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Textbook of Psychopharmacology >
Chapter 34. Drugs to Treat Extrapyramidal Side Effects
EXTRAPYRAMIDAL SIDE EFFECTS
History
The discovery of the therapeutic properties of chlorpromazine (Delay and Deniker 1952; Laborit et
- 1952) was soon followed by the description of its tendency to produce extrapyramidal side
effects (EPS) that were indistinguishable from classical Parkinson’s syndrome. A debate soon arose
regarding the relationship between EPS and therapeutic efficacy. Flügel (1953) suggested that a
therapeutic response from chlorpromazine required the development of EPS. Haase (1954)
postulated that the neuroleptic dose that produced minimal subclinical rigidity and hypokinesis
(i.e., the “neuroleptic threshold”) was the minimal neuroleptic dose necessary for therapeutic
antipsychotic effect and that it was manifested by micrographic handwriting changes. Other
investigators also reported that EPS were necessary for therapeutic efficacy (see Denham and
Carrick 1960; Karn and Kasper 1959).
Brooks (1956), on the other hand, suggested that “signs of parkinsonism heralded the particular
effect being sought” (p. 1122) but that “the therapeutic effects were not dependent on
extrapyramidal dysfunction. On the contrary, alleviation of such dysfunction, as soon as it occurred,
sped the progress of recovery” (p. 1122). The need to develop EPS for therapeutic efficacy was also
questioned by others. The differences in opinion regarding EPS and neuroleptic efficacy were
partially attributable to differences in the definitions of EPS and in the methodologies of the studies
(Chien and DiMascio 1967).
Haase’s concept—that mild subclinical EPS manifested by handwriting changes were indicative of a
therapeutic dose—was demonstrated in studies that found no difference in therapeutic response at
doses beyond the neuroleptic threshold (Angus and Simpson 1970a; G. M. Simpson et al. 1970).
Patients treated with doses beyond the neuroleptic threshold received significantly larger doses of
medication without further therapeutic benefit. This finding has been discussed more fully
(Baldessarini et al. 1988) and has been replicated (McEvoy et al. 1991).
When clozapine was first developed in 1960, it sparked little interest as a potential antipsychotic.
Many investigators believed that EPS were necessary for antipsychotic effect, and clozapine
appeared not to produce EPS. Even after studies showed that clozapine possessed antipsychotic
activity, interest regarding commercial development was still limited. The hesitancy on the part of
the pharmaceutical company was related to the belief held by many members of the psychiatric
community—that is, that a drug could not have antipsychotic effect without producing EPS (Hippius
1989).
In contrast, the current goal in the development of new antipsychotic medications is to replicate
the EPS profile of clozapine and to develop antipsychotics that do not produce EPS. This situation
essentially brings the story of EPS full circle.
The terms used to name and characterize antipsychotic medications have also evolved. The term
tranquilizer was initially introduced to characterize the psychic effects of reserpine. The term
neuroleptic, derived from Greek and meaning “to clasp the neuron,” was introduced to describe
chlorpromazine and the extrapyramidal effects that it produced (Delay et al. 1952). Until clozapine
was approved for use, all commercially available drugs with antipsychotic properties possessed the
following neuroleptic properties: blocking apomorphine and amphetamine-induced stereotypy;Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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antagonizing the conditioned avoidance response; and producing catalepsy, elevated serum
prolactin levels, and EPS. For that reason, all antipsychotic drugs were referred to as neuroleptics.
With the subsequent development of clozapine and other antipsychotic drugs that possess reduced
EPS profiles, the term neuroleptic no longer correctly categorizes all drugs with antipsychotic
effects; therefore, the term antipsychotic is more accurate and more preferable.
Severe EPS can have a significantly negative effect on treatment outcome by contributing to poor
compliance and exacerbation of psychiatric symptoms (Van Putten et al. 1981). Akathisia, in
particular, is associated with poor clinical outcome (Levinson et al. 1990; Van Putten et al. 1984),
increased violence (Keckich 1978), and even suicide (Shear et al. 1983). The presence of EPS early
in treatment may place a patient at increased risk of developing tardive dyskinesia (TD) (Saltz et al.
1991). Orofacial TD may have a negative effect on the social acceptability of patients, even though
they are often unaware of the movements (Boumans et al. 1994). Laryngeal dystonia can adversely
affect speech, breathing, and swallowing (Feve et al. 1995; Khan et al. 1994) and can be potentially
life-threatening (Koek and Pi 1989). Clearly, EPS are significant, need to be assessed, and should
be minimized so that the overall treatment and health of patients may be optimized.
Types
Four types of EPS have been delineated, and the treatment of each type should be individualized.
Acute dystonic reactions (ADRs) are generally the first EPS to appear and are often the most
dramatic (Angus and Simpson 1970b). Dystonias are involuntary sustained or spasmodic muscle
contractions that cause abnormal twisting or rhythmical movements and/or postures. ADRs tend to
occur suddenly and generally involve muscles of the head and neck (as in torticollis, facial
grimacing, or oculogyric crisis). Nearly 90% of all ADRs occur within 4 days of antipsychotic
initiation or dosage increase, and virtually 100% of all ADRs occur by day 10 (Singh et al. 1990;
Sramek et al. 1986). Although tardive dystonia can occur after this period, movements occurring
beyond this time frame are much less likely to be ADRs. Instead, other conditions, including
seizures, need to be considered.
Akathisia is the second type of EPS to appear. Akathisia, meaning “inability to sit,” consists of both
an objective restless movement and a subjective feeling of restlessness that the patient
experiences as the need to move. It may be difficult for a patient to explain the sensation of
akathisia, and the diagnosis can be missed. At times, patients may display the classical movements
of akathisia, but they may not have the subjective distress—a condition that has been termed
pseudoakathisia, which may be a type of tardive syndrome (Barnes 1990).
The third type of EPS, (pseudo)parkinsonism, is virtually indistinguishable from classical
Parkinson’s syndrome. The symptoms include a generalized slowing of movement (akinesia),
masked facies, rigidity (including cogwheeling rigidity), resting tremor, and hypersalivation.
Parkinsonism generally occurs after a few weeks or more of neuroleptic treatment. Akinesia needs
to be differentiated from primary depression and the blunted affect of schizophrenia (Rifkin et al.
1975).
Tardive syndromes make up the fourth group of EPS. TD, although clearly associated with the use of
antipsychotic medications, was actually described prior to the advent of antipsychotics (G. M.
Simpson 2000). TD consists of irregular stereotypical movements of the mouth, face, and tongue
and choreoathetoid movements of the fingers, arms, legs, and trunk. It tends to occur after months
to years of use of antipsychotic medications. Patients frequently have no awareness of the
abnormal movements. The lack of awareness may be related to frontal lobe dysfunction (Sandyk et
- 1993).
Tardive dystonia, a variant of TD, also generally emerges months to years after treatment with
antipsychotics (Burke et al. 1982) Unlike in ADRs, the movements associated with tardive dystonia
tend to be persistent and more resistant to medical treatment (Kang et al. 1988).
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Ayd (1961) was the first to report the incidence of EPS, noting an overall incidence of 39%, with
21% demonstrating akathisia, 15% demonstrating parkinsonism, and only 2% having ADRs.
Varying rates of occurrence, including much higher incidences of ADRs, have been reported since
that time. A prospective study found that the range of incidence of ADRs was between 17% and
38%, with the higher rate occurring with haloperidol (Sramek et al. 1986). In general, higher
prevalence rates for all types of EPS occur at higher doses and with higher-potency antipsychotics.
In a series of surveys of 721 patients with schizophrenia conducted over 10 years, McCreadie
(1992) found that the point prevalence was 27% for parkinsonism, 23% for akathisia or
pseudoakathisia, and 29% for TD. Forty-four percent of patients had no movement disorder. A
10-year prospective study found that the overall incidence of TD within a group remained fairly
stable—30% at baseline, 37% at 5 years, and 32% at 10 years (Gardos et al. 1994).
Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies found the
presence of probable TD by Schooler-Kane criteria in 212 (15%) of 1,460 subjects (D. D. Miller et
- 2005). Tardive dystonia has been reported to occur in 1%–2% of patients taking antipsychotic
medications (Yassa et al. 1986).
Extrapyramidal movements have been reported to occur in 17%–29% of neuroleptic-naive patients
with schizophrenia (Caligiuri et al. 1993; Chatterjee et al. 1995). This finding raises questions
regarding the role of antipsychotics in the etiology of TD (see G. M. Simpson et al. 1981).
These data refer to first-generation typical antipsychotics. Data from the CATIE trials include
subjects treated with second-generation atypical antipsychotics as well as typical antipsychotics.
The presence of probable TD by Schooler-Kane criteria was found in 212 of 1,460 subjects (15%),
which is lower than rates noted above (D. D. Miller et al. 2005). The incidence for all types of EPS
has been shown to be less with the second-generation atypical antipsychotics.
Etiology
The exact mechanisms involved in the production of EPS are not known. Control of motor activity
apparently involves an interaction between nigrostriatal dopaminergic, intrastriatal cholinergic, and
-aminobutyric acid (GABA)–ergic neurons (Côté and Crutcher 1991). Extrapyramidal movements of
parkinsonism and dystonia classically have been thought to result from antipsychotic blockade of
dopaminergic nigrostriatal tracts, resulting in a relative increase in cholinergic activity (Snyder et
- 1974). Drugs that either decrease cholinergic activity or increase dopaminergic activity reduce
EPS, presumably by restoring the two systems to their previous equilibrium, as demonstrated in
ADRs in monkeys (Casey et al. 1980). This feature is the basis for the use of anticholinergics in the
treatment of EPS.
The etiology of TD is thought to result from more complex changes, which include increased
dopamine receptor sensitivity following prolonged dopamine blockade (Gerlach 1977). The
production of EPS probably involves more complex interactions of other factors and receptor types,
which have become the subject of investigation.
