Clozapine is used for the symptomatic management of psychotic disorders (e.g., schizophrenia). Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.
Clozapine has been shown to be an effective, relatively rapid-acting, broad-spectrum antipsychotic agent in both uncontrolled and controlled studies of patients with schizophrenia. In these studies, improvement in manifestations of schizophrenia was based on the results of various psychiatric rating scales, principally the Brief Psychiatric Rating Scale (BPRS) that assesses factors such as anergy, thought disturbance, activation, hostility/suspiciousness, and anxiety/depression. In clinical studies, clozapine improved both positive (florid symptomatology such as hallucinations, conceptual disorganization, and suspiciousness) and negative (''deficit'' symptomatology such as emotional withdrawal, motor retardation, blunted affect, and disorientation) manifestations of schizophrenia; conventional (typical) antipsychotic agents appear to have lesser effects on negative manifestations of the disorder. In comparative studies, clozapine was at least as effective as, or more effective than several conventional antipsychotic agents, including chlorpromazine, haloperidol, perphenazine, or trifluoperazine.
Unlike conventional antipsychotic agents, however, clozapine generally does not induce extrapyramidal effects and has not been clearly implicated as a causative agent in tardive dyskinesia.
While the risks of adverse neurologic effects with long-term clozapine therapy remain to be fully elucidated, other adverse effects, including some potentially serious effects (e.g., severe neutropenia, seizures), may occur more frequently with clozapine therapy. Consequently, the manufacturers and most clinicians state that use of clozapine should be reserved for patients with severe disease that fails to respond adequately to other antipsychotic therapy. The American Psychiatric Association (APA) recommends that a trial of clozapine be considered in patients with schizophrenia who fail to respond or experience a partial or suboptimal response to adequate trials of 2 antipsychotic agents (including at least one second-generation [atypical] antipsychotic), in patients with a history of chronic and persistent suicidal ideation and behavior that has not responded to other treatments, and in patients with persistent hostility and aggression.
Clozapine is used for the management of schizophrenia in severely ill patients who fail to respond adequately to standard antipsychotic therapy. Because of the risk of severe neutropenia and seizures associated with its use, clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. (
See Severe Neutropenia under Cautions: Hematologic Effectsand also under Cautions: Precautions and Contraindications.)
Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms, and more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.
Evidence from both retrospective and controlled prospective studies indicates that clozapine is effective in many patients who fail to respond adequately to other antipsychotic therapy and/or in whom such therapy produces intolerable adverse effects. In a controlled, comparative study in patients with at least moderately severe schizophrenia whose disease was refractory to at least 3 antipsychotic agents from at least 2 different chemical classes during the past 5 years, an adequate clinical response (a 20% or greater decrease in total BPRS score and either a posttreatment Clinical Global Impressions [CGI] scale rating of mildly ill or a posttreatment BPRS score of 35 or less) was noted after 1-6 weeks of therapy in 30% of patients receiving clozapine (mean maximum dosage exceeding 600 mg daily) compared with 4% of patients receiving chlorpromazine (mean maximum dosage exceeding 1200 mg daily) plus benztropine. In addition, clozapine was substantially more effective than chlorpromazine plus benztropine in improving both positive and negative manifestations of schizophrenia. In this study, resistance to antipsychotic treatment prior to entry into the clozapine/chlorpromazine comparative phase was confirmed by a 6-week trial of haloperidol (mean dosage of 61 mg daily) combined with benztropine. This study provides evidence from both categorical and continuous measures not only of clozapine's efficacy as an antipsychotic agent but also of its superiority over conventional antipsychotic drug therapy in a well-defined group of antipsychotic-resistant patients. Similar 6-week response rates in treatment-resistant schizophrenia have been reported in other studies with the drug. Clinically important improvement in quality of life and social functioning, including deinstitutionalization, interpersonal relationships, and ability to hold a job or attend school, also have been reported following initiation of clozapine therapy in patients with antipsychotic-resistant schizophrenia.
For additional information on the symptomatic management of schizophrenia, including treatment recommendations,
Although the manufacturers state that the safety and efficacy of clozapine in pediatric patients have not been established, the drug has been successfully used for the management of childhood-onset schizophrenia in a limited number of treatment-resistant children and adolescents. While the lower risk of extrapyramidal adverse effects and tardive dyskinesia during treatment with atypical antipsychotic agents such as clozapine compared with conventional antipsychotic agents represents an advantage in the treatment of childhood-onset schizophrenia, concerns regarding serious adverse effects (e.g., neutropenia, seizures) associated with clozapine limit its use in clinical practice.
(See Cautions: Pediatric Precautions.)Therefore, the American Academy of Child and Adolescent Psychiatry (AACAP) states that clozapine is not considered a first-line agent, and should be reserved for treatment-refractory patients who have failed to respond to adequate therapeutic trials (i.e., use of sufficient dosages over a period of 6 weeks) of at least 2 other first-line antipsychotic agents. For additional information on the symptomatic management of childhood-onset schizophrenia,
In one randomized, double-blind, clinical study conducted by the National Institute of Mental Health (NIMH), a limited number of children and adolescents (mean: 14 years of age) with childhood-onset schizophrenia (i.e., development of the disorder by 12 years of age or younger) who were intolerant and/or nonresponsive to at least 2 different antipsychotic agents were treated with either clozapine (up to 525 mg daily; mean final dosage 176 mg daily) or haloperidol (up to 27 mg daily; mean final dosage 16 mg daily) for 6 weeks. In this study, children and adolescents receiving clozapine had substantially greater reductions in both positive and negative symptoms of schizophrenia than those receiving haloperidol. Additional follow-up of these patients over a 2-year period indicated that, as reported in adults, maximal antipsychotic effects in schizophrenic children and adolescents may not be evident until after 6-9 months of clozapine therapy. For most children and adolescents in the study, clozapine improved interpersonal functioning and enabled a return to a less restrictive setting. However, mild to moderate neutropenia occurred in 24% of the patients, and 29% required therapy with an anticonvulsant.
