Clozapine utilization and outcomes by race in a public mental health system: 1994-2000

OBJECTIVE: 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. METHOD: 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. RESULTS: 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). CONCLUSION: 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.     

Reversible neutropenia during treatment with olanzapine: three case reports.

Olanzapine is an atypical antipsychotic with a low incidence of extrapyramidal-motoric side effects. Its chemical structure is related to clozapine, which is known to induce neutropenia in up to 3% and agranulocytosis in approximately 1% of patients. It has been discussed controversially whether olanzapine also has a potential to induce neutropenia and agranulocytosis. Up to now, seven case reports of haematopoetic disturbances during olanzapine treatment have been published, including one case of olanzapine-induced agranulocytosis (Naumann et al. 1999), two cases of neutropenia (Steinwachs et al. 1999) and one leucopenia (Meissner et al. 1999). We report three subjects with reversible neutropenia under olanzapine, with rapid normalisation of neutrophil cell counts after discontinuation of olanzapine. In one case neutropenia occurred after administration of a single dose of olanzapine, in another case after 6 weeks of treatment. In both cases, patients had no clinical complications. In the third case, neutropenia appeared after 1.5 years of treatment followed by development of pneumonia. Two cases were recorded within the German drug surveillance project (AMSP); the third case was observed in a randomised, double-blind, multicentre study comparing olanzapine with clozapine.     

Hematological adverse events in clozapine-treated children and adolescents

OBJECTIVE: To retrospectively examine rates of hematological adverse events (HAEs) in psychiatrically ill, hospitalized children treated with clozapine. METHOD: 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. RESULTS: 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). CONCLUSIONS: 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.     

Ethnicity and four personality disorders

The current study examined the relationship between ethnicity and DSM-IV personality disorders. The distribution of four personality disorders--borderline (BPD), schizotypal (STPD), avoidant (AVPD), and obsessive-compulsive (OCPD)--along with their criteria sets, were compared across three ethnic groups (Caucasians, African Americans, and Hispanics) using both a clinician-administered diagnostic interview and a self-report instrument. Participants were 554 patients drawn from the Collaborative Longitudinal Personality Disorders Study (CLPS) who comprised these three ethnic groups and met personality disorder criteria based on reliably administered semistructured interviews. Chi-square analyses revealed disproportionately higher rates of BPD in Hispanic than in Caucasian and African American participants and higher rates of STPD among African Americans when compared to Caucasians. Self-report data reflected similar patterns. The findings suggest that in treatment-seeking samples, Caucasians, Hispanics, and African Americans may present with different patterns of personality pathology. The factors contributing to these differences warrant further investigation.     

Interferon-α-assoziierte Agranulozytose während Clozapin-Behandlung Kasuistik und Wissensstand

Little is known about possibilities of chronic hepatitis C treatment with interferon-alpha (IFN-alpha) in psychiatric patients continuously taking antipsychotics. We report on a 28-year-old hepatitis C-positive man with paranoid psychosis. He was successfully treated with clozapine, an atypical antipsychotic drug which is known for the risk of granulocytopenia and agranulocytosis. With doses up to 200 mg/day over 3 years, he showed no remarkable changes in WBC. Because of the chronic hepatitis C with genotype 3a, additional treatment was started with IFN-alpha (s.c., 3 x 6 million IU/week). After 2 months of therapy he developed a severe agranulocytosis. Both clozapine and IFN-alpha were discontinued, and his WBC returned to normal. Results from bone marrow examination were compatible with a toxic reaction possibly caused by either or both medications. We discuss possible problems with IFN-alpha during the treatment of psychiatric patients, interactions with psychiatric medication, and hematotoxic side effects like those from clozapine. We recommend combining IFN-alpha with less "toxic" antipsychotics and weekly checks of WBC.     

Clozapine-induced neutropenia in children: management with lithium carbonate

Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 microg/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children.     

A case study; ethnicity and clozapine, a risky combination?

Agranulocytosis is a very serious side-effect of treatment with clozapine. For this reason, the Dutch guidelines state the specific values of leukocyte and neutrophil counts at which treatment with clozapine should be discontinued. We focus on a patient with a benign ethnic neutropenia who, despite a low neutrophil count, was allowed to continue taking clozapine. We discuss a number of important practical considerations that can affect the way in which leukocyte and neutrophil counts are interpreted in relation to the use of clozapine.     

HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia

Agranulocytosis develops in approximately 1% of patients with chronic schizophrenia treated with the atypical neuroleptic drug clozapine. Previous studies have not identified the mechanism or risk factors for this adverse reaction. Because of an observed association between Jewish ethnic background and the development of agranulocytosis in our patient sample treated with clozapine for refractory symptoms, HLA typing was performed in 31 patients (19.4% of whom had developed agranulocytosis). The HLA-B38 phenotype was found in 83% of patients who developed agranulocytosis and in 20% of clozapine-treated patients who did not develop agranulocytosis. Because B38 is part of a haplotype known to occur frequently in the Ashkenazi Jewish population, the frequencies of the combined alleles HLA-B38, DR4, and DQw3 were examined. The incidence of HLA-B38, DR4, DQw3 was significantly increased in patients with agranulocytosis (five of five patients) compared with control patients of Ashkenazi Jewish ancestry (two of 17 patients). These findings indicate that genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis. We postulate that gene products contained in the haplotype may be involved in mediating drug toxicity.     

Granulocytopenia associated with neuroleptic therapy in a patient with benign familial leukopenia

Benign familial leukopenia (BFL) has been reported in several ethnic groups, including Ethiopians of Jewish origin. To date, there are no reported cases of patients with BFL developing granulocytopenia following administration of neuroleptics. We report a case of a young Ethiopian Jew suffering from schizophrenia, who exhibited premorbid benign reduced white blood cells (WBC) count and developed leukopenia and neutropenia following exposure to typical (zuclopentixol, perphenazine, haloperidol) antipsychotics and the atypical antipsychotic risperidone. The diagnosis of BFL was established and tissue typing of the patient was determined. To the best of our knowledge, this is the first report of leukopenia with neutropenia in an ethnically susceptible (due to BFL) schizophrenia patient following exposure to typical and atypical antipsychotics. HLA typing of this patient was distinct from that reported in patients susceptible to clozapine-induced agranulocytosis. Further extensive investigations including HLA typing in a larger cohort of schizophrenic patients is needed in order to define the association between HLA haplotypes and neuroleptic-induced hematological reactions and to identify the potentially vulnerable individuals.     

Racial/ethnic variation in the reliability of DSM-IV pathological gambling disorder

Racial/ethnic disparities in mental disorders, including pathological gambling disorder (PGD), may be either real or artifacts of how they are conceptualized and measured. We aimed to assess racial/ethnic variation in the reliability of self-reported lifetime PGD determined by meeting > or = 5 criteria of the Diagnostic and Statistical Manual of Mental Disorders. Using community advertising, we recruited 15-85-year-old Caucasians (n = 225) and African (American/other minorities (n = 87), who had gambled more than 5 times lifetime), for 2 interviews, held 1 week apart, about gambling and associated behaviors. Results indicate substantial to almost-perfect DSM-IV PGD reliability for Caucasians (kappa = 0.82) and African Americans/other minorities (kappa = 0.68). Reliability for symptoms and for game-specific disorders was fair to almost perfect (kappa = 0.37-0.90). After adjusting results for confounding variables and multiple comparisons, racial/ethnic variation in PGD and game-specific reliability failed to persist. Implications exist for increased attention to screening and prevention efforts critical to reducing racial/ethnic disparities in PGD prevalence.     

Clozapine-induced agranulocytosis in a Native American: HLA typing and further support for an immune-mediated mechanism.

BACKGROUND: Approximately 30% of schizophrenic patients defined as treatment refractory significantly improve with clozapine. However, clozapine produces agranulocytosis in approximately 1% to 2% of patients in the United States. The mechanism of clozapine-induced agranulocytosis has not been established, but evidence suggests an immune-mediated mechanism. METHOD: Human leukocyte antigen (HLA) typing was performed in a native American with clozapine-induced agranulocytosis. RESULTS: Our findings support previous observations of a role of the HLA-B16, DR4, DQw3 haplotype in predicting susceptibility to agranulocytosis in clozapine-treated patients. CONCLUSION: We suggest that HLA typing of clozapine candidates may be useful for predicting the risk for clozapine-induced agranulocytosis.     

