Joseph K. Stanilla, M.D.
George M. Simpson, M.D.
The discovery of the therapeutic properties of chlorpromazine (Delay and Deniker 1952; Laborit et al. 1952) was soon followed by the description of its tendency to produce extrapyramidal side effects (EPS) that were indistinguishable from the symptoms of classic Parkinson’s disease. A debate soon arose regarding the relationship between EPS and therapeutic efficacy, with some investigators suggesting that EPS were necessary for efficacy (Flügel 1953; Haase 1954).
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).
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 classic movements of akathisia but without 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, pseudoparkinsonism, is virtually indistinguishable from classic Parkinson’s disease. Symptoms of pseudoparkinsonism include a generalized slowing of movement (akinesia), masked facies, rigidity (including cogwheeling rigidity), resting tremor, and hypersalivation. Parkinson-like symptoms generally appear after a few weeks or more of antipsychotic treatment. Akinesia needs to be differentiated from both primary depression and the blunted affect of schizophrenia (Rifkin et al. 1975).
Tardive syndromes make up the fourth group of EPS. Tardive dyskinesia (TD), although clearly associated with the use of antipsychotic medications, was actually described prior to the advent of antipsychotics (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 appear 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 al. 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).
Antiparkinsonian medications primarily have been used to treat EPS and include anticholinergic, antihistaminic, and dopaminergic agents (Table 35–1).
Compound |
Relative equivalence (mg)a |
Route |
Availability |
Dosing |
Dosage range (mg/day) |
Anticholinergics |
|||||
Trihexyphenidyl (Artane) |
2 |
Oral |
Tablets: 2, 5 mg Elixir: 2 mg/mL |
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–bid Every 30 minutes (until symptom relief) |
2–24 2–8 |
Procyclidine (Kemadrin) |
2 |
Oral |
Tablets: 5 mg (scored) |
bid–tid |
5–20 |
Antihistaminics |
|||||
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 |
Dopaminergics |
|||||
Amantadine (Symmetrel) |
N/A |
Oral |
Tablets: 100 mg Syrup: 50 mg/5 mL |
qd–bid |
100–300 |
Note. bid=twice daily; N/A=not applicable; qd=once daily; tid=three times daily. aAdapted from Klett and Caffey 1972. bNo longer available as an injectable in the United States. |
|||||
Trihexyphenidyl.
History and discovery. Trihexyphenidyl, a synthetic analog of atropine, was introduced as benzhexol hydrochloride in 1949. 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). (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].)
Structure–activity relations. Trihexyphenidyl, a tertiary-amine analog 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, trihexyphenidyl 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, preventing 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, trihexyphenidyl crosses the blood–brain barrier to enter the central nervous system (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. 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 dosages 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 dosages 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 dosage must be determined empirically and can vary widely.
Side effects and toxicology. 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 leads to dry mouth and contributes to the high incidence of dental caries found among patients with chronic psychiatric problems (Winer and Bahn 1967). Treatment for this condition is unsatisfactory; relief obtained from 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 heatstroke, 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 men).
The next effects are inhibition of urinary bladder function and bowel motility, which can produce urinary retention, constipation, and obstipation. Sufficiently high dosages of anticholinergics will inhibit gastric secretion and motility (Brown and Taylor 1996).
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 dosages (Stephens 1967). Patients receiving an antipsychotic and benztropine had 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 dosages, because of the natural loss of cholinergic neurons with aging (Perry et al. 1977). Toxic dosages can produce a clinical situation identical to atropine poisoning, manifesting as 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.
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).
