, Chan Hyung Kim, Shin Young Seo, Ho Suk Suh, Young Sam Kwon, Tae Sub Chung. Therapeutic predictors of clozapine treatment in patients with refractory schizophrenia. Kor J Psychopharmacol 1999; 10: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder 4th ed. Washington DC, American Psychiatric Press; Guy W. ECDEU assessment manual for psychopharmacology revised. Rockville Pike MD, US Department of Health, Education and Welfare; Meltzer HY. Duration of a clozapine in neuroleptic-resistant schizophrenia letter. Arch Gen Psychiatry 1989; 46: Hong Shik Lee, Chan Hyung Kim, Hee Sang Lee, Do Hoon Kim, Dong Ho Song, Kae Joon Yoo. Efficacy of long term treatment with clozapine in refractory chronic schizophrenia. J Korean Neuropsychitr Assoc 1995; 34: Lieberman JA, Kane KM, Johns C. Clozapine; Guidline for clinical management. J Cli Psychiatry 1989;50: Hong Shik Lee, Ji Yong Jeon, Chan Hyung Kim, Hee Sang

5 26 CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2003; 1: 22-6 Lee. Clozapine related transient nocturnal enuresis. J Korean Neuropsychitr Assoc 1995; 34: Byung Jo Kang. Clozapine-induced enuresis. A case report. Kor J Biol Ther Psychiatr 1996; 2: Marder S, van puttern T. Who should receive clozapine? Arch Gen Psychiatry 1988; 45: Picker D, Owen RR, Litman RE, Konicki PE, Guitierrez R, Rapaport MH. Clinical and biologic response to clozapine in patients with schizophrenia. Arch Gen Psychiatry 1992; 43: Honer WG, MacEwan GW, Kopla L, Aitman S, Chisolm-Hay S, Singh K, Smith GN, Ehmann T, Ganesan S, Lang M. A clinical study of clozapine treatment and predictors of response in a Canadian sample. Can J Psychiatry 1995; 40: Angermeyer KC, Kuhn L, Goldstein JM. Gender and the course of schizophrenia: differences in treated outcomes, Schizophr Bull 1990; 16: Goldstein JM. Gender differences in the course of schizophrenia. Am J Psychiatry 1988; 145: Szymanscki S, Lieberman J, Pollack S, Kane JM, Safferman A, Munne R, Umbricht D, Woerner M, Masiar S, Kronig M. Gender differences in neuroleptic non-responsive clozapinetreated schizophrenics. Biol Psychiatry 1996; 39: