Use of clozapine in a state child and adolescent psychiatric hospital.

We assessed the predictors of clozapine initiation among youth 18 years and younger within a state psychiatric hospital. Administrative data (n = 358) were evaluated of inpatients from a long-term state child and adolescent psychiatric hospital. We investigated 25 background and clinical patient characteristics to determine which factors predicted clozapine initiation following the first 21 days of hospital admission. A Cox proportional model was used to evaluate factors that independently predicted the hazard rate of clozapine initiation. Emergency medication administration during the first 3 weeks of admission, which was more common among the clozapine (84.9 %) than control (61.7 %) patients (p < 0.001), was associated with a significantly increased probability of clozapine initiation (Hazard Ratio = 1.9, 95 % Confidence Interval = 1.2-3.1). Use of a mood stabilizer during the first 3 weeks of the inpatient was non-significantly related to an increased probability of clozapine initiation (Hazard Ratio = 1.7, 95 % Confidence Interval = 1.0-2.9). In this setting, emergency medication use predicts clozapine initiation suggesting that it may be used to treat patients with aggressive behavior.

Treatment-refractory schizophrenia in children and adolescents: an update on clozapine and other pharmacologic interventions.

Treatment-refractory early-onset schizophrenia is a rare but severe form of the disorder associated with poor premorbid function and long-term disability. The currently available evidence suggests that clozapine remains the most efficacious treatment for the amelioration of both positive and negative symptoms of the disorder and problematic aggressive behaviors. Clozapine use in children and adolescents, however, is limited by its association with hematologic adverse events and an increased frequency of seizure activity. Further studies are needed to examine the usefulness of antipsychotic combinations and of augmentation therapies to antipsychotic medications in order to treat persistent residual psychotic symptoms in children and adolescents who have schizophrenia and who have not responded to several sequential trials of antipsychotic monotherapy.

Clozapine: its impact on aggressive behavior among children and adolescents with schizophrenia.

OBJECTIVE: To evaluate the effectiveness of clozapine on aggressive behavior for treatment-refractory adolescents (age range 8.5-18) with schizophrenia (295.x) at Bronx Children's Psychiatric Center. METHOD: Clozapine treatment was administered in an open-label fashion using a flexible titration schedule. The frequency of administration of emergency oral and injectable medications and the frequency of seclusion events 3 months immediately before and from 12 to 24 weeks of clozapine treatment (when optimal clozapine levels were achieved) were compared. RESULTS: Twenty clozapine-treated children (mean +/- SD dose at week 24, 476 +/- 119 mg) were included. A statistically significant decrease in the frequency of the administration of emergency oral medications, the administration of emergency injectable medications, and seclusion events was found in adolescents during weeks 12 to 24 of clozapine treatment compared with their baseline condition before clozapine initiation. CONCLUSIONS: These preliminary data indicate the benefits of clozapine treatment in adolescents with treatment-refractory schizophrenia for aggressive behaviors. Although open data limit conclusions from this study, it is important that there was a clinically significant improvement in aggressive behaviors that enabled patients to be discharged to a less restrictive setting. Additional controlled clinical trials of clozapine are needed in treatment-refractory children and adolescents.

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.

Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II.

OBJECTIVE: To develop treatment recommendations for the use of antipsychotic medications for children and adolescents with serious psychiatric disorders and externalizing behavior problems. METHOD: Using a combination of evidence- and consensus-based methodologies, recommendations were developed in six phases as informed by three primary sources of information: (1) current scientific evidence (published and unpublished), (2) the expressed needs for treatment-relevant information and guidance specified by clinicians in a series of focus groups, and (3) consensus of clinical and research experts derived from a formal survey and a consensus workshop. RESULTS: Fourteen treatment recommendations on the use of atypical antipsychotics for aggression in youth with comorbid psychiatric conditions were developed. Each recommendation corresponds to one of the phases of care (evaluation, treatment, stabilization, and maintenance) and includes a brief clinical rationale that draws upon the available scientific evidence and consensus expert opinion derived from survey data and a consensus workshop. CONCLUSION: Until additional research from controlled trials becomes available, these evidence- and consensus-based treatment recommendations may be a useful approach to guide the use of antipsychotics in youth with aggression.

