Drug-Induced Movement Disorders: A Primer

US Pharm. 32(11)HS16-HS32

Drug-induced movement disorders (DIMDs), also commonly referred to as extrapyramidal symptoms (EPS), represent a variety of iatrogenic and clinically distinct movement disorders, including akathisia, tardive dyskinesia, dystonia, and parkinsonism ( TABLE 1 ) . DIMDs remain a significant burden among certain patient populations, such as those receiving treatment with dopamine receptorÒblocking agents (DRBAs; e.g., various psychotropic agents and antiemetics) ( TABLE 2 ) . DIMDs are often underrecognized, and knowledge of DIMDs will allow clinicians, pharmacists, and other health care professionals to better identify and manage patients with these conditions.

Symptoms of DIMDs interfere with social functioning, interpersonal communication, and performance of motor tasks and activities of daily living. In addition to reduced quality of life, patients experiencing DIMDs tend to abandon therapy (which may result in disease relapse and rehospitalization).

The onset of a DIMD can be classified as acute (i.e., occurring within hours to days after exposure), subacute (i.e., occurring weeks after drug exposure), and tardive (i.e., occurring months to years after drug exposure). The symptomatology of DIMDs ( TABLE 1 ) is often indistinguishable from that of idiopathic movement disorders and may resemble that of several other medical conditions. However, with a careful drug history, recognition of a DIMD may be relatively straightforward, as in the case of a patient with a history of DRBA treatment presenting with classic symptoms of tardive dyskinesia (TDk). As with idiopathic movement disorders, anxiety and stress will also exacerbate symptoms associated with DIMDs. In general, elderly females are more susceptible to develop TDk, young males more susceptible to dystonic reactions, and the elderly more prone to drug-induced parkinsonism. Also notable is that patients may develop mixed DIMDs (i.e., they may have more than one type of DIMD).

Drugs
Agents implicated in DIMDs are listed in TABLE 2. The centrally acting DRBAs, such as haloperidol and phenothiazine neuroleptics, are the agents most commonly associated with DIMDs. DIMDs are less frequently associated with the atypical antipsychotics, but dose-related EPS occurs with olanzapine and risperidone (especially at dosages greater than 6 mg/day).

Movement disorders are also associated with other medications, such as antiemetics that block central dopamine receptors (i.e., droperidol, metoclopramide, and prochlorperazine), lithium, selective serotonin reuptake inhibitors (SSRIs), stimulants, and tricyclic antidepressants (TCAs). Tremor commonly occurs with lithium treatment and occasionally chorea.¹ SSRIs can commonly cause tremor and, less commonly, dyskinesia, dystonia, or parkinsonism.² Stimulant drugs (e.g., amphetamine, methylphenidate, and pemoline) have been known to produce a variety of movement disorders such as dyskinesias, dystonia, stereotypic behavior, and tics.³ The most common movement disorders associated with TCAs are myoclonus and tremor.⁴ The antiepileptic drug valproate is commonly associated with tremor. For many years, chorea has been recognized as a complication of estrogen- and progesterone-containing products.⁵ Psychotherapeutic combination products containing a neuroleptic, such as perphenazine/amitriptyline, should not be overlooked as causative agents.

Prevalence
Neuroleptic-induced movement disorder occurs in a significant number of patients who are treated with conventional neuroleptics. In one study of chronic institutionalized patients with schizophrenia, conventional neuroleptics were associated with movement disorders in 61.6% of patients. ⁶ Of those patients, 31.3% had akathisia, 23.2% had parkinsonism, and 32.3% had TDk. However, with the advent of the atypical antipsychotics, rates of neuroleptic-induced movement disorders may have declined. In another study of 125 patients who developed movement disorders from DRBAs, 63% had tardive dyskinesia, 30% had parkinsonism, 24% had dystonia, and 7% had akathisia.⁷ Haloperidol was implicated in 37% of cases, followed by the combination amitriptyline with perphenazine in 30%, thioridazine in 27%, chlorpromazine in 20%, and metoclopramide in 8%.

