In contrast to acute EPS, TD is insidious in onset, arises only after prolonged treatment and is often masked by ongoing treatment. In addition, TD is irreversible in most cases but usually mild, whereas acute EPS are transient but unmistakable and incapacitating. Even so, TD can become socially disfiguring and severe enough to compromise eating, speaking, breathing or ambulation.
TD presents as a polymorphous involuntary movement disorder.32, 87, 88
In its most common form, TD is characterized by involuntary, non-rhythmic, repetitive, purposeless hyperkinetic movements. Most often, TD affects orofacial and lingual musculature (“buccolinguomasticatory syndrome”) with chewing or bruxism of the jaw, protrusion, curling or twisting of the tongue, lip smacking, puckering, sucking and pursing, retraction, grimacing or bridling of the mouth, bulging of the cheeks, or eye blinking and blepharospasm. Choreoathetoid movements of the fingers, hands, upper or lower extremities are common. Axial symptoms affecting the neck, shoulders, spine or pelvis may be observed. Dyskinesias can affect breathing, swallowing or speech.
TD may present with other than choreoathetoid symptoms that can be difficult to distinguish from acute EPS. These may co-exist with classic TD symptoms, but represent separate subtypes with increased risk of progression, persistence and severe disability. For example, tardive dystonia, estimated to occur in up to 1% to 4% of treated patients,42
may be more generalized and disabling than TD, and may respond to anticholinergic agents. Akathisia, as well as other movement disorders, also occur as tardive variants. 89
Dyskinesias increase with emotional arousal, activation or distraction, and diminish with relaxation, sleep, or volitional effort. As a result, symptoms of TD fluctuate over time, such that repeated measurements are necessary for reliable assessment of severity and persistence.
Although different diagnostic schemes for TD have been proposed, criteria proposed by Schooler and Kane have been widely accepted. 90
These authors require at least three months of exposure to antipsychotics, ratings of at least moderate severity in one or more body areas, or ratings of at least mild severity in two or more body areas, and the absence of other conditions that might cause dyskinesias. Ratings are obtained using the Abnormal Involuntary Movement Scale (AIMS). 91
A careful neurologic evaluation is indicated for all patients with new-onset dyskinesias. Clues to neurological causes include family history, sudden onset or progressive course, associated medical or neurological abnormalities, and asymmetry. The differential diagnosis of TD includes acute EPS, transient withdrawal dyskinesias, spontaneous dyskinesias associated with schizophrenia and aging, Wilson’s disease, Huntington’s disease, Sydenham’s chorea, chorea gravidarum, Fahr’s syndrome, systemic lupus, senile chorea, Meige syndrome, edentulous chorea, infarction or lesions of the basal ganglia, post-anoxic and encephalitic states, Tourette’s syndrome, torsion dystonia, spasmodic torticollis, hyperthyroidism, hypoparathyroidism, and conversion disorder. Several drugs and toxins are associated with dyskinesias including caffeine, phenytoin, estrogens, levodopa, antidepressants, antihistamines, stimulants, and manganese poisoning.
The onset of TD occurs insidiously over three months or more of treatment and may begin with tic-like movements or increased eye blink frequency. TD is often suppressed or masked by ongoing antipsychotic treatment, becoming apparent only when treatment is reduced, switched or discontinued.
The natural course of TD is unclear. Early studies showed that withdrawal of antipsychotics may lead to an initial worsening of TD in 33% to 53% of patients (unmasking or withdrawal dyskinesia), but with long-term follow-up, 36% to 55% of patients eventually improve, which led to recommendations for drug reduction or withdrawal. 92
However, complete and permanent reversibility beyond the withdrawal period is rare; Glazer et al found that only 2% of patients showed complete reversal of TD after drug discontinuation. 93, 94
In a meta-analysis of treatments for TD, Soares and McGrath 95
reported that 37.3% of patients assigned to placebo across studies showed some improvement in TD, but concluded that insufficient evidence existed to support drug cessation or reduction as effective treatments for TD, especially when contrasted with robust evidence for the risk of psychotic relapse. 96
Data on the change in prevalence of TD during continued treatment have been inconclusive with some studies showing an increase, others a decrease, or no change at all.97
However, prevalence rates obscure the dynamics of TD in individual patients. Roughly 50% of patients have persistent TD symptoms, 10% to 30% have a reduction and 10% to 30% show increased symptoms during treatment. 98
Long-term studies estimated that from 2% to 23% of patients show loss of observable TD symptoms during treatment with FGAs.97
Similarly, studies of SGAs have shown reduction of TD ratings, with some showing greater reductions, less, or no difference, compared with first generation agents. 97
Improved outcome of TD correlates in some studies with younger age, lower doses, reduced duration of drug treatment and dyskinesia, and increased length of follow-up.
