Clinical Psychopharmacology Seminar 1996-1997
Paul J. Perry, Ph.D., Bruce Alexander, Pharm.D., Vicki L.
Ellingrod, Pharm.D.
Peer Review Status: None
INTRODUCTION
Early-onset extrapyramidal symptoms (EPS) usually appear within the first four weeks of antipsychotic treatment and include dystonia, akathisia, and parkinsonism. Incidence estimates of EPS vary widely, ranging from 2.2% to 95% (Tarsy 1983, Ayd 1961). Much of the variation in the reported percentages may be explained by differences in the antipsychotic prescribed, length of treatment, dose of antipsychotic, individual characteristics such as sex and age, and definitions of EPS. EPS has been reported with metoclopramide and amoxapine (Tonda & Guthrie 1994).
Generally, these reactions are more common with high-potency antipsychotics (i.e., haloperidol, fluphenazine, trifluoperazine) than low-potency (i.e., thioridazine, chlorpromazine). Sheppard and Merlis (1967) reported that, among phenothiazines, thioridazine was the least likely to produce EPS reactions since only 4% of patients treated with the drug required antiparkinsonian medication as opposed to 7% with chlorpromazine (Thorazine), 12% with trifluoperazine (Stelazine), 13% with perphenazine (Trilafon), 18% with fluphenazine (Prolixin) and 19% with prochlorperazine (Compazine). Man (1973) reported an EPS incidence of 77% in his study on the long-term effects of haloperidol (Haldol). However, the average dose of haloperidol in these patients was 29 mg/d which corresponds to a chlorpromazine dose of 1800 mg/d. See antipsychotic dosing lecture for explanation of potency ratings.
These syndromes wax and wane over time, disappear during sleep, and are exacerbated by emotionally disturbing experiences. These early-onset reactions may coexist in the same patient. These EPS disappear upon discontinuation of the antipsychotic but this may take days to months depending upon the drug, its dose, and the patient.
A significant benefit in preventing or reducing antipsychotic-induced EPS can be achieved by initiating and maintaining antipsychotic doses in the low therapeutic range as all early-onset EPS are dose-related (Fleischhacker et al 1990, Tonda & Guthrie 1994). These side effects can be quite uncomfortable for the patient and disturbing to family and friends. Their recognition and appropriate management are an important part of patient care. The use of clozapine and risperidone in patients with EPS is discussed in their respective sections in this syllabus.
DYSTONIC REACTIONS
Presentation
These reactions consist of involuntary, tonic contractions of skeletal muscles of virtually any striated muscle group (Lee 1979). The most common dystonias involve the muscles of the head and face producing buccal spasms, oculogyric crisis, facial grimacing, tics, or trismus. Involvement of the neck musculature produces torticollis or retrocollis. If the trunk is involved, shoulder shrugging, tortipelvis, opisthotonus, or scoliosis may occur. Carpopedal spasms, dorsiflexion of the toes, contraction of muscle groups of arms or legs, or a dystonic gait may be seen if the limbs are involved. Rare complications include chipped teeth, dislocation of the temporomandibular joint, tongue injuries, and respiratory distress secondary to pharyngeal muscles being affected. Seventy-two percent of dystonias are classified as simple dystonias with 50% being buccolingual, 16% torticollic, and 6% opisthotonic. Combined dystonias are observed in 28% of patients.
Fifty percent occur within 48 hours and 90% within the first four days of initiation of antipsychotic treatment (Ayd 1961). They may occur after one dose of an antipsychotic regardless of the route of administration. Dystonias may occur abruptly or in a stuttering fashion over several hours. They usually occur once but occasionally reoccur when there is an increase in dosage.
The reported incidence of dystonia ranges from 2.3% to 64% depending on the many factors noted above (Smith and Denner 1962, Donlon 1976). The incidence studies of this adverse effect have been reviewed (Gelenberg 1987). Although a dystonic reaction may occur at any age, it is 15 times more common in patients under 35 (Addonizio and Alexopoulos 1988). Men less than 50 years of age are twice as likely to develop dystonia than women (Swett 1975). The dystonic reaction rate in patients over 50 is the same for men and women. A retrospective study indicated a 26% incidence of dystonia in mania compared to a 6% rate in schizophrenia (Nasrallah et al 1988). More recent prospective studies reported no differences between the diagnoses (Remington et al 1990, Khanna et al 1992). However, one study treated patients with high doses of intramuscular haloperidol (e.g., average 26 to 42 mg), which may have obscured a possible diagnosis-related difference (Remington et al 1990). Additionally, in the other study the number of subjects in each group may have been to small to detect a difference (Khanna et al 1992).