AKATHISIA
The word akathisia is a derivative of the Greek word meaning "not to sit." Neuroleptic-induced acute and tardive akathisia is a common and distressing adverse effect that is associated with poor treatment adherence and, ultimately, an increased risk of psychiatric relapse. Conventional neuroleptics and phenothiazine antiemetics are most commonly implicated. Other drugs commonly associated with akathisia are listed in TABLE 2. The atypical antipsychotics are associated with lower rates of akathisia, with reported values approximately two to three times less than those of conventional neuroleptics. In one study, the prevalence of akathisia associated with clozapine, risperidone, and conventional neuroleptics was 7.3%, 13%, and 23.8%, respectively.⁸ Akathisia is also an adverse effect of SSRIs and appears to occur in at least 4.5% of exposed patients. ⁹

Clinical Features and Risk Factors: Neuroleptic-induced akathisia is comprised of both a subjective and an objective component ( TABLE 1 ). Acute drug- induced akathisia should be suspected if symptoms developed soon after initiation of implicated drugs and in the absence of other conditions associated with restlessness. Symptoms of acute akathisia typically occur within four weeks of initiating or increasing the dosage of the offending drug and may also develop after neuroleptic cessation or dosage reduction (i.e., withdrawal akathisia). Risk factors for akathisia are listed in TABLE 3.^10,11 The symptoms of drug-induced akathisia can be mistaken for other medical conditions (e.g., restless legs syndrome), for agitation and anxiety presenting as part of a psychiatric disorder, and for drug withdrawal syndromes.

Therapeutic Management: When left untreated, the symptoms of acute akathisia may gradually subside or may wax and wane over time. In some patients, acute akathisia may become chronic and persistent for months or years. Acute akathisia has been associated with promoting aggression, psychopathology, suicidal behavior, and treatment nonadherence in patients with schizophrenia.¹² Therefore, prevention is a key component of treatment. Standardized titration to avoid excessive dosage escalation and the use of atypical antipsychotics are successful measures of prevention. Although iron deficiency has been associated with akathisia, routine iron supplementation as a preventive or treatment intervention is not supported by the available evidence.¹³ It is reasonable to correct underlying iron deficiencies or to administer oral iron supplementation in akathisia unresponsive to standard measures. In a patient at high risk for akathisia, prophylactic treatment with an antimuscarinic agent or beta-blocker is reasonable.

The management of akathisia is summarized in TABLE 4. In the patient experiencing acute akathisia, the causative agent should be discontinued, if possible. A switch to an atypical antipsychotic or alternative agent should be considered. Administration of a lipophilic beta-blocker, such as propranolol, is effective and well tolerated.¹⁴ Beta₂-receptor blockade appears to be crucial for efficacy as beta ₁-receptor selective agents are less effective.¹⁵ However, a trial of a cardioselective, beta₁-receptor blocker is recommended if a nonselective beta-blocker is contraindicated or is not tolerated. The hydrophilic beta-blockers (e.g., atenolol and nadolol) do not appear to be effective. Administration of antimuscarinic agents (e.g., benztropine, diphenhydramine), benzodiazepines, or antiserotonergic agents (cyproheptadine) are also effective and may be preferred if sedation is desired.^16-18

TARDIVE DYSKINESIA

Since it was first reported in the United States in 1960, TDk has become the most recognized movement disorder induced by neuroleptic treatment.¹⁹ Tardive dyskinesia develops after at least one month's exposure to DRBAs, and, if the offending drug is continued, remission is rare. Drugs that are associated with TDk are listed in TABLE 2. The term tardive emphasizes the delayed onset of involuntary, choreiform, orofacial movements secondary to neuroleptic use. Although symptoms may initially be mild, many patients develop progressively severe TDk, resulting in meaningful disability and disfigurement. Use of high-dose neuroleptics and longer duration of treatment are associated with increased risk of developing TDk. In young patients, approximately 5% will develop TDk with each year of neuroleptic exposure.²⁰ The elderly population appears to have the highest incidence and prevalence of TDk and is at least five times more at risk for developing TDk as compared to young patients. ²¹ However, with the use of the newer atypical antipsychotics, the risk of developing TDk is reduced.²² In one review of 11 studies, atypical antipsychotics were associated with a mean annual incidence of new-onset tardive dyskinesia of 0.8% in the adults as compared to 5.4% in adults treated with haloperidol.²² These data suggest that the risk of TDk associated with atypical antipsychotics is at least one-fifth that of conventional neuroleptics. In general, if patients do not develop TDk during the initial five years of neuroleptic treatment, the risk of developing TDk during later years is reduced.

