Tardive Dyskinesia

Original Author: Bruce Alexander, Pharm.D, BCPP

Latest Revisers: Bruce Alexander, Pharm.D, BCPP, Brian C. Lund, Pharm.D.
Creation Date: 1996
Last Revision Date: October 1999
Peer Review Status: Internally Peer Reviewed

CLINICAL PRESENTATION

The term "tardive" or late dyskinesia was introduced in 1964 and refers to an iatrogenic disease
associated with neuroleptic drug use (American College of Neuropsychopharmacology FDA Task
Force 1973, Fann and Lake 1976).

Tardive dyskinesia (TD) is a syndrome of hyperkinetic involuntary movements characterized by a

mix of orofacial dyskinesia, tics, chorea and/or athetosis (American College of
Neuropsychopharmacology FDA Task Force, 1973). Orofacial dyskinesia is the most characteristic
feature of TD. It is slow in onset, which may begin as mild tongue movements, followed by
exaggerated movements of the tongue and lips. Bulging of the cheeks, chewing movements,
blinking, blepharospasm, grimacing, and arching of the eyebrows also occur. Movements of the
extremities and trunk are also noted in some patients. These include choreoathetoid-like movements
of the fingers, hands, arms, and feet. Truncal involvement may produce rocking and swaying and
rotational pelvic movements.

Late-appearing dystonias involving the neck and trunk have been reported. Recently these cases
have been referred to as "tardive dystonia." (Tarsy 1983). "Tardive akathisia" has been suggested to
occur concurrently with the typical movements of TD (Tarsy 1983).

TD occasionally interferes with manual dexterity and eating. Diaphragmatic involvement produces
grunting, difficulty in speaking, and, sometimes, in breathing.

Usually TD appears while patients are taking neuroleptics, although movements often appear for the
first time or increase following a dose reduction or discontinuation of the drug.

Movements in TD may worsen with emotional stress, volitional motor activity, and attempts to
inhibit portions of the dyskinesia. On the other hand, movements decrease with sedation and
disappear during sleep. Patients should be evaluated at least several hours after awakening and about
the same time each day since movements tend to be worse in the afternoon and least severe just after
the patient has awoken in the morning (Hyde et al 1995).

DIFFERENTIAL DIAGNOSIS
The only drug other than neuroleptics that regularly produces dyskinesia is L-DOPA, in patients
receiving the drug for Parkinson's. L-DOPA actually can improve neuroleptic-induced TD. However,
reports have associated TD with reserpine, tetrabenazine, metoclopramide, tricyclic antidepressants,
benztropine, phenytoin, and amphetamines. Depending upon the type of onset, a differential
diagnosis might include Sydenham's chorea, Huntington's chorea, congenital torsion dystonia,
hysteria, and the stereotyped behavior or mannerism of schizophrenia (American College of
Neuropsychopharmacology FDA Task Force, 1973).

CLASSIFICATION

The following classification of TD has been suggested to help study the epidemiology, etiology, and
treatment of TD patients (Schooler and Kane 1982):

(1) Probable TD: includes (a) a history of at least 3 months of total cumulative neuroleptic drug
exposure; (b) the presence of at least "moderate" (severity determined by a rating scale) abnormal
involuntary movements in one or more body areas of "mild" movements in two or more body areas;
and (c) the absence of other conditions that might produce abnormal involuntary movements. To be
"probable" the dyskinesia is observed only on one occasion.

(2) Masked Probable TD: patients with previous probable TD in whom either reintroducing or
increasing the dose of the neuroleptic drug results in disappearance of significant dyskinesia.

(3) Transient TD: patients with previous probable TD who on reexamination within 3 months no
longer have significant dyskinesia without reintroduction or increasing the neuroleptic dose.

(4) Withdrawal TD: patients who develop significant dyskinesia within 2 weeks following
discontinuation of neuroleptics.

(5) Persistent TD: patients who meet the criteria for probable TD and continue to do so for 3 months.
This is qualified by concurrent neuroleptics, neuroleptic-free, or unspecified if the patient has
received neuroleptics for only part of the 3 month period.

(6) Masked Persistent TD: patients who meet the criteria for persistent TD but in whom significant
dyskinesia disappears within 3 weeks of introduction or increase in the neuroleptic dose.

Gureje (1988) examined 57 neuroleptic treated schizophrenic patients aged less than 60 years (mean
= 37.5 years) with TD. These patients underwent neurophysiologic testing and AIMS rating. Three
dependent variables were generated, two for oro-facial and one for limb-truncal TD. The variables
were examined using multiple logistic regression in a stepwise fashion with 21 demographic,
treatment, and physiological variables. Oro-facial symptoms were negatively associated with
positive symptoms while limb-truncal symptoms were negatively associated with the neuroleptic
dose on the day of examination. This indicates that resolution of positive symptoms through an dose
increase results in a worsening of oro-facial TD. Conversely, limb-truncal TD appear to resolve with
an increase in daily dose of neuroleptic.

EPIDEMIOLOGY
The prevalence of TD reported in the literature ranges from 0.5% to 65% (Gerlach and Casey 1988,
Casey and Hansen 1984, Tepper and Haas 1979). The variability in prevalence rates is attributed to
differences in the patient population heterogenicity (age, neuroleptics used, presence or absence of
antiparkinsonian agents), TD definition, and research design. An estimate of the true TD prevalence
figures requires a baseline prevalence rate for spontaneous dyskinesia, which is clinically similar to
TD but arises independently of neuroleptic treatment, especially in elderly patients (Gerlach and
Casey 1988). Casey and Hansen (1984) compiled the findings of 18 clinical TD studies. They
estimated the spontaneous dyskinesia rate at 6% (5900 patients) and the total dyskinesia rate at 20%
(7200 patients). Thus the net rate or true TD prevalence rate is 14%. Because increasing age is a TD
risk factor, it is not surprising that rate is much higher, around 50% in the elderly (Kane et al 1992).
Additionally, Kane et al (1992) suggested the new case incidence rate ranges between 3% to 5%.
However, Casey (1994) notes that this rate is offset by a TD resolution rate of approximately 5% per
year. Thus the TD prevalence rate tends to remain relatively stable. Miller et al (1995) conducted a
10 year follow-up study of 254 chronically institutionalized psychiatric inpatients. The patients were
examined in 1982 for TD and then re-examined in 1992. The prevalence rate increased from 3.1%
(8/254) to 12.2% (31/254). Three of the 8 patients with TD in 1982 had it remit. Thus there were 26
new TD cases in the 254 cases or a new TD rate of 1% per year. These data again suggest a relatively
stable prevalence rate for TD.

RISK FACTORS (Casey 1999)

Age
Advancing age is the most consistent risk factor capable of predicting TD. By examining pooled
epidemiological data, Smith and Baldessarini (1980) found a strong linear relationship between age
and both the prevalence and severity of TD. Additionally, they found that TD occurring in patients <
60 years of age was over three times more likely to remit spontaneously. Gureje (1988) was able to
confirm previous reports that indicated an age related incidence of oro-facial and limb-truncal TD.
Older patients appear to exhibit more oro-facial symptoms while younger patients more limb-truncal
symptoms.

A more recent study confirms the age-related risk of TD. Woerner et al (1998) reported that the
cumulative rates of TD for patients >55 years of age were 25%, 34%, and 53% after 1, 2, and 3
years, respectively.

Duration of Neuroleptic Treatment

TD is usually first recognized after several years of neuroleptic treatment, but onset within three
months has been reported in geropsychiatric patients (Sweet et al 1995). Two studies that have
examined this question have concluded that a duration of neuroleptic treatment of greater than 5
(Chouinard et al 1988) or 6 (Morgenstern 1987) years is a risk factor in the occurrence of TD.
However this risk factor is confounded by age. Sweet et al (1995) examined 386 consecutively
admitted geropsychiatric patients (mean = 75 yo, 60-100 yo) for evidence of TD. Of these, 234 had
been exposed to neuroleptics. The TD rate for the unexposed patients was 10% (15/152). The TD
rate for the exposed patients was a function of duration of neuroleptic use. The prevalence of TD
was 16% for patients with < 3 months of exposure, 29% for 3 to 12 months, 30% for 1 to 10 years,
and 41% for greater than 10 years of exposure. TD risk covaries with age and duration of
antipsychotic exposure, thus it is not possible to determine how much increased risk of TD over time
is due to each of these factors.

Diagnosis
It is hypothesized that schizophrenia might be associated with abnormal involuntary movements
and the neuroleptics accelerate and exacerbate this process. This is especially true in patients whose
illness is characterized by an excessive number of negative symptoms (blunting of affect, social and
emotional withdrawal, psychomotor retardation, self-neglect, and muteness). Interestingly, it has
been observed that these patients tend to have a poor prognosis and be drug-therapy resistant (Barnes
1987).

Reports involving patients with schizophrenia have suggested that both a positive family history of
affective disorder and the presence of depressive symptoms are markers for an increased likelihood
of patients developing TD as well as neuroleptic-induced parkinsonism. However, attempts to
replicate these findings have either not been successful or not repeated (Barnes 1987).

Following six years of exposure to neuroleptic drugs, patients with affective or schizoaffective
illness demonstrated a 26% TD rate contrasted to 18% in schizophrenic patients. It may be that
neuroleptics when combined with affective disorder treatments such as ECT, lithium, and tricyclic
antidepressants may produce a greater risk of developing TD (Barnes 1987).

Studies conducted in the 1960's found TD to be more prevalent in patients with organic brain
syndromes than those with schizophrenia (Barnes 1987). Today, this finding still remains true. Yassa
et al (1984), after assessing TD risk in over 300 patients treated with neuroleptics, found that OBS
patients (mental retardation with psychosis, alcoholism, epilepsy with psychosis) demonstrated a
significantly higher prevalence rate for TD than did those with schizophrenia (Smith and
Baldessarini 1980).

Neuroleptic Class
Of 13 studies, none indicated a higher or lower occurrence of TD with any neuroleptic or class of
neuroleptic (Tepper and Haas 1979). Cseransky et al (1981) reported a positive relationship between
fluphenazine decanoate and total neuroleptic dose. The authors concluded that long-acting injectable
neuroleptics may carry a greater risk for TD than other neuroleptics. However, primate studies do
suggest that the stronger D2 antagonist neuroleptics (haloperidol, fluphenazine, flupenthixol) carry a
greater risk for TD development than the weaker D2 antagonists (clozapine, thioridazine,
chlorprothixene) (Barnes 1987). At least with respect to clozapine (Small et al 1987, Lieberman et al
1991) and olanzapine (Tollefson et al 1997) this seems to be true. Risperidone has been associated
with TD (Casey 1999).

History of Extrapyramidal Reactions and Anticholinergic Agents

Six studies addressed the relationship of early onset neuroleptic-induced EPS (dystonia, akathisia,
and/or pseudoparkinsonism) and TD. Three studies demonstrated no association, two showed a
relationship, and one was inconclusive (Tepper and Haas 1979). Additionally, the use of
anticholinergic agents has been postulated to increase the prevalence of developing TD. However,
three studies found anticholinergics were not associated with an increased incidence of TD (Tepper
and Haas 1979). Thus the question arises is the risk factor the predisposition to early EPS or the
treatment of the early EPS with the anticholinergic drugs. Kane et al (1988) after examining this
question have noted that patients with clinically significant neuroleptic-induced drug-induced
parkinsonism have a two-fold greater risk of developing TD than patients without such a history.
Obviously the former patients are more likely to receive anticholinergic drugs. This observation
leads to the false conclusion that the administration of anticholinergic drugs increases the risk for
developing TD. Thus the predisposition to drug-induced parkinsonism is the risk factor not the
anticholinergic drugs.