Treatment
Anticholinergics
Acute Treatment. Dystonias rarely result in significant morbidity and disappear without treatment within seven to ten days, even though the antipsychotic is continued. However, because of discomfort to the patient, dystonic reactions are treated as soon after their appearance as possible. Diphenhydramine (Benadryl®, generic) 50 mg or benztropine (Cogentin®) 2 mg IV or IM, for example, reverse dystonia in 100% of cases after a single injection or, rarely, with a repeat dose within five minutes (Gelenberg 1983, Donlon and Stenson 1976).
The preferred route of administration is intravenous. If this is not feasible IM drug administration can be used. Lee treated 32 cases of acute dystonia with either benztropine or diphenhydramine (Lee 1979). Sixteen patients received single doses of benztropine 2 mg, half of the patients IM and half IV, while the other 16 patients received diphenhydramine 50 mg, half of the patients IM and half IV. The mean objective recovery time, (e.g., no spasms and able to perform voluntary movements) for benztropine was 27 minutes IM and 2.2 minutes IV while the mean objective recovery time for diphenhydramine was 41 minutes IM and 3.1 minutes IV. Subjective improvement followed a similar pattern: benztropine 37 minutes IM versus 6.4 minutes IV while diphenhydramine was 68 minutes IM versus 9.5 minutes IV. Oral treatment with anticholinergics is not recommended because of the slower onset of action and because some patients may have difficulty in swallowing during acute dystonic reactions.
Because dystonia is usually self-limiting, the antipsychotic need not be discontinued or changed nor the dose lowered. If recurrences are frequent and/or severe, lowering the dose of the antipsychotic or switching the patient to a lower potency agent is recommended (Gelenberg 1983, Donlon and Stenson 1976). Finally, the drug-induced nature of the syndrome and its benign course should be explained to the patient and the family.
Prophylactic Treatment. There is evidence that prophylactic treatment is successful in lowering the incidence of acute dystonic reactions (Gelenberg 1983, Arana et al 1988). In 9 open and controlled trials (n = 1,366) of no prophylaxis versus prophylaxis, the risk of a dystonic reaction was reduced from 14.8% to 7.7%, respectively (Arana et al 1988). These studies included a mix of low- and high-potency antipsychotics. In the five studies involving 330 patients receiving only high-potency antipsychotics (primarily haloperidol) the difference was 51.2% versus 9.5%, respectively. In patients typically older than 45 years no difference was demonstrated between no prophylaxis and prophylaxis because the rate of dystonia is rare above this age. Also, patients receiving low-potency antipsychotics (i.e., chlorpromazine) rarely experienced dystonic reactions.
Prophylaxis would be appropriate in a patient at a great risk of developing dystonia (i.e., a young male receiving a piperazine phenothiazine or butyrophenone with a past history of dystonia or a patient likely to develop a reaction without ready access to medical treatment).
Duration of Treatment. After acute treatment of dystonia, the reaction may recur. Inpatients can be treated with repeat parenteral anticholinergics if the condition recurs. Duration of prophylactic treatment should cover the risk period of five to seven days.
Amantadine
Amantadine HCL was introduced in 1966 for prophylaxis of A2 (Asian) influenza. A patient receiving the drug for this indication noted improvement in her parkinsonian symptomatology.
One study reported amantadine 200-400 mg/d po was more effective than benztropine 4-6 mg/d po in 19 patients with recurrent dystonias receiving haloperidol 8-20 mg/d (Borison 1983).
Benzodiazepines
In a single-dose study diazepam 5 mg IV was as effective as diphenhydramine 50 mg IV in reversing dystonia (Gagrat et al 1978).
AKATHISIA
Presentation
This refers to the subjective experience of motor restlessness (Tarsy 1983, Van Putten et al 1984). Patients may complain of an inability to sit or stand still, or a compulsion to pace or cross and uncross their legs. They may also complain of being restless and having to be in constant motion. While standing they may rock to and fro or shift their weight from one leg to another. Patients may also suffer from initial insomnia because they cannot lie motionless in bed long enough to fall asleep. Ninety percent of cases develop within the first 73 days of treatment and 50% within the first month of initiation of the antipsychotic (Ayd 1961).
