Clozapine Initiation Research Articles

Prescribing practices of clozapine in India: Results of a opinion survey of psychiatrists

Byline: Amresh. Shrivastava, Nilesh. Shah Sir, Clozapine has emerged as a gold standard for treatment resistant schizophrenia. It is also effective in a variety of clinical conditions. It is additionally approved for suicide in schizophrenia. However practice of clozapine therapy is complex due to its side effect profile, need for regular blood monitoring, continued clinical monitoring and requirements of logistical support system for the same. Indian conditions are diverse not only socio-economically but also in pattern of prescribing. Practice of psychiatry in India is therefore challenging. Internationally clozapine is a centrally monitored and guided therapy involving a number of agencies. The present report attempts to examine prescribing and monitoring practices of clozapine in Indian context. Clozapine is an atypical antipsychotic, which is credited to have the distinction of bringing in the second revolution in psychopharmacology. It has been main focus of management for treatment-resistant schizophrenia. It has also provided a probe for the biological mechanism of schizophrenia. Many patients became functional with clozapine therapy and have returned to college and work.[sup] [1] After several deaths due to agranulocytosis, the drug was approved with a condition of stringent blood monitoring, and this practice is strictly adhered to in each and every western countries. Clinical practice in India does not have the benefit of a centralized blood monitoring system. The present study is aimed to explore the prescribing practice of clozapine in this context. Serum level monitoring is also not available in routine clinical practice. These constrains may change the practice of clozapine therapy.[sup] [2],[3] The study was done using a specifically prepared semi- structured performa containing 32 items and the questionnaire circulated to about 500 psychiatrists in India. A sizable number of posting was done in urban areas besides metro cities and the survey was voluntary. The responses received were analyzed. A total of 117 responses were received in this study, 9.4% of the psychiatrists have reported using clozapine even before it was launched in Indian Market. Antipsychotic prescribing practices are influenced by several factors. Chong et al. noted that Japan had a high frequency of prescribing high doses and polypharmacy; Singapore had a high utilization of depot injections, while China had a higher prescription of clozapine. First-generation drugs were mainly for controlling aggressive behavior, while second-generation drugs were targeted at the alleviation of positive, negative psychotic symptoms as well as disruptive behavior in schizophrenia. The pattern of antipsychotic medication use varies in different countries and is likely to be influenced by the prevailing health-care system, the availability and cost of the drugs.[sup] [4] Most of the psychiatrists using clozapine have an experience of more than 10 years (51%, between 10 and 20 yrs; 28%> 20 years). In the present study, 50% doctors have been using clozapine because they had one more option, and only 28% doctors felt that the knowledge of efficacy has guided their clinical decision.[sup] [5] Further, 43% doctors felt that clozapine provides very good and excellent outcome. The majority opinion was that clozapine provided an efficacy from 40 to 70% in terms of symptom reduction. Switching to clozapine is recommended under strict monitoring with a definite washout period either on outpatient or on inpatient basis.[sup] [6] However, in this study, only 39% preferred stopping ongoing antipsychotic before starting clozapine. A majority of them used the gradual introduction method, 41% preferred to start clozapine gradually, while gradually withdrawing the existing antipsychotic. Eighty-four percent preferred to maintain patients on single drug clozapine as per best practices norm. …

The Incidence and Characteristics of Clozapine-Induced Fever in a Local Psychiatric Unit in Hong Kong

To determine the incidence, characteristics, and predictors of clozapine-induced fever in a sample of patients in a local psychiatric unit. A retrospective review of case notes of 227 inpatients newly started on clozapine from March 2003 to December 2006 was conducted. Demographic characteristics, presence of fever, investigations carried out, fever characteristics, and complications of fever were recorded and analyzed. Patients with clozapine-induced fever were compared with their fever-free counterparts on demographic and clinical factors. Multivariate logistic regression was performed to identify predictors of clozapine-induced fever. Thirty-one out of 227 patients (13.7%) developed clozapine-induced fever. The means for day of onset of clozapine-induced fever after clozapine initiation and duration of fever were 13.7 and 4.7 days, respectively. The mean highest body temperature was 38.8 degrees C. Fever resolved within 48 hours after clozapine discontinuation in 79% of the patients with clozapine-induced fever. One out of 7 patients (14.3%) had fever on re-challenge. Clozapine-induced fever was associated with rate of titration more than 50 mg/wk (OR 18.9; 95% CI 5.3 to 66.7; P < 0.01), concomitant use of valproate (OR 3.6; 95% CI 1.5 to 8.9; P = 0.01), and presence of physical illnesses (OR 3.2; 95% CI 1.2 to 8.3; P = 0.02). Clozapine-induced fever is common. Temporary withdrawal of clozapine may result in resolution of fever, and clozapine re-challenge may be considered after fever subsides. Slower rate of clozapine titration may be helpful in patients with underlying physical illness and concomitant valproate treatment.

