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Introduction
The tardive syndromes are a group of involuntary movement disorders which appear in delayed fashion and very often persist following prolonged exposure to dopamine receptor blocking agents (DRBA) such as the antipsychotic drugs (APDs), also known as neuroleptics, certain antiemetics such as metoclopramide and prochlorperazine, the antidepressant amoxapine, and certain calcium channel blockers not available in the United States such as cinnarizine and flunarizine. Tardive dyskinesia (TD) is the best known of the tardive syndromes and is characterized by hyperkinetic involuntary movements of the tongue, jaw, face, trunk, and extremities in the form of chorea, dystonia, athetosis, akathisia, stereotypies, and very rarely tremor. The term tardive was originally introduced to differentiate TD from acute dyskinesia (acute dystonic reactions), akathisia, and parkinsonism which were the first drug-induced extrapyramidal disorders (EPS) reported soon after the introduction of APDs in the 1950s and which were known to appear very shortly after initial exposure to an APD. TD was identified somewhat later and was initially believed to be a permanent condition. However, it was later recognized that it is often reversible and in fact occurs in several different temporal patterns including transient TD, withdrawal or withdrawal emergent TD, and persistent TD.
In this chapter, we will provide an overview of the clinical manifestations, pathophysiology, and epidemiology of TD [1–3]. Although TD will be the main focus of this review, we will also discuss other late appearing hyperkinetic as well as hypokinetic movement disorders sometimes referred to as “tardive syndromes” such as tardive dystonia, tardive akathisia, tardive stereotypy, tardive myoclonus, tardive tic disorders, and tardive parkinsonism [4–6].
Clinical manifestations of the tardive syndromes
TD may manifest as one or more relatively stereotyped hyperkinetic movements localized to one body region or as a complex combination of more widely distributed movements. The spectrum of movements which have been described in TD include chorea, athetosis, akathisia, stereotypy, tics, myoclonus, and rarely tremor. Collectively these hyperkinetic movements are typically referred to as “dyskinesias”. “Classical TD” refers to involuntary repetitive stereotypic movements of the perioral region, such as protruding and twisting movements of the tongue; pouting, puckering, or smacking movements of the lips; retraction of the corners of the mouth; bulging of the cheeks; chewing movements; and blepharospasm [5, 6]. TD may also include stereotypic twisting, tapping, and posturing movements of the fingers and toes. Repetitive and stereotyped dyskinesias of the perioral region and limbs have been referred to by some authors as tardive stereotypy rather than TD [5, 7] although these findings overlap considerably with classic manifestations of TD and, in addition, may also lead to confusion with stereotypies sometimes associated with chronic psychosis and autism [7, 8]. Perioral movements are more prevalent in older individuals with TD while extremity and truncal involvement is often more severe in younger individuals in whom dystonic postures and even ballistic movements may also occur.
Clinical subtypes and other tardive syndromes
Clinical subtypes may be based on the temporal pattern of TD including transient TD, withdrawal or withdrawal emergent TD, and persistent TD and will be discussed later in the discussion of the clinical course of TD. Several TD clinical variants or subtypes also exist based on the type of involuntary movements which predominate in these conditions. Tardive dystonia refers to TD in which more sustained dystonic manifestations such as cervical retrocollis, opisthotonus, shoulder dystonia, hyperextension of the arms or legs, blepharospasm, dystonic facial expressions, or jaw dystonia predominate. Dystonia of the trunk may include retrocollis, torticollis, axial dystonia, rocking and swaying movements of the body, and rotatory or thrusting movements of the hips. Tardive dystonia may occur at any age but is more frequent in patients under age 40 and appears to have a lower spontaneous remission rate than TD [9–11].
Tardive akathisia which means inability to sit presents as a feeling of late appearing inner restlessness which may involve the entire body or may be limited to the lower extremities [12]. Although tardive akathisia has the appearance of being uncomfortable, unlike acute akathisia it often lacks the strong subjective feeling of internal discomfort which is typical of acute akathisia. Some typical manifestations of more severe akathisia are repetitive marching movements of the legs while standing in place or repeated tapping of the feet while seated.