Clinical Features and Risk Factors: Signs and symptoms of TDk are listed in TABLE 1. Frequently, TDk may occur in the presence of other movement disorders, such as akathisia, dystonia, or parkinsonism. The onset of TDk is insidious and symptoms are initially mild. Often, the symptoms are unnoticeable to patients but are more apparent to family members or bystanders. Even mild cases of TDk are associated with social impairment such as employment difficulties, social isolation, and stigma. In more severe cases, functional impairment occurs. Patients experience difficulties with chewing, speaking, and swallowing. Orofacial dyskinesias may also result in dental problems, denture displacement, and damage to the soft tissues within the oral cavity.

When assessing for presence and severity of TDk, the Abnormal Involuntary Movements Scale (AIMS), developed by the National Institute of Mental Health, is a commonly employed instrument, particularly in the psychiatric field.²³ The AIMS rates dyskinetic movements in seven body regions and includes assessments for global severity, functional impairment, and self-awareness of symptoms. Assessment tools, such as the AIMS, may be utilized every three months to reassess specific symptoms of TDk. Factors associated with exacerbation of TDk symptoms include administration of antimuscarinics or sympathomimetic stimulants and emotional extremes. As with most dyskinesias, symptoms subside during sleep and, in mild cases, patients may be unaware of the movements.

Age is a well-established risk factor for TDk. Other risk factors are listed in TABLE 3. Not only is TDk more common in the elderly, but the condition tends to be more severe and irreversible in this age group. If multiple risk factors are present, an additive effect on risk potential is observed; for example, elderly females are very susceptible to TDk.

Therapeutic Management: Once TDk develops, remission rates are low if the antipsychotic is continued. In one study, only 11% of patients improved over the course of five years. ²⁴ Early detection of TDk is imperative, as remission rates are inversely correlated with duration and severity of TDk. If detected early and the offending agent is discontinued, TDk remission rates are favorable, especially in the younger population, but may require several months to years to resolve. However, the benefit of discontinuing the offending antipsychotic for the purpose of treating TDk should be weighed against the likelihood of psychotic decompensation. Additionally, patients with severe TDk and the elderly are less likely to experience remission, even with elimination of the offending agent. Occasionally, TDk may occur also after withdrawal of chronic DRBA treatment (withdrawal TDk). This type of TDk is reported most commonly in children and generally improves within three months.²⁵

A summary of the management of TDk is provided in TABLE 4. Treatment for TDk varies and includes drug discontinuation, switching to or initiating an atypical antipsychotic,²⁶ discontinuing anticholinergics (except in tardive dystonia), and initiating adjunctive vitamin E or benzodiazepines. For patients with severe and refractory TDk, neurosurgical treatments may be effective.²⁷ Anxiety often exacerbates TDk and should be treated appropriately. In a recent meta-analyses of evidence from randomized, controlled trials, more than 500 trials evaluating over 90 different interventions were identified.²⁸ The analysis did not yield any definitive information on how best to treat TDk. Given the lack of good evidence, emphasis is placed on primary prevention, prompt recognition, and management of early and potentially reversible causes. It is reasonable for clinicians to consider the use of atypical antipsychotics for long-term therapy over that of the older neuroleptics as a means to prevent or reduce the risk for TDk. Other strategies include use of the lowest effective DRBA dosage and elimination unnecessary, prolonged drug exposure. Although the use of intermittent antipsychotic treatment (or drug holidays) may seem like a logical strategy for reducing TDk risk, it is actually associated with an increased risk of TDk and higher rates of psychosis relapse and rehospitalization.²⁹ For neuroleptic-induced TDk, withdrawal of the offending agent may result in partial improvement in up to 50% of patients. But overall, complete and long-lasting resolution of TDk is uncommon.³⁰