Suicide Risk Reduction in Schizophrenia and Schizoaffective Disorder
Clozapine is used to reduce the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for such behavior, based on history and recent clinical state. Efficacy of clozapine for this indication has been established in a multicenter, randomized, open-label clinical study (the International Suicide Prevention Trial [InterSePT]) of 2 years' duration comparing clozapine and olanzapine in patients with schizophrenia (62%) or schizoaffective disorder (38%) who were judged to be at risk for recurrent suicidal behavior. These patients either had attempted suicide or had been hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation or had demonstrated moderate-to-severe suicidal ideation with a depressive component or command hallucinations to do self-harm within 1 week prior to their baseline evaluation. Treatment resistance (i.e., resistance to standard antipsychotic drug therapies) was not a requirement for inclusion in this study, and only 27% of the total patient population was identified as being treatment resistant at baseline.
In the InterSePT study, patients who received flexible dosages of clozapine (mean dosage: 274.2 mg daily) for approximately 2 years had a 26% reduction in their risk for suicide attempts or hospitalization to prevent suicide compared with those who received flexible dosages of olanzapine (mean dosage: 16.6 mg daily); the treatment-resistant status of patients was not predictive of response to clozapine or olanzapine. The cumulative probability of experiencing a suicide attempt, including a completed suicide, or hospitalization due to imminent suicide risk (including increased level of surveillance for suicidal behavior for patients already hospitalized) also was lower for patients receiving clozapine (24%) than for those receiving olanzapine (32%) at year 2. In addition, patients receiving clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior than those receiving olanzapine. These results, however, may have been confounded by extensive use of other treatments to reduce the suicide risk, including concomitant psychotropic agents (84% with antipsychotics; 65% with anxiolytics; 53% with antidepressants; 28% with mood stabilizers), hospitalization, and psychotherapy, the contributions of which to clozapine's efficacy are unknown.
Some clinicians state that methodologic problems (e.g., lack of actively suicidal patients in the study, possible bias and unblinding of suicide monitoring board members during the study, use of concomitant psychotropic agents) associated with the InterSePT study limit definitive conclusions about the efficacy of clozapine for prevention of suicide in patients with schizophrenia or schizoaffective disorder. The FDA advises clinicians to interpret the results of the InterSePT study only as evidence of the efficacy of clozapine in delaying time to recurrent suicidal behavior, and not as efficacy of the drug for treatment of suicidal behaviors or as a demonstration of the superior efficacy of clozapine over olanzapine. However, the APA states that, based on the available evidence from the InterSePT study, clozapine should be preferentially considered for schizophrenia patients with a history of chronic and persistent suicidal ideation and behaviors. Decisions to initiate clozapine therapy or switch patients from other antipsychotics to clozapine, therefore, should be individualized. In addition, safety and efficacy of clozapine in actively suicidal patients have yet to be determined.
Clozapine has been used in a limited number of patients with advanced, idiopathic parkinsonian syndrome for the management of dopaminomimetic psychosis associated with antiparkinsonian drug therapy, but adverse effects such as sedation, confusion, and increased parkinsonian manifestations may limit the benefit of clozapine therapy in these patients. Attempts to relieve antiparkinsonian drug-induced delusions, paranoia, and hallucinations by reduction of antiparkinsonian drug dosage or administration of typical antipsychotic agents often aggravate parkinsonian symptoms. Limited data suggest that administration of clozapine in dosages of 6.25-400 mg daily can improve psychotic symptoms within a few days, reportedly without exacerbating parkinsonian manifestations. However, in a controlled study in a limited number of patients receiving clozapine dosages up to 250 mg daily, exacerbation of parkinsonian manifestations and development of delirium occurred frequently despite prevention of antiparkinsonian drug-induced deterioration of psychosis; it has been suggested that rapid clozapine dosage escalation may have contributed to the observed negative effect on parkinsonian manifestations and delirium. Clozapine dosages of 100-250 mg daily reportedly have been associated with hypersalivation, hypophonia, bradykinesia, and considerable sedation in patients with idiopathic parkinsonian syndrome, and withdrawal of clozapine therapy or a decrease in dosage also has exacerbated parkinsonian manifestations. Some clinicians suggest that the dosage of clozapine required to treat drug-induced dopaminomimetic psychosis may be substantially less than that required for treatment of psychosis in young, otherwise healthy individuals and that clozapine therapy should be initiated at low dosages (e.g., 6.25-50 mg daily) with cautious upward titration (e.g., to a maximum of 100-200 mg daily). Other clinicians have suggested that clozapine be used only as a last resort in patients with drug-induced dopaminomimetic psychosis.