Estimates of the incidence of akathisia range from 21 to 75% (Ayd 1961, Van Putten 1984). Females are approximately twice as likely to develop akathisia compared to males; it demonstrates equal prevalence across all age groups (Ayd 1961, Ganzini et al 1991, Casey 1994). An accurate diagnosis is important since misdiagnosis may lead to an unnecessary increase in antipsychotic dose with potential worsening of akathisia.
Treatment
Anticholinergics
Although numerous anticholinergics are available for management of antipsychotic-induced EPS, comparative studies between agents comparing efficacy and side effects have not been performed. If a patient does not respond to one anticholinergic at maximal doses, a trial with another may be done empirically. There is no support for combining anticholinergics.
Doses of anticholinergics should be initiated with benztropine 1-2 mg/d or its equivalent (i.e., trihexyphenidyl 2-4 mg/d). Smaller initial doses should be used with geriatric patients. Benztropine can usually be administered effectively and safely in doses up to 6 mg/d, though some patients may require and tolerate doses to 8 mg/d. The dose is administered preferably at bedtime because of possible sedation. No information is available on single-daily dosing of other anticholinergics; these are usually administered two to three times per day.
Acute Treatment. When akathisia develops, it is appropriate in some clinical situations to change to an antipsychotic less likely to produce EPS (i.e., thioridazine, chlorpromazine) or to lower the dose of the antipsychotic causing the reaction. These drugs should be considered for patients at a high risk of developing specific types of acute-onset EPS. Upon discontinuation of the antipsychotic, akathisia symptoms generally resolves in seven to ten days, but may take several weeks depending upon the drug, the dose, and the patient.
The use of anticholinergics in the treatment of akathisia has been recently reviewed (Fleischhacker et al 1990). Of nine studies, four were double-blind in design. Five reports indicated anticholinergics were effective in akathisia, two had negative findings, and two had equivocal results. In studies that reported their results in percent response, the range was 30 to 100 percent (average 62 percent). However, not all patients in the positive studies had complete resolution of their akathisia. The time for akathisia to respond to anticholinergics is usually three to seven days. Most studies reported they were effective for akathisia in patients that had concomitant parkinsonism. Therefore, anticholinergics might be considered first-line treatment for patients with akathisia with concurrent parkinsonism.
Prophylactic Treatment. The prophylactic management of akathisia is typically included in the parkinsonism literature. (See prophylactic treatment under parkinsonism.)
Duration of Treatment. (See duration of treatment under parkinsonism.)
b-Adrenergic Blocking Agents
The topic of b-adrenergic blocking agents in akathisia has been reviewed (Fleischhacker et al 1990). Of 14 reports, 13 included propranolol alone or in comparison to another agent. Additional b-adrenergic blocking agents studied included atenolol, metoprolol, pindolol, nadolol, stadol, and betaxolol. Only six of the 16 reports were performed blind, most were of short duration (i.e., < one week), and in half of the studies patients received additional anticholinergic agents.
In summary, reports with propranolol indicate a 50 to 65% response rate at doses of 20 to 80 mg/d. Onset of action varied from 36 hours to five days with minimal side effects. In comparison studies, propranolol has been shown to be equal to betaxolol 10 to 20 mg/d (Dumon et al 1992, Adler et al 1991a), but more effective than atenolol, pindolol, and stadol. Propranolol and metoprolol comparisons have produced conflicting results. One study reported metoprolol was as effective as propranolol but only at higher doses that produced beta-2 effects (Zubenko et al 1984). Two reports indicated equal efficacy at low metoprolol doses (e.g., <100 mg/d) (Adler et al 1989, Adler et al 1990). Nadolol in an open study was reported effective (Adler et al 1991b), but not in a blinded study (Wells et al 1991).
If a patient fails a propranolol trial or cannot tolerate it, metoprolol or betaxolol might be considered (Fleischhacker et al 1990).
Discontinuation of propranolol will result in return of symptoms within three to five days (Zubenko et al 1984). One report indicated tolerance did not develop to propranolol over a six-month treatment period.
Limited evidence supports beta-blockers as a treatment for antipsychotic-induced akathisia. Based on preliminary reports propranolol is the first-line beta-blocker.
