Antipsychotic drugs are commonly called neuroleptics because they often induce parkinsonism. They also cause other movement and sensory disorders, such as akathisia, acute dystonic reactions, neuroleptic malignant syndrome, and tardive dyskinesia syndromes, which are the most feared because they are persistent even after the offending drugs are discontinued (Table 80.1). The common pathophysiologic mechanism of neuroleptics is binding to and antagonizing dopamine D2 receptors. The dopamine receptor-blocking agents (DRBAs) are used not only as antipsychotic agents (e.g., the phenothiazines and the butyrophenones) but also for the treatment of gastrointestinal disorders (e.g., metoclopramide). Tardive and other neuroleptic-induced disorders are iatrogenic, and hence, the prescribing physician bears primary responsibility for causing these disorders. The physician to whom affected patients seek a consultation has the responsibility to make the diagnosis and institute appropriate treatment.

The neuroleptic-induced neurologic complications are often referred to as extrapyramidal syndromes (EPS). Their prevalence ranges from 20% to 50% of exposed. Drug-induced parkinsonism is the most common form. Acute dystonic reactions occur in about 2% to 5% of patients, more commonly in younger patients and in males than females. Tardive syndromes may occur in about one-third of patients exposed to these drugs. Classic tardive dyskinesia is most common and estimates of prevalence range widely but mostly from 15% to 30% with an annual incidence rate of about 5% in the first 4 to 5 years. Prevalence and incidence increase with age; it is more severe among elderly women and more likely to occur with longer duration of exposure to antipsychotic drugs. Tardive dystonia is more rare than the classic type and is more common in younger patients. Other tardive syndromes, including tardive akathisia, account for about 10% of all tardive syndromes.

The pathogenesis of the tardive dyskinesia syndromes is not well understood. Dopamine receptor supersensitivity occurs with these agents, but other drugs that induce similar supersensitivity, such as dopamine-depleting drugs (e.g., reserpine and tetrabenazine), do not cause tardive dyskinesia. The DRBAs that bind most tightly to the receptors are the ones most likely to induce tardive dyskinesia. To explain its delayed onset and persistence, maladaptive synaptic plasticity has been proposed as an underlying mechanism. Others proposed a neurodegenerative process triggered by oxidative stress or by the drugs binding to neuromelanin with resulting internalization of the cell membrane, but all these hypotheses remain to be validated. Genetic polymorphism studies have noted association of variations of monoamine receptors or metabolism genes with tardive dyskinesia, but these findings have not been consistently replicated.

So-called atypical neuroleptics (also called second-generation antipsychotics) have been developed and were initially thought to reduce the incidence of the various movement disorders, but subsequent studies have noted similar incidence of these complications from both second- and first-generation antipsychotics. Some second-generation antipsychotics, however, are definitely atypical in that they have less propensity to produce these movement disorders. Clozapine (Clozaril), a drug that predominantly blocks the D4 receptor and serotonin receptor subtypes, is free of these complications, except for acute akathisia. Quetiapine is also relatively free from the adverse effects listed earlier. The dopamine-depleting drugs, reserpine and tetrabenazine, can induce acute akathisia and drug-induced parkinsonism. Tetrabenazine has also been implicated in acute dystonic reactions and neuroleptic malignant syndrome. But neither drug has been convincingly implicated in causing persistent dyskinesias. In addition, calcium channel blockers, such as flunarizine and cinnarizine, and rarely selective serotonin reuptake inhibitors and lithium can produce parkinsonism and tardive syndromes, and the mechanism by which these drugs produce these complications is not known.

It is important to recognize the different phenomenologies caused by the DRBAs; each requires specific treatment.

