Drug-Induced Movement Disorders: A Clinical Review

30 mar 2009--The use of dopamine receptor-blocking drugs (DRBD) may result in a variety of acute or tardive involuntary movements. Acute-onset movement disorders arising from initiation or escalation of the dose of drugs that block dopamine receptors (primarily D₂ receptors) include dystonia, parkinsonism, akathisia, and neuroleptic malignant syndrome (NMS). Late-onset (tardive) movement disorders typically manifest three months or later (this varies) after the exposure to a DRBD, with stable therapy, an increase in the dosage of the offending agent, or after discontinuation of treatment with the same. These late-onset disorders are referred to in general as tardive syndromes and may include classical dyskinesia (often referred to as a stereotypy), dystonia, chorea, akathisia and others.^[1] Historically, the field of psychiatry has used the terms tardive dyskinesia and extrapyramidal symptoms to describe oro-bucco-lingual dyskinesia (OBLD) or facial dyskinesia, that result from the use of typical or atypical antipsychotic drugs. For our purposes the term tardive dyskinesia, will be used in this overview provides information on drugs that have been shown to cause movement disorders.

Types of Drug-Induced Movement Disorders (DIMD)

Drug-induced dystonia, a twisting movement or abnormal posture (or a combination thereof) may manifest as acute or tardive involuntary limb movements, facial grimacing, cervical dystonia, oculogyric crisis, rhythmic tongue protrusion, jaw opening or closing, spasmodic dysphonia, and, rarely, stridor and dyspnea. The acute form typically occurs within 2 to 5 days after initiation of treatment with a DRBD.

The features of idiopathic Parkinson disease comprise the same primary characteristics of drug-induced parkinsonism: rest tremor, bradykinesia, rigidity, and postural instability. Lack of recognition is a primary impediment to treatment, as cessation of the causal agent will lead to resolution of symptoms in drug-induced parkinsonism.^[2] In some patients, however, symptoms may endure for 18 months or even longer.

The stereotypies of classic tardive dyskinesia (i.e., OBLD) are characterized by well-coordinated continual movements of the mouth, tongue, jaw, and cheeks and may include lip smacking, cheek puffing, and tongue thrusting. Jaw movements may be lateral or resemble chewing motions. The tongue movements may be writhing or twisting (choreoathetoid). In addition to having OBLD, patients treated with antipsychotic drugs may also have trunk movements, which are typically in the form of pelvic thrusting, trunk twisting, or choreoathetotic or flicking of the extremities. Some patients may have a mix of movement disorders that include OBLD, dystonia, myoclonus, akathisia, parkinsonism.

Akathisia (literally meaning, an inability to sit) manifests as an inner feeling of restlessness and stereotypic movements, such as marching in place and crossing and uncrossing the legs while sitting. Akathisia is the only drug-induced movement disorder that does not have an idiopathic counterpart, although it may be a manifestation of Parkinson's disease.

Neuroleptic malignant syndrome is an abrupt, life-threatening, idiosyncratic response that occurs in approximately 0.2% of patients after they receive a therapeutic dose of a DRBD. The symptoms include hyperthermia (> 38°C), mental status change, muscle rigidity and other movement disorders, and autonomic dysregulation.

Epidemiology

The true incidence and prevalence of drug-induced movement disorders is unknown and likely vastly underappreciated because of lack of recognition. Even among neurologists, drug-induced parkinsonism, for example, is often not recognized and, therefore, not appropriately treated.^[2] Studies have shown that parkinsonism in patients in nursing homes is not recognized,^[3] and, even among psychiatrists, tardive dyskinesia and akathisia are also frequently overlooked.^[4] In addition, identifying the exact prevalence and incidence of DIMD has proven to be difficult because of factors such as fluctuation in symptoms; the use of drugs that can mask DIMD, thereby causing an underestimation of the prevalence; and a lack of validated criteria for the diagnosis of DIMD.

