Clozapine incidences

Haloperidol, phenothiazines, thioxanthenes, clozapine, olanzapine, quetiapine, and risperidone 0 Parenteral agents may have a higher incidence... 

Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300 mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. 

Agranulocytosis is a potentially catastrophic idiosyncratic reaction that usually appears within the first 3 months of therapy. Although the incidence is extremely low (except for clozapine), mortality is high. Thus, any fever, sore throat, or cellulitis is an indication for discontinuing the antipsychotic and immediately conducting white blood cell and differential counts. 

Most conventional antipsychotics are associated with a dose-depen-dent risk of a lowered seizure threshold, although the incidence of seizures with most of these drugs is quite small (Devinsky et al. 1991). Of all the conventional antipsychotics, molindone and fluphenazine have been shown most consistently to have the lowest potential for this side effect (ltd and Soldatos 1980 Ohver et al. 1982). The atypical antipsychotic clozapine is associated with a dose-dependent risk of seizure. 

Cardiovascular effects. Hypotension and tachycardia occur in most patients taking clozapine. Cases of potentially fatal myocarditis and dilated cardiomyopathy have been reported in association with clozapine (Kilian et al. 1999). Myocarditis typically occurred within 3 weeks of starting clozapine, but cardiomyopathy may not be apparent for several years. Although rare, treatment-emergent myocarditis and cardiomyopathy occur at a reportedly higher incidence with clozapine than with other antipsychotics (Coulter et al. 2001). The mechanism by which clozapine may cause myocarditis has not been established, but some authors have speculated that clozapine may cause an immunoglobuhn E (IgE)-mediated type 1 hypersensitivity reaction (Kihan et al. 1999) or a hypereosinophilic syndrome (Hagg et al. 2001). 

Alvir JM, Lieberman JA, Safferman AZ, et al Clozapine-induced agranulocytosis incidence and risk factors in the United States. N Engl J Med... 

Lower potency neuroleptics, such as thioridazine and chlorpromazine, have a decreased incidence of EPS when compared with higher potency agents, such as haloperidol or fluphenazine. Novel agents, such as clozapine and quetiapine, are virtually devoid of EPS effects when given at their recommended dosing range. 

Clozapine. Clozapine produces seizures at a greater rate than other antipsychotics, especially in the dose range of 600 to 900 mg/day. Fortunately, these levels are substantially above the usual therapeutic range of 300 to 400 mg/day, but seizures can occur on lower doses, as well. A more rapid escalation of the clozapine dose may also predispose to the development of seizures. According to the drug s manufacturer, the reported incidence of seizures, based on daily dosage, is as follows ... 

Two of three patients suffering from agranulocytosis are female, but any relationship to age or dose of clozapine is unclear. Agranulocytosis is rare in the first 4 weeks of treatment, peaking in incidence during the period between the 5th and 25th weeks of treatment. 

Initially, the mortality rate from clozapine-induced agranulocytosis was about 40%, but it has decreased by more than half. Now, while the mortality rate of agranulocytosis complicated by infection is still 40%, without infection, it is approximately 15%. In U.S. clinical trials, the incidence is about one per 100, but because this outcome is based on only 1,000 patients, it may not be an accurate estimate. It is notable that some who developed clozapine-induced agranulocytosis were later able to tolerate other antipsychotics without a recurrence, again implying a different underlying mechanism. 

Early reports found clozapine to benefit some affectively disordered patients (e.g., bipolar, schizoaffective) who had previously been treatment-refractory, but improved rapidly and significantly on this agent ( 108, 109, 278). Further, many patients were able to sustain their early gains in psychosocial functioning over a 3-5-year period. The low incidence of EPS and TD also increased interest in potentially new indications for these agents. 

Clozaril (Clozapine), for example, can cause agranulocytosis (a potentially lethal suppression of white blood cells by the bone marrow). Parkinsonian symptoms and weight gain occur with risperidone (Risperdal) and olanzapine (Zyprexa). In addition, quetiapine (Seroquel) has been associated with an increased incidence of cataracts. 

Many earlier reports considered extrapyramidal side effects unavoidable when treating patients with neuroleptics. There appeared to he a parallel between antipsychotic action and the incidence of unwanted neurological effects. However, the development of newer neuroleptics has changed this view. Drugs like clozapine have a high antipsychotic potency and yet produce few neurological problems. It has therefore been proposed that the DA receptors involved in the beneficial actions of neuroleptics in the treatment of psychiatric disorders are situated in mesolimbic areas, such as the nucleus accumbens, whereas the extrapyramidal effects are mediated by striatal receptors. 

Extrapyramidal effects Parkinsonian symptoms, akathisia (motor restlessness), and tardive dyskinesia (inappropriate postures of the neck, trunk, and limbs) occur with chronic treatment. Blocking of dopamine receptors in the nigrostriatal pathway probably causes these unwanted parkinsonian symptoms. Clozapine and risperidone exhibit a low incidence of these symptoms. 

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