DYSTONIA: ACUTE AND TARDIVE
Drugs associated with dystonia are listed in TABLE 2. The development of drug-induced acute dystonia (DIAD) is more commonly associated with butyrophenone antipsychotics (e.g., haloperidol) as compared to phenothiazine antipsychotics (e.g., chlorpromazine).³¹ Tardive dystonia, defined as an involuntary movement predominated by dystonia and associated with the use of a DRBA, is distinct from TDk, although both often coexist in the same patient. ³²

Clinical Features and Risk Factors: The onset of DIAD is sudden, and most cases occur within hours to several days of initial exposure to DRBAs or, less commonly, after a DRBA dosage increase or a reduction in concomitant antimuscarinic agent. The occurrence of DIAD appears to be greater in younger patients and in patients receiving parenteral DRBAs. Signs and symptoms of dystonia are listed in TABLE 1. The severity of symptoms and anatomical distribution vary, but the classic clinical presentation is characterized by the "three O's": oculogyric crisis (conjugate deviation of the eyes upward or laterally), opisthotonos (involuntary posturing in which the head, neck, and spine are arched backward), and oromandibular dystonia (causing difficulty in opening or closing the mouth). Symptoms are usually painful and, in severe cases, DIAD may be life threatening. Rhabdomyolysis due to sustained muscle contraction may also occur. If dystonia occurs in the presence of fever, generalized rigidity, altered level of consciousness, and autonomic instability, a diagnosis of neuroleptic malignant syndrome should be considered. Owing to the discomfort associated with DIAD, patients are at higher risk for abandoning medication therapy, or nonadherence.

Risk factors for the development of acute dystonia are listed in TABLE 3.³³ As with other DIMDs, the presence of multiple risk factors has an additive effective on risk. An inverse relationship exists between the incidence of DIAD and age. In contrast to TDk, dystonia is uncommon in older patients. The highest risk population is young males on high-potency neuroleptics.

Unlike acute dystonia, tardive dystonia develops insidiously after months to years of treatment with a DRBA or within three months after treatment discontinuation and often coexists with TDk. In tardive dystonia, remission is uncommon. Children are at particularly greater risk of tardive dystonia compared to adults. Symptoms may or may not be painful and can be isolated to one body part or may spread to contiguous body parts (segmental dystonia), or even generalize to multiple body parts. Other medical conditions that present with insidious development of dystonia include idiopathic dystonia, Huntington's disease, Wilson's disease, levodopa-responsive dystonia, and conversion reaction. In addition, other conditions that cause a twisted neck, such as orthopedic or congenital problems of the neck, ophthalmologic conditions resulting in head tilt to compensate for vision problems, stiff neck, arthritis, or wry neck, should be ruled out.

Therapeutic Management: The management of acute and tardive dystonias is summarized in TABLE 4 . Several studies have reported that the administration of concurrent antimuscarinic agents (e.g., benztropine, diphenhydramine, and trihexyphenidyl) as a preventative measure reduces the overall rate of dystonia by at least two-fold.^31,34,35 In patients treated with high-potency neuroleptics, the reduction is even greater at five- to 11-fold. ^34,36 Since the greatest risk of neuroleptic-induced acute dystonia occurs within the first week of drug treatment, the short-term administration of oral antimuscarinic agents may be considered, especially in young patients receiving high-potency antipsychotics. The efficacy of antimuscarinic prophylaxis appears to be inversely related to age of the patient. Due to reduced prophylactic efficacy and undesirable antimuscarinic adverse reactions, the use of antimuscarinic agents in elderly patients for primary prevention of DIAD is disfavored.

An acute dystonic episode can be effectively relieved with a short course of a potent antimuscarinic agent (e.g., benztropine, diphenhydramine) administered orally, intramuscularly, or intravenously. If life-threatening dystonia is present, intravenous administration is warranted and supportive measures are required. Benzodiazepines may be administered if use of an antimuscarinic agent is contraindicated.