In the CATIE trial, there was a significant decline in ratings of TD severity among 200 patients with TD at baseline, but there were no significant differences between SGAs in the decline in AIMS scores. 97
Fifty-five percent of these patients met criteria for TD at two consecutive visits post-baseline, 76% met criteria at some or all post-baseline visits, 24% did not meet criteria at any subsequent visit, 32% showed ≥50% decrease and 7% showed ≥50% increase in AIMS scores. Thus, similar to past evidence on the course of TD during treatment with FGAs or SGAs, most patients showed either persistence or fluctuation in observable symptoms.
The frequency of TD occurring has been extensively studied but with varied results affected by spontaneous dyskinesias, sensitivity and definitions of diagnosis, susceptibility of the patient sample, fluctuation in TD symptoms, the dynamics of emergence and remission, and the influence of drug treatment on suppression and unmasking of TD. Estimates of the cross-sectional prevalence of TD with FGA antipsychotics range from 3% to 62% with a mean of 24%. 87, 99
Several studies have shown a cumulative incidence of TD of about 5% annually.87
In studies of first-episode patients with limited prior drug exposure, the incidence of TD was 6% to 12% in the first year even when low doses of antipsychotics were used.100, 101
The annual incidence of TD in patients over the age of 45 years was 25% to 30% after one year of treatment.102
Previous studies of TD risk have suggested an association with increasing age, female gender, psychiatric diagnosis, longer duration of antipsychotic treatment, higher cumulative drug doses, concomitant drug treatments, higher ratings of negative symptoms and thought disorder, greater cognitive impairments, presence of acute EPS, and diabetes. The patients with TD at baseline in the CATIE trial were found to be significantly older, and had been treated with an antipsychotic significantly longer, were more likely to be currently treated with an FGA and to be currently treated with an anticholinergic agent, had greater neurocognitive impairment, higher levels of psychopathology, and higher ratings of parkinsonism and akathisia compared with non-TD patients.103
Gender, race, and ethnicity were not differentially distributed between patients with TD versus those without TD. Patients with diabetes or hypertension did not have higher rates of TD. However, alcohol and drug abuse or dependence were significantly associated with TD.
Differences in liability for TD between FGAs and SGAs have been studied extensively. In contrast to the incidence of TD with FGAs, numerous industry sponsored trials of SGAs found a significant six to 12 fold reduction in risk for TD. 12, 27, 104-106
Correll et al, in a meta-analysis, found a 4.6% reduction in the risk of TD for SGAs compared with studies using haloperidol, but later found only a 1.6% difference in attributable risk when studies using mid-potency FGAs were included. 12, 27
It remains unlikely that clozapine causes TD. 107
In contrast to industry studies using haloperidol, there were no significant differences among groups in the CATIE trial receiving perphenazine or four SGAs in the incidence of TD defined by scores of two or more on the AIMS global severity score ().28
In a second analysis, patients were considered to have persistent TD if they met full Schooler-Kane (S-K) criteria. 29, 90
Analyses were also conducted using modified S-K criteria such that meeting the AIMS criteria on only one assessment was required, i.e., “probable” TD. Few patients who had no evidence of TD at baseline met full S-K TD criteria during treatment (1.1% to 4.5% receiving SGAs and 3.3% receiving perphenazine (). The proportion of patients who met modified S-K TD criteria ranged from 8.3% to 9.6% with SGAs and 11.8% for perphenazine. There were no statistically significant differences between treatment groups on any TD indicator.