Dose of Neuroleptic
Four studies reviewed showed a positive relationship between dose and TD, while seven were unable
to detect a relationship (Tepper and Haas 1979). However, the neuroleptic being administered at the
time of observation can mask TD, especially the stronger D2 antagonist agents if the dose has
recently been increased (Branchey et al 1982).

"Drug Holidays"
It has been suggested that TD prevalence may be decreased with drug-free periods or "drug
vacations (Crane 1973). Jus et al (1976) found this to be true for piperazine phenothiazines and/or
butyrophenones but not other classes of neuroleptics. A study by Jeste et al (1979) in a small number
of patients suggested drug holidays were associated with persistent dyskinesias. However, these
patients received larger doses of neuroleptics and for a longer period of time, overall, than the
comparison group. It should be remembered when discontinuing the neuroleptic initially one
observes either improvement or worsening which is later followed by slow improvement.

Family History
Yassa and Ananth (1981) suggest that if one member of a family develops TD, it is likely other
members exposed to chronic neuroleptic treatment will develop it as well.

Electroconvulsive Therapy
Five of six studies found no association between prior ECT exposure and predisposition to TD
(Tepper and Haas 1979).

Sex
Twelve of seventeen studies found a higher proportion of TD in females, while five did not find an
association (Barnes 1987). It should be noted in several of the populations studied, females were
somewhat older than males.

Glazer et al (1981) investigated the relationship between serum prolactin levels and severity of
tardive dyskinesia. Postmenopausal women with severe TD had higher prolactin levels than women
with mild TD and men with or without TD. The authors speculated that persistent
hyperprolactinemia and lowered estrogen levels from menopause in a subgroup of women may
aggravate their TD.

Smoking
Three different groups have demonstrated that smoking increases the risk of TD (Kirch 1988). It is
postulated that nicotine decreases striatal DA turnover (MHPG production) and decreases the
amount of catecholamines that are metabolized thereby resulting in increased free radical production
which can damage DA neurons. Nilsson et al (1997) studied a randomly selected population of 59 yo
(n=559) males. Regardless of AP expsoure, dyskinesia was diagnosed in 46 (8.2%). The AIMS score
of 5 + 1.8 was suggestive of mild to moderate dyskinesia. A logistic regression analysis model
identifed exposure to neuroleptics and smoking (> 20 cigarettes/day) as independent risk factors
associated with dyskinesia. The probability of dykinesia occuring in smokers was 19% whereas the
probability in patient exposed to neuroleptics was 30%. However, in the smoker exposed to
neuroleptics the risk was 64%.

Diabetes
There is preliminary evidence that diabetes may be a risk factor for the development of TD (Ganzini
et al 1991). Thirty-eight neuroleptic-treated diabetic patients were compared to a matched group of
non-diabetic patients receiving neuroleptics. The prevalence of TD by research criteria was 79% in
the diabetic group and 53% in the non-diabetic control group. Furthermore, the mean AIMS score
was 7.6 in the diabetic group and 5.2 in the non-diabetic group. Both of these differences were
statistically significant (Ganzini et al 1991). Interestingly, the rate of TD in a control group of non-
psychotic diabetic patients was 21%. This is considerably higher than the expected rate of 5-10%
and suggests that patients with diabetes may be have a higher rate of spontaneous dyskinesias.
Therefore, diabetes may be independent from neuroleptics as a risk factor for dyskinesia.

Summary
Elderly smoking diabetic female patients appear to be at higher risk of developing TD. Also, they
appear to have a much poorer prognosis for eventual TD remission following discontinuation of the
offending drug. Additionally, strong risk variables include neuroleptic-induced drug-induced
parkinsonism and a duration of chronic neuroleptic treatment of greater than 3 months.

PATHOPHYSIOLOGIC MECHANISMS UNDERLYING NEUROLEPTIC-INDUCED

MOVEMENT DISORDERS

There are three major classifications for EPS. These include initial EPS, tardive EPS, and age and
disease related EPS (Gerlach 1985).

Initial EPS
This group consists of dystonic reactions, pseudoparkinsonism, and hyperkinetic movement
disorders, i.e., initial dyskinesia (ID) and akathisia. These symptoms may occur individually or
simultaneously. They have been directly related to the dopamine antagonist activity of the
antipsychotics. Because they improve with a decrease in dose and are aggravated by an increase in
dose, they are considered as AP intoxications. Following AP withdrawal they resolve quickly in
some cases (7-10 days), but in other cases they are prolonged and diminish slowly over several
months, and in a few cases they appear to be irreversible.

Tardive EPS
This group of syndromes develops during or following prolonged AP treatment and consists
primarily of tardive dyskinesia (TD). In some cases, tardive akathisia which is indistinguishable
from initial akathisia and tardive dystonia may occur.
Age- and Disease-Related EPS
Dystonia, parkinsonism, and hyperkinesia all occur in elderly, untreated people. The spontaneous
(senile) oral dyskinesia cannot be distinguished from TD in elderly patients, just as parkinsonism
cannot be differentiated from AP-induced parkinsonism. Senile dystonia and akathisia are relatively
rare, although they have been described in a few cases. Historically, prior to the use of neuroleptic
drugs, schizophrenic symptomatology could include various types of hyperkinetic, stereotypic
movements and restlessness, which can look exactly like the AP-induced movement disorders.
Schizophrenic akinesia and catatonic symptoms may similarly resemble parkinsonian and dystonic
symptoms.

