1. Compliance It is essential for long-term management of schizophrenic patients that a regularity of neuroleptic administration is maintained. EPS as a result of neuroleptic administration can be severe and disturbing to the patient. An already reluctant patient may find EPS a reasonable excuse to stop taking neuroleptic medication. The issue of endangering therapeutic alliance secondary to a severe and distressing EPS has to be taken seriously (Lavin & Rifkin, 1991b).
Several authors have suggested that the incidence of side effects with anticholinergic drugs is actually low (Goldstein et al, 1964; Grove & Crammer, 1972; Winslow et al, 1986), however, anticholinergic drugs have their own side effects which can be very distressing to the patient (also see above). Antimuscarinic side effects of dry mouth, blurred vision, urinary retention and constipation are some of the reasons given by patients to avoid taking their medication (DiMascio & Demirgian, 1970).
It may be difficult at times to distinguish several symptoms of schizophrenia from EPS. Dystonia & other involuntary movements may resemble mannerisms of schizophrenic psychosis; agitation and psychic and somatic anxiety may resemble akathisia; psychomotor retardation and bradikinesia are difficult to distinguish from depression and negative and residual symptoms of schizophrenia (Rifkin et al, 1978). Therefore, treatment of EPS with anticholinergic drugs may facilitate the process of differential diagnosis. However, Simpson et al (1970) on the other hand, suggested that hypokinesia and rigidity can be good markers of therapeutic dose monitoring of a neuroleptic and use of anticholinergic drugs may mask this effect and may prove to be a disadvantage in objective monitoring of neuroleptic administration.
3. Influence on psychopathology
It is assumed that anticholinergic drugs do not affect schizophrenic symptomatology, however, several reports in the literature suggest that use of anticholinergic drugs may result in worsening of positive schizophrenic symptomatology (Gershon & Olariu, 1960; Itil et al, 1969; Tandon & Greden, 1989; Tandon et al, 1990) although this finding has not been found to be consistent across studies (Manos et al, 1981; Baker et al, 1983; Manos & Gkiouzepas, 1981). Anticholinergic drugs have also been reported to help relieve negative symptoms of schizophrenia (Fayen et al, 1988; Tandon et al, 1988; Tandon & Greden, 1989).
Several authors have suggested that anticholinergic agents may antagonise the therapeutic effect of neuroleptics in schizophrenia (Singh & Kay, 1979; Johnstone et al, 1983, 1988; Singh et al, 1987). There have been several reports of exacerbation of psychotic symptomatology in schizophrenic patients with concomitant treatment of anticholinergic drugs. Others, have suggested that withdrawal of maintenance antiparkinsonian drugs may lead to an increase in psychopathology in some patients (Ananth et al, 1970; McClelland et al, 1974; Rifkin et al, 1975; Jellinek et al, 1981; Manos et al, 1981; Baker et al, 1983; Manos & Gkiouzepas, 1981).
4. Some patients may abuse or misuse anticholinergic drugs.
The potential for abuse or misuse of anticholinergic drugs has been a cause of concern for psychiatrists for a long time (Macvicar, 1977). Although reviews of literature on abuse of anticholinergic drugs failed to derive any conclusions on the epidemiology, demography and extent of abuse of anticholinergic drugs (Smith, 1980; Dilsaver, 1988), several anecdotal reports and other reviews have highlighted the potential of abuse and misuse of anticholinergic drugs (also see above).
5. Added cost to patient Results of some studies suggest that use of prophylactic antiparkinsonian agents may not be necessary as many patients will never manifest EPS with the use of neuroleptic medication (DiMascio & Demirgian, 1970). Therefore, the total cost to the patient is increased. However, if control of EPS leads to better compliance with neuroleptic medication and thus to fewer exacerbations, decreased incidence of hospitalisation and a better quality of life, possibly the cost of the anticholinergic drug is well compensated for.
