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Treatment of Tardive Dyskinesia
by Michael F. Egan, Jose Apud, and Richard Jed Wyatt
Although the new generation of atypical antipsychotic
agents could some day eliminate concerns about tardive dyskinesia (TD), this disorder remains a significant clinical problem for both patients and physicians.
Fortunately, many, if not most, cases of TD are mild.
For patients with mild to moderate TD, therapeutic
efforts are primarily directed at minimizing neuroleptic exposure or, when possible, changing to atypical
agents. Most cases of TD do not seem to progress, suggesting that the risk of remaining on typical neurolepHcs is probably small. Patients with moderate to severe
forms of TD present greater challenges. These patients
frequently require medication to suppress their dyskinesias. A variety of suppressive agents have been tried
with limited success. No treatment strategy has
emerged that is clearly superior or even successful in
most patients. Increasing doses of typical neuroleptics
may be useful for short-term suppression; however,
the long-term efficacy and risk of this strategy have
not been studied carefully. Data on atypical neuroleptics are scant. Clozapine's short-term suppressive
effects seem, at best, weak, but patients may improve
with long-term treatment Medications with relatively
few side effects that may have suppressive efficacy for
some patients include calcium channel blockers,
adrenergic antagonists, and vitamin E. Gammaamino-butyric acid agonists agents and dopamine
depleters are frequently useful, but have troubling side
effects of their own. A variety of other medications
have been employed, but are not well studied. For
patients with tardive dystonia, anticholinergic agents
or botulinum toxin has been particularly effective.
Efforts to understand the neurobiology of TD may
shed light on this persistent clinical conundrum.
Schizophrenia Bulletin, 23(4):583-609,1997.
HistoryFive years after the introduction of chlorpromazine
(Delay and Deniker 1952), Schonecker (1957) described
what were probably the first reported cases of TD: After 2
to 8 weeks of exposure to chlorpromazine, three elderly
women developed lip-smacking dyskinetic movements.
TD was first described in the American literature in 1960
(Kruse 1960). Several years later, Hunter et al. (1964)
described dyskinesias in 13 female inpatients with chronic
psychiatric illness, all of whom had been treated with phenothiazines. The notion that TD was uncommon persisted
until studies in the late 1960s began to reveal relatively
high prevalence rates. General acceptance of the association of TD with long-term neuroleptic treatment came in
the early 1970s. The first therapeutic trials for TD followed shortly thereafter (Kazamatsuri et al. 1972a,
19726; Jeste and Wyatt 1982a). In the 1970s, reports of
TD in children and of severe disabling TD in adults
Reprint requests should be sent to Dr. M.F. Egan, Neuropsychiatry
Branch, NIMH Neuroscience Or., St. Elizabeths Hospital, 2700 Martin
Luther King, Jr. Ave. SE, Washington, DC 20032.
The introduction of neuroleptics in 1954 for the treatment
of psychotic disorders was a major landmark in medicine.
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Although the clinical efficacy of these agents was established quickly, the subsequent discovery of a sometimes
persistent, involuntary movement disorder, tardive dyskinesia (TD), that was associated with long-term administration led to more cautious use. The introduction of
clozapine and other putative atypical neuroleptics has
raised hopes that TD will disappear. It is unclear, however, whether the new atypical agents will or will not produce TD. Thus, for the near future at least, clinicians will
continue to face the conundrum of how to manage
patients with TD. In this article, we discuss clinical issues
related to TD, including minimizing its risk, whether to
continue neuroleptics in patients with TD, and what medications may be useful for suppressing it.
Abstract
M.F. Eganet al.
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
age, psychiatric diagnosis (mood disorders have increased
risk), and gender. However, the findings regarding gender
are equivocal. Initial studies suggested that females had
increased rates of TD, but these findings were confounded
by differences in age or treatment variables between
groups. More recent, controlled studies find higher rates
only in women over 65, whereas gender effects are not
apparent in younger cohorts. In fact, some studies have
found greater severity in young men than in young
women (see Yassa and Jeste 1992 for a review).