Haase and Janssen (1965) reported from open studies that when anticholinergic medications are added to antipsychotic medications given at dosages that reach the neuroleptic threshold, rigidity, hypokinesia, and therapeutic effects disappear, but psychopathology worsens. (Haase [1954] postulated that the neuroleptic dosage that produced minimal subclinical rigidity and hypokinesis [i.e., the “neuroleptic threshold”] was the minimum neuroleptic dosage necessary for therapeutic antipsychotic effect and that it was manifested by micrographic handwriting changes.) Other studies have reported no change or an improvement in scores of psychopathology with the addition of anticholinergics (Hanlon et al. 1966; 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 dosages of 1–4 mg once daily for older patients and 2–8 mg once daily for younger ones. Dosages of 15–30 mg once daily caused excessive flaccidity in some patients, who became 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. As a tertiary amine, benztropine 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 documented (Tune and Coyle 1980). There is little correlation between the total daily dosage of benztropine and the serum anticholinergic level, with the serum activity for a given dosage varying 100-fold between subjects. When treated with higher dosages of anticholinergics, patients with EPS show increased serum anticholinergic activity and decreased EPS. Relatively small increments in the oral dosage 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.
Mechanism of action, side effects, and drug–drug interactions. The mechanism 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.
Indications. Benztropine has FDA approval for the treatment of all forms of parkinsonism, including NIP. Total daily dosages of 1–8 mg generally have been used to treat NIP.
Biperiden. Biperiden is an analog 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, although 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 dosages of 2–24 mg have been used in studies of biperiden for the treatment of parkinsonism and NIP.
Procyclidine. Procyclidine is an analog 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 dosages of 5–30 mg have been used in studies of procyclidine for the treatment of parkinsonism and NIP.
Diphenhydramine.
History and discovery. Antihistaminic agents have been used for the treatment of Parkinson’s disease. Diphenhydramine, 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 histamine-1 (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, whereas 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. Diphenhydramine has FDA approval for treatment of parkinsonism, including NIP, in the elderly and for mild cases of parkinsonism 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 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.
Amantadine.
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 a dosage range of 50–300 mg/day. It reaches steady state in 4–7 days. Plasma concentrations (0.12–1.12 μg/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 antiparkinsonian 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 via 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. Amantadine has undergone more extensive investigation than have anticholinergic agents with regard to the efficacy for EPS. Most studies, although 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; König 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 no clear data 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. 1972). Similar studies evaluating the long-term efficacy of amantadine have not been conducted for EPS.
Amantadine also has 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, 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 Van 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 μg/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 through 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.
History and discovery. Propranolol was reported to be effective for the treatment of restless legs syndrome (Ekbom syndrome; Ekbom 1965), which resembles the physical movements of akathisia (Strang 1967). Later it was reported to be effective in the treatment of medication-induced akathisia (Kulik and Wilbur 1983; Lipinski et al. 1983). Subsequently, other β-blockers have been investigated for the treatment of akathisia.
Structure–activity relations. Competitive β-adrenergic receptor antagonism is a property common to all β-blockers. β-Blockers are distinguished by the additional properties of their relative affinity for β1 and β2 receptors (selectivity), lipid solubility, intrinsic β-adrenergic receptor agonist activity, blockade of receptors, capacity to induce vasodilation, and general pharmacokinetic properties (Hoffman and Lefkowitz 1996). β-Blockers with high lipid solubility readily cross the blood–brain barrier.
Pharmacological profile. The major pharmacological effects of β-blockers involve the cardiovascular system. β-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 (Hoffman and Lefkowitz 1996). β-Blockers affect lipid metabolism by preventing release of free fatty acids while elevating triglycerides (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 β-blockers, except atenolol and nadolol, are well absorbed from the gastrointestinal tract (McDevitt 1987). All β-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 dosages (Hoffman and Lefkowitz 1996). Metabolites appear to have limited β-receptor antagonistic activity. The degree to which a particular β-blocker enters the CNS is related directly to its lipid solubility (Table 35–2).
Compound |
β1 blockade |
β2 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 dosages; + at high dosages |
++ |
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; 0=insignificant; +=low; ++=moderate; +++=high; ++++=very high. Source. Adapted from Hoffman and Lefkowitz 1996. |
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Mechanism of action. The exact mechanism of action of β-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 β-blocker in treating akathisia and perhaps other types of EPS (Adler et al. 1991).
Indications. β-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.