A review of recorded information given to patients starting to take clozapine and the development of guidelines on disclosure, a key component of informed consent

Clozapine is a very effective drug with both significant benefits and significant risks in treatment-resistant schizophrenia. Informed consent is generally accepted as both desirable and necessary in order to ensure...

Case Report: Clozapine use in two women with schizophrenia during pregnancy

Stabilized patients who receive clozapine may wish to have children; but studies on pregnant women receiving clozapine treatment are limited. In this study, we report on clozapine use during pregnancy in two women. The first woman (Case 1) had two deliveries while she was receiving clozapine treatment for schizophrenia. Both her deliveries were term, uncomplicated vaginal deliveries, and the clozapine dose was reduced throughout pregnancy. The second woman (Case 2) developed schizophrenia after her first child was born. She became pregnant after clozapine initiation. She delivered twins by term, uncomplicated vaginal delivery. In our cases, no specific risks for the mothers and their children can be attributed to the use of clozapine. Physicians must be aware of the changes in fertility induced by prolactin-sparing drugs. Mothers who receive clozapine treatment should not be advised to breastfeed their children.

Diabetic ketoacidosis among patients receiving clozapine: a case series and review of socio-demographic risk factors.

Diabetic ketoacidosis (DKA) has been associated with clozapine. The purpose of this study is to examine the clinical-demographic correlates of DKA among outpatients receiving clozapine. A literature search was conducted from 1966 to present using Medline to identify 23 case reports of clozapine-associated DKA. In addition, a cohort of twenty-six patients with clozapine-associated diabetes at the University of Rochester Medical Center Department of Psychiatry were examined for histories of DKA through review of medical records. Based on a total sample of 26 case reports including three unpublished cases at University of Rochester, associations between clinical and demographic variables and DKA were examined. African American patients were significantly more likely than other patients to have DKA (p < 0.0001). Clozapine treatment duration was significantly shorter among patients with DKA than those without DKA (p < 0.0001), with 61.5% of patients developing DKA within three months of clozapine initiation. Also, presence of antidiabetic medications was negatively correlated with DKA (p < 0.0001). Trends were noted toward an association between low doses of clozapine (p < 0.0583) and toward a negative association between family history of diabetes (p < 0.0696). Clozapine is associated with DKA that usually presents in patients who have not previously been diagnosed with diabetes. DKA typically occurs early in the course of treatment, when clozapine treatment duration is short and doses are low.

Clozapine Utilization and Outcomes by Race in a Public Mental Health System: 1994-2000