Other TD subtypes are much less common and include tardive tics, tardive myoclonus, tardive tremor, and tardive oral pain syndromes. However, these are often difficult to distinguish from other manifestations of classical TD or even from behavioral effects of the individual’s psychosis. Tardive myoclonus presents as prominent postural myoclonic jerks of the upper extremities. Tardive tremor presents as a mixture of postural, kinetic, and rest tremor which is typically large in amplitude and low in frequency [13, 14]. Tardive pain syndromes are uncommon but may manifest as chronic pain or other unpleasant sensations in either the oral or genital regions which usually accompany the motor features of TD [4]. Many of these subtypes do not usually occur in isolation but usually coexist with the other more common manifestations of TD. This indicates that TD encompasses a mixture of motor manifestations without necessarily delineating an entirely specific or characteristic movement disorder [15].
Respiratory dyskinesia usually occurs in individuals also suffering from other dyskinetic features of TD. This often manifests as pharyngeal dyskinesia which causes dysphagia, and laryngeal dyskinesia sometimes associated with grunting noises, gasps, and interrupted speech. Typically, patients will complain of dyspnea and voice disturbance but may be unaware of its other visible and audible manifestations. Tachypnea, which often accompanies the subjective dyspnea, presents as an irregular respiratory rhythm and amplitude, to which are contributed spontaneous and uncoordinated movements of the mouth, buccal muscles, and palate moving spontaneously in an uncoordinated manner [16].
The late appearance of “tardive parkinsonism” is usually due to an increase in APD dose or a switch to a more potent DRBA but in some cases its “tardy” appearance is unexplained. In most cases, tardive parkinsonism improves and disappears after DRBAs have been discontinued, indicating that an individual has experienced temporary DIP rather than persistent or permanent parkinsonism as a complication of long-term DRBA exposure. By contrast, if DIP persists long after DRBAs have been discontinued, in most cases this is because clinical features of unsuspected, preexisting, subclinical PD have been precipitated and aggravated by exposure to DRBAs. This scenario has long been suspected, particularly since the incidence of both DIP and PD increase with age together with evidence that underlying preclinical PD is a risk factor for DIP [17–19]. More recently this has been more firmly established by the use of (123) Ioflupane DaTSCAN-SPECT brain imaging of striatal dopamine uptake [20]. Using this brain imaging technique, patients with parkinsonism on chronic APD treatment showing evidence for presynaptic dopamine terminal degeneration are presumed to have underlying PD, the symptoms of which have been aggravated by dopamine receptor blockade. By contrast, patients with normal DaTSCAN imaging are presumed to have DIP without underlying PD, which can be expected to disappear once APDs are discontinued [20]. What remains unproven is whether there are also patients proven by DaTSCAN to have no evidence of underlying PD who have permanent parkinsonism long after APDs are discontinued, which is due to long-term effects of exposure to APDs [5]. Since patients with DIP with normal DaTSCAN imaging may require as much as 6–9 months and possibly even longer after APDs are discontinued for parkinsonism to clear, caution should be exercised before concluding that DRBAs can cause permanent parkinsonism [21].
Clinical course of TD
TD may appear as early as 1–6 months following initial exposure to DRBAs although, in the early literature, due to lack of awareness of the disorder, TD very often did not come to attention until after two or more years of treatment. Onset is usually insidious and occurs while the patient is being actively treated with a DRBA. However, TD very commonly first appears after a reduction in dose, following discontinuation of a DRBA or, as in the case of APDs, after switching to a less potent APD for psychiatric reasons or because of other adverse effects. When TD appears under these circumstances it is referred to as a “withdrawal dyskinesia” which usually makes its appearance within several weeks after stopping a DRBA [22]. TD is much less common in children where it has been called “withdrawal emergent symptoms” because they have been said to appear for the first time when APDs are discontinued [23]. This “unmasking” of TD is due to the hypokinetic parkinsonian effects of APDs which often suppress the hyperkinetic clinical manifestations of TD and thereby delay its recognition and diagnosis.
Cognitively intact and psychiatrically stable patients are usually aware of and disturbed by even mild manifestations of TD, while failure to complain of symptoms of TD more commonly occurs in chronically institutionalized or psychotic patients. In fact, however, severe orofacial dyskinesia or dystonia is often highly disfiguring and may interfere with speech, eating, swallowing, or breathing, while truncal dystonia can be extremely distressing and disabling by interfering with gait and mobility.