Traditionally, initial and tardive EPS are regarded as opposite movement disorders, i.e., the initial
EPS resulting from DA hypoactivity while tardive EPS resulting from DA hyperactivity in the CNS.
This view of EPS is too simple and inconsistent an explanation for initial and tardive EPS. ID are
TD-like movements that develop in about 15-20% of AP-treated patients, usually early in the course
of AP treatment. The syndrome has most often been seen in young patients and has a widespread and
varied localization including the extremities and the trunk, whereas TD preferentially occurs in
elderly patients and is confined to the oral region. This apparently different localization of ID and
TD may, however, be a age-related difference rather than being related to the late versus early stage
in the treatment course. It is well known that hyperkinetic movements, including withdrawal TD in
younger patients, are mainly confined to the extremities, whereas a rising tendency to oral
preponderance of hyperkinesia is seen with increasing age, both for TD and for L-dopa-induced
hyperkinesia in Parkinson's disease. In some cases, however, ID occurs solely in the oral region, and
in such cases it is impossible to distinguish it from TD.

At one time is was thought that ID and TD could be distinguished by discontinuation of the AP
treatment after which TD would temporarily become worse and later diminish, while ID would
resolve relatively quickly. However, recent observations suggest that in some cases ID diminishes
slowly over months or remains irreversible, like TD. This means that ID and TD can be
indistinguishable and may be one and the same phenomenon. If these results can be confirmed it
might be necessary to change the terminology.

This overlap between ID- and TD-EPS poses the clinician an insoluble problem. The hyperkinetic
movements may be very severe and disturbing, but any antidopaminergic treatment may eventually
worsen the symptoms and perhneuroleptics add a severe akathisia. Clinical observations suggest that
the hyperkinetic EPS, akathisia, ID, and TD are closely related symptoms, often overlapping and
sometimes phenomenologically indistinguishable. Thus this clinical observation suggests that the
underlying pathogenetic mechanisms may be partly the same.

The Hypersensitivity Theory

Traditional Neuroleptics block postsynaptic D2 receptors, leading to an increased dopamine
turnover. Clinically, this appears to be related to parkinsonism. During long-term AP treatment,
various phenomena of adaptation occur: the DA receptor blockade leads to a dopaminergic
hypersensitivity, which can be shown by an increased DA receptor sensitivity. However, several
observations suggest that there is no clear correlation between TD and DA hypersensitivity:

1. Parkinsonism and TD can occur simultaneously, in different regions or in the same region.
2. In some cases, ID and TD may be indistinguishable, both phenomenologically and
pharmacologically.

3. During long-term, stable, decreased, or increased AP treatment, TD may decrease, in contrast to

AP-induced DA hypersensitivity.

4. TD in psychiatric patients shows only slight deterioration or improvement during treatment with
DA agonists such as L-dopa, in contrast to the animal hypersensitivity model. Only in patients with a
concomitant idiopathic parkinsonism does L-dopa clearly aggravate/precipitate TD, at least partly by
counteracting the parkinsonism.

5. Endocrine studies do not suggest any increased DA hypersensitivity in TD patients, but rather the
opposite.

6. One study has found no increased number of DA receptors in postmortem brains from patients
with TD compared with patients without TD.

7. During AP treatment, there is no correlation between the time course of development of DA

hypersensitivity in animals and TD in patients. For example the DA hypersensitivity in animals
develops in all cases and after one single dose, whereas TD develops in only some patients and only
after treatment for some months/years.

These observations indicate that the DA hypersensitivity theory cannot fully explain the
pathophysiology of TD. Therefore, other possibilities should be considered.

Dopamine/GABA TD Hypothesis
During recent years, the knowledge about various neurotransmitters and their interactions in the
brain has increased rapidly. One of the most interesting aspects in relation to TD is the observation
of distinct types of DA receptors and GABA neurons. Regarding the interaction of DA and GABA
neurotransmitters and receptors in the brain there seem to be two types of GABA receptors enervated
by DA. One type (from the anterior part of the striatum to the globus pallidus, lateral segment) is
inhibited by DA, while another type (from the posterior part of the striatum to zona reticulata of
substantia nigra and to globus pallidus, median segment) is excited by DA. Since the Neuroleptics
block these effects, GABA neurons projecting to the lateral segment of globus pallidus are
facilitated, while the GABA neurons projecting to substantia nigra and medial globus pallidus are
inhibited. From animal studies using intracerebral injection technique it is known that increased
GABA activity in lateral globus pallidus induces parkinsonism in animals, while the decreased
GABA function in the medial segment of the globus pallidus and in reticular zone of the substantia
nigra seems to be associated with hyperkinetic movements. The last observation mentioned is in
agreement with that of a decreased glutamic acid decarboxylase (a GABA-synthesizing enzyme)
activity in substantia nigra and in the median pallidal segment in postmortem brains from Cebus
monkeys with persistent dyskinesias.

These observations clearly suggest that a DA receptor blockade has distinct behavioral effects
depending on the localization of the DA receptors in the brain. Blockade of some DA receptors leads
to hyperkinetic disturbances, while blockade of others results in decreased mobility.
From a clinical point of view, these observations indicate that APs might be able to induce
hyperkinetic movement disturbances including akathisia, ID and TD, and at the same time,
parkinsonism and dystonia. In most cases, parkinsonism and/or sedation may suppress the
hyperkinetic movements at the initial stage of the treatment. Later, when tolerance has developed to
parkinsonism and sedation, the hyperkinetic movements may become manifest.