This study aimed to assess racial differences in clozapine prescribing, dosing, symptom presentation and response, and hospitalization status. This study extends previous studies of clozapine by examining patient- and treatment-related factors that may help explain or eliminate reasons for differential prescribing. Clozapine records for 373 white and African American patients with schizophrenia or schizoaffective disorder treated between March 1, 1994, and December 31, 2000, in inpatient mental health facilities in the state of Maryland were examined. Records for this study were derived from 3 state of Maryland databases: the Clozapine Authorization and Monitoring Program, the State of Maryland Antipsychotic Database, and the Health Maintenance Information System Database. A total of 10.3% of African Americans (150/1458) with schizophrenia received clozapine treatment compared with 15.3% of whites (223/1453) (chi2 = 16.74, df = 1, p < .001) during inpatient treatment in the public mental health system in Maryland. Clozapine doses were lower in African Americans relative to whites (385.3 +/- 200.6 vs. 447.3 +/- 230.3 mg/day) (t = -2.66, df = 366, p = .008). At the time of clozapine initiation, whites had more activating symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) (t = -3.98, df = 301, p < .0001); however, African Americans had significantly greater improvements in BPRS total symptoms (F = 4.80, df = 301, p = .03) and in anxiety/ depressive symptoms during 1 year of treatment with clozapine (F = 10.04, df = 303, p = .002). The estimated rate of hospital discharge was not significantly different for African Americans compared to whites prescribed clozapine (log-rank chi2 = 0.523, df = 1, p = .470); however, African Americans were more likely than whites to discontinue clozapine during hospitalization (log-rank chi2 = 4.19, df = 1, p = .041). Our data suggest underutilization of clozapine in African American populations. This racial disparity in clozapine treatment is of special concern because of the favorable outcomes associated with clozapine in treatment-resistant schizophrenia and in the specific benefits observed in African American patients. More research is needed to determine why disparities with clozapine treatment occur and why African Americans may be discontinued from clozapine at a higher rate, despite potential indicators of equal or greater effectiveness among African Americans compared with whites.

Myocarditis During Clozapine Treatment

The prototypical second-generation antipsychotic clozapine has been associated with various hematologic and metabolic adverse effects. Less attention has been given to clozapine’s adverse cardiac effects, including myocarditis and cardiomyopathy, despite a high associated mortality rate. Here we present the case of a young man with psychosis who developed near-fatal myocarditis after the initiation of clozapine. We review the diagnosis, management, and hypothesized pathophysiology of clozapine-induced myocarditis. We urge clinicians to be vigilant for the condition and to balance the risk of myocarditis and other side effects against the many benefits of clozapine for patients with treatment-resistant symptoms of schizophrenia.

Table of Contents

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Hematological Adverse Events in Clozapine-Treated Children and Adolescents

To retrospectively examine rates of hematological adverse events (HAEs) in psychiatrically ill, hospitalized children treated with clozapine. Clozapine treatment was administered in an open-label fashion using a flexible titration schedule, and data from weekly complete blood counts was obtained. The rate of neutropenia and agranulocytosis (HAEs) development was determined for 172 eligible patients (mean age at clozapine initiation, 15.03 +/- 2.13 years) with a median observation period of 8 months. Neutropenia (absolute neutrophil count <1,500/mm) developed in 23 (13%) patients and agranulocytosis (absolute neutrophil count <500/mm) in one (0.6%) patient. The cumulative probability of developing an initial HAE at 1 year of clozapine treatment was 16.1% (95% confidence interval 9.7%-22.5%). Eleven (48%) of 24 patients who developed an HAE were successfully rechallenged on clozapine. Eight (5%) of 172 patients from this sample eventually discontinued clozapine because of an HAE (one agranulocytosis, seven neutropenia). The occurrence of HAEs is a significant risk associated with the administration of clozapine. However, in this sample, few children actually discontinued therapy because of an HAE and the incidence of agranulocytosis does not appear higher than what has been reported in the adult literature.

Clozapine, Diabetes Mellitus, Hyperlipidemia, and Cardiovascular Risks and Mortality

The goal of this 10-year naturalistic study was to examine, in clozapine-treated patients, the change in cardiovascular risk factors following clozapine initiation and the mortality estimates from cardiovascular disease. Data were collected from medical records from January 1992 to December 2003 and included age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation for clozapine-treated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria). Clozapine dosage and laboratory results were recorded at 12-month intervals. At the time of clozapine initiation, the mean +/-?SD age of the 96 patients studied was 36.5 +/- 7.9 years; 28% (N = 27) were women. The Kaplan-Meier estimate for 10-year mortality from cardiovascular disease was 9%. African American and Hispanic American patients exhibited elevated risk of cardiovascular disease-related mortality (odds ratio [OR] = 7.2, p = .09; OR = 11.3, p = .04, respectively) compared to white patients. Body mass index (BMI) significantly increased the odds ratio of mortality (OR = 1.2, p < .01). The Kaplan-Meier estimate for new-onset diabetes mellitus was approximately 43%, and Hispanic American (OR = 4.3, p = .027) and African American (OR = 11.5, p = .0001) patients showed elevated risks of developing diabetes mellitus compared to white patients. Additionally, BMI (OR = 1.11, p = .0006), total cholesterol level (OR = 1.006, p = .04), and serum triglyceride level (OR = 1.002, p = .04) modestly increased the odds ratio for the development of diabetes mellitus. These results support the hypothesis that clozapine-treated patients appear to be at risk for death from cardiovascular disease secondary to clozapine-associated medical disorders such as obesity, diabetes, hypertension, and hyperlipidemia.

