Clozapine typical antipsychotics

Clozapine versus typical antipsychotic drugs uncontrolled mirror-image studies. 

Clozapine randomized, controlled trials versus typical antipsychotic drugs. 

Kaiser etal. (2000) DRD4 (48-bp repeat) Typical antipsychotic drugs, clozapine No association. Schizophrenia Caucasian... 

Clozapine is the prototype of atypical antipsychotic drugs, and it has been used effectively to treat patients with schizophrenia who are unresponsive or intolerant to typical antipsychotics [7]. Clozapine is characterized as atypical by its preferential binding to serotonin (5-HT2) and dopamine D4 receptors (D4) relative to dopamine D2 receptors [8]. A recent body of work also suggests that atypicality may be defined by the rate at which clozapine dissociates from D2 receptors. Specifically, clo-... 

Clozapine (Clozaril). Clozapine was introduced over 30 years ago but has only been available in the United States since 1990. It remains the medication of choice for treatment-resistant schizophrenia. Since its introduction, it has been used to treat acute mania with excellent results. Furthermore, it avoids the potential for tardive dyskinesia posed by haloperidol and the other typical antipsychotics. 

Loxapine (Loxitane). Loxapine is a medium potency antipsychotic, and it has several interesting features. First, it is chemically very similar to clozapine, the first of the atypical antipsychotics. In the test tube, loxapine actually behaves more like an atypical antipsychotic (more on that later), but when patients are treated with it, loxapine acts more like a traditional typical antipsychotic. A second point of interest is that loxapine is actually the major active metabolite of the antidepressant amoxa-pine (Ascendin). As a result, one can use a single medication (amoxapine) to treat both depression and psychosis. In practice, however, the use of what is essentially a fixed dose combination medication should be avoided. Using amoxapine does not allow separate adjustment of the antipsychotic and antidepressant, and most importantly, amoxapine is the only antidepressant associated with the risk of TD. 

Therefore, we believe that this alone is not a sufficient definition for atypicality. We prefer to define atypical antipsychotics as those that are less prone to causing EPS because they work differently than the typical antipsychotics. This, of course, raises the question of just how these medications work. Using clozapine as the starting point to answer this question has proved difficult. Why The problem is that clozapine interacts with so many different types of nerve cell receptors that it becomes hard to tell which of these actions makes the difference. 

Efficacy in short-term treatment. From studies in adult schizophrenia, it is evident that clozapine treatment has at least the same or superior antipsychotic effect, compared to typical antipsychotics. In some studies, clozapine was superior with regard to symptom reduction in severe and acute schizophrenic patients. As the guidelines do not allow the use of clozapine as a first-choice drug, most patients have been treated before with at least two atypical or typical antipsychotics. Only one controlled trial has assessed the efficacy of clozapine in child and adolescent psychiatry. In this study (Kumra et ah, 1996), clozapine was found to be superior to haloperidol in all measures of psychosis, and showed a striking superiority for both positive and negative symptoms. 

Among the atypical antipsychotics, clozapine has the most convincing evidence of efficacy in children and adolescents with schizophrenia ( 166,167, 170). Kumar and colleagues (171) conducted a double-blind, randomized trial of clozapine versus haloperidol in 21 children and adolescents (mean age = 14 years) whose psychosis had been previously unresponsive to typical antipsychotics. Clozapine at a mean dose of 176 mg per day was superior to haloperidol for both positive and negative symptoms. These results are consistent with an open-label study by Remschmidt and colleagues (172). This group found that clozapine at a mean dose of 154 mg per day produced notable improvement in 27 of 36 (75%) adolescents with schizophrenia previously unresponsive to at least two trials of typical antipsychotics. 

Thus, most of the atypical and some typical antipsychotic agents are at least as potent in inhibiting 5-HT2 receptors as they are in inhibiting D2 receptors. The newest, aripiprazole, appears to be a partial agonist of D2 receptors. Varying degrees of antagonism of 0-2 adrenoceptors are also seen with risperidone, clozapine, olanzapine, quetiapine, and aripiprazole. The clinical relevance of these actions remains to be ascertained. 

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