The pathogenetic implication of these considerations may be the ID and TD do not have to be
considered as distinct entities. It may be that both result from DA receptor blockade, merely of DA
receptors sited at different points in the brain. In some cases the parkinsonism may be dominating
and long standing, in other cases the hyperkinesia.

This new hypothesis does not disregard the traditional DA hypersensitivity theory. TD is probably a
heterogeneous syndrome which depends on a multitude of pathogenetic mechanisms. It turns on a
subtle balance between various neurotransmitters and the sensitivity of receptors of different type
and localization. Furthermore, an unknown predisposition for TD is a necessary prerequisite for
development of the syndrome. The DA hypersensitivity may still play a role and lower the threshold
for manifestation of dyskinetic disturbances.

Serotonin-Dopamine Antagonist (SDA) TD Hypothesis

Clozapine's low affinity for D2 receptors and high affinity for 5-HT2 receptors producing a high 5-
HT/D2 ratio, is hypothesized to be responsible for its improved efficacy and decreased rate of
extrapyramidal side effects (Meltzer et al 1991). Figures 1 and 2 contrast the differing effects of the
conventional neuroleptics and the SDA neuroleptics on the limbic and striatal areas of the brain. For
the conventional neuroleptics, the antagonism of dopamine in the mesolimbic system relieves some
of the symptoms of schizophrenia but at the same time, the blockade of transmission in the
nigrostriatal system causes EPS. Likewise for the SDAs, antagonism of dopamine in the mesolimbic
system relieves some of the symptoms of schizophrenia. However, the dopamine (D2) blockade in
the nigrostriatal system is overcome by increased release of dopamine secondary to serotonin
(5HT2) blockade in this area (Huttunen 1995, Tollefson et al 1997).

Figure 1. Hypothetical mechanism of action of conventional neuroleptics.

Figure 2. Hypothetical mechanism of action of SDA neuroleptics.

The question of the pathophysiology of TD is far from solved. However, the biochemical
background for various movement abnormalities has expanded enormously, and postmortem brain
studies in human and monkey organs have contributed to a clarification. From a clinical point of
view, the major objective is still prevention of the syndrome, and in this respect attempts to find new
neuroleptics with little or no antidopaminergic effect appear to be the most promising.

PHARMACOLOGIC THERAPY

There is no accepted treatment for tardive dyskinesia (Casey 1999). Either discontinuing the
offending antipsychotic or switching a patient to an atypical antipsychotic (with the possible
exception of risperidone) may alleviate the movement disorder. The treatment of TD has been
recently reviewed (Egan et al 1997).

Most pharmacologic treatment strategies are directed toward reducing dopamine activity or
enhancing CNS cholinergic effect. If the etiology of TD relates to chronic dopaminergic receptor site
blockade and the pathophysiology relates to the denervation hypersensitivity, agents that interrupt
this sequence would, theoretically, be of potential benefit. Many drugs have been tried in treating
neuroleptic-induced TD. Because of differences in patient populations, study design, and doses of
agents used, the results for individual agents are conflicting. All of the drugs that have attempted to
treat TD using the DA hypersensitivity hypothesis as the rationale for their use have been ineffective
in treating TD. Table 1 summarizes the differential pharmacology of TD (Baldessarini and Tarsy
1978, Klawans 1980).

Amine-Depleting Agents
These agents e.g., reserpine, tetrabenazine, act by blocking the reuptake of dopamine,
norepinephrine, and serotonin into the presynaptic neuronal storage vesicles, thereby depleting the
brain of these substances. Studies with these agents have indicated improvement in TD but side
effects have limited their use and the studies are of short duration. Short-term suppression may occur
as reported with neuroleptics.

Blocker of Catecholamine Synthesis

Alpha-methyldopa studies have not demonstrated a beneficial effect on TD. AMPT, an experimental
agent that inhibits tyrosine hydroxylase, the rate-limiting step in the synthesis of dopamine and
norepinephrine, has shown partial reduction of dyskinesia.
Dopamine Antagonists
Formerly, TD was often treated by increasing the dose of the neuroleptic. This initially treats the
pathophysiology of TD but can aggravate the pathogenesis by further denervation and subsequent
hypersensitivity. Thus, the movements may decrease or disappear initially but then reappear later.
This mode of treatment with the typical neuroleptic such as the phenothiazines and butyrophenones
is not recommended as an unending cycle of neuroleptic dose escalation results. However, the use of
the atypical neuroleptic, clozapine, may be useful in certain situations in which patients with
disfiguring TD need to a neuroleptic treatment alternative. Simpson et al (1978) were the first
investigators to observe the potential usefulness of clozapine in the treatment of 12 chronic
schizophrenic patients with TD. The first controlled study (Caine et al 1979) that evaluated
clozapine's value in the treatment of abnormal involuntary movement disorders (Huntington's,
Tourette's and TD, n=12) found that only 2 patients with Huntington's experienced any benefit from
clozapine. Small et al (1987) used clozapine to treat 7 patients with severe TD. A 7-week course of
clozapine with a final mean dose of 269 mg/d reduced the AIMS score from 18 to 4. Lieberman et al
(1991) treated 30 patients with severe TD with a mean clozapine dose of 486 mg/d for 36 months.
Sixteen of the 30 patients experience > 50% decrease in their TD symptoms (Simpson Dyskinesia
Scale) while 10 had a complete remission of the TD on follow-up at 100 weeks. As shown in Figure
2, it appears that switching a schizophrenic patient from a typical neuroleptic to an atypical
neuroleptic such as clozapine will only partially effect the rate of spontaneous remission. If the
neuroleptic is completely discontinued, the remission rate is estimated to be 60% over a 2-3 year
follow-up period . However, clozapine actually accelerates the remission rate as opposed to having
the patient remain on a typical neuroleptic such as chlorpromazine which ought to increase the TD
rate. Clozapine treatment does not mask TD according to Lieberman's (1991) findings. TD
symptoms did not re-emerge over the follow-up period. The most impressive findings suggesting a
therapeutic effect for clozapine on TD were those of Gerbino et al (1980). Twenty-four TD patients
were treated with clozapine in an open trial for a minimum of 4 weeks. They then followed 17
patients for a year of maintenance clozapine treatment. The average dose in the acute phase of the
study was 650 mg/d. All 24 patients experienced at least a 50% decrease in their AIMS score. In the
follow-up portion of the study, none of the 17 patients experienced a recurrence of TD symptoms
when the clozapine was discontinued. Tollefson et al (1997) analyzed the followup data base from
three phase III olanzapine trials. Patients were treated with either olanzapine (n=707, < 20 mg/d,
median = 237 days) or haloperidol (n=197, < 20 mg/d, median = 203 days). According to the final
AIMS assessment, 16 (2.3%) olanzapine patients and 15 (7.6%) patients had TD (p < 0.001).
Olanzapine has a significantly lower risk of TD than the typical antipsychotic haloperidol.