Prevalence of Diabetes Mellitus in Patients Receiving Depot Neuroleptics or Clozapine

This retrospective study compared the prevalence of diabetes mellitus/hyperglycemia between patients receiving treatment with clozapine (n = 24) and patients receiving treatment with depot (n = 27) neuroleptics in a Department of Veterans Affairs outpatient mental health clinic in the Mid-Atlantic region. Of the clozapine cases without a history of diabetes/hyperglycemia, 27.7% developed diabetes after initiation of clozapine. There were no new cases of diabetes/hyperglycemia in the depot group after initiation of depot neuroleptic. All patients receiving neuroleptic treatment should be monitored for changes in weight, lipid, and glucose levels so that appropriate preventive and therapeutic measures can be promptly initiated.

Clozapine and Hypertension: A Chart Review of 82 Patients

Clozapine has been linked to significant weight gain and increase in serum lipids and appears to negatively impact glucose metabolism. In this retrospective chart review study, we examine changes in systolic and diastolic blood pressure and treatment for hypertension in clozapine-treated patients. Data on demographics and systolic and diastolic blood pressure were examined for up to 5 years (September 1987 to September 1992) in 82 patients treated with clozapine. Rates of hypertension treatment in clozapine-treated patients were compared with patients receiving conventional antipsychotics (N = 56) and other atypical antipsychotic agents (N = 102). The mean age of the 82 patients at the time of clozapine initiation was 36.4 +/- 7.8 years, with 22 (27%) female, 75 (91%) white, 3 (4%) black, 3 (4%) Hispanic, and 1 (1%) Asian. The baseline weight was 175.5 +/- 34.0 lb (79.0 +/- 15.3 kg) and baseline body mass index was 26.9 +/- 5.0 kg/m(2). There was a significant increase in systolic blood pressure (p =.0004) and diastolic blood pressure (p =.0001). Overall, 22 patients (27%) received treatment for hypertension following clozapine initiation. Only 2 (4%) of 56 patients in the conventional antipsychotic group and 9 (9%) of 102 patients in the other atypical antipsychotic group (olanzapine, N = 6; risperidone, N = 3) received treatment for hypertension. Our findings suggest that long-term clozapine treatment is associated with increased rates of hypertension, which may have a significant impact on medical morbidity and mortality.

Starting Clozapine in the Community

Clozapine is the most effective antipsychotic available for the treatment of schizophrenia that has proved resistant to other medications and the only antipsychotic licensed for this indication. Although the drug is increasingly being used more widely in patients with schizophrenia and with other psychiatric and neurological disorders, it is still underused. The main reasons for this are that it can cause adverse effects such as weight gain and sedation, and the need for regular blood test monitoring because of the risk of agranulocytosis. While these hurdles are unavoidable, another problem in the UK has been the historical practice of admitting patients to hospital to initiate treatment with clozapine. However, protocols have now been developed for both home and day-hospital initiation. The experience of one assertive community treatment team of starting clozapine in patients' own homes has been positive, with no major adverse events reported. This approach is, however, extremely demanding of staff resources and for many services the use of day-hospitals to initiate treatment with clozapine is more appropriate. Research into staff and patients' views about community initiation of clozapine, and its economic costs, would be welcome.

