Until about 15 years ago, psychiatrists had only one class of antipsychotics available to treat patients with severe mental illness—the typicals or conventional agents. A major side effect of long-term use of typicals is tardive dyskinesia (TD). TD is a neurologic condition caused by prolonged use of neuroleptic drugs, such as antipsychotics. TD is characterized by repetitive, involuntary, purposeless movements of different parts of the body. The most common symptoms are orofacial and may include grimacing; tongue thrusting; jaw rolling; lip smacking, puckering, and pursing; and forced eye blinking. TD also may involve dancing or writhing movements of the arms, legs, and trunk or involuntary finger movements, in which patients may appear to be playing a piano or guitar.1 While some symptoms are mild and visible only to trained providers, others are far more severe and easily recognized by nonmedical personnel.

The involuntary movements can be embarrassing and affect basic life functions, such as eating, breathing, and walking. In addition to physical challenges, persons with TD may be faced with not only the stigma associated with mental illness, but also the stigma of having a very visible movement disorder, all of which may lead to reduced quality of life.

The incidence of cases of TD has been estimated at 5% per year on antipsychotic therapy with conventional antipsychotic medications.2 This rate is cumulative, so after 20 years of treatment with conventional agents, it is estimated that 70% of patients will develop TD.3

This high incidence of TD, a major limitation of the conventional agents, is one reason for continuing research that led to the development of a new class of antipsychotics, the atypicals. The first of these agents became available in the late 1980s for the treatment of patients with schizophrenia. Patients are less likely to develop TD with atypical antipsychotics,4 although the condition remains a concern.

Etiology

Antipsychotics work primarily by blocking dopamine neurotransmission in the brain, but dopamine blockade is also related to side effects called extrapyramidal symptoms (EPS). The degree of blockade is associated with the incidence of EPS. Conventional agents have a higher degree of dopamine blockade than the atypicals, and as a result as many as 60% of patients treated with conventional agents develop EPS.5,6 While EPS are not always a precursor to TD, drug regimens and disease processes that increase EPS are likely to result in an increased risk of TD.7

EPS are characterized as either hyperkinetic (excessive movements) or bradykinetic (diminished movements). Examples of hyperkinetic activity include akathisia (restlessness) and tremor. Examples of bradykinesia include characteristics of parkinsonism, such as slow gait and rigidity.8

The leading etiologic hypothesis suggests that in patients who develop EPS, the brain adjusts or compensates for the basic action of antipsychotics (blocking dopamine) by growing more dopamine receptors. Under this theory, the brain actually overgrows dopamine receptors, which, in association with the continuing presence of the dopamine neurotransmitter, may result in the development of TD. If a person has too many dopamine receptors in areas of the brain connected to movement, the resultant overactive signals then produce excessive movements, typically involving the face (lips, tongue, and jaw), extremities, and trunk.

Risk Factors

Risk factors associated with the conventional agents for the development of TD include aging, dose of medication (the higher the dose, the greater the risk), and increased length of exposure to the medication.9 In some recent prospective studies, nonwhites were found to be twice as likely to develop TD as whites.2,10–12 Females were formerly believed to be at greater risk than males, but more recent analyses suggest that gender may not be a risk factor for TD.11 Other risk factors that have been suggested include the development of EPS early in the course of antipsychotic therapy, and the presence of diabetes and other chronic medical illnesses.

Drug-induced movement disorders are considerably more common and more persistent in elderly patients than in younger patients. Movement disorders can be detrimental to an elderly patient's quality of life and may transform what were otherwise routine activities into difficult tasks.

Diagnosis

There is no laboratory test to conclusively diagnose TD, so professionals must rely on patient history and medical examination to generate a differential diagnosis.13–16 To untrained observers, some movements associated with parkinsonism can be confused with TD.

In general, movements associated with parkinsonism:

• occur shortly after exposure to antipsychotics;

• are tremors (repetitive, constant movements occurring usually more than four times per second); and

• can involve dystonia (e.g., eyes rolling up and staying in a fixed position).

On the other hand, movements associated with TD:

• occur months to years after exposure to antipsychotics (tardive, in fact, means “late onset”);

• occur irregularly; and

• often are referred to as choreathetoid (dance-like or writhing in nature) and occur fewer than two times per second.

