Extrapyramidal symptoms with antipsychotics

Akathisia has been reported in 16% of patients taking olanzapine (SEDA-21, 56). Three patients developed severe akathisia during treatment with olanzapine (20-25 mg/day) (87). In two, the akathisia resolved after withdrawal of olanzapine and in one of those olanzapine was well tolerated when reintroduced in combination with lorazepam. In the third patient, the akathisia was controlled by dosage reduction. A 33-year-old man with AIDS and a prior history of extrapyramidal symptoms with both typical antipsychotic drugs and risperidone developed dose-dependent akathisia with olanzapine 15-19 mg/day the akathisia responded to dosage reduction and beta-blockade (88). 

Extrapyramidal side-effects generally appear with blockade of dopamine D2 receptors in excess of 80%, whereas clinical efficacy in treating psychosis is associated with 60-70% D2 receptor blockade [12]. Recently, a partial agonist for the D2 receptor known as aripiprazole has been developed, which results in approximately 70% antagonism/30% agonism at the D2 receptor. It is an effective antipsychotic, has low risk for extrapyramidal symptoms, and does not cause elevated levels of prolactin as do the full antagonists at D2 receptors. 

Combining lithium with typical antipsychotics may cause neurotoxicity (e.g., delirium, cerebellar dysfunction, extrapyramidal symptoms). Lithium should be withdrawn and discontinued at least 2 days before electroconvulsive therapy. 

Areca may interact adversely with antipsychotic medications (Deahl 1989). Two cases have been reported of schizophrenic patients who were taking neuroleptics and developed severe extrapyramidal symptoms after areca chewing. Given the functional antagonism between dopamine and acetylcholine in the striatum, it is likely that arecoline amplified the dyskinetic effect of neuroleptic medications. 

Delusions/Psychosis. Demented patients who are acutely psychotic and agitated should be treated in much the same manner as demented patients with delirium. Low doses of a high potency conventional antipsychotic like haloperidol were once preferred. This was mainly because it can be given both orally and by injection. In recent years, the atypical antipsychotic ziprasidone, which is now also available in oral and injectable forms, has superseded haloperidol as the preferred agent when treating the acutely psychotic and agitated patient with dementia. As previously noted, ziprasidone affords the same tranquilizing benefit as haloperidol, it can now be administered via injection when necessary, and it avoids the problematic extrapyramidal symptoms of haloperidol to which patients with dementia are often keenly sensitive. 

Extrapyramidal symptoms (EPS) Dystonic reactions develop primarily with the use of traditional antipsychotics. EPS has occurred during the administration of haloperidol and pimozide frequently, often during the first few days of treatment. Neuroleptic malignant syndrome (NMS) A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, rhabdomyolysis, and acute renal failure. 

Encephalopathic syndrome - An encephalopathic syndrome (characterized by weakness, lethargy, fever, tremulousness, confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, blood urea nitrogen, fasting blood sugar) has occurred in a few patients treated with lithium plus an antipsychotic (haloperidol). 

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). 

Some of the H antagonists, especially diphenhydramine, have significant acute suppressant effects on the extrapyramidal symptoms associated with certain antipsychotic drugs. This drug is given parenterally for acute dystonic reactions to antipsychotics. 

FIGURE 11 — 11. One compensation for the overactivity of acetylcholine that occurs when dopamine receptors are blocked is to block the acetylcholine receptors with an anticholinergic agent. Thus, anticholinergics overcome excess acetylcholine activity caused by removal of dopamine inhibition when dopamine receptors are blocked by conventional antipsychotics. This also means that extrapyramidal symptoms (EPS) are reduced. 

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). 

Four patients developed tardive dyskinesia while taking conventional antipsychotic drugs and were switched to sertindole (5). Three apparently recovered from the movement disorder. In the other patient sertindole monotherapy was not sufficient to reduce the movement effects, but combination treatment with tetrabe-nazine resulted in a greater reduction in extrapyramidal symptoms. There was no evidence of QTC prolongation in these patients, but one patient gained 8 kg in weight. 

ANTIPSYCHOTICS TETRABENAZINE Case report of extrapyramidal symptoms when tetrabenazine is given with chlorpromazine Uncertain Warn patients to report any extrapyramidal symptoms... 

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