Extrapyramidal symptoms antipsychotics

Extrapyramidal symptoms (EPS) Adverse effects of medications such as antipsychotics. EPS include dystonia (involuntary muscle contractions), tardive dyskinesia (repetitive, involuntary movements), parkinsonian symptoms (akinesia and tremors), and akathisia (motor restlessness or anxiety). 

Thirty-five to eighty-seven percent of the patients studied received antiparkinson drugs. Compared to other countries, Japan and Singapore used the most of these antidotes for drug-induced extrapyramidal symptoms. This is most likely related to the frequent use of high-dosage antipsychotic drugs and poly-antipsychotics (see Table 12.3). 

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. 

A metaanalysis showed that 17% to 18% of dementia patients showed a modest treatment response to atypical antipsychotics. Adverse events included somnolence, extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and increased risk of death. 

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 Lithium should be withdrawn and discontinued at least 2 days before electroconvulsive therapy.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. 

We prefer low doses of atypical antipsychotics as a first-line treatment. In this way, the threat of extrapyramidal symptoms is largely avoided without having to use a second anticholinergic medication to offset antipsychotic side effects. Risperidone 0.25-0.5mg/day, olanzapine 2.5mg/day, quetiapine 25mg/day, ziprasidone 20mg/day, or aripiprazole 2.5-5mg/day are reasonable starting doses. The typically higher doses used to treat schizophrenia are usually not necessary. 

In addition to parkinsonism, another extrapyramidal side effect is the so-called acute dystonic reaction in which muscles (usually of the face or neck) go into an acute spasm. A dystonic reaction is painful and unpleasant, usually occurs early in treatment, and sometimes occurs after the very first dose of an antipsychotic. Another extrapyramidal symptom is akathisia, a restless inability to relax and sit still. Akathisia can range from a mild restlessness to extreme agitation. Rarely, patients have been known to attempt suicide during severe episodes of akathisia. It is easy to overlook akathisia, because it can easily be mistaken for a worsening of psychosis or anxiety. 

Haloperidol decanoate (Haldol Decanoate) Antipsychotic Inj 50,100 mg/mL 25-100 mg IM q4 weel long acting. Reduce dose in elderly extrapyramidal symptoms, alpha-blocking effects, high doses may prolong QT interval. 

Extrapyramidal symptoms may occur as a side-effect of antipsychotic drugs. 

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). 

Most antipsychotics and especially the piperazines and the butyrophenones can cause extrapyra-midal symptoms. Blockade of dopamine receptors mainly in the corpus striatum is held responsible for these extrapyramidal effects. They may become manifest as a variety of clinical symptoms and it should be noted that within 24 8 hours after the beginning of treatment acute dystonic reactions like torticollis, facial grimacing and opisthotonos may occur. Parkinsonism-like symptoms such as bradyki-nesia, rigidity and tremor occur after weeks or months of therapy and are more common in the elderly. Motor restlessness, i.e. akathisia, also mostly occurs not before weeks or months after starting therapy. The tendency of an antipsychotic agent to produce extrapyramidal symptoms appears to be inversely related to its ability to block cholinergic 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). 

As in adults, the main acute untoward effects of high-potency, typical antipsychotics are extrapyramidal symptoms (EPS) syndromes, particularly acute dystonia, and sedation (167). Parkinsonism is rare in preschool-aged children but does occur in school-aged children and adolescents. 

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. 

From a clinical perspective, an atypical antipsychotic, however, is defined in part by the clinical properties that distinguish such drugs from conventional antipsychotics, namely, low extrapyramidal symptoms and efficacy for negative symptoms. By understanding the difference between blocking dopamine D2 receptors alone... 

Shirzadi, A. A. Ghaemi, S. N. 2006, Side effects of atypical antipsychotics extrapyramidal symptoms and the metabolic syndrome, Harv.Rev.Psychiatry, vol. 14, no. 3, pp. 152-164. 

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). 

Lewis R. Typical and atypical antipsychotics in adolescent schizophrenia efficacy, tolerability, and differential sensitivity to extrapyramidal symptoms. Can J Psychiatry 1998 43(6) 596-604. 

---