Decreased serum calcium has been associated with increased EPS. Calcium is involved in the
function of the cholinergic system and in the metabolism of dopamine (Kuny and Binswanger
1989), and antipsychotic drugs bind to the calcium-dependent activator of several enzyme systems.
(Calmodulin has been studied by el-Defrawi and Craig [1984].)
GABA may have an effect on EPS through inhibitory feedback on the dopaminergic system. Reduced
GABA synthesis and reduced GABA levels have been found with TD (Gunne et al. 1984; Thaker et al.
1987). The effect of GABA on ADRs is not as clear. ADRs in baboons were found to be increased by
drugs that increased GABA levels, as well as by drugs that decreased GABA (Casey et al. 1980).
-Adrenergic mechanisms may be involved in TD, akathisia, and tremor (Wilbur et al. 1988).
Clozapine is a potent 1-adrenergic receptor antagonist in the brain, causing 1 receptor
upregulation and increased noradrenergic metabolism, factors that may affect the EPS profile of
clozapine (Baldessarini et al. 1992).Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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Free radicals, possibly produced by chronic neuroleptic use, have been proposed as contributors to
the development of neuropathic damage and TD. Vitamin E, as an antioxidant that binds free
radicals, has been suggested as a treatment for TD by limiting the process (Cadet et al. 1986).
Levels of lipid peroxides, theoretically produced by free radicals, have not been found to correlate
with TD (McCreadie et al. 1995), nor have changes in levels correlated with treatment with vitamin
E, although it was noted that these changes could be occurring centrally (Corrigan et al. 1993).
A somewhat related theory suggests that increased iron levels in the basal ganglia may contribute
to TD because of the involvement of iron in the production of free radicals (Ben-Shachar and
Youdim 1987). However, neuroimaging and pathological studies have not demonstrated increased
iron levels on a consistent basis (Elkashef et al. 1994).
The metabolism of antipsychotics may contribute to EPS. Haloperidol, when given intravenously,
has a much lower incidence of EPS than when it is used orally or intramuscularly, even when given
at extremely high doses. Haloperidol is metabolized to reduced haloperidol in the liver. When
administered intravenously, haloperidol enters the central nervous system (CNS) before
metabolites are produced. It has been proposed that dopamine2 (D2) receptor saturation by
haloperidol, rather than by reduced haloperidol, could account for the difference in EPS production
(Menza et al. 1987).
More recent investigations of clozapine and other novel antipsychotics have focused on dopamine
and serotonin (5-HT) receptors (Kapur and Remington 1996). Clozapine, olanzapine, quetiapine,
risperidone, and ziprasidone are potent serotonin2A (5-HT2A) receptor antagonists and relatively
weaker D2 antagonists, compared with typical antipsychotics. They all have a reduced EPS profile,
compared with typical antipsychotics (Meltzer 1999).
Typical antipsychotics initially increase dopamine synthesis, turnover, and release in the striatum
of baboons (Meldrum et al. 1977). This increased dopamine production reaches a maximum 1–5
hours after a single neuroleptic injection, which corresponds in time with the development of ADRs
in baboons. During chronic treatment (up to 11 days), there is a marked diminution in the capacity
of the antipsychotics to provoke an increased turnover of dopamine. Chronic haloperidol treatment
causes decreased striatal dopaminergic neurotransmission and upregulation of postsynaptic D2
receptors (Ichikawa and Meltzer 1991). In contrast, chronic clozapine treatment causes a slight
increase in striatal dopaminergic neurotransmission and no changes in D2 receptors. This has
recently also been demonstrated in humans (Silvestri et al. 2000). These differences may partly
explain the lack of occurrence of EPS and TD with clozapine and perhaps also with the other novel
antipsychotics.
Dopamine1 (D1) receptor antagonists have a lower EPS potential than do traditional D2
antipsychotics in nonhuman primates (Coffin et al. 1989). Patients who were clinical responders to
antipsychotics and who had lower D2 receptor occupancy by positron emission tomography (PET)
analysis were found to have a lower incidence of EPS. Patients treated with clozapine had lower D2
receptor occupancy than patients treated with typical antipsychotics (Farde et al. 1992). The
balanced D1/D2 receptor function may prevent development of EPS and TD (Gerlach and Hansen
1992).
The rate of dissociation from the D2 receptor may be as important as the degree of D2 blockade,
with regard to EPS. Novel antipsychotics have a faster dissociation rate from the D2 receptor than
do traditional antipsychotics (Kapur and Seeman 2001).
The high ratio of serotonin2 (5-HT2) receptor blockade to striatal D2 receptor blockade that occurs
with clozapine may account for clozapine’s lack of EPS (Meltzer et al. 1989). Evidence suggests that
decreasing serotonergic neurotransmission reverses or prevents catalepsy induced by D2 receptor
blockade (Meltzer and Nash 1991).
Clozapine also has a high affinity for dopamine3 (D3) and dopamine4 (D4) receptors (Sokoloff et al.
1990; Van Tol et al. 1991). The binding of clozapine to these receptors has also been proposed as a
possible mechanism involved in the favorable EPS profile of clozapine.Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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Rating
Investigations of treatment for EPS led to the need to develop instruments to evaluate and quantify
them. An initial EPS scale was shown to have both clinical validity and high interrater reliability, but
it did not adequately assess salivation and tremor (G. M. Simpson et al. 1964). Scores were low,
despite obvious and disabling tremor or salivation that required treatment with antiparkinson
medication. Subsequently, the scale was expanded to 10 items (rated on a five-point scale),
including tremor and salivation (G. M. Simpson and Angus 1970). This scale has good psychometric
properties and is simple to use and score. It has been modified for outpatient use by eliminating the
leg rigidity item and by replacing head dropping with head rotation. Studies using this scale have
shown that scores correlate with the dosages and plasma levels of an antipsychotic. The scale is
widely used in clinical trials and can be completed by nurses for the routine monitoring of
neuroleptic treatment.
The Simpson-Angus Scale does not include a direct rating for bradykinesia or akinesia. Mindham
(1976) modified the scale to include an item for lack of facial expression. Additional rating scales
for EPS have since been developed, including the Chouinard Extrapyramidal Rating Scale
(Chouinard et al. 1980), Targeting of Abnormal Kinetic Effects (TAKE) Scale (Wojcik et al. 1980),
St. Hans Rating Scale for Extrapyramidal Syndromes (Gerlach et al. 1993), and Dyskinesia
Identification System Condensed User Scale (DISCUS; Kalachnik and Sprague 1993).
The Modified Simpson-Angus Scale includes a single item for rating akathisia. More comprehensive
scales have been devised specifically to rate akathisia, including the Barnes Akathisia Rating Scale
(Barnes 1989), Hillside Akathisia Scale (Fleischhacker et al. 1989), and Prince Henry Hospital
Akathisia Rating Scale (PHH Scale; Sachdev 1994).
Scales have also been developed for the assessment of dyskinetic movements. These include the
Abnormal Involuntary Movement Scale (AIMS; Guy 1976) and the Simpson/Rockland Scale (G. M.
Simpson et al. 1979).
Instrumental devices have been developed for the assessment of EPS, and several have been
shown to correlate with clinical scales (Büchel et al. 1995). Instrumental devices have the
advantage of increased reliability of quantitative measures, primarily through the elimination of
subjective error associated with clinical raters; however, instrumental devices also have
disadvantages. They often require greater patient cooperation than do clinical scales. They may
require physical contact with the subject, which can affect measurements. They often evaluate a
limited area, unlike clinical scales, which evaluate a patient in multiple areas as well as globally. As
of this writing, clinical scales generally can be considered to have better global clinical validity with
greater ease of use, while instrumental measures provide greater reliability (Büchel et al. 1995).
ANTICHOLINERGIC MEDICATIONS
Trihexyphenidyl
History and Discovery
Antiparkinsonian medications are drugs that have primarily been used to treat EPS and include
anticholinergic, antihistaminic, and dopaminergic agents (Table 34–1).
TABLE 34–1. Pharmacological agents for the treatment of neuroleptic-induced parkinsonism and
acute dystonic reactions
Compound Relative
equivalence
(mg)a
Route Availability Dosing Dosage range
(mg/day)
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Compound Relative
equivalence
(mg)a
Route Availability Dosing Dosage range
(mg/day)
Trihexyphenidyl 2 Oral Tablets: 2, 5 mg
Elixir: 2 mg/mL
Sequels: 5 mg
(sustained release)
qd–bid 2–30
Benztropine
(Cogentin)
1 Oral
Injectable
Tablets: 0.5, 1, 2
mg
Ampules: 1 mg/mL
(2 mL)
qd–bid
Every 30 minutes
(until symptom
relief)
1–12
2–8
Biperiden
(Akineton)b
2 Oral
Injectable
Tablets: 2 mg
Ampules: 5 mg/mL
(1 mL)b
qd–tid
Every 30 minutes
(until symptom
relief)
2–24
2–8
Procyclidine
(Kemadrin)
2 Oral Tablets: 5 mg
(scored)
bid–tid 5–20
Antihistaminic
Diphenhydramine
(Benadryl)
50 Oral
Injectable
Tablets: 25, 50 mg
Ampules: 50
mg/mL (1 mL, 10
mL)
Syringe (prefilled):
1 mL
bid–qd 50–200
Dopaminergic
Amantadine
(Symmetrel)
N/A Oral Tablets: 100 mg
Syrup: 50 mg/5
mL
qd–bid 100–300
Note. N/A = not applicable; qd = once daily; bid = twice daily; tid = three times daily.
aAdapted from Klett and Caffey 1972.
bNo longer available as an injectable in the United States.
Trihexyphenidyl, a synthetic analogue of atropine, was introduced as benzhexol hydrochloride in
- It was found to be effective in the treatment of Parkinson’s disease in a study of 411 patients
(Doshay et al. 1954). Thereafter, it was also used to treat neuroleptic-induced parkinsonism (NIP)
(Rashkis and Smarr 1957).