Several formal scales are used to monitor and measure TD. The most frequently used is the Abnormal Involuntary Movement Scale (AIMS),17 which is reproduced at the end of this article.

Managing Risk

In deciding on a course of treatment for a patient with schizophrenia or other severe mental illnesses, the possible occurrence of TD is an important factor to consider. If TD is observed in a patient, the first step is to discontinue the agent, but only if warranted.10 Not all mental illnesses requiring continuous therapy need to be treated with antipsychotic drugs. However, clinicians must keep in mind that conditions such as schizophrenia and psychosis are chronic and recurrent, and thus there is a risk-benefit decision that needs to take place when considering stopping the offending agent when movements appear.

While the risk of TD can be reduced, it cannot be prevented in patients taking antipsychotics. Some dietary supplements and pharmacologic interventions (such as benzodiazepines, calcium channel blockers, branch-chained amino acids, vitamin E, and beta blockers) have been associated with a reduction in the magnitude of symptoms, but no agents have yet been approved by the FDA for treatment of TD. In fact, some of the agents typically used to ameliorate some movements may have their own side effects, such as blunted cognition, or have the potential for abuse, which can lead to other treatment problems.18

More Research Needed

Clinicians and healthcare policy makers must recognize that the current literature on TD has substantial methodologic limitations, and much more research is needed to determine the long-term effects of antipsychotics on TD. There appear to be no well-designed studies that compare the TD liability of typicals and atypicals in the treatment of severe mental illness.

We need more narrowly defined studies that specifically address the incidence of TD from use of atypical agents, and not just efficacy and safety issues involving antipsychotics in general. The majority of the meta-analyses on antipsychotics do not involve studies that were designed to measure TD, i.e., TD was a “secondary” measure. We need studies that can examine the long-term effects of both typical and atypical agents on TD outcomes, since we know that the impact of antipsychotics is cumulative and sometimes not fully revealed until years after initial exposure.

In this discussion of research limitations, it's worth noting an aspect of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a landmark study sponsored by the National Institute of Mental Health.19 The study compared the “mid-potency” conventional agent perphenazine with the newer atypicals. Because typical antipsychotics are generally known to have a higher TD liability than atypical agents, patients in this study who had pre-existing TD were not assigned to treatment with perphenazine. It was believed to be in the patients’ best interest to randomize them to one of the atypical agents instead.

Policy Implications

Some healthcare policy makers have revisited the use of the conventional agents as first-line treatments for various reasons, such as their lower acquisition cost relative to the atypicals. This practice would appear to be a major step backward with respect to controlling the rate of TD development.

TD itself is costly in a number of ways. Patients may not adhere to treatments for their underlying diseases because of the risk of developing TD and its debilitating characteristics; treatment interruption may in turn lead to symptom relapse and increased healthcare utilization. In addition, clinicians must keep in mind the potential for malpractice suits that may arise from the development of this condition throughout the course of treatment. Most importantly, patients and their families may suffer needlessly if conventional agents are once again regarded as the drugs of choice for persons with severe psychotic illness. Relying on atypicals as first-line treatments can reduce the risk of TD and its direct and indirect consequences. It is important to remember, however, that the atypicals have the same information about TD in their product labeling as the typicals. Because TD is still a risk, although reduced, with the newer agents, clinicians should continually monitor their patients for the condition.

Concerns about TD and the number of cases have decreased considerably, primarily because of the introduction of the atypicals in the late 1980s and early 1990s. This lessened vigilance toward TD may have indirectly led to the renewed interest in the possible use of conventional agents. Images of patients with severe TD have perhaps faded from the minds of many policy makers, the general public, and newer clinicians, who may have less experience with TD. An analogy can be made to HIV. Cases of new HIV infection now are on the rise, in part because there is less sensitivity and institutional memory among the public about this condition, especially among young people who did not witness the devastating effects of AIDS in the 1980s.

Implementation of policies emphasizing conventional agents as first-line treatments would be a major step back from the advances that the atypicals have provided for the treatment of severe mental illness. Since TD is largely an irreversible condition for which no uniformly effective treatment exists, prevention is the best strategy. This is best achieved by using the lowest effective dose of an antipsychotic and using atypicals as the first choice for antipsychotic therapy because they have a lower risk of TD.20