Remission rates in individuals with TD vary depending on a number of factors. By its definition, withdrawal dyskinesia disappears within several weeks of discontinuation of DRBAs but should be considered a precursor of more persistent forms of TD which are likely to recur if DRBAs are later resumed. In early studies, when there was much less awareness of TD, reported remission rates of TD were only 5%–40%. However, when TD is identified earlier, as in younger and less severely psychotic outpatient populations, a remission rate of 50%–90% has been observed, which usually occurs within several months but sometimes requires as long as 1–3 years after APD withdrawal [2]. In one long-term follow-up study concerning tardive dystonia, the remission rate was only 14% over a follow-up period of 8.5 years [11]. When TD persists after drug discontinuation it is referred to as persistent or permanent TD. The prognosis of TD in patients in whom continued treatment with APDs remains necessary for psychiatric indications is unknown but, in the vast majority of cases, TD either remains unchanged, is suppressed by the hypokinetic effects of APDs, or may even fluctuate in severity over time depending to some extent on changes in mood, psychosis, or variations in drugs or drug dosages [24, 25].
Differential diagnosis of TD
It is important to identify TD as early as possible since the potential for remission appears to be related to duration of symptoms before the DRBA is discontinued. The diagnosis of TD is based on the presence of dyskinetic or dystonic involuntary movements, a history of at least three months of APD treatment, the exclusion of other causes of abnormal dyskinesias, and the persistence of abnormal movements for at least 3 months after discontinuation of DRBAs. Tongue movements are insidious in onset and at first may be limited to subtle back and forth or lateral movements of the tongue. In other patients, tic-like facial movements or increased blink frequency may be initial manifestations of TD. Although the diagnosis is usually straightforward, it is important to consider other important causes of involuntary movements in a patient being treated for a psychiatric disorder such as Wilson’s disease or Huntington’s disease.
Akathisia occurs both early and late in treatment with APDs and may continue to persist after cessation of APD exposure. When akathisia occurs late in treatment it is referred to as tardive akathisia and is usually associated with dyskinesias elsewhere in the body and is a coexisting manifestation of TD. Acute dyskinesias or acute dystonic reactions typically only occur immediately after introduction of APD, but may resemble TD and can sometimes occur later in treatment following switching to a more potent APD or recurrently during treatment with long-acting injectable fluphenazine esters. Acute dyskinesias may also occur after treatment with certain antidepressants but do not represent TD and, with the exception of amoxapine, which has dopamine receptor blocking properties, these remit following discontinuation of the antidepressant [26].
Tardive dystonia involving axial or cervical muscles in a relatively young individual is differentiated from primary torsion dystonia by the absence of exposure to DRBAs and a slowly progressive course. Cervical dystonia characterized by severe retrocollis is particularly common in tardive dystonia. Huntington’s disease is clinically readily identified by a positive family history, a significant gait abnormality, and dementia. Tourette syndrome is easily identified by a history of fluctuating motor and vocal tics since early childhood. Other less common diagnostic possibilities include facial grimacing and choreoathetosis associated with chronic liver disease; chorea or dystonia due to antiphospholipid antibody syndrome; chorea due to hyperthyroidism or hypoparathyroidism; rheumatic or lupus chorea; acute drug-induced dyskinesias due to levodopa, amphetamines, anticholinergic drugs, antidepressants, certain calcium channel blockers, and anticonvulsants; and structural disorders of the basal ganglia.
Spontaneous dyskinesias which resemble TD
TD must be distinguished from stereotyped movements and psychotic mannerisms which may be associated with chronic schizophrenia, as well as the spontaneous orofacial dyskinesias which often occur in elderly, edentulous, and sometimes demented individuals [8, 27]. The mean prevalence of dyskinesia among APD-treated patients has been estimated at 20% compared with a mean prevalence of 5% in untreated patients, indicating a significant background level of various spontaneous dyskinesias that must be differentiated from TD [27]. Stereotyped and manneristic movements which are observed in schizophrenia are usually less rhythmic, may appear semipurposeful, are more stereotyped and complex, and are not usually choreoathetotic or dystonic [8, 27]. Meige syndrome is an idiopathic cranial dystonia with onset in middle age which is manifested by blepharospasm and oromandibular dystonia. Meige syndrome, blepharospasm, and oromandibular dystonia are all spontaneous movement disorders which are indistinguishable in appearance from classical orofacial forms of TD so that differentiation from TD therefore depends on a thorough drug history.