Structure–Activity Relations
Trihexyphenidyl, a tertiary-amine analogue of atropine, is a competitive antagonist of acetylcholine
and other muscarinic agonists that compete for a common binding site on muscarinic receptors
(Yamamura and Snyder 1974). It exerts little blockade at nicotinic receptors (Timberlake et al.
1961). Trihexyphenidyl and all drugs in this class are referred to as anticholinergic, antimuscarinic,
or atropine-like drugs. As a tertiary amine, it readily crosses the blood–brain barrier (Brown and
Taylor 1996).
Pharmacological Profile
The pharmacological properties of trihexyphenidyl are qualitatively similar to those of atropine and
other anticholinergic drugs, although trihexyphenidyl acts primarily centrally, with few peripheral
effects and little sedation. In the eye, anticholinergic drugs block both the sphincter muscle of the
iris, causing the pupil to dilate (mydriasis), and the ciliary muscle of the lens, preventingPrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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accommodation and causing cycloplegia. In the heart, anticholinergic drugs usually produce a mild
tachycardia through vagal blockade at the sinoatrial node pacemaker, although a mild slowing can
occur. In the gastrointestinal tract, anticholinergic drugs reduce gut motility and salivary and
gastric secretions. Salivary secretion is particularly sensitive and can be completely abolished. In
the respiratory system, anticholinergic agents reduce secretions and can produce mild
bronchodilatation. Anticholinergics inhibit the activity of sweat glands and mildly decrease
contractions in the urinary and biliary tracts (Brown and Taylor 1996).
Pharmacokinetics and Disposition
Peak concentration for trihexyphenidyl is reached 1–2 hours after oral administration, and its
half-life is 10–12 hours (Cedarbaum and McDowell 1987). As a tertiary amine, it crosses the
blood–brain barrier to enter the CNS.
Mechanism of Action
The presumed mechanism of action of trihexyphenidyl for treatment of EPS is the blockade of
intrastriatal cholinergic activity, which is relatively increased, compared with nigrostriatal
dopaminergic activity, which has become decreased by antipsychotic blockade. The blockade of
cholinergic activity returns the system to its previous equilibrium.
Indications and Efficacy
Anticholinergic agents were reported to have been effective treatment for NIP from open empirical
trials (Medina et al. 1962; Rashkis and Smarr 1957). Eventually, controlled trials were conducted,
with most involving comparisons only with different anticholinergics and not with placebo. Despite
the limited evidence of efficacy against placebo, anticholinergic agents became the mainstay of
treatment for NIP, and they remain so today.
Trihexyphenidyl has U.S. Food and Drug Administration (FDA) approval for treatment of all forms of
parkinsonism, including NIP. Daily doses of 5–30 mg have been used in studies of trihexyphenidyl
in the treatment of Parkinson’s disease and NIP. Much higher dosages (up to 75 mg/day) have
been used for the treatment of primary dystonia. However, the benefits of high doses have been
limited by the adverse effects on cognition and memory (Jabbari et al. 1989; Taylor et al. 1991).
Side effects correlate with blood levels, but efficacy does not (Burke and Fahn 1985). The individual
therapeutic dose must be determined empirically and can vary widely.
Side Effects and Toxicology
Peripheral side effects
The peripheral side effects of trihexyphenidyl result from parasympathetic muscarinic blockade,
and they occur in a consistent hierarchy among different organs. They are qualitatively similar to
the side effects of atropine and other anticholinergic drugs, but they are quantitatively less because
of the reduced peripheral activity of trihexyphenidyl (Brown 1990).
Anticholinergic drugs initially depress salivary and bronchial secretions and sweat production.
Reduced salivation produces dry mouth and contributes to the high incidence of dental caries
among patients with chronic psychiatric problems (Winer and Bahn 1967). Treatment for this
condition is unsatisfactory, and chewing sugar-free gum or sucking on hard candy is limited by the
need for constant use. Reduced sweating can contribute to heat prostration and heat stroke,
particularly in warmer ambient temperatures. The next physiological effects occur in the eyes and
heart. Pupillary dilatation and inhibition of accommodation in the eye lead to photophobia and
blurred vision. Attacks of acute glaucoma can occur in susceptible subjects with narrow-angle
glaucoma, although this is relatively uncommon. Vagus nerve blockade leads to increased heart
rate and is more apparent in patients with high vagal tone (usually younger males). The next
effects are inhibition of urinary bladder function and bowel motility, which can produce urinary
retention, constipation, and obstipation. Sufficiently high doses of anticholinergics will inhibit
gastric secretion and motility (Brown and Taylor 1996).Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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Central side effects
Memory disturbance is the most common central side effect of anticholinergic medications because
memory is dependent on the cholinergic system (Drachman 1977). Patients with underlying brain
pathology are more susceptible to memory disturbance (Fayen et al. 1988). Patients with chronic
psychiatric conditions often have a decreased ability to express themselves, making evaluation of
memory more difficult; therefore, subtle memory changes can be missed or attributed to the
underlying illness. Memory disturbances have been identified in patients with Parkinson’s disease
treated with anticholinergics (Yahr and Duvoisin 1968), even in some patients receiving only small
doses (Stephens 1967). Patients receiving an antipsychotic and benztropine demonstrated
significantly increased overall scores on the Wechsler Memory Scale when benztropine was
withdrawn (Baker et al. 1983).
Anticholinergic toxicity produces restlessness, irritability, disorientation, hallucinations, and
delirium. Elderly patients are at increased risk for both memory loss and toxic delirium, even at
very low anticholinergic doses, because of the natural loss of cholinergic neurons with aging (Perry
et al. 1977). Toxic doses can produce a clinical situation identical to atropine poisoning, including
fixed dilated pupils, flushed face, sinus tachycardia, urinary retention, dry mouth, and fever. This
condition can proceed to coma, cardiorespiratory collapse, and death.
Drug–Drug Interactions
There may be increased anticholinergic effects, including side effects, when trihexyphenidyl or any
anticholinergic is combined with amantadine. Anticholinergic side effects are also much more likely
to occur when drugs with anticholinergic properties are combined.
Anticholinergic effect on antipsychotic blood levels
Some investigators have suggested that anticholinergic medications can affect antipsychotic blood
levels. However, a review of this subject suggests that the available data are too limited to reach a
definite conclusion on this matter. The best studies indicate that anticholinergic drugs do not affect
antipsychotic blood levels or, at most, that they lower these levels only transiently (McEvoy 1983).
Anticholinergic effect on antipsychotic activity
Haase and Janssen (1965) reported from open studies that when anticholinergic drugs are added to
antipsychotic drugs given at the neuroleptic threshold, rigidity, hypokinesia, and therapeutic effects
disappear but psychopathology worsens. Other studies have demonstrated no change or an
improvement in scores of psychopathology, with the addition of anticholinergics (Hanlon et al.
1966; G. M. Simpson et al. 1980).
Anticholinergic Abuse
Anticholinergic drugs may be abused for their euphoriant and hallucinogenic effects, and they may
be combined with street drugs for enhanced effect (Crawshaw and Mullen 1984). Patients with a
history of substance abuse are more likely to abuse anticholinergics (Wells et al. 1989). Cases of
abuse have been reported with all anticholinergics, but trihexyphenidyl apparently is the
anticholinergic most likely to be abused (MacVicar 1977). Theoretically, one anticholinergic should
be as effective as another, although an idiosyncratic response is possible. The potential for abuse
needs to be considered, particularly in patients with a history of substance abuse.
Benztropine
History and Discovery
Benztropine was synthesized by uniting the tropine portion of atropine with the benzhydryl portion
of diphenhydramine hydrochloride. Benztropine was found to be effective in the treatment of 302
patients with Parkinson’s disease (Doshay 1956). The best results in the control of rigidity,
contracture, and tremor were obtained at doses of 1–4 mg qd for older patients and 2–8 mg qd for
younger ones. Doses of 15–30 mg qd caused excessive flaccidity in some patients, who becamePrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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unable to lift their arms or raise their heads off the bed. Subsequently, benztropine was found to be
effective for the treatment of NIP (Karn and Kasper 1959).
Structure–Activity Relations
Benztropine is a tertiary amine with activity similar to that of trihexyphenidyl, and as a tertiary
amine, it enters the CNS.
Pharmacological Profile
Benztropine has the pharmacological properties of an anticholinergic and an antihistaminic;
however, it produces less sedation (in experimental animals) than does diphenhydramine.
Pharmacokinetics and Disposition
Little is known about the pharmacokinetics of benztropine. A correlation between serum
anticholinergic levels and the presence of EPS has been demonstrated (Tune and Coyle 1980).
There is little correlation between the total daily dose of benztropine and the serum anticholinergic
level, with the serum activity for a given dose varying 100-fold between subjects. When treated
with increased doses of anticholinergics, patients with EPS demonstrated increased serum
anticholinergic activity and decreased EPS. Relatively small increments in the oral dose of an
anticholinergic drug can result in significant nonlinear increases in serum anticholinergic activity
levels. Benztropine has a long-acting effect and can be given once or twice a day.
Indications and Efficacy
Benztropine has FDA approval for the treatment of all forms of parkinsonism, including NIP. Total
daily doses of 1–8 mg have generally been used to treat NIP.
Mechanism of Action, Side Effects, and Drug–Drug Interactions
The mechanisms of action and the drug interactions for benztropine are similar to those of
trihexyphenidyl. The side effects of these two drugs are also similar, but the degree of sedation
produced by benztropine may be less (Doshay 1956). Although not yet confirmed in double-blind
studies, this reported difference in sedation might account for the fact that trihexyphenidyl is
reportedly the anticholinergic drug more likely to be abused.
Biperiden
Biperiden is an analogue of trihexyphenidyl that has greater peripheral anticholinergic activity than
trihexyphenidyl and greater activity against nicotinic receptors (Timberlake et al. 1961). Biperiden
is well absorbed from the gastrointestinal tract. Its metabolism, though not completely understood,
involves hydroxylation in the liver. Its activity, pharmacological profile, and side effects are similar
to those of other anticholinergics. It has FDA approval for use in the treatment of all forms of
parkinsonism, including NIP. Total daily doses of 2–24 mg have been used in studies of biperiden
for the treatment of parkinsonism and NIP.