Beta-blockers vs. anticholinergics
Two studies have directed compared benztropine and propranolol in antipsychotic-induced akathisia. One study of 6 patients compared intravenous benztropine 2 mg, propranolol 1 mg, and saline placebo in a double-blind, cross-over study (Sachdev et al 1993). In subjective and objective ratings, benztropine was significantly more effective than propranolol in clinical improvement. However, equivalent doses of benztropine and propranolol have not been determined. In another placebo-controlled, blinded study involving 28 patients, both propranolol 80 mg/d and benztropine 6 mg/d produced equal and significantly greater improvement in akathisia symptoms compared to placebo (Adler et al 1993). Maximal effect with drug treatment occurred at day 3-5. However, 3 patients on benztropine developed confusion or forgetfulness by day 3; these effects cleared upon drug discontinuation.
Benzodiazepines
The use of benzodiazepines (BZDs) for the management of antipsychotic-induced akathisia has recently been reviewed (Fleischhacker et al 1990). Four reports used diazepam, while two each investigated lorazepam and clonazepam (Fleischhacker et al 1990, Kutcher et al 1989). Of the eight studies, the six with positive results indicated improvement within three to seven days. It is unknown if tolerance develops to this effect as most reports are of short duration (i.e., <1 week). Currently, there is no evidence to suggest one benzodiazepine is more effective than another.
Amantadine
Amantadine treatment is initiated at 100 mg/d and increased to 200 mg/d at one week. Doses of 300 mg/d may produce further improvement and 400 mg/d has been tried. Dosing may be once or twice daily (Kelly et al 1974).
Three reports have investigated the use of amantadine in akathisia (Fleischhacker et al 1990). The total number of patients treated is 42. One study reported amantadine was very effective, while another reported minimal effect in a group with anticholinergic-refractory akathisia. The third report indicated tolerance developed to the antiakathistic effect of amantadine within one week of treatment initiation (Zubenko et al 1984a). The efficacy of amantadine in the treatment of antipsychotic-induced akathisia remains to be demonstrated. Amantadine is an alternative to anticholinergics and beta-blockers.
Clonidine
Clonidine has been investigated in an open, on-drug/off-drug trial in the treatment of akathisia (Zubenko et al 1984c). Four of the six patients had complete remission of their symptoms, while the other two demonstrated substantial improvement of their akathisia. Daily doses ranged from 0.2 to 0.8 mg/d and maximal response occurred within 24 to 48 hours. Symptomatic orthostatic hypotension occurred in two patients. The authors recommended clonidine be instituted at 0.1 mg twice daily and to increase the daily dose at a maximum 0.1 mg twice daily every other day until akathisia remits, hypotension or sedation develops, or the maximum daily dose of 2.4 mg is reached.
This initial report was followed by a single-blind trial (Adler et al 1987). Six patients with antipsychotic-induced akathisia receiving clonidine 0.15 to 0.4 mg/d improved significantly by both objective and subjective ratings. However, increases in clonidine doses were limited by sedation in four patients and hypotension in five patients.
Current evidence suggests that propranolol is better tolerated than clonidine in patients with antipsychotic-induced akathisia. These preliminary results need to be replicated in double-blind, controlled trials. However, in patients with akathisia who are unresponsive to primary treatments, clonidine may be considered.
Presentation
The parkinsonian side effects manifest themselves as tremor, rigidity, and akinesia individually or in combination (Tarsy 1983). Drooling, festinating gait, oily skin, dysarthria, and dysphagia may accompany the symptoms. Akinesia may present early as slowness in initiating motor tasks and fatigue when performing activities requiring repetitive movements (bradykinesia). Affected persons appear apathetic with little facial expression, have difficulty walking, and their handwriting may take on a cramped appearance, (e.g., micrographia). The typical antipsychotic-induced parkinsonian tremor can be present during movement as well as at rest. Usually tremor begins in one or both upper extremities and in severe cases may involve the tongue, jaw, and lower extremities. Cogwheel rigidity, in which a ratchet-like phenomenon can be elicited upon passive movement of a limb, is the result of the presence of both rigidity and tremor. Drug-induced parkinsonism is likely bilateral in its presentation, while idiopathic disease is typically unilateral.
As with all drug-induced EPS, there is a wide variance in the reported incidence. The range is from 15 to 61% (Ayd 1961, Korczyn and Goldberg 1976). A recent prospective study of 17 elderly patients treated with antipsychotics reported a 71% rate of parkinsonism (Ganzini et al 1991). This compared to a 34% rate in a recent study of antipsychotic-treated children and adolescents treated for 6 months (Richardson et al 1991). Parkinsonism occurs at varying intervals after the initiation of the antipsychotic but 90% usually will occur within the first 72 days of treatment. Fifty percent of cases occur within the first month of drug initiation. Like akathisia, parkinsonism's occurrence is usually dose- and patient-related. Drug-induced parkinsonism tends to occur most often in the elderly with women twice as likely to develop it.