Pathophysiology of TD
The prolonged and often permanent course of TD suggests that structural alterations in the brain must be responsible for the disorder. However, standard pathological studies in laboratory animals and humans have failed to demonstrate consistent findings following chronic exposure to APDs [28]. TD is believed to result from chronic blockade of D2 dopamine receptors by DRBAs. While older first-generation APDs bind tightly to D2 receptors and remain attached for a few days, “atypical” second-generation APDs possess a lower degree of D2 receptor antagonism with rapid dissociation from the D2 receptor [29], thus possibly explaining their somewhat lower risk of TD which will be discussed later in the section on epidemiology of TD.
One theory used to explain TD pathogenesis postulates that, as demonstrated in laboratory animals, chronic exposure to DRBAs leads to upregulation of D2 receptors due to postsynaptic dopamine receptor supersensitivity [30, 31]. Although there is also evidence for upregulation of striatal dopamine receptors in humans following chronic exposure to DRBAs, this finding has not been correlated with the clinical presence of TD in these individuals [32]. Also, dopamine supersensitivity following prolonged dopamine receptor blockade in animal models is a universal and rapidly appearing pharmacologic phenomenon which lasts for only several weeks, raising some doubt about its relevance to persistent TD in humans.
Another hypothesis suggests that an imbalance between D-1 and D-2 receptor–mediated effects in basal ganglia may be responsible for TD [33]. According to this theory, classical or first-generation APDs preferentially block D-2 receptors thereby inhibiting the indirect striatopallidal outflow pathway. This results in unbalanced excessive activity of D-1 mediated striatopallidal output which causes altered firing patterns in the medial globus pallidus which in turn leads to hyperkinetic movement disorders [33]. According to this model, the ability of clozapine, a second-generation neuroleptic, to produce relatively less D-2 and relatively more D-1 blockade may account for the fact that it very uniquely does not produce TD [33].
Changes in other neuronal systems in the basal ganglia may also play a role in causing TD. In Huntington’s disease, which TD closely resembles, a loss of medium spiny striatal interneurons results in choreiform dyskinesia. These striatal interneurons utilize GABA, acetylcholine, or peptides as their neurotransmitter. From this has emerged the GABA hypothesis of TD. Chronic treatment of monkeys with APDs over a period of several years produced persistent dyskinesia and reduced GABA and glutamic acid decarboxylase levels in several regions of the basal ganglia [34]. It has been proposed that excitotoxicity may account for selective destruction of a localized population of basal ganglia neurons. According to this hypothesis, chronic blockade of D-2 receptors may lead to increased glutamate release within the striatum, thereby causing excitotoxic destruction of striatopallidal GABA and peptide-containing neurons [35]. There are two potential mechanisms by which this might occur. Firstly, interference with the inhibitory action of dopamine on corticostriatal terminal D-2 receptors could cause excessive release of glutamate in the striatum leading to excitotoxic degeneration of striatopallidal GABA and peptide neurons. Secondly, blockade of nigrostriatal dopamine activity could, as in Parkinson’s disease, lead to increased firing of glutamate-mediated subthalamic neurons causing excitotoxic degeneration of globus pallidus neurons.
Two other theories of TD pathogenesis have proposed the possible roles of oxidative stress and synaptic plasticity in the brain. Regarding the possible role of oxidative stress, chronic blockade of dopamine receptors leads to increased neuronal dopamine turnover, thereby generating free radicals and hydrogen peroxide [36]. This may result in neuronal damage and degeneration of multiple neurotransmitter systems. According to this hypothesis, irreversible structural changes due to neuronal loss and gliosis would occur, therefore supporting a possible “neurodegenerative” hypothesis of TD.
