Extrapyramidal side effects clozapine

Non-motor signs of the disorder are also treatable with symptomatic medications. The frequent mood disorder can be treated with standard antidepressants, including tricyclics (such as amitryptiline) or serotonin reuptake inhibitors (SSRIs, such as fluoxetine or sertraline). This treatment is not without risks in these patients, as it may trigger manic episodes or may even precipitate suicide. Anxiety responds to benzodiazepines, as well as to effective treatment of depression. Long-acting benzodiazepines are favored over short-acting ones because of the lesser abuse potential. Some of the behavioral abnormalities may respond to treatment with the neuroleptics as well. The use of atypical neuroleptics, such as clozapine is preferred over the typical neuroleptics as they may help to control dyskinesias with relatively few extrapyramidal side-effects (Ch. 54). 

SGAs cause few or no acutely occurring extrapyramidal side effects. Other attributes ascribed include minimal or no propensity to cause tardive dyskinesia (TD) and less effect on serum prolactin than the FGAs. Clozapine is the only SGA that fulfills all these criteria. 

Clozapine causes virtually no extrapyramidal side effects and can actually relieve tardive dyskinesia. Nevertheless, it is a difficult medication to tolerate. Its common side effects include drowsiness, weight gain, dizziness, constipation, and drooling (sialorrhea). Clozapine also increases the risk that vulnerable individuals may have seizures. 

The conventional antipsychotics have little effect on the negative psychotic symptoms such as autism, stupor and emotional withdrawal. The so-called atypical antipsychotics, or second-generation antipsychotics, like the heterocyclic compound risperidone, the benzamide sulpiride and several diben-zepines of which clozapine is the best known, have a broader spectrum which means that they also have an effect on the negative psychotic symptoms. Most share a common attribute of working on serotonin receptors as well as dopamine receptors. They have a low risk of extrapyramidal side effects. 

Neurological Extrapyramidal side effects, sedation, seizures Dopamine 2, histamine Examine for Parkinsonism, akath-isia, and abnormal involuntary movements at each visit Baseline electroencephalogram if treated with clozapine. 

Extrapyramidal side effects. EPS are uncommon at any dose of clozapine, although some patients experience akathisia or hand tremors. There have been reports of NMS in patients medicated with clozapine alone (Anderson and Powers 1991 DasGupta and Young 1991 Miller et al. 1991). 

Although it was (and still is) not known which pharmacological effects are responsible for the unique clinical action of clozapine, two new hypotheses were put forward the so-called 5-HT2 D2 and the D1 D2 equilibrium hypotheses. According to the former, the beneficial actions of clozapine are the result of simultaneous blockade of (serotonin) 5-HT2 and (dopamine) D2 receptors (Meltzer. 1989). According to the latter hypothesis, the clinical effects of clozapine and particularly the absence of extrapyramidal side effects are due to the balanced action of clozapine on dopamine D1 and D2 receptors... 

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). 

Farde L, Nordstrom A-L, Wiesel FA, et al. PET analysis of central D and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine relation to extrapyramidal side effects. Arch Gen Psychiatry 1992 49 536-544. 

The cost to the patient - 9000 annually. The effectiveness of clozapine in the treatment of schizophrenia was considered very good especially in light of the fact that the extrapyramidal side effects, compared to other... 

Clozapine is considered to be the prototype of the atypical antipsychotics, as it was the first to be recognized as having few if any extrapyramidal side effects, not causing tardive dyskinesia, and not elevating prolactin. Clozapine is one of five antipsychotics with somewhat related chemical structures (Fig. 11-36). Although certainly a serotonin 2A-dopamine 2 antagonist, clozapine also has one of the most complex... 

Quetiapine also has a chemical structure related to that of clozapine (Fig. 11—36), but it has several differentiating pharmacologic (Fig. 11—41) and clinical features, not only as compared with clozapine (Fig. 11—37) but also as compared with risperidone (Fig. 11-39) and olanzapine (Fig. 11-40). Quetiapine is very atypical in that it causes virtually no EPS at any dose and no prolactin elevations. Thus, quetiapine tends to be the preferred atypical antipsychotic for patients with Parkinson s disease and psychosis. It is also useful in schizophrenia, bipolar disorder, and other types of psychosis, in which it has few extrapyramidal side effects. 

An important breakthrough in the development of novel neuroleptics arose over 25 years ago with the discovery of the dibenzazepine neuroleptic clozapine. This neuroleptic was novel because it attenuated both the positive and negative symptoms of schizophrenia without causing extrapyramidal side effects or elevating serum prolactin concentrations, effects which characterize most typical neuroleptics such as chlorpromazine and haloperidol. 

Clinical studies have demonstrated that olanzapine has a similar profile to clozapine without causing agranulocytosis preliminary studies also show that it does not cause extrapyramidal side effects or increase prolactin release. Olanzapine has recently been introduced for the treatment of mania. 

Risperidone has been developed as a combined D2/5-HT2A receptor antagonist. In addition, it has a high affinity for 5-HT1A and 5-HT7 receptors. Whether such an effect has any relevance to its beneficial effects on the negative symptoms of schizophrenia, and lack of extrapyramidal side effects at moderate therapeutic doses, is unknown. An important advantage of risperidone over clozapine lies in its lack of antagonism of muscarinic receptors. 

Quetiapine. This has a somewhat similar pharmacological profile to clozapine and olanzapine due to its multiple receptor antagonists action. It has been shown to reduce both the positive and negative symptoms of schizophrenia and has a low frequency of extrapyramidal side effects. 

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. 

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