β-Blockers have been studied primarily for the treatment of akathisia. Both nonselective (β1 and β2 antagonism) and selective (β1 antagonism) β-blockers have been reported to be efficacious. The studies generally have 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 β-blockers had been added (Fleischhacker et al. 1990). From these studies, it is difficult to draw any firm conclusions, but β-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 β-blocker of choice in patients with lung disease and smokers because of its β1 selectivity at lower dosages (5–10 mg/day).
In addition to essential tremor, β-blockers have 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 β-blockers result from β-receptor blockade. β2 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. β-Blockers can contribute to heart failure in susceptible individuals, such as those with compensated heart failure, acute myocardial infarction, or cardiomegaly. Abrupt cessation of β-blockers can also exacerbate coronary heart disease in susceptible patients, producing angina or, potentially, myocardial infarction (see Hoffman and Lefkowitz 1996 for details).
In individuals with normal heart function, bradycardia produced by β-blockers is insignificant; however, in patients with conduction defects or when combined with other drugs that impair cardiac conduction, β-blockers can contribute to serious conduction problems.
β-Blockers can block the tachycardia associated with hypoglycemia, eliminating this warning sign in patients with diabetes. β2 blockade also can inhibit glycogenolysis and glucose mobilization, interfering with recovery from hypoglycemia (Hoffman and Lefkowitz 1996).
β-Blockers can impair exercise performance and produce fatigue, insomnia, and major depressive disorder. However, the development of major depressive disorder probably only occurs in individuals with a predisposition to developing depression.
Drug–drug interactions. β-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 β-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 β-blockers (Hoffman and Lefkowitz 1996).
Diazepam was initially shown to be effective in the treatment of restless legs syndrome (Ekbom syndrome), which resembles the physical movements of akathisia (Ekbom 1965). Subsequently, diazepam, lorazepam, and clonazepam were reported to be beneficial for medication-induced akathisia (Adler et al. 1985; Donlon 1973; Kutcher et al. 1987). Clonazepam also has been reported to be beneficial for drug-induced dystonia (O’Flanagan 1975) and TD (Thaker et al. 1987).
All benzodiazepines promote the binding of γ-aminobutyric acid (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 augmentation of the inhibitory GABAergic effect (Hobbs et al. 1996). For a complete discussion of the properties of benzodiazepines, see Chapter 22 in this volume, “Benzodiazepines,” by Sheehan.
Benzodiazepines have FDA approval for use in treatment of anxiety disorders, agoraphobia, insomnia, and seizure disorders; management of alcohol withdrawal; anesthetic premedication; and skeletal muscle relaxation; however, they are not approved for use in treating any type of EPS. As noted earlier, a few initial reports have indicated that benzodiazepines are beneficial for the treatment of akathisia. Other studies also have 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 been reported to be effective in the treatment of TD (Bobruff et al. 1981; Thaker et al. 1990). Dosages of 1–10 mg/day 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 often can be given once a day. Lorazepam has the advantage of having no active metabolites, which eliminates potential side effects and toxicity.
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 several other conditions associated with excessive muscle activity, including medication-induced dystonias (Hughes 1994).
There are seven immunologically distinct botulinum toxins (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).
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 or size of active muscle fibers is reduced (Odergren et al. 1994).
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.
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).
The FDA has approved the use of botulinum toxin for strabismus, blepharospasm, and other facial 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).
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 early age at first treatment with the toxin 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 also can 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).
Botulinum toxin has 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).
Botulinum toxin has no known interactions with other drugs.
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 antipsychotic 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).
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 (Bieri and Farrell 1976).
Early studies of vitamin E treatment of TD reported 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 double-blind study comparing vitamin E with placebo found that vitamin E was no more beneficial than placebo (Adler et al. 1999). There were no significant effects of vitamin E on total scores or subscale scores for the Abnormal Involuntary Movement Scale (AIMS; Guy 1976), 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 association between vitamin E dosage and all-cause mortality, with increased risk for dosages greater than 150 IU/day (E.R. Miller et al. 2005). Given the lack of data showing consistent effectiveness for TD, we do not recommend that vitamin E be used for this purpose.