Regarding the possible role of synaptic plasticity, chronic blockade of D2 receptors may lead to hypersensitization of D2 receptors at both a cortical and basal ganglia level. Such hypersensitization may cause secondary effects on the synaptic plasticity of glutamatergic synapses on striatal interneurons, leading to abnormal striatopallidal output. This might be accompanied by maladaptive plasticity at the cortical level. According to this theory, the combination of maladaptive cortical synaptic plasticity and abnormal striatopallidal output produces abnormal movements [37].
Epidemiology of tardive dyskinesia due to antipsychotic drugs
Prevalence of TD
Prevalence estimates of TD have significant limitations when used to establish the risks of certain conditions among patient populations with different treatment exposures. APDs cause TD but can also mask its clinical manifestations by hypokinetic effects of their dopamine receptor blocking properties thereby reducing case ascertainment. In addition, the severity of TD often fluctuates with behavioral and emotional arousal so that in milder forms it may be less apparent. Differences in population age, gender, treatment duration, and type and dose of APDs also add to the complexity of determining the prevalence of TD in a particular population at a particular time.
When first described in the 1960s, the frequency of TD was widely regarded to be low due to failure of chronic psychotic patients to complain of dyskinesia, the limited familiarity of psychiatric clinicians with movement disorders in general, and the reluctance of some psychiatric clinicians to accept the possibility of a persistent disorder caused by APDs [1, 38, 39]. By the late 1970s, with greater awareness and increased vigilance, it became apparent that the prevalence of TD was substantial. Published prevalence figures varied widely between 5% and 45% among samples of hospitalized psychiatric patients and 30% among psychiatric outpatients [1, 2, 39]. Variable definitions of what was considered TD, varying ascertainment methods, patient age, and other risk factors among patient samples explain the wide variations in reported prevalence at that time. In addition, spontaneous dyskinesias independent of treatment with APDs may have inflated estimates of prevalence. Kane and colleagues analyzed 56 studies involving nearly 35,000 APD-treated patients and estimated the overall prevalence of TD to be 20%. In 19 studies involving 11,000 untreated patients not exposed to neuroleptic drugs, the prevalence of spontaneous dyskinesia was approximately 5%, suggesting a best-estimate, corrected rate for neuroleptic-associated TD of about 15% [27].
Incidence of TD
The incidence of new cases of TD appearing in a population during a specified period of exposure is a better measure of risk than cross-sectional estimates of prevalence at a particular point in time. However, incidence data are more difficult to acquire since they require repeated prospective observations over time. In order to study prospective incidence as well as identify risk factors, Kane and colleagues at the Hillside Hospital in New York enrolled 908 consecutive patients aged 19–40 years who were admitted to a single psychiatric service and monitored them for up to 20 years for the presence of dyskinesia [40]. All patients had been treated with conventional and predominantly “high-potency” standard APDs such as haloperidol or fluphenazine. Of 908 enrolled patients, 5.6% met diagnostic criteria for TD at initial evaluation or entered with a prior diagnosis of probable TD. Cumulative new incidence of TD was 5% after one year, 27% after 5 years, 43% after 10 years, and 52% after 15 years of APD exposure [40; Kane et al. personal communication]. The cumulative incidence of persistent TD lasting for at least three months was 3% after one year, 20% after 5 years, and 34% after 10 years [40]. These rates indicate an annual new incidence of TD of about 5% per year, with about 3% for cases persisting for at least 3 months.
Similar results were obtained in other prospective studies done at Yale in patients with chronic schizophrenia [41, 42]. However, the time of antecedent exposure to APDs in these patients was much longer, with a mean of 8 years. The incidence of TD persisting for at least six months yielded a cumulative five-year total of 25%, remarkably similar to the incidence of persistent TD described above in the Hillside study.
Incidence of TD in the elderly
In a prospective study, a population of patients never previously treated with APDs and older than 55 years, of whom 63% had dementia, had a cumulative incidence of 23% over 2.2 years. TD persisted for at least six months in 67% of these cases [43]. Another prospective study carried out for a longer period of time in older patients with a mean age of 65 years, found a cumulative TD incidence of 26.1% at one year and 59.8% after three years, or approximately 20% per year during continuous exposure to various older neuroleptics [44]. Thus, even with shorter exposure times, old age increased the risk of incidence for TD more than for younger patients.
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