Concurrent administration of anticholinergic agents with neuroleptic drugs has been blamed for increasing the risk of developing tardive dyskinesia. This assumption has been strongly suggested by both uncontrolled (Fann & Lake, 1974; Chouinard et al, 1979; Klawans & Rubovits, 1974; Gerlach, 1977) and controlled (Gerlach & Thorsen, 1976; Greil et al, 1984) studies. The administration of anticholinergic drugs to patients with tardive dyskinesia was found to lead to exacerbation of tardive dyskinesia (Turek et al, 1972; Chouinard et al, 1979), while withdrawal of anticholinergic medication led to a significant reduction in the severity of tardive dyskinesia (Burnett et al, 1980; Reunanen et al, 1988). It has been suggested that stopping anticholinergic drugs may increase the neuroleptic plasma levels which may be the reason for suppression of signs of tardive dyskinesia (Greil et al, 1984). Birket-Smith (1974) had earlier suggested that anticholinergic drugs alone (without neuroleptics) are capable of producing tardive dyskinesia. However, there are other reports of no association of increased prevalence of tardive dyskinesia with anticholinergics (Jus et al, 1976; Bell & Smith, 1978; Kennedy et al, 1971) and even of improvement of tardive dyskinesia with high doses of anticholinergics (Crane, 1973; Vale & Espejel, 1971; Granacher et al, 1975; Casey & Denney, 1977).
7. Drug interactions Significant drug interactions occur with concomitant use of anticholinergics and other psychotropic medication including neuroleptics and antidepressants as some have strong anticholinergic activity of their own and therefore can result in exacerbation of peripheral and central anticholinergic side effects. Additive CNS effects with use of anticholinergic drugs with antihistaminics and alcohol can result in confusion and disorientation (Tatro, 1993; Bezchlibuyk-Butler & Remington, 1991).
8. Decrease in therapeutic activity of neuroleptics
Use of anticholinergic drugs to control neuroleptic-induced parkinsonism may inadvertently result in the decrease in therapeutic activity of neuroleptic drugs (Haase, 1965; Singh & Smith, 1973; Singh & Kay, 1975ab). It has been suggested that anticholinergic drugs may reverse the effects of blockade of cerebral dopamine receptors caused by neuroleptic therapy by blocking cholinergic receptors and thus causing functional increase in cerebral dopamine activity. Anticholinergic effects of these drugs may also result in delayed gastric evacuation of a neuroleptic, decreased absorption from the gut and also increased metabolism as a result of enzyme induction (Bolvig et al, 1979).
Some investigators have found worsening of psychotic symptoms with addition of anticholinergics to existing treatment regime (Tandon et al, 1989), however, the same group had reported an improvement in symptoms earlier (Tandon et al, 1988). Anticholinergic drugs have been reported to improve negative symptoms of schizophrenia (Tandon et al, 1988;1989) and to worsen positive symptoms (Wilcox & Tsuang, 1990). However, withdrawal of anticholinergic drugs has been associated with worsening of psychotic symptoms (Greil et al, 1984; Jellineck et al, 1981).
Selection of a particular treatment option will also be determined by the type of EPS. Review of the literature and clinical experience suggest that acute dystonia will respond well to anticholinergic drugs, while akathisia does not respond very well to these agents. If akathisia is distressing, benzodiazepines such as diazepam or clonazepam should be tried. Benzodiazepines are particularly useful to suppress motor restlessness and mental distress. Beta blocker propranolol in doses of 30-80mg has also been used and found to be moderately effective.
Other risk factors (as discussed above) should be kept in mind and may help tailor anticholinergic treatment to individual needs.
If EPS continues in spite of an increase in dose of one anticholinergic agent, change to another anticholinergic agent should be considered. The WHO consensus statement on the use of anticholinergic drugs recommends the continuation of anticholinergic drugs for approximately three months after which a slow reduction in doses of anticholinergic drugs should be tried. Drugs should be withdrawn if it is at all possible. If EPS recurs, an anticholinergic drug may need to be reinstituted. However, an attempt to reduce and discontinue the anticholinergic drug should be made again after another 3-4 months.
Side effects of anticholinergic agents and their potential for abuse may further complicate the process of selection. If there are sufficient reasons not to commence treatment with anticholinergic drugs, a non-anticholinergic treatment (e.g. amantadine) can be tried.