Add-on filgrastim during clozapine rechallenge unsuccessful in preventing agranulocytosis

Granulocyte colony-stimulating factor agents such as filgrastim can be administered in order to reduce the duration of clozapine-induced agranulocytosis. Successful long-term combination treatment with filgrastim and clozapine in patients with previous clozapine-induced agranulocytosis has been described in several cases. We describe a patient with schizophrenia who developed agranulocytosis during treatment with clozapine and who did not respond to other antipsychotics. Add-on treatment with filgrastim during a clozapine rechallenge did not prevent the reoccurrence of agranulocytosis, and clozapine treatment had to be discontinued. Our case suggests that add-on filgrastim is a therapeutic option when clozapine is rechallenged, but physicians should be aware of the potential dangers especially severe clozapine-induced agranulocytosis.     

氯氮平引起粒细胞缺乏的Meta分析

目的 进一步认识氯氮平与其他抗精神病药物致粒细胞缺乏的差异。方法 按标准对收集的,关于氯氮平与其他抗精神药致粒细胞缺乏的对照研究论文结果作Ｍｅｔａ分析。结果 （１）氯氮平与其他抗精神病药物导致细胞缺乏有非常显著性差异;（２）氯氮平引起粒细胞缺乏的危险性是其他抗精神病药物的８．８倍;（３）病因学分数：ＥＦ暴露因素＝０．８８,即氯氮平治疗组中出现粒缺者,８８％是由氯氮平引起的ＥＦ总体＝０．８８,即在全     

The effect of long-term treatment with clozapine in schizophrenia: a retrospective study in 96 patients treated with clozapine for up to 13 years

A retrospective study was performed to evaluate the effect of long-term treatment with clozapine in 96 schizophrenic or schizoaffective patients hospitalized at the Psychiatric Research Center in Uppsala during the period 1974-1986. All patients had previously been treated with different neuroleptics but with inadequate response or distressing side effects. The mean duration of the disorder at the start of clozapine treatment was 8 years and 9 months and the mean duration of the treatment 3 years and 11 months. Clozapine treatment was discontinued in 36% of the patients, mainly due to lack of efficacy, poor compliance or temporary withdrawal of the drug from the market in 1975. In two patients the reason was leukopenia or agranulocytosis. In another 10 patients a transient decrement of WBC was seen, which was normalized during ongoing treatment. Four patients died when on clozapine during the follow-up period, but no causal relationship to the treatment could be established. Eighty-five per cent of the patients could be discharged from the hospital. Of the 62 patients who were still on clozapine after 2 years, 18% had full time and 21% half-time employment. A global evaluation of the clinical efficacy revealed a significant improvement in 43% and a moderate improvement in 38% of the patients compared to previous neuroleptic treatments. Common but usually mild side effects were sedation, hypersalivation, weight gain, and obstipation. Four patients had grand mal seizures. No extrapyramidal side effects were observed during clozapine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

The off-label use of clozapine in adolescents with bipolar disorder, intermittent explosive disorder, or posttraumatic stress disorder

