1. Potency of neuroleptic
The prevalance of acute dystonia in the 1960's was found to be 2.3% (Ayd, 1961), which gradually increased to reach 40% by the 1980's (Keepers et al, 1983). This steady increase in the prevalance of acute EPS is thought to be related to greater use of high potency compounds. Low milligram high potency compounds (such as haloperidol and fluphenazine) have little anticholinergic activity and produce many more EPS than high milligram, low potency compounds (such as chlorpromazine and thioridazine). These latter compounds have considerably more anticholinergic activity. Newer neuroleptics (e.g. clozapine and risperidone) pose less risk of causing EPS, which may be due to regional specificity of their action or because of their action on other neurotransmitter systems (Meltzer et al, 1989).
2. Neuroleptic dose
The relationship between neuroleptic drug dose and acute EPS is complex. Lower doses have been found to produce fewer EPS than moderate and high doses, but very high or magadoses produce few EPS than "high doses" (Casey & Keepers, 1988; Keepers et al, 1983). Keepers & Casey (1987) also found that the risk of dystonia was greatest at `intermediate' doses. It has been proposed that with intermediate doses near complete blockade of central dopamine receptors occurs and further dose increase may thus not affect the dopamine system further. On the other hand, Garver et al (1976) found a correlation of dystonia with decreasing neuroleptic serum levels suggesting that dystonia may result from compensatory cholinergic and dopaminergic hyperactivity when dopamine blockade is incomplete (Marsden & Jenner, 1980). If this is correct, reduced risk for dystonia at higher doses of neuroleptics can be explained by a more complete dopaminergic blockade caused by large doses (Keepers & Casey, 1987).
3. Type of neuroleptic
Atypical neuroleptics produce fewer EPS. Substituted benzamides which are highly selective D-2 antagonists have unexpectedly low rates of acute EPS (Lewander et al, 1990). This observation actually challanges the hypothesis that EPS are solely due to D-2 receptor antagonism. It is proposed, however, that some D-2 antagonists may selectively antagonise dopamine receptors in the limbic and prefrontal cortical regions, while sparing the basal ganglia, thus producing fewer EPS. Other newer antipsychotics (e.g. clozapine, risperidone, etc) also produce fewer EPS which is thought to be due to their action on multiple neurotransmitters (Meltzer et al, 1989).
Age and gender have been found to be important factors in the development of EPS. Acute dystonia is seen more frequently in children, adolescents and young adults, whereas it is infrequent in the elderly (Keepers et al, 1983; Addonizio & Alexopoulos, 1988). Moleman et al (1982) found that young age was a significant factor in developing parkinsonism secondary to neuroleptic use.
Asian race has been implicated a risk factor for EPS (Binder & Levy, 1981) and has demonstrated an increased incidence of EPS when given similar neuroleptic doses (Un & Finder, 1983), although others (e.g. Sramek et al, 1986) have failed to replicate this finding.
Different EPS make their appearance in a characteristic temporal pattern after initiation of neuroleptic treatment (Casey, 1994). Akathisia appears within a few hours to a few days of initiating treatment with neuroleptics. Acute dystonia most commonly occurs on the second day and almost always occurs within the first 96 hours of beginning or rapidly increasing neuroleptic dosages. Parkinsonian symptoms usually develop after a few days (sometimes over weeks) after beginning neuroleptic treatment (Ayd, 1961). After continuous treatment over weeks or months many patients develop tolerance to their EPS. This acclimatization is thought to decrease the need for anticholinergic treatment and many authors have suggested that antiparkinsonian treatment may be unnecessary after three months of initiation of neuroleptic treatment (see above).
Patients who have experienced EPS with prior neuroleptic treatment are vulnerable to further EPS, if a similar drug type and dose is re-prescribed. If this information is available, it is thought that recurrance risk of EPS can be reliably predicted with 75-85% accuracy (Keepers & Casey, 1987; 1991).