Psychopharmacologic treatment of psychosis in children and adolescents: efficacy and management.

The efficacy of antipsychotic use in children and adolescents with psychosis has been shown in an increasing number of randomized controlled trials. Chronic use of second-generation and third-generation antipsychotics has the potential for significant side effects, especially metabolic syndrome. A review of the literature on side effect profiles of antipsychotic medications used in children and adolescents is provided to help clinicians develop treatment plans for their patients. Clozapine has the best efficacy of all antipsychotic medications in adults as well as children and adolescents who are treatment resistant. Guidance is provided for the management of clozapine side effects.

Clozapine versus "high-dose" olanzapine in refractory early-onset schizophrenia: an open-label extension study.

OBJECTIVE: A recent 12-week controlled comparison demonstrated the superiority of clozapine to "high-dose" olanzapine in adolescents with treatment-refractory schizophrenia. In the present study, the authors conducted a 12-week, open-label, follow-up study to examine changes in lipid and glucose metabolism in youths maintained on clozapine and to determine whether patients who were previously randomized to high-dose olanzapine (up to 30 mg/day) responded to clozapine. METHOD: Thirty three (14 clozapine, 19 olanzapine) (85%) of 39 patients were available for the present 12-week, open-label extension study. Extended safety data using an intention-to-treat analysis from the 14 subjects treated with clozapine for a total of 24 weeks are presented. In addition, we report the clinical outcomes for 10 of 19 olanzapine-treated patients who were switched after 12 weeks to clozapine due to treatment nonresponse. Clinical response was defined as a decrease of 30% or more in total Brief Psychiatric Rating score from week 12 and a Clinical Global Impression-Improvement rating of 1 (very much improved) or 2 (much improved). RESULTS: The incidence of hypertriglyceridemia (defined as fasting triglycerides >125 mg/dL) (10/14 = 71%) and the incidence of "prediabetes" (defined as fasting blood glucose > or =100) (4/14 = 29%) at week 24 in the clozapine-treated subjects were notable. Seven (70%) of 10 of young patients with schizophrenia who failed treatment with "high-dose" olanzapine were found to respond to a 12-week, open-label clozapine trial. CONCLUSIONS: Clinicians and caregivers need to be aware of potential metabolic adverse events of long-term clozapine treatment. Adolescents with a poor response to olanzapine may do better on clozapine.

Clozapine and "high-dose" olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison.

BACKGROUND: The present study evaluated the effectiveness and safety of clozapine versus "high-dose" olanzapine in treatment-refractory adolescents with schizophrenia. METHODS: Children, ages 10-18 years, who met DSM-IV criteria for schizophrenia and who were resistant or intolerant to at least two antipsychotic drugs were randomized to receive 12 weeks of double-blind flexibly dosed treatment with clozapine (n = 18) or "high-dose" olanzapine (up to 30 mg/day) (n = 21). The primary efficacy measure was response (improvement), defined as a decrease of 30% or more in total Brief Psychiatric Rating Scale score from baseline and a Clinical Global Impression Scale improvement rating of "1" (very much improved) or "2" (much improved). RESULTS: Significantly more clozapine-treated adolescents met response criteria (66%) compared with olanzapine-treated subjects (33%). Clozapine was superior to olanzapine in terms of reduction of the psychosis cluster scores and negative symptoms from baseline to end point. However, both treatments were associated with significant weight-gain and related metabolic abnormalities. CONCLUSIONS: This double-blind randomized comparison of two second-generation antipsychotic drugs for treatment-refractory adolescents with schizophrenia supports clozapine as the agent of choice. The development of interventions to limit weight gain and metabolic side effects are needed to enhance the risk-benefit profile for both study treatments.