Procyclidine
Procyclidine is an analogue of trihexyphenidyl (Schwab and Chafetz 1955). Its activity,
pharmacology, and side effects are similar to those of other anticholinergics. There is little
information about its pharmacokinetics. Procyclidine has FDA approval for use in treating all forms
of parkinsonism, including NIP. Total daily doses of 5–30 mg have been used in studies of
procyclidine for the treatment of parkinsonism and NIP.
ANTIHISTAMINIC MEDICATIONS
Diphenhydramine
History and Discovery
Antihistaminic agents have been used for the treatment of Parkinson’s disease. Diphenhydramine,Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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one of the first antihistamines developed and used clinically (Bovet 1950), has been the primary
antihistamine studied in the treatment of EPS. Although some antihistamines may be effective,
other antihistamines have not been systematically studied for the treatment of EPS.
Structure–Activity Relations
All drugs referred to as antihistamines are reversible competitive inhibitors of histamine at the H1
receptor. Some antihistamines also inhibit the action of acetylcholine at the muscarinic receptor. It
is believed that central muscarinic blockade, rather than histaminic blockade, is responsible for the
therapeutic effect of antihistamines for EPS. Ethanolamine antihistamines (diphenhydramine,
dimenhydrinate, and carbinoxamine maleate) have the greatest anticholinergic activity, and
ethylenediamine antihistamines have the least anticholinergic activity. Antihistamines such as
terfenadine and astemizole have no anticholinergic activity, while many of the remaining
antihistamines have very mild anticholinergic activity (Babe and Serafin 1996).
Pharmacological Profile
Antihistamines inhibit the constrictor action of histamine on respiratory smooth muscle. They
restrict the vasoconstrictor and vasodilatory effects of histamine on vascular smooth muscle and
block histamine-induced capillary permeability. Antihistamines with CNS activity are depressants,
producing diminished alertness, slowed reaction times, and somnolence. They can also block
motion sickness. Antihistaminic drugs with anticholinergic activity also possess mild antimuscarinic
pharmacological properties similar to those of other atropine-like drugs (Babe and Serafin 1996).
Pharmacokinetics and Disposition
Diphenhydramine is well absorbed from the gastrointestinal tract. Peak concentrations occur 2–3
hours after oral administration. Its therapeutic effects usually last 4–6 hours, and it has a half-life
of 3–9 hours. Diphenhydramine is widely distributed throughout the body, and as a tertiary amine,
it enters the CNS. Age does not affect its pharmacokinetics. It undergoes demethylations in the
liver and is then oxidized to carboxylic acid (Paton and Webster 1985).
Mechanism of Action
Diphenhydramine possesses some anticholinergic activity, which is believed to be the basis for its
effect in diminishing EPS.
Indications and Efficacy
Diphenhydramine has FDA approval for parkinsonism, including NIP, in the elderly and for mild
cases in other age groups. It is probably not as efficacious for treating EPS as are pure
anticholinergic drugs, but it may be better tolerated in patients bothered by anticholinergic side
effects, such as geriatric patients. Diphenhydramine also tends to be more sedating than
anticholinergics, which can also be beneficial for some patients. The dosage generally ranges from
50 to 400 mg/day, given in divided doses.
Diphenhydramine also has indications for multiple other conditions that are unrelated to EPS.
Side Effects and Toxicology
The primary side effect of diphenhydramine is sedation. Although other antihistamines may cause
gastrointestinal distress, diphenhydramine has a low incidence of such an effect. Drying of the
mouth and respiratory passages can occur. In general, the toxic effects are similar to those of
trihexyphenidyl and of other anticholinergics.
Drug–Drug Interactions
Diphenhydramine has no reported interactions with other drugs, but it has an additive depressant
effect when used in combination with alcohol or with other CNS depressants.
DOPAMINERGIC MEDICATIONS
AmantadinePrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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History and Discovery
Anticholinergic side effects and inadequate treatment response eventually led to the investigation
of other agents to treat EPS. Initially, both methylphenidate and intravenous caffeine were
investigated as treatments for NIP. Neither agent achieved general use, despite apparent efficacy
(Brooks 1956; Freyhan 1959).
Amantadine is an antiviral agent that is effective against A2 (Asian) influenza (Wingfield et al.
1969). It was unexpectedly found to produce symptomatic improvement in patients with
Parkinson’s disease (Parkes et al. 1970; Schwab et al. 1969), and soon thereafter, it was reported
to be effective for NIP (Kelly and Abuzzahab 1971).
Structure–Activity Relations
Amantadine is a water-soluble tricyclic amine. It binds to the M2 protein, a membrane protein that
functions as an ion channel on the influenza A virus (Hay 1992). Its activity in reducing EPS is not
known, although it has been shown to have activity at glutamate receptors (Stoof et al. 1992).
Pharmacological Profile
Amantadine is effective in preventing and treating illness from influenza A virus. It also reduces the
symptoms of parkinsonism.
Pharmacokinetics and Disposition
In young healthy subjects, amantadine is slowly and well absorbed from the gastrointestinal tract,
with unchanged oral bioavailability over the dose range of 50–300 mg. It reaches steady state in
4–7 days. Plasma concentrations (0.12–1.12 g/mL) may have some correlation with improvement
in EPS (Greenblatt et al. 1977; Pacifici et al. 1976). Amantadine has relatively constant blood levels
and a long duration of action (Aoki et al. 1979) and is excreted unchanged by the kidneys. Its
half-life for elimination is about 16 hours, which is prolonged in elderly patients and in patients
with impaired renal function (Hayden et al. 1985).
Mechanism of Action
Amantadine inhibits viral replication by binding to the M2 protein on the viral membrane and
inhibiting replication (Hay 1992). Its mechanism of action as an antiparkinson agent is less clear. It
has no anticholinergic activity in tests on animals, being only 1/209,000th as potent as atropine
(Grelak et al. 1970). It appears to cause the release of dopamine and other catecholamines from
intraneuronal storage sites in an amphetamine-like mechanism. It has also been shown to have
activity at glutamate receptors, which may contribute to its antiparkinsonian effect (Stoof et al.
1992). Amantadine has preferential selectivity for central catecholamine neurons (Grelak et al.
1970; Strömberg et al. 1970).
Indications and Efficacy
Amantadine has undergone more extensive investigation than have anticholinergic agents with
regard to the efficacy of EPS. Most studies, though not all, found amantadine to be equal in efficacy
to benztropine or biperiden in the treatment of parkinsonism (DiMascio et al. 1976; Fann and Lake
1976; Konig et al. 1996; Silver et al. 1995; Stenson et al. 1976). Some studies found amantadine to
be more effective than benztropine (Merrick and Schmitt 1973) or effective for EPS that are
refractory to benztropine (Gelenberg 1978). However, other studies found that amantadine was
inferior to benztropine (Kelly et al. 1974), no more effective than placebo (Mindham et al. 1972), or
unable to control EPS when used to replace an anticholinergic agent (McEvoy et al. 1987). The
varying results can be attributed to differing methodologies and patient populations. The conclusion
that can be drawn from these studies is that amantadine is an effective drug for treating
parkinsonism but that there are no clear data to support its use prior to using anticholinergic
agents. Most of the studies were of short duration, and in patients with Parkinson’s disease,
amantadine appears to lose efficacy after several weeks (Mawdsley et al. 1972; Schwab et al.Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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1972). Similar studies evaluating the long-term efficacy of amantadine have not been conducted for
EPS.
Amantadine has also been evaluated for the treatment of akathisia, but in only a small number of
patients. The conclusion from these studies is that amantadine is probably not effective for treating
akathisia (Fleischhacker et al. 1990).
Amantadine has FDA approval for the treatment of NIP and Parkinson’s disease/syndrome, as well
as for the treatment and prophylaxis of influenza A respiratory illness. Dosages of 100–300 mg/day
are used for the treatment of NIP, and plasma concentrations may have some correlation with
improvement.
Side Effects and Toxicology
At dosages of 100–300 mg/day, amantadine does not produce adverse effects as readily as do
anticholinergic medications. Side effects of amantadine result from CNS stimulation, with symptoms
including irritability, tremor, dysarthria, ataxia, vertigo, agitation, reduced concentration,
hallucinations, and delirium (Postma and Tilburg 1975). Hallucinations are often visual. Side effects
are more likely to occur in elderly patients and in patients with reduced renal function (Borison
1979; Ing et al. 1979). Toxic effects are directly related to elevated amantadine serum levels (>1.5
g/mL). Resolution of toxic symptoms is dependent on renal clearance and may require dialysis in
extreme cases, although less than 5% of amantadine is removed by dialysis.
Patients with congestive heart failure or peripheral edema should be monitored because of
amantadine’s ability to increase the availability of catecholamines. Long-term use of amantadine
may produce livedo reticularis in the lower extremities from the local release of catecholamines and
resulting vasoconstriction (Cedarbaum and Schleifer 1990). Amantadine should be used with
caution in patients with seizures because of possible increased seizure activity. Amantadine is
embryotoxic and teratogenic in animals, but there are no well-controlled studies in women
regarding teratogenicity.
Drug–Drug Interactions
There are no reported interactions between amantadine and other drugs. There may be increased
anticholinergic side effects when amantadine is used in combination with an anticholinergic agent.
-Adrenergic Receptor Antagonists
History and Discovery
Propranolol was reported to be effective for the treatment of restless legs syndrome (Ekbom’s
syndrome; Ekbom 1965), which resembles the physical movements of akathisia (Strang 1967).
Later it was reported to be effective in the treatment of neuroleptic-induced akathisia (Kulik and
Wilbur 1983; Lipinski et al. 1983). Subsequently, other -blockers have also been investigated for
the treatment of akathisia.