Since there is no uniformly effective treatment for TD, it is important to minimize the risk of TD by early detection (). Some preventive principles are to confirm the indication for antipsychotics, use conservative doses opting for lower potency agents, inform patients and caregivers of risk, assess on a regular basis for incipient signs, consider differential diagnosis and reconsider drug treatment if symptoms emerge.
Proposed treatment algorithm for tardive dyskinesia.
The first step in treatment is the decision on antipsychotic treatment. Although drug withdrawal had been recommended in the past as increasing the odds of resolution of TD, about 33% to 53% of patients will experience worsening of dyskinesias initially, 36% to 55% may show improvement over time,92
but few will show complete resolution of symptoms,94
and the risk of psychotic relapse is 53% within nine months.96
A second option in a patient with good control of psychotic symptoms is to decide not to change the antipsychotic, try to gradually reduce the dose, inform patients and caregivers of risks, document the decision and monitor carefully. In most cases, TD is not progressive even with continued antipsychotic treatment, although symptoms may worsen in a few cases (7% in the CATIE trial).97
Another alternative is to switch antipsychotics; more potent antipsychotics, like haloperidol, can be used to suppress disabling symptoms of TD in about 67% of patients. 98
SGAs have also been associated with reduction of TD symptoms; 14, 15
results of the CATIE trial indicated that while most patients treated with SGAs show a persistent (34%) or fluctuating course (42%), 24% did not meet criteria on any visit at follow-up, and 32% showed greater than 50% reduction in AIMS scores.97
Clozapine has been recommended for suppressing tardive dystonia. While there have been speculations that SGAs may increase the possibility of remission on an active or passive basis, existing data are inconclusive whether recovery rather than suppression occurs during treatment with SGAs or FGAs.
After discontinuing or optimizing antipsychotic therapy, there are a large number of agents that have been tested in the treatment of TD ().98, 108
These include dopamine depleting agents, dopamine agonists, noradrenergic agonists and antagonists, GABAergic drugs (benzodiazepines, valproate, baclofen, levetiracetam), lithium, calcium channel blockers, serotonergic drugs, vitamins (vitamin E), branched-chain amino acids, neuropeptides, cholinergic precursors and cholinesterase inhibitors, ECT, and botulinum toxin or surgical intervention (for tardive dystonia). Anticholinergic agents can worsen TD (expect for tardive dystonia) with improvement noted in 60% of cases after discontinuation.98
Several hypotheses have been proposed to explain the pathophysiology of TD including dopamine receptor hypersensitivity, GABA insufficiency, and structural damage resulting from increased catecholamine metabolism and oxidative free radical production. 109
Another hypothesis proposes that TD results from damage to striatal cholinergic interneurons due to the loss of dopamine mediated inhibition. 110
If correct, this implies that cholinesterase inhibitors or cholinergic agonists may be effective in suppressing TD by directly enhancing post-synaptic cholinergic activity, thereby compensating for the loss of pre-synaptic cholinergic neurons. Several preliminary trials have explored the use of cholinesterase inhibitors with mixed results. 111-113
However, this hypothesis is supported by animal and human evidence correlating cholinergic mechanisms with the delay in onset, irreversibility, age-related risk, worsening with anticholinergic drugs, and reduced risk with the newer SGA drugs, suggesting further investigation of cholinergic mechanisms may be worthwhile.
As a genetic basis for TD has been assumed, an increasing number of candidate genes have been selected for study. Using the CATIE trial sample, a total of 128 candidate genes selected from the literature were studied in 710 subjects (207 or 29.2% with TD). 114
No single marker or haplotype association reached statistical significance after adjustment for multiple comparisons, therefore providing no support for either novel or prior associations from the literature. In a genome wide association study of the CATIE sample, Aberg et al genotyped 738 schizophrenia patients for 492K SNPs in association with scale scores for EPS, and found two SNPs and one SNP reaching genomewide significance for parkinsonism and TD, respectively.115
Though these findings require replication, they demonstrate the potential of candidate gene and genomewide association studies to discover genetic pathways that mediate TD.