Thus clozapine and olanzapine unlike typical neuroleptics does not mask TD but instead produces a
sustained beneficial effect on the TD.

Short-term EPS treatment with Clozapine. Twenty neuroleptic-resistant (defined as failure to

respond to 3 neuroleptic agents of different classes during 6 weeks of treatment for each and no
episodes of complete symptomatic remission during the last 5 years) chronic schizophrenics with
TD, parkinsonism and chronic akathisia were enrolled in a 18 week treatment study with clozapine,
mean age was 43.1 + 7.1 years, mean duration of disease was 17+8.7 years and mean number of
hospitalizations were 4.5+3.6 (Spivak et al 1997). Tardive Dyskinesia was measured according to the
Abnormal Involuntary Movement Scale (AIMS), parkinsonism was measured by Simpson-Angus
Rating Scale for Extrapyramidal Side Effects (Simpson-Angus) and akathisia according to the
Barnes Rating Scale for Drug-Induced Akathisia (BAS). The above scales in addition to the PANSS,
HAM-D, HAM-A were assessed weekly. Baseline PANSS score was 114.9+24.2. The mean
clozapine dose at week 18 was 208.7+176.6 mg/day. By week 18, rates of improvement were 74%
for TD, 69% for parkinsonism and 78% for akathisia (p<0.0001). A significant reduction in TD and
parkinsonism was achieved at week 5 (35 and 32%, respectively), and in chronic akathisia (41%) at
week 6. At week 18, the total PANSS score had decreased by 32%, positive score subscale decreased
by 36% and the negative subscale by 27% and was significant starting at week 4 (p<0.0001). The
final improvement in the HAM-D and HAM-A was 57% and 48%, respectively. A strong negative
correlation between clozapine dose and the AIMS, Simpson-Angus and BAS was seen, the higher
doses of clozapine were associated with less extrapyramidal symptoms.

Blocker of Catecholamine Release

Lithium interferes with the presynaptic release of monoamines as well as having other actions on the
CNS. Two studies report mild improvement in TD with lithium while two others report no
improvement or exacerbation (Tepper and Haas 1979).

Cholinergic Agents
There is a well-known and accepted balance between dopamine and acetylcholine in the striatum. If
TD relates to a relative increase in dopaminergic effect, then elevating the cholinergic effect would
reestablish the former homeostasis, at a new level. With this theory in mind, several cholinergic
agonists have administered to patients with TD.

Choline chloride and phosphatidylcholine (lecithin), which are orally bioavailable precursors of
acetylcholine, have been reported to be useful in short- term studies. Lecithin may be preferred to
choline because there are fewer side effects associated with it. Physostigmine cannot be given orally.
Deanol was originally reported to be efficacious in the treatment of TD, but recent studies have not
confirmed these findings (Gelenberg et al 1990).

Figure 4. Spontaneous remission rate of TD while typical and atypical neuroleptics are continued
according to Lieberman et al (1991).

GABA Agonists
Based on preclinical evidence that GABA, an inhibitory neurotransmitter in the CNS, appears to
exert an inhibitory influence on nigrostriatal dopaminergic neurons, there have been several recent
attempts to treat tardive dyskinesia with drugs believed to potentiate central GABA mechanisms.
Thaker et al (1990) using a double-blind placebo controlled crossover design found clonazepam 2. to
4.5 mg/d for 4 weeks more effective than placebo in treating TD. TD severity decreased by an
average of 37%. Patients with primarily dystonic rather than choreoatheotoid dyskinesia responded
best. Although tolerance did develop to the long-term use of the drug of up to nine months, a 2-week
drug holiday resulted in restoration of the anti-dyskinesia effect of the drug. Since GABA neuron
inhibition cause hyperkinetics movements it is logical that a GABA agonist such as clonazepam
would decrease hyperkinetic movements.

Anxiolytics
Buspirone is another anxiolytic that has been studied as a possible treatment option in TD. In a open
label study, Lori et al (1993) found that in 8 patients buspirone used in dosages of up to 180 mg/day
for 12 weeks produced a mean decrease of 4.4 from baseline in AIMS scores (p<0.01). Patients were
started on 10 mg/day and increased by 10 mg every 3 days as tolerated. The main dose limiting
adverse effects were lightheadedness, nausea, insomnia, and loose stools. The maximum dose used
was either the highest dose tolerated or 180 mg/day. This dosage is different than that previously
reported by Neppe (1989; 1990), where four case reports used a maximum of 240 mg/day of
buspirone for the treatment of TD. Buspirone is believed to mediate it's antidyskinetic effect via
either serotonergic or dopaminergic mechanisms. In addition to exerting anxiolytic effects as a
partial agonist at the 5HT1A receptor, buspirone also exerts mixed agonist and antagonists effects at
D2 receptors. In rats buspirone reverses the DA receptor subsensitivity induced by chronic
neuroleptic administration, and it is this effect that may also occur in humans due to partial agonist
effects at D2 receptors.