Factors affecting the rate of DIMD related to the use of antipsychotic drugs include age of the population, the drug being used and the dose, the definition of the movement being employed in the study, and the design of the study.^[5] DIMD related to exposure to antipsychotic drugs is estimated to occur in 19% and 42% of patients receiving atypical (second-generation) and typical (first-generation) antipsychotic drugs, respectively.^[6] With the increasing use of antipsychotic drugs in young children, the incidence of DIMD is growing in this population. In one study, 9% of children who had received an antipsychotic drug for six months or longer developed OBLD (as opposed to none in a control population), including those children who had only received atypical antipsychotics. Of note, the results of additional studies in children have been published since this was written, including those showing both and higher and a lower incidence of EPS.^[7] Because of the perceived safety of atypical antipsychotics in relation to DIMD these drugs are more widely used off label for a variety of disorders, including as a sleep remedy, and this is leading to increased frequency as well.

One in 500 people who take metoclopromide are likely to develop extrapyramidal symptoms (EPS). The risk for the development of EPS is highest in infants and children and adults younger than 30 years of age. The risk of developing EPS or TD and the likely irreversibility of TD are related to the length of exposure and total accumulative exposure to the drug.^[8]

Pathophysiology

The pathophysiology of DIMD is not clearly elucidated, yet is complex and multifactorial, likely related to a combination of genetic predisposition,^[9] dopaminergic system hypersensitivity in the basal ganglia, decreased functional reserve, and over activation of the cholinergic system.

Postsynaptic Dopamine Receptor Hypersensitivity Theory

The chronic blocking of presynaptic dopamine receptors enhances excitatory glutamatergic neurotransmission. The neurotoxic stress in the striatum, which is caused by increasing glutamate release and extracellular glutamate levels at corticostriatal terminals, ultimately destroys the output neurons, leading to dopaminergic hypersensitivity.^[9] Although this theory has been the long-held hypothesis as the cause of DIMD, it cannot completely account for the clinical findings, primarily because it does explain the fact that DIMD are not a universal phenomenon among people exposed to DRBDs.^[10]

Neurotoxicity Theory

Because the use of DRBDs increases the turnover of neurotransmitters and because the basal ganglia are particularly vulnerable to the effects of membrane lipid peroxidation, this premise proposes that DIMD are caused by the neurotoxic effects of free radicals that are created as a byproduct of catecholamine metabolism. The support for this theory comes primarily from the treatment of oral buccal lingual dyskinesias with the use of branched-chain amino acids in studies in humans^[11,12] and antioxidants in animal studies.^[13]

Dopamine-GABA Hypothesis

In this theory, which does not disregard the fact that dopamine receptors become increasingly sensitive to the effects of DRBD, the interaction between the dopamine and gamma-aminobutyric acid (GABA) neurons plays a greater role, likely accounting for the different, yet simultaneous, effects of the DRBD. Dopamine has both inhibitory and excitatory effects on GABA neurons, determined by the location and type of the dopamine receptors in the brain. Unfortunately, this theory has not been able to be converted into a treatment paradigm because of the toxicity of the agents.^[14]

Diagnosis

The differential diagnosis of a DIMD is the same as that for the primary movement disorder that is not drug induced. The diagnosis of DIMD is a two-step process: the first entails the recognition of the abnormal movement and, the second, the identification of the temporal relationship between institution of therapy with a DRBD (acute) or exposure to a DRBD within the previous three months (tardive) and the abnormal movement. DIMDs manifest identically to other movement disorders that are not caused by drugs. For example, drug-induced parkinsonism looks like Parkinson's disease and tardive craniocervical dystonia looks like idiopathic craniocervical dystonia. However, with DIMD, a few clues may assist the clinician in correctly identifying the cause of the movement. The etiology is more likely to be drug induced when the patient has:

• Both hypokinetic and hyperkinetic movements occurring simultaneously; ie parkinsonism and OBLD
  
  
• Certain patterns such as axial distribution dystonia, which is more typical of tardive dystonia than other forms
  
  
• When the DIMD occurs in conjunction with an OBLD
  
  
• A subacute onset of parkinsonism.