The presence of diabetes, organic brain damage, and
negative symptoms (in patients with schizophrenia) also
may significantly increase risk, perhaps through their
effects on corticostriatal input or on striatal function itself
(see below). Studies that focus on patients with organic
brain damage, patients with diabetes, or the elderly suggest these factors may increase 1-year incidence rates up
to 20 percent or more.
Treatment variables associated with increased risk
include higher neuroleptic dose, number of medicationfree periods, and a history of acute extrapyramidal side
effects (EPS). The association with increased dose has not
been found in many studies, but has intuitive appeal
(Morgenstern and Glazer 1993; Kane 1995). How medication-free periods and acute EPS increase TD incidence
is unclear, but it could theoretically be mediated through
their impact on the Dj-mediated striatonigral pathway
(e.g., see Egan et al. 1994).
Since the introduction of clozapine into the United
States, it has become apparent that this unusual antipsychotic agent is rarely associated with TD, if at all (Kane
1995). This observation indicates for the first time that it
is possible for a medication to have full antipsychotic efficacy while not causing TD. Unfortunately, the use of
clozapine has been limited severely by a variety of other
side effects, such as agranulocytosis. As a consequence,
new medications have been designed to mimic clozapine's therapeutic profile. Several such putative, atypical
agents have recently been tested in relatively brief clinical
trials and appear to be promising. These agents, which
include risperidone, olanzapine, seroquel (Fleischhacker
et al. 1996), sertindole, and ziprasidone, seem to cause
fewer acute EPS than older "typical" agents. It is unclear,
however, whether their long-term use will be associated
with a lower incidence of TD.
Estimates of the prevalence of TD have ranged from
0.5 to 62 percent (Kane 1984; Yassa and Jeste 1992).
Several factors may complicate these estimates and
explain differences among studies. These factors include
variability of diagnostic criteria, assessment methods, and
the duration of neuroleptic exposure; differences in
patient age and gender; and the possibility of coexisting
medical and neurological illnesses. Studies reported in the
1980s have estimated the average prevalence to be about
30 percent (Baldessarini et al. 1980; Casey and Hansen
1984; Kane et al. 1985; Chouinard et al. 1988).
Data on incidence provide a more accurate estimate
of risk per year of exposure to neuroleptics. These data
have been generated from several rigorous, large-scale,
prospective studies. Results indicate that the average
yearly rate of developing TD is about 5 percent per year
for the first several years. The cumulative 5-year incidence rate appears to be 20 to 26 percent (Morgenstern
and Glazer 1993; Kane 1995). It is unclear whether the
risk levels off after 5 years or continues to increase linearly. Glazer et al. (1993) have suggested that the risk
may indeed be linear for 10 years or longer, with the 10year risk estimated to be 49 percent and the 25-year risk
to be 68 percent.
Although one hopes that the new generation of atypical neuroleptics will eliminate TD, this promise has yet to
be fully realized. Many patients continue to develop and
suffer from TD. In addition, for the near future, many
patients will probably continue to depend on typical neuroleptics. Thus, TD remains a therapeutic conundrum. The
challenges facing clinicians include how to minimize the
Epidemiological studies have uncovered a variety of
risk factors that increase the chances of developing TD
(e.g., see Kane 1984; Waddington 1987; Morgenstem and
Glazer 1993). Demographic risk factors include increased
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(Keegan and Rajput 1973; Tarsy et al. 1977; Casey and
Rabins 1978) began to appear (Tarsy 1983).