Anticholinergics
In a study involving 10 patients with TD of greater than a 6 month duration benztropine 2 mg IV
increased dyskinetic movements in 7 patients and reduced them in the remaining three (Moores and
Bowers 1980).

Beta-adrenergic-blocking agents
In a preliminary report (Wilbur and Kulik 1980) the _-adrenergic blocking agent propranolol
(Inderal) in a dose of 30-60 mg/day has been shown to produce marked resolution of TD within 1 to
10 days of treatment in four patients.

Vitamin E
Twelve studies have examined the effectiveness of treating TD with vitamin E (Adler et al 1999).
Nine of the twelve these studies reported that vitamin E to be more effective than placebo. Changes
in the mean AIMS score ranged from -18% to -47% for vitamin E versus +20% to -31% in the
placebo group (Lohr and Caligiuri 1996). Summary of some of the studies are presented.

Lohr et al (1988), in a double-blind placebo controlled crossover study, evaluated the efficacy of
vitamin E in the treatment of TD. Fifteen persistent TD patients were treated with vitamin E (week 1
= 400 iU/d, week 2 = 400 iU bid, weeks 3-4 = 400 iU tid). The mean reduction in the AIMS score
with vitamin E was 43%, with seven (47%) patients showing a greater than 50% reduction in the
dyskinesia.

Elkashef et al (1990) recently attempted to replicate these results using the same protocol as Lohr et
al (1988). Although the results were statistically significant, they were less impressive than those of
Lohr et al (1988) with a decrease in AIMS score of 21% from 8.56 to 6.75 between placebo and
vitamin E. Five of the eight patients studied achieved the a priori definition of a "good response" to
vitamin E, a 30% decrease in AIMS score. Shriqui et al (1992) compared vitamin E 1200 IU/day
with placebo in a 6-week double-blind randomized crossover study of 27 patients with tardive
dyskinesia. Vitamin E showed no differences from placebo in the treatment of tardive dyskinesia.
Both treatments produced the similar AIMS ratings after six weeks of treatment. A recent NIMH
study (Egan et al 1992) administered up to 1600 IU/day of vitamin E for 6 weeks in a double-blind,
placebo-controlled crossover study. In the 18 patients with significant vitamin E levels, there were
no significant differences between AIMS scores after receiving vitamin E and AIMS scores after
receiving placebo. However, in the nine patients who had tardive dyskinesia for 5 years or less
significantly lower AIMS scores after receiving vitamin E than after receiving placebo were
observed. Thus vitamin E had a minor beneficial effect on tardive dyskinesia ratings in a selected
group of patients who had had tardive dyskinesia for 5 years or less. In a randomized double-blind
controlled study Adler et al (1993a) treated 28 patients with tardive dyskinesia with either placebo or
vitamin E 1600 IU/d for 8-12 weeks. According to the AIMS ratings significantly greater
improvement resulted from vitamin E (32.5% than placebo (-3.0%). A subsequent 36 week trial of
Vitamin E 1600 IU/d followed by 12 weeks of placebo treatment found that although the vitamin E
treatment reduced the mean AIMS scores by 21%, placebo substitution resulted in the scores
returning to baseline (Adler et al 1993b).

Lohr and Caligiuri (1996) using a double-blind placebo controlled parallel design randomized 35
patients (29 schizophrenics) to vitamin E 800 IU bid or placebo for 2 months. The mean modified
AIMS score decreased 24% in the vitamin E group in contrast to 1% in the placebo group. When
patients were divided according to duration of TD, patients with TD of < 5 years duration had a 35%
decrease in the AIMS score. In contrast, patients with TD present for > 5 years had only a 11%
decrease in the AIMS score (p < 0.02).

The most recent and largest controlled trial of vitamin E for tardive dyskinesia involved 158 patients
from nine centers (Adler et al 1999). Patients were randomized to double-blind treatment with either
vitamin E 1600 IU/day or placebo for one year. No significant effect of vitamin E was observed. The
authors suggest that this negative finding is likely a result of differences between this patient
population and those in previous studies. Furthermore, the authors cite a trend in prescribing
practices towards the use of atypical antipsychotics and lower doses of typical antipsychotics, which
may minimize the potential benefit of vitamin E.

There is considerable doubt concerning the efficacy of vitamin E in the treatment of TD. However,
the relative safety of this agent increases the likelihood of clinicians to consider a trial. An adequate
trial of vitamin E should consist of at least 1600 IU/day for 3 months. It is important that the
clinician be committed to stopping vitamin E therapy if a clear benefit is not observed. The
monitoring of AIMS scores at baseline at subsequent visits can aid the clinician in determining
efficacy.

The positive effects of vitamin E in TD are thought to be related to vitamin E's effect as a lipid
soluble antioxidant. According to this theory, free radicals (highly reactive chemical species with an
unpaired outermost electron) cause tissue damage leading to a lesion that results in TD. As an
antioxidant, vitamin E functions as a free radical scavenger to prevent the resulting structural
damage.
The prophylactic efficacy of vitamin E in the prevention of TD has been speculated but not
demonstrated in controlled trials.

REVERSIBILITY OF TARDIVE DYSKINESIA

The older literature would lead one to conclude that in the majority of patients with TD the
syndrome is permanent or irreversible. However, this is not necessarily the case. The earlier TD is
diagnosed and the neuroleptic is discontinued, the better is the prognosis for reversal of the disorder.
Thus, not surprising are the reports in young adults, where TD disappeared within several weeks
after the early withdrawal of the drug.