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 dosages of vitamin E can exacerbate the coagulation abnormalities in both cases and therefore are contraindicated (Kappus and Diplock 1992).
No drug with antipsychotic activity has been identified that does not have significant affinity for D2 dopamine receptors. D2 receptor blockade is the pharmacodynamic property of all antipsychotics, and without this property, a drug will not show any antipsychotic effects. This is true for both typical (first-generation) and atypical (second-generation) antipsychotics. The antipsychotic effects of typical antipsychotics are directly related to the degree of D2 receptor blockade. The antipsychotic effects of atypical antipsychotics, however, are more complicated (Meltzer 2002).
All of the atypical antipsychotics are potent serotonin type 2A (5-HT2A) receptor antagonists and relatively weak D2 receptor antagonists compared with the typical antipsychotics (except for cariprazine, which has relatively weak blockade of 5-HT2A receptors compared with the other atypical antipsychotics [Gyertyán et al. 2011]). The high ratio of 5-HT2A receptor blockade to striatal D2 receptor blockade that characterizes clozapine is thought to contribute to its lack of EPS (Meltzer et al. 1989).
Blockade of 5-HT2A and dopamine receptors was first labeled in 1989 as a pharmacodynamic mechanism that differentiated conventional from second-generation antipsychotics (Meltzer 1989). Meltzer (2002) defined atypical antipsychotics as drugs showing a higher affinity for 5-HT2A receptors than for D2 receptors and a lower affinity for D2 receptors than that seen with conventional antipsychotics. For the nigrostriatal dopaminergic pathway, one proposed model suggested that blockade of 5-HT2A receptors would lead to increased output of dopaminergic neurons into the striatum, causing an antipsychotic drug to be displaced from its binding to D2 receptors. It was theorized that this displacement could decrease the risk of EPS development (Horacek et al. 2006).
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 complete recovery does not occur. 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 dosages of high-potency antipsychotics are being used or unless the dosage is increased. A more complete discussion of prophylaxis is provided in the section “Prophylactic Use of Antiparkinsonian Agents” later in this chapter.
The initial steps in treatment of parkinsonism (Table 35–3) and of akathisia (also referred to here as EPS) are identical: evaluating the dosage and type of antipsychotic. It has been shown that an increase in dosage 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 also has been found 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).
Step |
Action |
1 |
Reduce dosage 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 dosage tolerated. |
5 |
Add amantadine in combination with anticholinergic or as a single agent. |
6 |
Add a benzodiazepine or a β-blocker. |
7 |
In severe cases of extrapyramidal side effects, 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 β-blocker, although fewer data support 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 al. 1990). Sodium valproate was reported to have had no significant effect on akathisia and was found to increase parkinsonism (Friis et al. 1983).
As experience with the use of atypical antipsychotics has increased, further data have been obtained about the risk of EPS. A review of studies involving atypical antipsychotics in which EPS were assessed found that EPS, especially akathisia, did occur with atypical antipsychotics, although the frequency was not as high as with typical antipsychotics. Risk factors include the use of high dosages of medication, high-potency atypical antipsychotics, combinations of atypical antipsychotics with other psychotropics, bipolar depression, palliative care settings, and substance abuse with psychosis (Kumar and Sachdev 2009).
Gao et al. (2008) conducted a review of studies of patients with schizophrenia or bipolar disorder. The studies included both typical and atypical antipsychotics. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania. Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania. Patients with mania treated with risperidone had a significantly increased risk for overall EPS and anticholinergic use. Patients taking aripiprazole for bipolar mania and bipolar depression had increased risk for akathisia. Patients with bipolar depression treated with quetiapine had an increased risk for overall EPS. The authors concluded that bipolar depressed patients are at the greatest risk for acute antipsychotic-induced movement disorders.
Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies showed 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 patients taking perphenazine than patients taking atypical antipsychotics discontinued treatment because of EPS (8% vs. 2%–4%), the EPS incidence was low and of limited clinical significance (D.D. Miller et al. 2005).
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 agent.
For severe refractory EPS that 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.
Clozapine. Patients taking clozapine (FDA approved in 1989) were found to have significantly less parkinsonism compared with patients taking a combination of chlorpromazine and an antiparkinsonian agent (benztropine) (Kane et al. 1988). The prevalence and incidence of akathisia also were shown to be lower in patients taking clozapine than in patients taking other first- or second-generation antipsychotics (Chengappa et al. 1994; Chouinard et al. 1993; Kurz et al. 1995; Stanilla et al. 1995). Clozapine is covered in detail elsewhere in this volume (see Chapter 25, “Clozapine,” by Marder and Yang).
Other atypical antipsychotics. The atypical antipsychotics approved for use in the United States after clozapine were also shown either to produce EPS at rates similar to those seen with haloperidol (risperidone, olanzapine, quetiapine, ziprasidone, asenapine, and iloperidone) or to produce EPS at rates comparable to those seen with placebo (aripiprazole, paliperidone, cariprazine, and brexpiprazole).
Risperidone. Risperidone (approved in 1993) was the first atypical antipsychotic to become available after clozapine (Claus et al. 1992). At lower dosages (4–6 mg/day), risperidone usually does not produce significant parkinsonism, but unlike clozapine, it can produce significant parkinsonism at higher dosages (Chouinard et al. 1993). In initial studies comparing risperidone with haloperidol, the extrapyramidal scores for patients receiving risperidone (6 mg once daily) were not significantly different from the scores of patients receiving placebo. Risperidone can cause ADRs, and patients with severe EPS at baseline were more likely to develop EPS when taking risperidone (Simpson and Lindenmayer 1997). Risperidone is covered in detail elsewhere in this volume (see Chapter 28, “Risperidone and Paliperidone,” by Hill and Goff).
Olanzapine. Olanzapine (approved in 1996) 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 was observed across the entire therapeutic dosage range of 5–24 mg/day. Olanzapine is covered in detail elsewhere in this volume (see Chapter 26, “Olanzapine,” by Silberschmidt et al.).
Quetiapine. Quetiapine (approved in 1997) has been found to have antipsychotic activity comparable to that of haloperidol at dosages 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). Most patients had no significant changes in AIMS scores from baseline to the end of a 6-week period of treatment. Quetiapine is covered in detail elsewhere in this volume (see Chapter 27, “Quetiapine,” by Buckley et al.).
Ziprasidone. Ziprasidone (approved in 2001) was compared with haloperidol in a double-blind, dose-ranging trial and found to have comparable antipsychotic effect at higher dosages. Benztropine use at any time during the study was less frequent with the highest dosage of ziprasidone (160 mg/day) than with haloperidol (15% vs. 53%) (Goff et al. 1998). Studies of ziprasidone found no significant differences in baseline-to-endpoint mean changes on Simpson-Angus Scale (Simpson and Angus 1970) and AIMS scores between placebo and ziprasidone (40–160 mg/day) (Keck et al. 2001). Ziprasidone is covered in detail elsewhere in this volume (see Chapter 30, “Ziprasidone,” by Newcomer et al.).
Aripiprazole. Aripiprazole (approved in 2002) 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). Aripiprazole is covered in detail elsewhere in this volume (see Chapter 29, “Aripiprazole and Brexpiprazole,” by Gonzalez and Strassnig).
Paliperidone. Extended-release paliperidone (approved in 2006) was found to have an incidence of EPS nearly comparable to that of placebo (7% vs. 3%) at a dosage range of 3–15 mg/day (Kramer et al. 2007). Paliperidone is covered in detail elsewhere in this volume (see Chapter 28, “Risperidone and Paliperidone,” by Hill and Goff).