Structure–Activity Relations
Competitive -adrenergic receptor antagonism is the property common to all -blockers. -Blockers
are distinguished by the additional properties of their relative affinity for 1 and 2 receptors
(selectivity), lipid solubility, intrinsic -adrenergic receptor agonist activity, blockade of
receptors, capacity to induce vasodilation, and general pharmacokinetic properties (Hoffman and
Lefkowitz 1996). -Blockers with high lipid solubility readily cross the blood–brain barrier.
Pharmacological Profile
The major pharmacological effects of -blockers involve the cardiovascular system. -Blockers slow
the heart rate and decrease cardiac contractility; however, these effects are modest in a normal
heart. In the lung, they can cause bronchospasm, although, again, there is little effect in normal
lungs. They block glycogenolysis, preventing production of glucose during hypoglycemia (HoffmanPrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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and Lefkowitz 1996). -Blockers affect lipid metabolism by preventing release of free fatty acids
while elevating triglycerides (N. E. Miller 1987). In the CNS, they produce fatigue, sleep
disturbance (insomnia and nightmares), and CNS depression (see Drayer 1987; Gengo et al. 1987).
Pharmacokinetics and Disposition
All -blockers, except atenolol and nadolol, are well absorbed from the gastrointestinal tract
(McDevitt 1987). All -blockers undergo metabolism in the liver. Propranolol and metoprolol
undergo significant first-pass effect, with bioavailability as low as 25%. Large interindividual
variation (as much as 20-fold) leads to wide variation in clinically therapeutic doses (Hoffman and
Lefkowitz 1996). Metabolites appear to have limited -receptor antagonistic activity. The degree to
which a particular -blocker enters the CNS is related directly to its lipid solubility (Table 34–2).
TABLE 34–2. Beta-blockers investigated in the treatment of akathisia
Compound
1
blockade
2 blockade Lipid
solubility
Effective for
EPS
Dosage range
(mg/day)
Propranolol
(Inderal)
++ ++ ++++ Yes 20–120
Nadolol (Corgard) ++ ++ + Yes 40–80
Metoprolol
(Lopressor)
++ 0 at low doses; + at
high doses
++ Yes ~300
Pindolol (Visken) ++ ++ ++ Yes 5
Atenolol (Tenormin) ++ 0 0 No 50–100
Betaxolol (Kerlone) ++ 0 +++ Yes 5–20
Sotalol (Betapace,
Sorine)
++ ++ 0 No 40–80
Note. EPS = extrapyramidal side effects.
Source. Adapted from Hoffman and Lefkowitz 1996.
Mechanism of Action
The exact mechanism of action of -blockers in the treatment of EPS is unclear. The existence of a
noradrenergic pathway from the locus coeruleus to the limbic system has been proposed as a
modulator involved in symptoms of TD, akathisia, and tremor (Wilbur et al. 1988). It appears that
lipid solubility and the corresponding ability to enter the CNS are the most important factors
determining the efficacy of a -blocker in treating akathisia and perhaps other types of EPS (Adler
et al. 1991).
Indications and Efficacy
-Blockers have FDA approval primarily for cardiovascular indications, and propranolol is also
indicated for familial essential tremor, but there are no FDA-approved indications for the treatment
of any type of EPS.
-Blockers have been studied primarily for the treatment of akathisia. Both nonselective ( 1 and 2
antagonism) and selective ( 1 antagonism) -blockers have been reported to be efficacious. The
studies have generally been for short periods of time, involving small numbers of patients who
were often receiving varying combinations of additional antiparkinsonian agents or
benzodiazepines to which -blockers had been added (Fleischhacker et al. 1990). From these
studies, it is difficult to draw any firm conclusions, but -blockers probably have some efficacy in
the treatment of akathisia. The maximum benefit for propranolol occurred at 5 days (Fleischhacker
et al. 1990). Betaxolol may be the -blocker of choice in patients with lung disease and smokers
because of its 1 selectivity at lower dosages (5–10 mg/day).Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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In addition to essential tremor, -blockers have also been reported to be beneficial for the tremor
of Parkinson’s disease (Foster et al. 1984) and lithium-induced tremor (Gelenberg and Jefferson
1995). However, for neuroleptic-induced tremor, propranolol was found to be not any better than
placebo (Metzer et al. 1993), which could be an indication of a difference in etiologies for the
different tremors.
Side Effects and Toxicology
The side effects of -blockers result from receptor blockade. 2 Blockade of bronchial smooth
muscle produces bronchospasm. Individuals with normal lung function are unlikely to be affected,
but smokers and others with lung disease can develop serious breathing difficulties. -Blockers can
contribute to heart failure in susceptible individuals, such as those with compensated heart failure,
acute myocardial infarction, or cardiomegaly. Abrupt cessation of -blockers can also exacerbate
coronary heart disease in susceptible patients, producing angina or, potentially, myocardial
infarction (for details, see Hoffman and Lefkowitz 1996).
In individuals with normal heart function, bradycardia produced by -blockers is insignificant;
however, in patients with conduction defects or when combined with other drugs that impair
cardiac conduction, -blockers can contribute to serious conduction problems.
-Blockers can block the tachycardia associated with hypoglycemia, eliminating this warning sign in
patients with diabetes. 2 Blockade also can inhibit glycogenolysis and glucose mobilization,
interfering with recovery from hypoglycemia (Hoffman and Lefkowitz 1996).
-Blockers can impair exercise performance and produce fatigue, insomnia, and major depression.
However, the development of major depression probably only occurs in individuals with a
predisposition to developing depression.
Drug–Drug Interactions
-Blockers can have significant interactions with other drugs. Chlorpromazine in combination with
propranolol may increase the blood levels of both drugs. Additive effects on cardiac conduction and
blood pressure can occur when -blockers are combined with drugs having similar effects (e.g.,
calcium channel blockers). Phenytoin, phenobarbital, and rifampin increase the clearance of
propranolol. Cimetidine increases propranolol blood levels by decreasing hepatic metabolism.
Theophylline clearance is reduced by propranolol. Aluminum salts (antacids), cholestyramine, and
colestipol may reduce the absorption of -blockers (Hoffman and Lefkowitz 1996).
BENZODIAZEPINES
History and Discovery
Diazepam was initially shown to be effective in the treatment of restless legs syndrome (Ekbom’s
syndrome), which resembles the physical movements of akathisia (Ekbom 1965). Subsequently,
diazepam, lorazepam, and clonazepam were reported to be beneficial for neuroleptic-induced
akathisia (Adler et al. 1985; Donlon 1973; Kutcher et al. 1987). Clonazepam has also been reported
to be beneficial for drug-induced dystonia (O’Flanagan 1975) and TD (Thaker et al. 1987).
Mechanism of Action
All benzodiazepines promote the binding of GABA to GABAA receptors, magnifying the effects of
GABA. The mechanism of action regarding improvement of EPS is unknown, but it may be related to
the augmentation of inhibitory GABAergic effect (Hobbs et al. 1996). For a complete discussion of
the properties of benzodiazepines, see Chapter 24.
Indications and Efficacy
Benzodiazepines have FDA approval for their use in treating anxiety disorders, agoraphobia,
insomnia, management of alcohol withdrawal, anesthetic premedication, seizure disorders, and
skeletal muscle relaxation; however, there is no approval for its use in treating any type of EPS. As
noted above, a few initial reports have indicated that benzodiazepines are beneficial for thePrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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treatment of akathisia. Other studies have also reported similar benefit (Bartels et al. 1987; Braude
et al. 1983; Gagrat et al. 1978; Horiguchi and Nishimatsu 1992; Kutcher et al. 1989; Pujalte et al.
1994).
Clonazepam has also been reported to be effective in the treatment of TD (Bobruff et al. 1981;
Thaker et al. 1990). Doses of 1–10 mg were used in the first study, although the optimal dosage
was found to be 4 mg/day, with many patients unable to tolerate higher dosages. In the second
study, dosages of 2–4.5 mg/day were used, and tolerance developed after 5–8 months.
Although some of the studies were limited by short duration and by the small number of subjects
also receiving other antiparkinsonian agents, the overall conclusion was that benzodiazepines
probably have some efficacy in the treatment of akathisia and TD. However, the potential problems
associated with the chronic use of benzodiazepines (i.e., tolerance and abuse) need to be kept in
mind.
Lorazepam (intermediate-acting) and clonazepam (long-acting) are the two primary
benzodiazepines that have been studied in the treatment of EPS. Because of its long duration of
action, clonazepam can often be given once a day. Lorazepam has the advantage of having no
active metabolites, which eliminates potential side effects and toxicity.
BOTULINUM TOXIN
History and Discovery
Botulinum toxin, produced by Clostridium botulinum, causes botulism when ingested. The first
clinical use of the toxin was in the treatment of childhood strabismus (Scott 1980). The first focal
dystonia treated was blepharospasm (Elston 1988). Botulinum toxin has been subsequently used to
treat a number of other conditions associated with excessive muscle activity, including
neuroleptic-induced dystonias (Hughes 1994).
Structure–Activity Relations
There are seven immunologically distinct botulinum toxins (L. L. Simpson 1981). Type A is the
primary type used clinically (Hambleton 1992). Type F and possibly type B also have clinical utility,
but they have much shorter durations of action ( 3 weeks, compared with 3 months for type A)
(Borodic et al. 1996). The toxin is quantified by bioassay and is expressed as mouse units, which
refers to the dose that is lethal to 50% of animals following intraperitoneal injection (Quinn and
Hallet 1989).
Pharmacological Profile
Botulinum toxin binds to cholinergic motor nerve terminals, preventing release of acetylcholine and
producing a functionally denervated muscle. The prevention of acetylcholine release occurs within a
few hours, but the clinical effect does not occur for 1–3 days. The innervation gradually becomes
restored, although the number and/or size of active muscle fibers is reduced (Odergren et al.
1994).
Pharmacokinetics and Disposition
After binding to the presynaptic nerve terminal, the toxin is taken into the nerve cell and is
metabolized. When antibodies are present, the toxin is metabolized by immunological processes.