Acute dystonic reactions tend to occur within the first few days of exposure to the DRBA and predominantly affect children and young adults, males more than females. Severe sustained twisting and uncomfortable postures of limbs, trunk, neck, tongue, and face are dramatic. Oculogyric crisis is a form of dystonia in which the eyes are deviated conjugately in a fixed posture for minutes or hours. Acute akathisia occurs within the first few days or weeks of drug use. It may also appear later in treatment when dosage is being increased. Akathisia consists of a subjective sense of restlessness or aversion to being still and is associated with motor features of restlessness.

These include frequent and repetitive stereotyped movements, such as pacing, repeatedly caressing the scalp, or crossing and uncrossing the legs. It can occur in subjects of any age. Druginduced parkinsonism resembles idiopathic parkinsonism in manifesting all the cardinal signs of parkinsonism, including tremor.

The neuroleptic malignant syndrome is characterized by a triad of fever, signs of autonomic dysfunction (e.g., pallor, diaphoresis, blood pressure (BP) instability, tachycardia, pulmonary congestion, tachypnea), and a movement disorder (usually akinesia and rigidity). The level of consciousness may be depressed, eventually leading to stupor or coma; death may occur.

The withdrawal emergent syndrome may be a mild variant of tardive dyskinesia. “Emergent” implies that the symptoms emerge after abrupt cessation of the chronic use of an antipsychotic drug. The syndrome is primarily one of children, and it persists only for a few weeks before dissipating. The abnormal movements resemble those of Sydenham chorea; they are not stereotyped and repetitive, as seen in classic tardive dyskinesia.

The persistent dyskinesia syndromes are the most feared complications of antipsychotic medications because the symptoms are long-lasting and often permanent. Classic tardive dyskinesia consists of repetitive (stereotypic) movements. The lower part of the face is most often involved. This orobuccolingual dyskinesia resembles continual chewing movements, with the tongue intermittently darting out of the mouth (Video 80.1). Movements of the trunk may cause a repetitive pattern of flexion and extension (body rocking). The distal parts of the limbs may show incessant flexion-extension movements. The proximal muscles are usually spared, but respiratory dyskinesias may occur. If not accompanied by akathisia or dystonia, the patient may not be aware of the dyskinesia.

Several other important forms of tardive dyskinesia syndrome are now recognized. Unlike the classic oral dyskinesia described earlier, these other forms are frequently quite disabling. Tardive dystonia is a chronic dystonia caused by DRBAs (Video 80.2). Individuals of all ages are susceptible to tardive dystonia, and younger individuals are more likely to have a more severe generalized form. In older individuals, tardive dystonia is usually focal (affecting a single body part), often in the face or neck, and may remain confined to these regions or may spread to the arms and trunk. The legs are infrequently affected. Often, neck involvement consists of retrocollis and the trunk arches backward. The arms are typically rotated internally, the elbows extended, and the wrists flexed. The differential diagnosis includes all of the many causes of dystonia. Wilson disease, in particular, must be excluded specifically in any patient with psychiatric symptoms and dystonia.

Tardive akathisia is another important disabling variant of tardive dyskinesia. It is a chronic akathisia consisting of a subjective aversion to being still. Motor signs of restlessness include frequent, repeated, stereotyped movements, such as marching in place, crossing and uncrossing the legs, and repetitively rubbing the face or hair with the hand (Video 80.3). Patients may make moaning sounds. Patients may not use the word “restless” to describe their symptoms; instead, they may use expressions such as “going to jump out of my skin” or “jittery” or “exploding inside.” Akathisia can be expressed as focal discomfort, such as pain. It can be an exceedingly distressing symptom. In contrast to acute akathisia, the delayed type tends to become worse when antipsychotic medication is withdrawn, similar to the worsening of classic tardive dyskinesia on discontinuance of these drugs. As with other types of tardive dyskinesia syndrome, tardive akathisia tends to persist. Usually, tardive akathisia is associated with classic oral dyskinesia. Classic tardive dyskinesia, tardive dystonia, and tardive akathisia may occur together. Less common variants of tardive dyskinesia include tardive tics, tardive myoclonus, and tardive tremor.