Asenapine. Asenapine (approved in 2009) was evaluated in a 6-week double-blind, placebo- and active-controlled (haloperidol) trial of 458 patients with acute schizophrenia. Patients were given asenapine (5 mg or 10 mg twice a day), haloperidol (4 mg twice a day), or placebo. The incidence of EPS for asenapine was 15% for 5 mg twice a day and 18% for 10 mg twice a day, 34% for haloperidol, and 10% for placebo (Kane et al. 2010).
In a study of 488 patients with manic or mixed episodes of bipolar disorder, patients receiving asenapine (5–10 mg twice a day) were compared with those receiving olanzapine (5–20 mg/day) or placebo. The incidence of EPS was found to be 10.3% for asenapine, 6.8% for olanzapine, and 3.1% for placebo (McIntyre et al. 2010).
Asenapine is covered in detail elsewhere in this volume (see Chapter 31, “Asenapine,” by Citrome).
Lurasidone. Lurasidone (approved in 2009) was compared with placebo in a 6-week double-blind study of 180 patients with acute schizophrenia. Patients receiving lurasidone 80 mg/day were found to have no clinically significant differences in the incidence of EPS compared with patients receiving placebo (Nakamura et al. 2009). Lurasidone is covered in detail elsewhere in this volume (see Chapter 33, “Lurasidone,” by Harvey).
Iloperidone. Iloperidone (approved in 2009) was evaluated from the pooled results of three double-blind studies of 1,912 patients with schizophrenia. Patients received iloperidone (4–24 mg/day), haloperidol (15 mg/day), risperidone (4–8 mg/day), or placebo. The incidences of akathisia and EPS were lower with iloperidone than with risperidone and haloperidol and generally were similar to the incidences with placebo (Potkin et al. 2008). Iloperidone is covered in detail elsewhere in this volume (see Chapter 32, “Iloperidone,” by Buckley et al.).
Brexpiprazole. Brexpiprazole was approved in 2015 for the treatment of schizophrenia. A double-blind study compared brexpiprazole (daily dosages of 0.25, 2, or 4 mg) with placebo in patients with acute schizophrenia. The incidence of akathisia was relatively low for both placebo (2%) and brexpiprazole 0.25 mg (0%), 2 mg (7%), and 4 mg (7%) (Correll et al. 2015). Brexpiprazole is covered in detail elsewhere in this volume (see Chapter 29, “Aripiprazole and Brexpiprazole,” by Gonzalez and Strassnig).
Cariprazine. Cariprazine was approved in 2015 for the treatment of schizophrenia and bipolar disorder in adults (Sachs et al. 2015). Cariprazine was evaluated in a 6-week double-blind, placebo- and active-controlled (aripiprazole) study in patients with acute schizophrenia. Patients were assigned to cariprazine 3 or 6 mg/day, aripiprazole 10 mg/day, or placebo. The only treatment-emergent adverse event that occurred in more than 5% of the patients was akathisia in the 6 mg/day cariprazine group (15%). The incidence was significantly greater than the incidence with placebo (4.6%; P=0.0034). The incidence for the 3 mg/day group was 7%. The incidence for aripiprazole was 7% (Durgam et al. 2015). Cariprazine is covered in detail elsewhere in this volume (see Chapter 34, “Cariprazine,” by Albrahim et al.).
Historically, TD has been refractory to treatment, which explains the large number of drugs used 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 these drugs, the American Psychiatric Association Task Force on Tardive Dyskinesia concluded that there is no consistently effective treatment for TD (Kane et al. 1992).
Evaluating the effects of any treatment for TD has inherent difficulties. These include the variability of clinical raters (Bergen et al. 1984), the variability of 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 such variations to show 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 dosage possible (Simpson 2000). Second, if anticholinergic antiparkinsonian medications are being used, the patient should be gradually weaned from these medications and the medications then discontinued. In contrast to their effect on other extrapyramidal movements, anticholinergic medications will make 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 al. 1999).