In tardive dystonia, few treatments have proven to be consistently useful, with the exception of botulinum toxin. Therefore, prevention is important. The chronic use of conventional DRBAs (e.g., neuroleptics and metoclopramide) should be carefully evaluated and alternatives considered. For medical management, atypical antipsychotics, benzodiazepines, muscle relaxants, and dopamine-depleting drugs, such as tetrabenazine, may be effective and can be used in combination with antimuscarinics. Less commonly used drugs include amantadine, beta-blockers, clonidine, dantrolene, levodopa, and antiepileptics such as levetiracetam, pregabalin, tiagabine, and zonisamide. For focal dystonic symptoms, local injections of botulinum toxin are preferred due to relative lack of systemic adverse effects and consistent efficacy among patients. In refractory and severe cases, intrathecal baclofen or neurosurgical interventions may be effective.^37,38

PARKINSONISM
Drug-induced parkinsonism (DIP) is considered the second most common form of parkinsonism. Drugs that may induce or exacerbate parkinsonism are listed in TABLE 2. Of all drugs, the DRBAs are most commonly implicated. In one study, the prevalence of parkinsonian rigidity associated with clozapine, risperidone, and conventional neuroleptics was 4.9%, 17.4%, and 35.7%, respectively.⁸ In addition, drugs that deplete presynaptic dopamine (e.g., reserpine, tetrabenazine) or act as dopamine "false transmitters" (e.g., alpha-methyldopa) may also induce parkinsonism. Valproate is an underrecognized source of DIP due to insidious onset of parkinsonian symptoms. ³⁹ The SSRIs are uncommonly associated with DIP, although SSRI-induced tremor is common.

Clinical Features and Risk Factors: In general, the clinical features are indistinguishable from idiopathic Parkinson's disease and include at least two of the following: tremor (rest or postural), rigidity, and bradykinesia (TABLE 1). In the absence of an accurate drug history, symptoms of DIP can be easily mistaken for idiopathic Parkinson's disease. The presence of DIP may be overlooked because symptoms such as reduced facial expression, reduced energy and motivation, and bradykinesia can mimic negative symptoms of schizophrenia as well as psychomotor retardation associated with depressive disorders. In the majority of cases, DIP is a subacute process that develops within three months of initiating the offending agent or, in some cases, after a dosage increase, and it is slowly reversible upon drug withdrawal. Risk factors for the development of DIP are listed in TABLE 3. Patients at greatest risk are those who are demented, elderly, or have preexisting Parkinson's disease. Also, patients with acquired immune deficiency syndrome (AIDS) appear to be very susceptible to DIP. In one study, the likelihood of developing EPS was 2.4 times higher among patients with AIDS as compared to psychotic patients without AIDS.⁴⁰

Therapeutic Management: The management of DIP is summarized in TABLE 4. Upon drug withdrawal, symptoms of DIP resolve slowly, over months to years. Other strategies utilized in the management of DIP include dosage reduction, switching to an atypical antipsychotic agent, and the use of amantadine and antimuscarinic agents. The routine use of antimuscarinic agents for primary prophylaxis of DIP is controversial, especially for elderly patients.

CONCLUSION
Drug-induced movement disorders (i.e., akathisia, tardive dyskinesia, dystonia, and parkinsonism) pose a significant burden to patients and may result in medication nonadherence or abandonment of therapy. Dopamine-receptor blocking agents such as conventional antipsychotics (e.g., haloperidol and chlorpromazine) and antiemetics (e.g., metoclopramide and prochlorperazine) are commonly implicated. Clinicians and pharmacists should recognized that DIMDs can occur acutely (i.e., hours to days after drug exposure), subacutely (i.e., within weeks after exposure), or months to years after drug exposure. With the exception of drug-induced acute dystonia, the medical and surgical treatment of most DIMDs does not consistently provide benefit; therefore, prevention is essential. Knowledge of DIMDs should allow health care professionals to better identify patients with DIMDs or those at risk for them and implement treatment and prevention plans.

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