Obtaining a detailed history of any medication use in the previous three months and having appropriate suspicion is important in delineating the cause of DIMD . Inquiries specifically about any anesthesia exposure during surgical procedures that the patient may have undergone, antinausea treatments, and use of weight-reduction, adrenergic agents, or antidepressant medications may aid in identifying often-overlooked causes of DIMD.

Treatment

Prevention and Recognition

Prevention and early recognition of the symptoms comprise the best method of managing DIMD.

Discontinuation of DRBD in Patients With DIMD

As iatrogenic conditions, DIMDs are typically treated by discontinuation or reduction of the offending drug, if possible. In most circumstances, this is a straightforward process, and an alternative medication is available that does not cause a movement disorder. However, some patients, particularly psychiatric patients, are unable to stop their medication. Discontinuation or reduction does not always result in a resolution of the DIMD (particularly tardive dyskinesia), highlighting, again, the need for prevention.

When the use of antipsychotic agents results in a DIMD, a dilemma arises in which the patient's need for treatment of the essential psychiatric condition must be weighed against a requisite level of tolerable dyskinetic movements. No pharmacologic treatment has been proven to be universally or even typically effective in this situation. Therefore, the treatment of a DIMD in this setting, as in all others, is instead aimed at preventing, recognizing, and managing the movements. Discontinuing or reducing the level of the causative agent may lead to a reduction in the movements; however, this may occur at the expense of exacerbating the underlying illness. An apparently contradictory practice holds that DRBD may be used to treat OBLD caused by antipsychotic drugs, an effect that actually occurs through suppression and not treatment of the movements; however, this method typically leads to a rebound phenomenon and exacerbation of the movements. When the use of a typical antipsychotic medication leads to TD, switching to an atypical antipsychotic medication, particularly clozapine, may prove to be the most efficacious strategy. Studies have shown that the resolution of the symptoms of tardive disorders vary from 33% for OBLD, to 12% and 8% for tardive dystonia and akathisia, respectively.

Medications Used in the Treatment of DIMD

Amine-depleting agents such as reserpine and tetrabenazine block the reuptake of dopamine, norepinephrine, and serotonin, thereby depleting central availability of these neurotransmitters. They are most effective in treating tardive dystonia (~60% to 90%), tardive akathisia (~75%), and tardive dyskinesia (~50% to 90%) of patients whose symptoms are not resolved through the discontinuation of the causative agent.^[1] Few controlled studies have been undertaken to evaluate the effectiveness of these drugs in the treatment of tardive syndromes, although they are in widespread use in clinical practice. Tetrabenazine, a monoamine-depleting drug acting as an inhibitor of vesicular monoamine transporter (VMAT₂), has been approved by the FDA for the treatment of chorea in Huntington disease.^[15-17] Amine-depleting agents seem to be most effective when not used concomitantly with neuroleptic therapy but, instead, when they are used after the neuroleptic drug is withdrawn. Significant side effects can limit the use of these drugs, including depression, orthostatic hypotension, and parkinsonism.

When treatment with amine-depleting drugs is not indicated, e.g., symptoms are mild or the patient has depression or another contraindication to the use of amine-depleting drugs, other medications may be effective but have not been well studied or have not been proven unequivocally in studies to provide benefit.^[18] These medications include anticholinergic agents,^[19] dopamine agonists,^[20] GABAergic agents,^[21] beta-adrenergic receptor-blocking agents, branched chain amino acids,^[11,12] essential fatty acids,^[22] and vitamins B₆^[23] and E.^[24] In addition, chemodenervation with botulinum toxin injection therapy may be used to treat drug-induced focal dystonia.^[25]

Summary

The use of atypical antipsychotic agents for populations that had never previously been exposed to the agents, i.e., children, adolescents, and the elderly, and a wider use in the adult population, combined with a lack of long-term trials that would accurately indicate the rate of DIMD in these populations portends an increase in the number of cases of DIMD. Other issues that may increase the number of cases of DIMD include lack of understanding or complacency among physicians when prescribing DRBD. Recognition of DIMD is often lacking, even among psychiatrists and neurologists, but is essential in the treatment of these disorders.