Clozapine-Induced Fevers and 1-Year Clozapine Discontinuation Rate

Clozapine-induced fever is a known side effect that can occur during clozapine initiation. This study aims to characterize patients who experience clozapine-induced fever, the nature of the fevers, and rates of clozapine continuation at 1 year in patients who develop fever versus those who do not. A retrospective chart review of 93 consecutive clozapine initiations (1991-1999) was conducted. Fever was defined as any 1 temperature at or above 38.0 degrees C (100.4 degrees F). Demographic information, presence or absence of clozapine-induced fevers, and continuation of clozapine treatment at 1 year were extracted from the charts. These variables were analyzed for significance, and subsample analysis was conducted for those with more severe fevers (at or above 38.5 degrees C [101.3 degrees F]). Of the 93 patients, 20.4% (N = 19) developed clozapine-induced fevers. At 1 year, there was no significant difference in clozapine discontinuation rate between those patients who experienced fever and those who did not. Patients who experienced higher fevers (> or = 38.5 degrees C [101.3 degrees F]) tended to be significantly older than those who did not (p < .027). The mean fever duration was 3.8 days (range, 1-9 days), with a mean temperature of 39.1 degrees C (102.4 degrees F) (range, 38.0-41.0 degrees C [100.4-105.8 degrees F]). At 1 year, the patients who experienced fever showed no increased risk of severe reactions such as agranulocytosis. All patients with fevers continued clozapine treatment with good 1-year continuation rate on treatment with this medication. Clozapine-induced fever is not an indication for discontinuing this effective medication. It is a benign, self-limited phenomenon not predictive of drug discontinuation at 1 year. Older age at time of treatment may be a risk factor for developing clozapine-induced fever.

Clozapine initiation in the community

Aims and MethodThe study aims to describe the experience of an assertive community treatment team when commencing clozapine at home rather than in hospital, following a locally-devised policy. Any failed attempts and problems experienced are described.ResultsThere have been no serious adverse events with 13 patients who have been started on clozapine at home.Clinical ImplicationsFor an assertive community treatment team, home-initiation of clozapine is a practical option, particularly when patients refuse to come in to hospital.

The cost-effectiveness of clozapine: a controlled, population-based, mirror-image study.

A retrospective cohort study, with a mirror-image design, was used to measure inpatient service utilization in 63 consecutive patients started on clozapine from a geographical catchment area compared to a control group matched for previous inpatient service use. An intent-to-treat analysis, including those patients (n = 28) who discontinued clozapine during the study period, showed a significant reduction in number of admissions and total time spent in hospital in the 2 years following clozapine initiation compared to the previous 2 years and to the follow-up period in the control group. This translated into a reduction of 7,300 pounds in hospitalization costs per patient started on clozapine, over the 2-year period. In those patients who continued clozapine treatment for the whole of the 2-year period, there was a two-thirds reduction in number of admissions and total time spent in hospital compared to no change in the clozapine discontinuers. These findings suggest that clozapine is a clinically and cost-effective intervention for severe schizophrenia in routine clinical settings.

Clozapine-associated diabetes

Purpose Clozapine is a potent antipsychotic agent that has been marketed since 1990. Several published reports of diabetes mellitus occurring with clozapine therapy have appeared during the past 5 years. Because the risk and characteristics of clozapine-associated diabetes mellitus remain unclear, we conducted a descriptive epidemiologic study of spontaneous adverse event reports of hyperglycemia occurring in clozapine-treated patients. Material and methods The Food and Drug Administration MedWatch surveillance program was queried (January 1990 through February 2001), and the results were pooled with published cases. Parameters assessed included documentation of diabetes, clinical severity, new-onset diabetes versus exacerbation of preexisting disease, demographic characteristics of patients, time to onset of hyperglycemia, and effect of drug discontinuation and rechallenge. Results We identified 384 reports. Of these, new-onset diabetes was diagnosed definitively in 242 patients, and 54 patients had exacerbation of preexisting disease. The mean (± SD) age was 40 ± 12 years (range, 13 to 77). The male:female ratio was 2:0. Most cases appeared within 6 months of initiating clozapine therapy. One patient developed diabetes following a single 500-mg dose. There were 80 cases of metabolic acidosis or ketosis. Twenty-five patients died during hyperglycemic episodes. Forty-six patients had improved glycemic control after discontinuation or dose reduction of the drug. Conclusions A causal relationship between clozapine and diabetes is suggested by the number of reports, the temporal relation to clozapine initiation, the relatively young age of the affected patients, and the prompt reversibility on withdrawal of the drug in some patients. The severity of reported cases ranged from mild glucose intolerance to diabetic ketoacidosis or hyperosmolar coma.