Mechanism of Action
Botulinum toxin acts presynaptically to prevent the release of acetylcholine at the neuromuscular
junction. This produces a functional chemical denervation and paralysis of the muscle. When
botulinum toxin is used clinically, the aim is to reduce the excessive muscle activity without
producing significant weakness (Hughes 1994).
Indications and Efficacy
The FDA has approved the use of botulinum toxin for strabismus, blepharospasm, and other facialPrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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nerve disorders (see Jankovic and Brin 1991). Botulinum toxin has been used to treat focal
neuroleptic-induced dystonias that may occur as part of TD, including laryngeal dystonia (Blitzer
and Brin 1991) and refractory torticollis (Kaufman 1994). For laryngeal dystonia, the toxin is
injected percutaneously through the cricothyroid membrane into the thyroarytenoid muscle
bilaterally. The response rate is 80%–90%, and the effect lasts 3–4 months and sometimes longer.
Botulinum treatment of tardive cervical dystonia has been found to be effective; the observed
improvement is similar to the improvement seen in the treatment of idiopathic cervical dystonia,
although patients with tardive cervical dystonia required higher doses (Brashear et al. 1998).
Side Effects and Toxicology
The major potential side effect of botulinum toxin is focal weakness in the muscle group
injected—an effect that is usually dose dependent. This effect is generally temporary, given the
mechanism of action. Transient weakness can occur through diffusion of the toxin into surrounding
noninjected muscles (Hughes 1994).
Antibodies to the toxin can occur and thus can prevent a therapeutic response, particularly during
subsequent treatments. The two main factors that apparently contribute to the development of
antibodies are receiving a dose of the toxin for the first time at an early age and total cumulative
dose (Jankovic and Schwartz 1995). Some patients with antibodies will respond to other botulinum
serotypes, such as type F (Greene and Fahn 1993). Local skin reactions can also occur. Some
degree of muscle atrophy is apparent in injected muscles (Hughes 1994). Reinnervation usually
takes place over the course of 3–4 months (Odergren et al. 1994).
There are no known contraindications. Because the effect on the fetus is unknown, use of the toxin
is not recommended during pregnancy. In conditions in which there are neuromuscular junction
disorders, such as myasthenia gravis, patients could theoretically experience increased weakness.
The long-term effects are unknown (Hughes 1994).
Drug–Drug Interactions
There are no known interactions of botulinum toxin with other drugs.
VITAMIN E ( -TOCOPHEROL)
History and Discovery
The existence of vitamin E was postulated in 1922, at which time it appeared that rats required an
unknown dietary supplement to sustain pregnancy. That supplement, vitamin E ( -tocopherol), was
eventually isolated from wheat germ oil (Evans et al. 1936). Vitamin E deficiency in animals leads
to several specific diseases; however, in humans, there is little evidence of any specific metabolic
effects or illnesses. Despite the paucity of evidence for its benefit, vitamin E has been used over the
years to treat multiple conditions, including infertility, various menstrual disorders, neurological
and muscular disorders, and anemias (Marcus and Coulston 1996).
Vitamin E was proposed as a treatment for TD after it was noted that a neurotoxin in rats induced
an irreversible movement disorder and axonal damage similar to that caused by vitamin E
deficiency. It was proposed that chronic neuroleptic use might produce free radicals, which would
contribute to neurological damage and TD, and that the antioxidant effect of vitamin E could
attenuate the damage (Cadet et al. 1986).
Pharmacological Profile
In humans, symptoms of vitamin E deficiency are not very common, and they almost always result
from malabsorption (Bieri and Farrell 1976). The only consistent laboratory finding is that subjects
with low serum vitamin E levels demonstrate increased hemolysis of erythrocytes exposed to
oxidizing agents (Leonard and Losowsky 1967). In addition, patients with glucose-6-phosphate
dehydrogenase deficiency may have improved erythrocyte survival when treated with large doses
(Corash et al. 1980).
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Side effects are minimal when vitamin E is given orally. High levels of vitamin E can exacerbate
bleeding abnormalities that are associated with vitamin K deficiency. Dosages of up to 3,200
mg/day in studies for other conditions have been used without significant adverse effects (Kappus
and Diplock 1992). The only known drug interactions are with vitamin K (when it is being given for
a deficiency) and bleeding abnormalities and possibly with oral anticoagulants. High doses of
vitamin E can exacerbate the coagulation abnormalities in both cases and therefore are
contraindicated (Kappus and Diplock 1992).
Indications and Efficacy
The only known indication for vitamin E is treatment of vitamin E deficiency, which almost always
results from malabsorption syndromes or abnormal transport, such as with abetalipoproteinemia.
In most cases, other vitamins and nutrients are also deficient; therefore, symptoms may not be the
result of only vitamin E deficiency. Supplementation in children has been shown to be effective for
the neurological symptoms resulting from malabsorption and vitamin E deficiency in chronic
cholestasis (Sokol et al. 1993). Apparently, there is also a rare condition of spinocerebellar
degeneration caused by deficiency without malabsorption (Sokol 1988).
Early studies of vitamin E treatment of TD demonstrated a range of results from general benefit
(Adler et al. 1993; Dabiri et al. 1994; Lohr et al. 1988) to benefit only in subjects with TD of less
than 5 years’ duration (Egan et al. 1992; Lohr and Caligiuri 1996) to no benefit (Schmidt et al.
1991; Shriqui et al. 1992).
Subsequently, a major prospective randomized trial treated 158 subjects with TD for up to 2 years
with d-vitamin E (1,600 IU/day) or placebo (Adler et al. 1999). There were no significant effects of
vitamin E on total scores or subscale scores for the AIMS, on electromechanical measures of
dyskinesia, or on scores for four other scales measuring dyskinesia. The authors concluded that
there was no evidence for efficacy of vitamin E in the treatment of TD (Adler et al. 1999).The use of
vitamin E supplementation is not without risk. A meta-analysis of high-dosage vitamin E
supplementation trials showed a statistically significant relationship between vitamin E dosage and
all-cause mortality, with increased risk of dosages greater than 150 IU/day (E. R. Miller et al.
2005). Given the lack the data demonstrating consistent effectiveness for TD, we do not
recommend that vitamin E be used for this purpose.
TREATMENT OF EXTRAPYRAMIDAL SIDE EFFECTS
Acute Dystonic Reactions
Intramuscular anticholinergics are the treatment of choice for ADRs. Benztropine 2 mg or
diphenhydramine 50–100 mg generally will produce complete resolution within 20–30 minutes,
with a second dose repeated after 30 minutes if there is not a complete recovery. Benztropine has
been shown to resolve ADRs in less time than diphenhydramine (Lee 1979). Starting a standing
dose of an antiparkinsonian agent afterward is generally not necessary. ADRs do not recur, unless
large doses of high-potency antipsychotics are being used or unless the dose is increased. A more
complete discussion of prophylaxis is given below.
Parkinsonism and Akathisia
The initial steps in treatment of parkinsonism (Table 34–3) and of akathisia (referred to here as
EPS) are identical: evaluating the dose and type of antipsychotic. It has been shown that an
increase in dose beyond the neuroleptic threshold will not produce any greater therapeutic benefit
but will increase EPS (Angus and Simpson 1970a; Baldessarini et al. 1988; McEvoy et al. 1991). It
has also been demonstrated that EPS frequently can be eliminated with a reduction in dosage or a
change to a lower-potency antipsychotic (Braude et al. 1983; Stratas et al. 1963).
TABLE 34–3. Treatment of parkinsonismPrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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Step Action
1 Reduce dose of antipsychotic, if clinically possible.
2 Substitute a lower-potency antipsychotic, or carry out step 8.
3 Add an anticholinergic agent.
4 Titrate anticholinergic to maximum dose tolerable.
5 Add amantadine in combination with anticholinergic or as a single agent.
6 Add a benzodiazepine or a -blocker.
7 In severe cases of EPS, stop antipsychotic temporarily and repeat process, beginning with step 3.
8 Substitute antipsychotic with atypical antipsychotic or clozapine.
If this approach does not resolve EPS, or if a lower-potency antipsychotic cannot be substituted, the
addition of an anticholinergic drug is the next step. Maximum therapeutic response occurs in 3–10
days, with more severe EPS taking a longer time to respond (DiMascio et al. 1976; Fann and Lake
1976). The anticholinergic dose should be increased until EPS are alleviated or until an
unacceptable degree of anticholinergic side effects is obtained. Akathisia frequently does not
respond as well to anticholinergic medications and amantadine as do parkinsonism and ADRs
(DiMascio et al. 1976). Akathisia is more likely to be responsive to anticholinergic agents if
symptoms of parkinsonism are also present (Fleischhacker et al. 1990).
If EPS remain uncontrolled, amantadine can be either added to the regimen or substituted as a
single agent. The next step would be the addition of a benzodiazepine or a -blocker, although
there are fewer data supporting both of these treatments.
In the case of severe EPS, the antipsychotic should be temporarily stopped, because severe EPS
may be a risk factor for the development of neuroleptic malignant syndrome (Levinson and Simpson
1986).
Additional drugs have been studied or suggested as treatments for akathisia. The data supporting
the use of amantadine for the treatment of akathisia are limited. Clonidine has been studied in a
small number of patients, but its benefit was limited by sedation and hypotension (Fleischhacker et
- 1990). Sodium valproate was reported to have had no significant effect on akathisia and was
found to increase parkinsonism (Friis et al. 1983).
Iron supplementation has been suggested as a possible treatment for akathisia (Blake et al. 1986).
A review of this subject concluded that iron supplements would, at best, have no effect on akathisia
but that they could potentially worsen the condition and promote further long-term damage (Gold
and Lenox 1995). Iron supplementation therefore should not be considered a treatment for
akathisia and should not be given indiscriminately.
