Extrapyramidal symptom clozapine

The four drugs were administered by psychiatrists blinded to treatment group assignment of patients. The 14-week study consisted of an 8-week dose escalation and fixed dose and a 6-week variable-dose period. The mean dose levels (mg/day) of the four compounds after the first 8 weeks were 452 for clozapine. 20.2 for olanzapine. 8.3 for risperidone and 19.6 for haloperidol. Patients on haloperidol received prophylactic anticholinergic medication to prevent extrapyramidal symptoms, and a few other drugs were permitted to treat agitation and insomnia. 

Because clozapine may block specific DA receptors, its antipsychotic activity could be consistent with an antidopaminergic mechanism of action. Conversely, clozapine does not typically induce extrapyramidal symptoms, which are presumably subserved by the A-9 system. Thus, while clozapine is known to block striatal DA receptors, in positron emission tomography (PET) studies, resolution is not sufficient to clarify effects on other tracts. Furthermore, low doses of metoclopramide, which significantly decrease the number of DA neurons spontaneously active in A-9, do not have antipsychotic effects (except at high doses) but can induce tardive dyskinesia (TD), as well as acute extrapyramidal side effects (EPS). 

Decision/Solution. These initial extrapyramidal symptoms suggested the onset of tardive dyskinesia. The therapist notified the patient s physician, and drug therapy was progressively shifted from haloperidol to the atypical agent clozapine (Clozaril), 450 mg/d. The extrapyramidal symptoms gradually diminished over the next 8 weeks and ultimately disappeared. 

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. 

The synthesis and discovery of the antipsychotic effects of the piperazinyl-dibenzoazepine, clozapine (Fig. 13.1) and its launch in 1972 was an important turning point in the drug treatment of schizophrenia [1-3]. Clozapine was called an atypical antipsychotic as it did not produce side effects characteristic for compounds of the chlorpromazine- or haloperidol-type (i.e., extrapyramidal symptoms) either in animal models or in the clinic. Its use, however, became very limited when it was recognized that clozapine might cause a severe, and sometimes fatal, form of agranulocytosis. 

In the in-vitro kinetic experiments, the rates of association (Kon) and dissociation (Kan) of various (labeled) antipsychotic compounds to dopamine D2 receptors were determined. Kapur and Seeman found that antipsychotics substantially differ (almost 1000-fold) in their Koff rate (whereas only 10-fold differences were found in the Kon rate), and that this value is highly correlated with their affinity to D2 receptors. These authors also demonstrated that Koff for clozapine, olanzapine and quetiapine was 1.386 min"1, 0.039 min"1, and 3.013 min"1, respectively, and assumed that the rate of how rapidly they left the receptor was an important mechanism in their atypical antipsychotic action. Indeed, this fully explained the lack of extrapyramidal symptoms (EPS) and hyperprolactinemia and the low risk for tardive dyskinesia [34—36]. In this regard, quetiapine (which has the lowest affinity to D2 receptors) seems to be the most atypical among all tested antipsychotics, followed by clozapine and olanzapine (nevertheless, olanzapine s Koff value is close to those of raclopride and chlorpromazine). 

Clozapine has been evaluated in an open study in seven patients (mean age 29 years mean dose 428 mg/day) with chronic exacerbated schizophrenia and severe tardive dyskinesia (92). Extrapyramidal Symptoms Rating Scale scores fell by 83% after 3 years and 88% after 5 years. None of the patients had adverse effects related to clozapine their weight did not change significantly and their serum glucose, cholesterol, and triglyceride concentrations remained within the reference ranges. 

The dibenzodiazepine clozapine (Table 12-14, X = NH), which is an antischizophrenic, has been approved on a limited basis (1989). Its atypical properties are that it does not bind to DA receptors and, as a result, does not appear to cause extrapyramidal symptoms. It may even reverse tardive dyskinesia. Unfortunately, reports of a high incidence of agranulocytosis severely restricts its use to patients who are refractory to standard antipsychotic medications. Fluperlapine (Table 12-14) is currently being investigated as an alternative... 

---