Valbenazine (NBI-98854) is a vesicular monoamine transporter inhibitor that is actively being studied in the treatment of TD. Tetrabenazine, the original agent in this class, is effective in treating movement disorders but has important dosing and safety limitations. In a recent report of a Phase II study in 102 patients, valbenazine was highly statistically significantly more effective than placebo in improving TD (O’Brien et al. 2016), with apparently better safety and tolerability and greater ease of administration relative to tetrabenazine. Valbenazine is currently being investigated in pivotal Phase III trials and has been granted a Breakthrough Therapy designation by the FDA (Müller 2015).
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).
Clozapine has been shown to decrease the symptoms of TD (Simpson and Varga 1974; 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.
More data indicating the potential benefit of the other novel antipsychotics in the prevention and treatment of TD are being reported.
In a prospective double-blind study of patients with schizophrenia receiving treatment with either olanzapine or haloperidol and followed for up to 2.6 years, the risk for the development of TD with olanzapine was significantly decreased. The 1-year risk was 0.52% for olanzapine and 7.45% for haloperidol (Beasley et al. 1999).
A prospective study examined the incidence of emergent dyskinesia in middle-aged to elderly patients (mean age=66 years) taking haloperidol or low-dosage risperidone (mean total daily dosage for both medications=1 mg/day). Compared with the patients taking haloperidol, those taking risperidone were significantly less likely to develop TD (Jeste et al. 1999). A double-blind prospective study comparing 397 patients with schizophrenia on stable dosages of antipsychotics who were randomly assigned to switch to either risperidone or haloperidol and followed up 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).
The data regarding the long-term effect of atypical antipsychotics in causing TD are more limited; however, any drug that is less likely to produce EPS is probably less likely to produce TD.
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 typical 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 (Simpson 2000).
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 for developing ADRs but that it is not beneficial in routine use across all patient groups (Hanlon et al. 1966; Sramek et al. 1986). Several retrospective studies also have found that the need for prophylaxis of EPS is limited (Swett et al. 1977). The retrospective studies that identified a greater benefit from prophylaxis involved the use of high antipsychotic dosages (Keepers et al. 1983; Stern and Anderson 1979).
Table 35–4 summarizes the risk factors for developing ADRs, which include younger age (<35 years), higher dosages of antipsychotic, higher potency of antipsychotic, intramuscular route of delivery, (possibly) male sex (Sramek et al. 1986), and a history of ADRs from a similar antipsychotic (Keepers and Casey 1991). The use of cocaine also has been suggested as a possible risk factor (van Harten et al. 1998).
High-potency antipsychotics |
Haloperidol |
Fluphenazine |
Trifluoperazine |
High dosages |
Younger age (<35 years)a |
Intramuscular route of delivery |
Previous dystonic reaction to similar antipsychotic and dosage |
Male sex (?) |
aApproaches 100% at age <20 years. |
Studies examining withdrawal of antiparkinsonian agents have found that not all subjects redevelop EPS when these agents are discontinued. In the first study to report this serendipitous finding (Cahan and Parrish 1960), patients were being withdrawn from benztropine in preparation for a trial of a new antiparkinsonian agent. The discovery that only 20% of the patients developed recurrent parkinsonian symptoms following withdrawal led the study authors to suggest that antiparkinsonian agents should be withdrawn after 2 months and that their use should be resumed only in patients who re-develop EPS (Cahan and Parrish 1960).
Other withdrawal studies have reported 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—also have been major factors in determining recurrence rates (Baker et al. 1983; McClelland et al. 1974).
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 found that a large percentage (up to 90%) of patients can be completely withdrawn from anticholinergic medications without developing EPS, and the remaining patients can have their EPS controlled with a considerably reduced dosage (Double et al. 1993; Ungvari et al. 1999).
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.
Among patients who experience a recurrence 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 dosages of antiparkinsonian medications for control while continuing to take the same antipsychotic dosage (McClelland et al. 1974).
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. Recognition of the benefits of reducing parkinsonian 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 with less frequency 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 the prevention of EPS and suggests that in the future, EPS will be 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 that anticholinergic drugs should be discontinued 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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