Anticholinergics
Acute Treatment. When parkinsonism develops, it is appropriate in some clinical situations to change to an antipsychotic (e.g., thioridazine, chlorpromazine) less likely to produce EPS or to lower the dose of the antipsychotic causing the reaction. These drugs should be considered for patients at a high risk of developing specific types of acute-onset EPS.
Typically, anticholinergics have been the first-line treatment for antipsychotic-induced parkinsonism (Chouinard et al 1987, Friis et al 1983). There is no consistent reported percentage of patients that respond to anticholinergics. Studies vary because of differences in study design and difficulties in diagnosing and assessing extrapyramidal reactions both objectively and subjectively.
The use of an initial parenteral dose may produce an immediate response, although it is not unusual for parkinsonism to show an inadequate response to maximal doses of such medication, either orally or parenterally (Tarsy 1983). The time for parkinsonism to respond to anticholinergics is usually three to seven days. However, this depends on the patient and dose of anticholinergic. No information exists to suggest one anticholinergic agent is more efficacious than another.
Upon discontinuation of the antipsychotic, parkinsonism symptoms generally resolve in seven to ten days, but may take several weeks to months for complete resolution, depending upon the drug, the dose, and the patient.
Prophylactic Treatment. The use of anticholinergic drugs at the time of the initiation of the antipsychotic to prevent the onset of drug-induced parkinsonism and akathisia has recently been reviewed (Tonda & Guthrie 1994). Three of six retrospective studies reported no benefit to the use of prophylactic treatments, while the other three reported benefit. Of eight prospective studies, six reported a benefit of prophylactic treatment, while 2 did not. However, in one of the six positive studies, the no treatment group received higher doses of the antipsychotic. The opponents of prophylactic and continuous anticholinergics cite the following reasons in support of their view: (1) the lack of demonstrated efficacy; (2) not all patients treated with antipsychotics develop EPS; (3) the possibility that anticholinergic drugs will produce side effects (i.e., memory impairment, anticholinergic effects); (4) the increased risk of anticholinergic drugs increasing susceptibility to tardive dyskinesia; and (5) studies have demonstrated that EPS do not recur when anticholinergic drug therapy is discontinued in the majority of the patients after three months of administration.
Those who favor prophylactic and continuous anticholinergics indicate even though some patients will receive these agents unnecessarily, the expense and toxicity of anticholinergics is balanced by the benefits of reducing the risk of misdiagnosing EPS (primarily akathisia) that mimic psychopathology and less discouragement of the patient who is minimally motivated to take antipsychotics and who would stop antipsychotics on emergence of EPS (Manos et al 1981; McEvoy 1983).
Studies indicate if high-potency antipsychotics (i.e., haloperidol, piperazine phenothiazines) are prescribed, prophylactic anticholinergics significantly reduce the reported incidence of early-onset EPS as compared to no treatment or placebo (Tonda & Guthrie 1994). Patients with a history of antipsychotic-induced EPS receiving high-potency antipsychotics at higher doses should receive preventative pharmacologic treatment. As a general rule, if a patient receiving an antipsychotic for the first time develops akathisia or drug-induced parkinsonism, initiate treatment at that time. For many patients the onset of EPS is gradual, and if it occurs, can be treated with anticholinergic medication.
Duration of Treatment. The percentage of patients that will require long-term maintenance anti-EPS medication is controversial as studies report that relapse rates of EPS varies from 4% to 72% (Manos et al 1986, Sramek et al 1986, Winslow et al 1986, WHO 1990, Lavin et al 1991). However, a more recent controlled study reported a relapse rate of only 14% when anti-EPS medication was discontinued in patients treated long-term (Double et al 1993).
In patients with drug-induced akathisia and parkinsonism, the duration of anticholinergic administration should individually be determined (Casey 1993, Bezchlibnyk-Butler & Remington 1994, Tonda & Guthrie 1994). Some patients may only require several months of concomitant anticholinergic drug treatment because antipsychotic doses are generally decreased when the patient is being managed as an outpatient. Therefore, dose-related EPS may disappear with lower doses. A general recommendation is to manage akathisia and drug-induced parkinsonism as described above, continue the anticholinergic for two to three months and then, if the patient has no symptoms of EPS, attempt to taper and discontinue the anticholinergic. A reasonable approach would be if EPS recur, reinstitute the anticholinergic drug for three more months, then again attempt to stop (Tonda & Guthrie 1994). If the anticholinergic can not be discontinued at this time, a six-month period of treatment is recommended. At least once a year the drug should be tapered to determine the lowest effective dose.