Although the first report of TD by Uhrbrand the Faurbye (1960) described TD as irreversible, it was
only persistent in 11 of 17 (65%) of the patients and they were only followed-up for between 4 to 22
months after discontinuing the drug. There is actually a report that describes a case of a patient
whose TD reversed itself 14 years after discontinuing the neuroleptic. Itoh et al (1981) identified 19
patients with apparently irreversible TD and followed these individuals for 5 years. They observed a
slow amelioration of the TD in the majority of the patients and no worsening of the TD in any of the
patients. Significantly all of the patients less than 60 years old showed improvement.

In the early stages of AP withdrawal several clinical courses can be initially expected, i.e.,
improvement, worsening, no change, but then slow gradual reduction in the symptomatology is
observed in most cases. The studies that have examined the question of whether TD is reversible or
not demonstrate different findings depending on their length of follow-up. If the evaluation took
place 2 to 5 years after discontinuation of the neuroleptic, 50 to 90% of patients are found to show an
improvement of at least 50% on the AIMS. In conclusion, it is now accepted that TD symptoms can
disappear or improve greatly in about 60% of patients during the course of 2-3 years, which reduces
the group of irreversible TDs to the number of spontaneously occurring dyskinesias (Driesens 1988).

In a ten year TD outcome study, Gardos et al (1994) found that the overall prevalence of TD did not
change significantly in 63 outpatients using neuroleptics during the study period. At baseline the
prevalence of TD was 30.2%, at 5 years it was 36.5%, and at 10 years of follow-up it was 31.7% . Of
interest is that of the 44 patients who started the study with no TD, 72.7% showed a decrease in
AIMS scores at 10 years, and 27.3% developed TD with mean AIMS scores similar to those patients
with chronic TD over the last 10 years. Also, of the 19 patients at baseline who had TD, 42.1%
continued to experience TD 10 years later, while 57.9% had a remission of their TD
symptomatology. TD was not found to be significantly related to neuroleptic treatment or to age. The
authors of this study concluded that this study provides evidence for the long term stability of TD
and for the feasibility of neuroleptic maintenance therapy for chronic psychotic patients with TD.

Finally, pharmacotherapy studies done in TD are extremely difficult to interpret. This is because
short-term clinical observation periods of only a few weeks or months are employed. Even if there is
any improvement from the drug, usually the symptoms reappear after discontinuing the drug. This
makes it extremely difficult to impossible to evaluate the long-term usefulness of any of the
potentially beneficial therapies. Thus long-term treatment studies are necessary in the future to
legitimately access the role of the various drugs in the treatment of TD.
PREVENTION OF TARDIVE DYSKINESIA

Gerlach and Casey (1988) recommend the following guidelines to minimize the risk of TD.

1. Restrict the use of neuroleptics to the treatment of acute psychosis and the positive symptoms of
SP. Do not treat sleep disorders and anxiety with APs.

2. Be especially judicious about the use of APs in elderly patients with OBS.

3. The anti-DA effect can be limited by the use of the smallest AP dose administered for the shortest
treatment period given over the longest dosing interval.

4. Use an neuroleptic with low anti-DA activity, e.g. clozapine and olanzapine. Use benzodiazepines,
carbamazepine, lithium, or propranolol as adjunctive agents to allow the AP dose to be reduced to
the lowest possible level.

5. There is no evidence that depot neuroleptics produce a greater risk of TD than oral neuroleptics.
However, be sure to titrate the dose downward.

6. Acute EPS must be avoided. Keep in mind that anticholinergic agents do not increase the risk of
TD.

7. "Drug holidays" should be avoided since they do not decrease and may even increase the risk of
TD.

8. Cholinergic agonists (deanol, physostigmine, choline, lecithin), GABA agonists, post-synaptic DA

agonists, peptides, lithium, and papaverine have no significant effects in the treatment of TD.

TABLE 1: The Differential Pharmacology of Tardive Dyskinesia

Agents that suppress tardive

specific agents
dyskinesia

Butyrophenones, clozapine, metoclopramide (Karp 1981), papaverine

Dopamine antagonists
(mechanism uncertain), phenothiazines, bromocriptine, pimozide

Dopamine D2 Agonists Buspirone

Amine-depleting agents Reserpine, tetrabenzine

Blocker of catecholamine
Alpha-methyldopa, Alpha-methyltyrosine (AMPT)
synthesis

Blocker of catecholamine Lithium salts

release

Cholinergic agents Deanol (mechanism uncertain), physostigmine, choline and lecithin

Progabide (Bartholini 1983), valproic acid (mechanism uncertain),

GABA agonists
baclofen (mechanism uncertain), iazepam, clonazepam

Anticholinergic agents
Benztropine, trihexyphenidyl
(Moore and Bowers 1980)

Alpha-methyldopa, Amantadine, Anticholinergics Antihistamines,

Agents with variable, Apomorphine, Barbiturates, Benzodiazepines, Methylphenidate,
negligible, or uncertain
effects Penicillamine, Physostigmine, Pyridoxine (B6), Tryptophan, a-
tocopherol (Vitamin E)

Agents that worsen tardive Anticholinergic agents, Antiparkinson agents (e.g., benztropine),
dyskinesia Dopamine agonists, Amphetamines, L-DOPA

Newer investigational agents

Endopioids, Substance P, Cholecystokinin, Ceruletide, Neurotensin,
(peptides) (Blurn and
Cyclo-Leucine-Glycine
Korczyn 1983)

Some drugs appear in more than one category, reflecting ambiguity in the literature.

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