OBJECTIVE: There are limited data in the literature regarding clozapine use in adolescents with diagnoses other than schizophrenia. This report describes the use of clozapine in adolescents with diagnoses of bipolar disorder, intermittent explosive disorder (IED), and posttraumatic stress disorder (PTSD). METHODS: A chart review of 39 adolescents treated with clozapine at two residential facilities was undertaken. Data extraction included demography, illness variables, medication information, and clinical outcomes. Categorical outcomes were analyzed using contingency statistics, and continuous variables were analyzed using a paired t test. RESULTS: The cohort included 26 females and 13 males with a mean age of 14 years. Clozapine was titrated slowly, and the mean daily dose was 102 mg. The diagnoses included bipolar disorder (n = 7), IED (n = 9), and PTSD (n = 19). There were significant reductions in polypharmacy once the clozapine dosage was stabilized. Prior to clozapine treatment, nearly 70% of the subjects were receiving either mood-stabilizing or antidepressant agents in combination with the previous antipsychotic drug. Once the clozapine dosage was stabilized, only 24% of the subjects required concomitant mood stabilizers (p < 0.001), and only 21% of the subjects required concomitant antidepressants (p < 0.001). Anxiolytic medication use was also significantly reduced during clozapine treatment. Most patients were discharged to a less restrictive setting. Eight subjects discontinued clozapine due to agranulocytosis (n = 1), neutropenia (n = 2), excessive weight gain (n = 2), or not requiring it long term (n = 1), and data were unavailable in 2 subjects. Significant weight gain (5% or greater change from baseline) was noted in 20 subjects. CONCLUSIONS: Clozapine, in relatively modest doses, appears to have clinical benefits for adolescent with bipolar disorder, IED, and PTSD. There is no labeled indication for clozapine use in these disorders. Clozapine is also associated with serious side effects in subsets of individuals. Therefore, a very careful evaluation of the risk-to-benefit ratio in each individual subject being considered for clozapine is highly recommended.     

Ethnic inequalities in clozapine use among people with treatment-resistant schizophrenia: a retrospective cohort study using data from electronic clinical records

Purpose

Clozapine is the most effective intervention for treatment-resistant schizophrenia (TRS). Several studies report ethnic disparities in clozapine treatment. However, few studies restrict analyses to TRS cohorts alone or address confounding by benign ethnic neutropenia. This study investigates ethnic equity in access to clozapine treatment for people with treatment-resistant schizophrenia spectrum disorder.

Methods

A retrospective cohort study, using information from 11 years of clinical records (2007–2017) from the South London and Maudsley NHS Trust. We identified a cohort of service-users with TRS using a validated algorithm. We investigated associations between ethnicity and clozapine treatment, adjusting for sociodemographic factors, psychiatric multi-morbidity, substance misuse, neutropenia, and service-use.

Results

Among 2239 cases of TRS, Black service-users were less likely to be receive clozapine compared with White British service-users after adjusting for confounders (Black African aOR = 0.49, 95% CI [0.33, 0.74], p = 0.001; Black Caribbean aOR = 0.64, 95% CI [0.43, 0.93], p = 0.019; Black British aOR = 0.61, 95% CI [0.41, 0.91], p = 0.016). It was additionally observed that neutropenia was not related to treatment with clozapine. Also, a detention under the Mental Health Act was negatively associated clozapine receipt, suggesting people with TRS who were detained are less likely to be treated with clozapine.

Conclusion

Black service-users with TRS were less likely to receive clozapine than White British service-users. Considering the protective effect of treatment with clozapine, these inequities may place Black service-users at higher risk for hospital admissions and mortality.

     

Circadian rhythm of neutrophil counts and granulocyte macrophage-colony stimulating factor (GM-CSF) under clozapine treatment: A case report

Agranulocytosis is a severe side effect of clozapine which requires stopping this medication immediately in the case of progressive neutropenia. There are, however, cases of benign neutropenia under clozapine that do not progress. The ability to predict progression vs. non-progression in neutropenia cases under clozapine would be highly valuable for avoiding unnecessary treatment withdrawals. In this context, we closely monitored circadian neutrophil counts and granulocyte macrophage-colony stimulating factor (GM-CSF) levels in a patient who had low normal neutrophil counts at baseline and developed neutropenia under clozapine treatment. Methods. Venous blood samples were drawn in close intervals for 4 weeks. At several time points blood was sampled in the morning between 08:30 and 9:30 h and a second time in the afternoon between 14:00 and 15:00 h. Results. The circadian rhythm of neutrophil counts and GM-CSF levels was unchanged. There was no progression to agranulocytosis, and clozapine could be continued. Conclusions. In view of the available literature and the presented case it is suggested that further studying of circadian profiles of neutrophil counts, neutrophil regulatory factors, such as GM-CSF, and their intercorrelation may help to find a biomarker of benign vs. malign neutropenia under clozapine.