Atypical Antipsychotics for Treatment of Parkinsonism and Akathisia
Patients treated with clozapine were found to have significantly less parkinsonism than patients
treated with the combination of chlorpromazine and an antiparkinsonian agent (benztropine) (Kane
et al. 1988). The prevalence and incidence of akathisia have also been shown to be less in patients
treated with clozapine than in patients treated with typical antipsychotics (Chengappa et al. 1994;
Kurz et al. 1995; Stanilla et al. 1995). Subsequently, the new atypical antipsychotics (risperidone,
olanzapine, quetiapine, ziprasidone, and aripiprazole) have also been shown to produce less EPS
than haloperidol. Paliperidone extended release was compared with placebo and found to have a
comparable incidence of EPS.
At lower doses, risperidone usually does not produce significant parkinsonism, but unlike clozapine,
it can produce significant parkinsonism at higher doses (Chouinard et al. 1993). In initial studies
comparing risperidone with haloperidol, the extrapyramidal scores for patients receiving
risperidone were not significantly different from the scores of patients receiving placebo at 6 mg
- Risperidone can cause ADRs, and patients with severe EPS at baseline were more likely toPrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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develop EPS when treated with risperidone (G. M. Simpson and Lindenmayer 1997). Subsequent
studies have confirmed a reduced level of EPS with risperidone, compared with haloperidol
(Csernansky et al. 2002). In general, risperidone has also been shown to produce less akathisia
than haloperidol (Wirshing et al. 1999).
Olanzapine has been shown to have an antipsychotic effect comparable to that of haloperidol while
producing less dystonia, parkinsonism, and akathisia (Tollefson et al. 1997). The reduced incidence
of EPS occurred across the entire therapeutic dosage range of 5–24 mg/day. Olanzapine has
subsequently been shown to produce less parkinsonism and akathisia, compared with haloperidol,
in patients with treatment-resistant schizophrenia (Breier and Hamilton 1999) and in patients with
first-episode psychosis (Sanger et al. 1999). Olanzapine has also been shown to have similar rates
of EPS and akathisia, compared with chlorpromazine, but without the need for any antiparkinsonian
drugs (see Conley et al. 1998).
Quetiapine has been found to have antipsychotic activity comparable to haloperidol at doses
ranging from 150 to 750 mg/day while producing parkinsonism at a level similar to that produced
by placebo across the entire dosage range (Arvanitis and Miller 1997; Small et al. 1997). For most
patients, there were no significant changes in AIMS scores at baseline and in scores at the end of a
6-week period of treatment.
A double-blind, dose-ranging trial comparing ziprasidone with haloperidol found comparable
antipsychotic effect at higher dosages of ziprasidone. Concomitant benztropine use at any time
during the study was less frequent with the highest dosage (160 mg/day) of ziprasidone (15%)
than with haloperidol (53%) (Goff et al. 1998). Studies of ziprasidone found no significant
differences in baseline-to-endpoint mean changes in Simpson-Angus Scale and AIMS scores with
placebo or ziprasidone (40–160 mg/day) (Keck et al. 2001).
Aripiprazole was found to be comparable to risperidone in antipsychotic effect while producing EPS
comparable to those seen with placebo (Kane et al. 2002; Potkin et al. 2003).
The most recent antipsychotic to gain FDA approval in the United States is paliperidone extended
release (ER). Paliperidone ER was found to have an incidence of EPS nearly comparable to placebo
(7% vs. 3%) at a dosage range of 3–15 mg/day (Kramer et al. 2007).
A study comparing 150 patients who were treated with either risperidone or olanzapine found that
a statistically significantly smaller percentage of patients treated with olanzapine (25.3%) required
anticholinergic treatment than did patients treated with risperidone (45.3%) (Egdell et al. 2000).
Another study involving 377 patients comparing risperidone with olanzapine found EPS to be
similar in both groups (24% and 20%, respectively) and of low severity (Conley and Mahmoud
2001).
Comparisons between clozapine and risperidone have found a reduced incidence of EPS for
clozapine (Azorin et al. 2001). A study comparing the incidence of EPS produced by clozapine,
risperidone, and typical antipsychotics found a hierarchy in the production of EPS, with clozapine
producing the fewest EPS, followed by risperidone and then the typical antipsychotics (C. H. Miller
et al. 1998).
In general, the novel antipsychotics have a reduced incidence of EPS compared with high-potency
typical antipsychotics. Data from the CATIE study suggest that the difference in incidence of EPS
with an atypical antipsychotic may not be as great when compared with a moderate-potency typical
antipsychotic.
The difference in the incidence of EPS between an atypical antipsychotic and a typical antipsychotic
has generally involved the comparison of a high-potency typical, specifically haloperidol. Data from
the CATIE studies showed that there was no clinically significant difference in the incidence of
parkinsonian symptoms and akathisia between the atypical agents and a moderate-potency typical
agent, perphenazine. Although a statistically significantly greater number of perphenazine-treated
subjects than of atypical-treated subjects discontinued treatment because of EPS (8% vs.Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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2%–4%), the incidence was low and of limited clinical significance.
In the past, if a patient receiving a typical antipsychotic developed severe parkinsonism or
akathisia and did not respond to antiparkinsonian treatment, the recommended strategy was to
switch to an atypical antipsychotic. Now, the recommendation can be made to consider the use of a
less potent typical antipsychotic as one of the options for treatment, along with possibly changing
to an atypical.
For patients with severe refractory EPS who have not responded to standard treatments, the use of
clozapine specifically to treat the EPS is indicated (Casey 1989). This is particularly true for
akathisia, given its significant negative correlation with the outcome of schizophrenia. This is also
true for patients who do not have any psychotic symptoms, if the EPS are judged to be severe
enough to be disabling or potentially life-threatening, such as laryngeal dystonia.
Tardive Dyskinesia and Tardive Dystonia
Historically, TD has been refractory to treatment, which explains the large number of drugs
employed in attempts to alleviate the condition. Treatments investigated have included, but are not
limited to, noradrenergic antagonists (propranolol and clonidine), antagonists of dopamine and
other catecholamines, dopamine agonists, catecholamine-depleting drugs (reserpine and
tetrabenazine), GABAergic drugs, cholinergic drugs (deanol, choline, and lecithin),
catecholaminergic drugs (Kane et al. 1992), calcium channel blockers (Cates et al. 1993), and
selective monoamine oxidase inhibitors (selegiline) (Goff et al. 1993). Based on the investigations
of the above drugs, the American Psychiatric Association Task Force on TD concluded that there is
no consistently effective treatment for TD (Kane et al. 1992).
There are inherent difficulties in evaluating the effects of any treatment for TD. These include the
variability of clinical raters (Bergen et al. 1984), placebo response (Sommer et al. 1994), and the
diurnal and longitudinal variability of TD (Hyde et al. 1995; Stanilla et al. 1996). The degree of
improvement needs to be greater than the sum of the above variations in order to demonstrate an
actual benefit.
The first step in evaluating TD is to determine the type of antipsychotic agent that is being used. If
a typical antipsychotic is necessary, it is important to use the lowest dose possible (G. M. Simpson
2000). Second, if anticholinergic antiparkinsonian medications are being used, the patient should
be gradually weaned from these medications and the medications then discontinued.
Anticholinergic medications will make, in contrast to their effect on other extrapyramidal
movements, TD movements worse (see Greil et al. 1984; Jeste and Wyatt 1982).
Some drugs have been shown to have some benefit in the treatment of TD, but they have
limitations. Clonazepam has been reported to reduce the movements of TD for up to 9 months,
although tolerance to the benefits developed (Thaker et al. 1990). Additional limitations are the
inherent problems associated with chronic use of a benzodiazepine. Botulinum toxin is beneficial
for treating localized tardive dystonias, particularly laryngeal and cervical dystonias (Hughes
1994). The injections need to be repeated every 3–6 months, and botulinum toxin is not a general
treatment for TD. Vitamin E has not consistently been shown to be beneficial in all studies, and a
large long-term double-blind study found no benefit for vitamin E compared with placebo (Adler et
- 1999).
Tardive dystonia also tends to be resistant to treatment; however, unlike TD, it may respond to
anticholinergic medications (Wojcik et al. 1991) and to reserpine (Kang et al. 1988).
Atypical Antipsychotics for Treatment of Tardive Dyskinesia
Clozapine has been shown to decrease the symptoms of TD (G. M. Simpson and Varga 1974; G. M.
Simpson et al. 1978), with the greatest improvement occurring in cases of severe TD and tardive
dystonia (Lieberman et al. 1991). These findings have been replicated and suggest that clozapine is
unlikely to cause TD (Chengappa et al. 1994; Kane et al. 1993). The disadvantages to clozapine are
the potential side effects of agranulocytosis and seizures and the need for regular blood monitoring.Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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Three possible mechanisms for clozapine’s benefit have been proposed. First, clozapine may
suppress TD movements in a fashion similar to that of typical antipsychotics. Second, TD may
improve spontaneously, given that the typical antipsychotics are no longer present to cause or
sustain TD. Such improvement occurs in some patients when antipsychotics are withdrawn. Third,
clozapine may have an active therapeutic effect on TD (Lieberman et al. 1991), but the issue
remains to be clarified. In some patients, TD movements have recurred on withdrawal of clozapine.
More data demonstrating the potential benefit of the other novel antipsychotics in the prevention
and treatment of TD are being reported. A prospective study examined the incidence of emergent
dyskinesia in middle-aged to elderly patients (mean age 66 years) being treated with haloperidol
and low-dose risperidone (mean total daily dose of 1 mg). The patients treated with risperidone
were significantly less likely to develop TD (Jeste et al. 1999). A double-blind prospective study
comparing 397 stable patients with schizophrenia who were switched to either risperidone or
haloperidol and followed for at least a year found that only 1 of the patients receiving risperidone
developed dyskinetic movements, compared with 5 of the patients receiving haloperidol
(Csernansky et al. 2002).
In a prospective double-blind study of patients with schizophrenia being treated with either
olanzapine or haloperidol and followed for up to 2.6 years, there was a significantly decreased risk
for the development of TD with olanzapine. The 1-year risk was 0.52% for olanzapine and 7.45%
for haloperidol (Beasley et al. 1999).