Although epidemiological data indicate neuroleptic
exposure as the most significant etiological factor in the
development of TD, some authors have continued to question this relationship (Owens et al. 1982; Waddington
1986). For example, in a study comparing chronic schizophrenia inpatients treated with neuroleptics with a neuroleptic-naive group, Owens et al. (1982) did not find a
significant difference between prevalence rates of spontaneous dyskinesia (53.2%) and TD (67%). When the data
were reanalyzed adjusting for a difference in the age of
the two groups, a slightly higher prevalence in the neuroleptic-treated patients was found (Owens 1985). More
recently, Fenton et al. (1994) found that the prevalence of
spontaneous orofacial dyskinesias was 15 percent among
patients with schizophrenia who had never been on neuroleptics. This study highlights the difficulty of distinguishing spontaneous dyskinesias from TD in any given
patient. Despite the presence of spontaneous dyskinesias
in patients with schizophrenia, epidemiological studies
(Kane 1984) strongly suggest that neuroleptics produce
dyskinesias in patients with a wide variety of psychiatric
diagnoses.
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Treatment of Tardive Dyskinesia
risk of TD and what to do with patients once they develop
it.
Prevention and TD
The mainstay of TD prevention has traditionally been to
limit neuroleptic exposure when possible. Unfortunately,
the best treatment for many psychiatric disorders is the
long-term administration of neuroleptics. For patients
who require neuroleptics, most experts recommend use of
the smallest effective dose (American Psychiatric
Association Task Force 1992). However, the idea that a
higher dose has a significant impact on the incidence or
severity of TD has intuitive appeal, but limited empirical
support (American Psychiatric Association Task Force
1992; Kane 1995). Most studies have actually failed to
find such a relationship. Those that have are often criticized for methodological inadequacies (Kane and Smith
1982; Kane et al. 1983, 1986; Kane 1995). A recently
published study that has addressed some of the typical
methodological pitfalls suggested that each increase in
dose equivalent to 100 mg chlorpromazine is associated
with a 5 percent increase in the chance of developing TD
(Chakos et al. 1996). Conversely, the risk of using very
low doses is that relapse rates are higher (Johnson et al.
1983; Kane et al. 1983; Marder et al. 1987). For longterm treatment, intermediate doses (e.g., 400 to 900 mg
chlorpromazine equivalents) may be as effective as the
higher doses often used in acute settings (e.g.,
Baldessarini and Davis 1980; Van Putten and Marder
1986; American Psychiatric Association Task Force
1992).
Intermittent treatment or the use of drug holidays has
been examined as a way to reduce neuroleptic exposure.
Although one study suggested that this strategy may benefit some patients (Jolley et al. 1989), it is probably not
useful for most. In fact, well-controlled studies suggest
that intermittent neuroleptic treatment is less effective
than long-term treatment in preventing psychotic relapse
(Carpenter et al. 1990), does not prevent the development
of TD (Jeste et al. 1979; Newton et al. 1989; Kane and
Marder 1993), and may even increase the likelihood of
developing TD (Jeste and Wyatt 19826). One report found
that depot neuroleptics have a higher tendency to cause
TD (Gibson 1978), but this finding requires additional
study. Such an association could be due to poor compliance and the subsequent intermittent treatment of patients
who are given depot preparations. The long-term use of
neuroleptics is indicated primarily for patients who
demonstrate a clear therapeutic response. Some patients
can be maintained on other agents that are much less
likely to produce TD. These agents include lithium, anti-
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convulsants (e.g., carbamazepine and valproic acid), tricyclics, and benzodiazepines.
A second, emerging strategy is to use neuroleptics
that may have a reduced propensity to cause TD.
Clozapine, as described earlier, has a minimal risk of producing TD; however, many other side effects limit its use.
Given the risk of agranulocytosis, most experts continue
to recommend clozapine as a second-line agent for
patients who are treatment refractory or who develop
moderate to severe TD. Of those who develop moderate
to severe TD, some will not respond as well to clozapine
as they do to other neuroleptics.
