Clozapine efficacy

By contrast, studies of the dopamine D -like receptors have found evidence for the association of the receptor with disease (66) these studies have been replicated (41,42). From among the multitude of these studies, only selected examples are reviewed here. For example, evidence both for and against the association of the dopamine D -like receptors with schizophrenia has been reported. Polymorphisms of the dopamine receptor, including the third intracellular loop VNTR, alter dopamine receptor expression. In addition to association with schizophrenia (3,67-70), the dopamine polymorphisms have been associated with the genetic basis of the variable efficacy of antipsychotics such as clozapine (or neuromuscular toxicity—tardive dyskinesia) (69,71,72). Similarly, promoter SNPs have been associated with altered clozapine efficacy (67,68,73). 

The second type is a pharmacogenetic test focused on clozapine efficacy [33] it combines genetic variants of the neurotransmitter genes (clozapine response test) [34] and is produced in the United Kingdom by LGC. The third type is a pharmacogenetic test for clozapine-induced agranulocytosis... 

PET studies show that at effective therapeutic plasma concentrations most neuroleptics occupy some 80% of brain Dj receptors (in the striatum at least) and this is therefore considered to be a requirement for efficacy (Pilowsky, Costa and Eli 1992 Farde 1996). If that is so then clozapine, which occupies only 20-40% of the Dj receptors at a therapeutic concentration, must have some other action which accounts for its therapeutic effectiveness. 

To date, clozapine remains the only drug with proven and superior efficacy in treatment-resistant patients, and it is currently the only drug approved for the treatment-resistant schizophrenic. Studies have shown a response of approximately 30% to 50% in these well-defined treatment-resistant patients. Clinical trials have consistently found clozapine to be superior to traditional antipsychotics for treatment-refractory patients, and it is efficacious even after nonresponse to other SGAs and in partially responsive patients. It is often rapidly effective even in those who have had a poor response to other medication for years. Recent studies have demonstrated that it has a beneficial effect for aggression and suicidality, which led to the Food and Drug Administration (FDA) approval for the treatment of suicidal behavior in people with psychosis.41... 

Matsuda, K.T. et al. (1996). Clozapine dosage, serum levels, efficacy, and side-effect profiles a comparison of Korean-American and Caucasian patients. Psychopharmacol. Bull, 32, 253-7. 

Rietschel, M., Naber, D., Fimmers, R. et al. (1997). Efficacy and side effects of clozapine not associated with variation in the 5-HT2C receptor. NeuroReport, 8, 1999-2003. 

Of the atypical antipsychotics, clozapine, olanzapine, and risperidone have been studied the most. Clozapine was used to treat 10 treatment refractory acutely manic patients and 15 schizomanic patients. Using reduction in the YMRS score as the outcome measure, 72% improved (non-rapid cycling, bipolar patients). Comparison of olanzapine (5-20 mg) with placebo showed significant reduction of the YMRS in 49% vs. 24% of subjects by 3 weeks, with significant change evident by the first week. In a trial comparing risperidone at 6 mg with haloperidol at 10 mg and low-dose lithium (800-1200 mg/day) efficacy was similar over the 28 days of the trial. 

The main indications for atypical antipsychotics are the acute and maintenance treatment of schizophrenic disorders, with an emphasis on the treatment of refractory and chronic disorders. However, because of the lower risk of EPS and in particular of tardive dyskinesia, there is a tendency toward a wider range of indications for some of the atypical neuroleptics. Favorable effects in drug-induced psychoses have been demonstrated for olanzapine. Clozapine seems effective in the treatment and relapse prevention of manic episodes and bipolar disorders, and risperidone has been shown to have good efficacy in conduct disorders and in the pervasive developmental disorders. 

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. 

Efficacy in maintenance treatment. Studies in adult schizophrenia concerning maintenance treatment have been especially interesting, because the majority of the patients were nonresponders to conventional antipsychotics. These studies demonstrate the superior efficacy of clozapine as maintenance treatment in therapy-refractory psychoses treated by classical antipsychotics. Beyond that, it could be demonstrated that clozapine was effective in reducing recurrence rates and duration of hospitalization. The superior efficacy of clozapine, although not its effects on recurrence or hospital stay, have also been demonstrated in adolescents suffering from chronic schizophrenia (Schulz et ah, 1996, 1997). 

Eigure 41.1 shows a decision tree for treatment with antipsychotics in EOS. Treatment is usually initiated with an atypical antipsychotic medication. Depending on the individual reaction (efficacy and side effects), the current medication can be switched or maintained. Only after two different compounds are not effective or not tolerated should treatment with clozapine be initiated. 

Further study of the efficacy of alternative strategies, including clozapine, steroid antagonists, and verapamil, for the treatment of PMD appears worthwhile. 

The efficacy and favorable neurological side-effect profiles of atypical antipsychotics have led to the recommendation for their uniform use as first-line agents—with the exception of clozapine. 

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