Amantadine
Most studies of drug-induced parkinsonism indicate amantadine is an effective therapy (Kelly et al 1974, DiMascio et al 1976, Merrick and Schmitt 1973, Fann and Lake 1976). Side effects were reported more commonly with anticholinergics than with amantadine, and the onset of action of amantadine was within seven days of initiation of treatment. Long-term efficacy has not been evaluated, as most studies are less than one month in duration. Amantadine is considerably more expensive than anticholinergics and is considered a second-line treatment.
Levodopa
That a dopamine agonist might be effective in antipsychotic-induced EPS is supported by amantadine's mechanism of action (see below). It has not been widely studied because of a concern for producing or exacerbating psychosis. A recent study indicated l-dopa <600 mg/d was slightly but nonsignificantly more effective than placebo (Chouinard et al 1987). However, some patients had significant improvement with these doses. The authors indicated higher doses might improve the response rate.
PATHOPHYSIOLOGY
The dopaminergic-cholinergic balance hypothesis is the foremost theory of antipsychotic-induced EPS. An equilibrium of dopaminergic (inhibitory) and cholinergic (excitatory) neuronal activity in the corpus striatum is required for normal motor functioning. The interneuronal dopaminergic blocking action of antipsychotics leads to an absolute decrease of dopamine and, hence, a relative increase in interneuronal acetylcholine, resulting in signs and symptoms of EPS (Marsden and Jenner 1980). Of all the EPS, drug-induced parkinsonism and dystonia best fit the dopaminergic-cholinergic equilibrium theory. However, at this time there is little evidence for concluding that akathisia is the result of disruption of this equilibrium (Fleischhacker et al 1990, Marsden et al 1980).
A hereditary predisposition to antipsychotic-induced parkinsonism has been reported as patients with HLA B44 have a 7.16 increase in risk of experiencing drug-induced parkinsonism (Metzer et al 1989).
Two recent reports indicate that patients with akathisia or dystonia had significantly lower serum iron concentrations (Horiguchi 1991) and significantly lower serum iron and transferrin levels than patients without EPS (O'Loughlin et al 1991). These findings are consistent with reports of lower serum ionized and ionized to total ratio in patients that experience dystonic reactions (Kuny and Binswanger 1989).
Interestingly, cigarette smoking decreases the severity and prevalence of EPSE compared to nonsmokers, despite being treated with higher doses of antipsychotics (Decina et al 1990). This finding is consistent with other studies and confirms reports that the rate of Parkinson's Disease is lower in smokers. Nicotine in animals has been shown to stimulate the release of dopamine and increase the firing rate of nigrostriatal neurons facilitating dopamine release.
MECHANISM OF ACTION
The mechanism to explain differences among antipsychotics to cause EPS is unknown. Some authors have attributed differences to the intrinsic anticholinergic effects of each drug. Other researchers indicate differing affinities for dopamine receptors are responsible for EPS. The clozapine chapter discusses mechanisms to explain differences in antipsychotic-induced EPS.
Historically, anticholinergics were believed to act in diminishing or eliminating EPS by reestablishing the dopamine-acetylcholine equilibrium by blocking acetylcholine in the corpus striatum (Marsden and Jenner 1980). However, recent evidence suggests these drugs may exert an indirect dopaminergic effect by blocking the presynaptic reuptake of dopamine (Modell et al 1989). In addition, they may have agonistic effects on the noradrenergic and serotonin systems.
Amantadine is a compound with little anticholinergic effects and presumably acts to increase CNS concentrations of dopamine by blocking its reuptake or increasing its release from presynaptic fibers. It is theorized that amantadine restores the dopamine-acetylcholine balance in the striatum through enhanced striatal dopamine activity rather than acetylcholine blockade (Fann and Lake 1976).
The exact mechanism by which beta-blockers may reduce akathisia is unknown. The effect may depend predominately on the blockade of central beta-adrenergic receptors (Fleischhacker et al 1990).
It is hypothesized that clonidine may decrease the activity of postsynaptic beta-2 receptors (Adler et al 1987).
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