Risperidone added to clozapine: impact on serum prolactin levels.

Several years ago, we reported that the addition of risperidone to clozapine improved response in some patients with schizophrenia. Risperidone, in general, is well tolerated when administered as monotherapy, but has been linked to a persistent elevation of serum prolactin and associated symptoms. The goal of this study was to determine whether the addition of risperidone to clozapine results in an elevation of serum prolactin levels in patients with chronic schizophrenia or schizoaffective disorder. Twenty patients on clozapine-risperidone combination therapy were matched for age and gender with 20 patients treated with clozapine monotherapy. Demographic information was gathered along with clozapine and risperidone dose and the length of time on risperidone. Serum prolactin levels were measured from a single blood sample. The 2 groups did not differ in age, race, gender, diagnosis, age at clozapine initiation, age at onset, Abnormal Involuntary Movement Scale scores, or clozapine dose. The mean +/- SD serum prolactin level was 8.42+/-4.17 ng/mL for clozapine monotherapy patients and 35.76+/-17.43 ng/mL for combination therapy patients. The 2 medication categories showed a significant difference in log prolactin values (t = -7.97, df = 38, p < or = .0001). Sixteen combination therapy patients (80%) exhibited elevated prolactin levels (range for entire group, 9.7-69.8 ng/mL) while only 2 clozapine monotherapy patients (10%) exhibited prolactin elevation levels (range for entire group, 2.4-20.2 ng/mL; df = 1, p < .0001). The combination of risperidone and clozapine appears to result in a moderate elevation of serum prolactin levels. Additionally, controlled prospective studies are needed to clarify the risks of long-term elevations of serum prolactin level.

Do maternal characteristics influence the relationship between obstetric complications and schizophrenia?

Early onset schizophrenia (EOS) begins in childhood or adolescence. EOS is associated with poor treatment response and may benefit from timely use of clozapine. This study aimed to identify the predictors of clozapine use in EOS and characterize the clinical profile and outcome of clozapine-treated youths with schizophrenia. We conducted a nationwide population-based study using linked data from Danish medical registries. We examined all incident cases of EOS (i.e., cases diagnosed prior to their 18th birthday) between December 31st 1994 and December 31st 2006 and characterized their demographic, clinical and treatment profiles. We then used multivariable cox proportional hazard models to identify predictors of clozapine treatment in this patient population. We identified 662 EOS cases (1.9% of all schizophrenia cases), of whom 108 (17.6%) had commenced clozapine by December 31st 2008. Patients had on average 3 antipsychotic trials prior to clozapine initiation. The mean interval between first antipsychotic treatment and clozapine initiation was 3.2 (2.9) years. Older age at diagnosis of schizophrenia [HR=1.2, 95% CI (1.05–1.4), p=0.01], family history of schizophrenia [HR=2.1, 95% CI (1.1–3.04), p=0.02] and attempted suicide [HR=1.8, 95% CI (1.1–3.04), p=0.02] emerged as significant predictors of clozapine use. The majority of patients (n=96, 88.8%) prescribed clozapine appeared to have a favorable clinical response as indicated by continued prescription redemption and improved occupational outcomes. Our findings support current recommendations for the timely use of clozapine in EOS.

Health status and health care costs for publicly funded patients with schizophrenia started on clozapine.

The study examined the effect of clozapine treatment on the health care costs and health status of people with schizophrenia who are supported by public funds. Thirty-three patients with schizophrenia hospitalized in a state facility were interviewed within one week of starting clozapine and six months later. Health status was assessed with four clinical rating scales measuring severity of psychopathology, negative symptoms, depression, and quality of life. Cost and health care utilization data were collected for the six months before and after initiation of clozapine. Only 52 percent of the subjects stayed on clozapine for six months. Subjects who continued on clozapine were more likely to be discharged within six months than those who did not continue. Six months after clozapine was started, health care costs showed a sayings of $11,464 per person, even after adjustment for pretreatment costs, and health status was improved. For subjects who continued on clozapine for six months, clozapine treatment was associated with reduced days of psychiatric hospital care, reduced overall costs despite increased outpatient treatment and residential costs, and improved health status.