The data regarding the effect of quetiapine, ziprasidone, aripiprazole, and paliperidone on TD are
more limited; however, any drug that is less likely to produce EPS is probably less likely to produce
The best treatment for TD is prevention. Of the 1,460 subjects involved in the CATIE study, D. D.
Miller et al. (2005) found 212 to have probable TD by Schooler-Kane criteria. They found that
subjects with TD were older, had a longer duration of receiving antipsychotic medications, and were
more likely to have been receiving a conventional antipsychotic and an anticholinergic agent. They
also found that substance abuse significantly predicted TD, as well as subjects with higher ratings
of psychopathology, parkinsonian symptoms, and akathisia (D. D. Miller et al. 2005).
Patients with TD who are taking typical antipsychotics are candidates for switching to an atypical
antipsychotic. In the case of severe TD or dystonia that has been unresponsive to other treatment,
the use of clozapine is indicated (G. M. Simpson 2000).
Prophylaxis of Extrapyramidal Side Effects
Prophylactic use of antiparkinsonian agents to prevent EPS is a common, but not completely
accepted, practice. Most controlled prospective studies regarding prophylactic use of
antiparkinsonian medication have shown that prophylaxis can be beneficial for certain patients who
are at high risk but that it is not beneficial in routine use across all patient groups (Hanlon et al.
1966; Sramek et al. 1986). Studies that have demonstrated a greater general benefit across all
groups have involved the use of very high doses of antipsychotics. Several retrospective studies
have also demonstrated that there is a limited need for prophylaxis of EPS (Swett et al. 1977). The
retrospective studies that demonstrated a greater benefit from prophylaxis also involved the use of
high antipsychotic dosages (Keepers et al. 1983; Stern and Anderson 1979). The prophylactic use of
antiparkinsonian medication is not routinely indicated for all patients but should be reserved for
those patients at high risk of developing ADRs.
The risk factors for developing ADRs include younger age (<35 years), higher doses of
antipsychotic, higher potency of antipsychotic, intramuscular route of delivery, (possibly) male
gender (Sramek et al. 1986), and history of ADRs from a similar antipsychotic (Keepers and Casey
1991). The use of cocaine has been suggested as a possible risk factor (van Harten et al. 1998; see
Table 34–4 for summary).
TABLE 34–4. Risk factors leading to acute dystonic reactionsPrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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High-potency neuroleptics
Haloperidol
Fluphenazine
Trifluoperazine
High dose
Younger age (<35 years of age)a
Intramuscular route of delivery
Previous dystonic reaction to similar neuroleptic and dose
Male sex?
aApproaches 100% at ages <20 years.
Dosages that have been used for prophylaxis are 1–4 mg/day for benztropine, 5–15 mg/day for
trihexyphenidyl, and 75–150 mg/day for diphenhydramine, although the dose required to achieve
prophylaxis is highly variable for each individual and can only be determined by trial and error
(Moleman et al. 1982; Sramek et al. 1986). Serious anticholinergic side effects, such as acute
urinary retention or paralytic ileus, can occur even in a young patient; therefore, high doses of
anticholinergics cannot be used with impunity, even for short periods.
Prophylactic anticholinergics for ADRs need only be used for a limited time because 85%–90% of
ADRs occur within the first 4 days of treatment, and the incidence drops to nearly zero after 10
days (Keepers et al. 1983; Singh et al. 1990; Sramek et al. 1986). After 10 days, anticholinergics
can be weaned slowly while the patient is being observed for development of parkinsonism or
akathisia.
Depot Antipsychotics
In patients receiving depot antipsychotics, prophylactic anticholinergics also only need to be used
for patients at high risk of developing ADRs (Idzorek 1976). However, the onset and
characterization of EPS may be different in people receiving depot antipsychotics, including more
bizarre dystonic reactions (G. M. Simpson 1970). The buildup of antipsychotic levels with depot
antipsychotics can lead to the development of EPS at later stages of treatment; therefore, an
ongoing evaluation is necessary. Some patients receiving fluphenazine decanoate were found to
experience EPS only between days 3 and 10 following injection (McClelland et al. 1974).
Duration of Treatment
Withdrawal Studies
Studies investigating the withdrawal of antiparkinsonian agents have demonstrated that not all
subjects redevelop EPS, a serendipitous finding noted when only 20% of patients withdrawn from
benztropine in preparation for a trial of a new antiparkinsonian agent developed recurrent
parkinsonian symptoms. This led to the suggestion that antiparkinsonian agents should be
withdrawn after 2 months and that their use should only be resumed in patients who develop EPS
again (Cahan and Parrish 1960).
Subsequently, other withdrawal studies have been conducted that revealed wide-ranging rates of
EPS recurrence. Differences in rates of recurrence are related to the varying methodologies
involved in the studies, including methods of rating and the initial reason for treatment with
anticholinergics—prophylaxis or active treatment (Ananth et al. 1970). The types, dosages, and
combinations of antipsychotics used—the same factors that contribute to the initial development of
EPS—have also been major factors in determining reoccurrence rates (Baker et al. 1983; McClelland
et al. 1974). In addition, there are inherent difficulties in evaluating EPS, including the role of
psychological factors and placebo effect (Ekdawi and Fowke 1966; G. M. Simpson et al. 1972; St.Print: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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Jean et al. 1964).
Almost all anticholinergic withdrawal studies have involved abrupt withdrawal of the
anticholinergic medications. Abrupt, compared with gradual, withdrawal is more likely to result in a
return of EPS. Gradual withdrawal studies have demonstrated that a large percentage (up to 90%)
of patients can be completely withdrawn from anticholinergic medications without developing EPS,
while the remaining patients can have their EPS controlled with a considerably reduced dose
(Double et al. 1993; Ungvari et al. 1999).
Withdrawal Syndrome
Almost all anticholinergic withdrawal studies have involved abrupt withdrawal of the
anticholinergic medications. Specific studies to evaluate the effect of cholinergic sensitization by
anticholinergic agents on the subsequent development of EPS following withdrawal of the
anticholinergic agent have not been done. There is evidence that sensitization can take place and
contribute to EPS and other symptoms. Some patients with no symptoms of EPS prior to treatment
with anticholinergics did develop EPS on withdrawal of the anticholinergics (Klett and Caffey 1972;
- M. Simpson et al. 1965). Withdrawal symptoms of nausea, vomiting, diaphoresis, sebaceous
secretion, and restlessness can occur following withdrawal of any psychotropic with anticholinergic
properties (Luchins et al. 1980). These symptoms are most likely the result of cholinergic rebound
and perhaps sensitization following removal of the cholinergic blockade of the drug (G. M. Simpson
et al. 1965). Abrupt clozapine withdrawal can produce agitation, delirium, and severe
choreoathetoid movements, which are also probably the result of cholinergic rebound related to the
very high antimuscarinic activity of clozapine (Stanilla et al. 1997).
The potential for cholinergic sensitization with the use of anticholinergic agents is significant
because EPS following withdrawal may initially be more severe but may diminish over time without
treatment. Potential cholinergic sensitization leading to subsequent EPS is also a reason for limiting
the routine use of prophylactic anticholinergic agents.
The conclusion that can be drawn from the withdrawal studies is that patients are more likely to
develop EPS on withdrawal of antiparkinsonian agents if the risk factors for developing EPS are
present. If these risk factors are minimized, the rate of EPS recurrence is lowered.
In patients who experience a reoccurrence of EPS, the EPS generally reappear within 2 weeks and
control is easily reestablished (Klett and Caffey 1972). Patients respond rapidly and often require
smaller doses of antiparkinsonian medications for control while continuing to take the same dose of
antipsychotic (McClelland et al. 1974).
It needs to be emphasized that the withdrawal of antiparkinsonian agents should be conducted
slowly and gradually over weeks or months, not abruptly, as was done in the reported studies.
Patients should be evaluated for recurrence of EPS following a partial dose reduction of the
antiparkinsonian agent. This process should be continued until the antiparkinsonian agent is
completely withdrawn or until the lowest dose for maintenance control is achieved.
CONCLUSION
The unique properties of chlorpromazine and other similarly active agents in ameliorating psychotic
symptoms and producing parkinsonian side effects were described in the early 1950s by French
psychiatrists. Theories soon arose regarding the relationship between these two properties. The
recognition of the benefits of reducing Parkinson-like side effects led to investigations of methods
to reduce EPS and to the development of instruments to measure EPS. The debate regarding the
routine and prophylactic use of antiparkinsonian agents has continued since that time. It appears
that prophylactic antiparkinsonian agents need to be used in some situations, but probably less
frequently and for briefer periods of time than has generally been the practice. The trend toward
the use of lower dosages of antipsychotics should also lead to a decreased need for the use of
antiparkinsonian agents. Finally, the advent of atypical antipsychotic agents has opened a new
chapter in both the treatment and prevention of EPS and suggests that, in the future, EPS will bePrint: Chapter 34. Drugs to Treat Extrapyramidal Side Effects http://www.psychiatryonline.com/popup.aspx?aID=430905&print=yes…
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less of a problem than they have been in the past.
A summary of an American Psychiatric Association Task Force report on TD suggested that “[a]
deliberate and sustained effort must be made to maintain patients on the lowest effective amount
of drug and to keep the treatment regimen as simple as possible” (Baldessarini et al. 1980, p.
1168) and to discontinue anticholinergic drugs as soon as possible. Apart from a greater emphasis
on avoiding the initial use of antiparkinsonian agents, this statement remains valid.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Extrapyramidal Side Effects
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Understanding Extrapyramidal Side Effects
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Common Symptoms of Extrapyramidal Side Effects
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Quiz on the Basics of Extrapyramidal Side Effects
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Risk Factors for Extrapyramidal Side Effects
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The Role of Dopamine in Extrapyramidal Side Effects
Pharmacological Mechanisms of EPS
Medications for Preventing EPS
Treatment Strategies for Managing EPS
Advanced Case Studies and Conclusion
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