Risperidone is the first of the new generation of putative atypical neuroleptics. Clinical and preclinical studies
indicated that it is less likely to produce acute EPS
(Klieser et al. 1995). Because lower acute EPS liability
has been hypothesized to be associated with a lower risk
of producing TD, such results are encouraging (Casey
1989). Recent case reports, however, indicate that risperidone can induce TD (Buzan 1996; Daniel et al. 1996;
Woemer et al. 1996). In one case, a schizophrenia patient
had been medication-free for 6 months before risperidone
was started but developed abnormal movements after 1
year on risperidone (Woerner et al. 1996). No controlled
studies on the incidence of TD induced by risperidone are
available, and such long-term data are critical for assessing risperidone's risk of inducing TD compared with older
typical agents.
The development of additional atypical neuroleptics
is proceeding rapidly. Olanzapine and sertindole have
been approved recently by the Food and Drug
Administration and released. Phase II and III studies convincingly demonstrated that both medications are very
effective in treating psychosis and have a low incidence of
EPS (Beasley et al. 1996; Schulz et al. 1996; Tollefson et
al. 1996). With such limited use, it is difficult to predict
whether they will assume their touted position as the medications of first choice for the treatment of psychosis. In
preclinical studies, sertindole produced dose-related EPS
in Cebus monkeys, but it was also effective in suppressing
spontaneous dyskinesias in other monkeys (Casey 1996),
suggesting that it might be effective in suppressing TD.
Of course, antipsychotics that induce EPS and suppress
dyskinesias also have the potential to produce TD.
Nevertheless, the introduction of these two new atypical
neuroleptics and indeed of the whole new generation of
agents to come is perhaps the most exciting development
related to TD in decades. Likely their use will become
widespread.
A third, untested strategy is the prophylactic use of
protective agents to reduce the incidence of TD. Data
using animal models indicate that antioxidants, such as
vitamin E (Klugewicz et al. 1996) and GM1 ganglioside
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
M.F. Egan et al.
Management of Patients With TD
When symptoms of TD first appear, a thorough medical
evaluation should be done, including a physical and neurological examination, laboratory testing, and a review of
the differential diagnosis (Hyde et al. 1991). Fortunately,
the incidence of organic disorders masquerading as TD
seems to be very low (Woerner et al. 1991). The next
issue is whether neuroleptics should be continued. Most
published recommendations suggest that drug withdrawal
or marked dose reduction, when possible, is indicated; the
likelihood of psychotic relapse, however, is fairly high—a
major risk of this approach. A third issue is whether additional medications are needed to suppress TD. Often, mild
to moderate symptoms are either unnoticed or have little
impact. Those for whom suppressive therapy is needed
can choose from several mildly to moderately successful
medications.
It is helpful to involve both patients and their family
from the outset so that informed decisions can be made
and documented. Patients educated with printed information sheets (Wyatt 1995) seem to be better informed than
those educated verbally (Kleinman et al. 1989). Routine
monitoring of TD is essential to track symptomatic
changes and response to medications. The most popular
rating procedure is the Abnormal Involuntary Movement
Scale (AIMS; Guy 1976) examination. Ratings should be
performed every 4 to 6 months on patients with TD and
perhaps more often when medication changes are made.
Moreover, an examination should also be performed at
least semiannually on patients at risk for developing TD.
(Gardos and Cole 1983; Casey and Gerlach 1986; Gardos
et al. 1988, 1994; Gerlach and Casey 1988; Bergen et al.
1989). This finding is supported by epidemiological studies indicating that the prevalence of moderately severe TD
is roughly 6 to 10 percent of patients with TD or about 4
percent of patients treated with neuroleptics (Kane et al.
1988; Yassa et al. 1990). The prevalence of very severe TD
is probably lower than these figures, but estimates are difficult to obtain (Gardos et al. 1987). By far the most common course for TD is a waxing and waning of mild to
moderate symptoms over many years (Barnes et al. 1983;
Robinson and McCreadie 1986; Gardos et al. 1988;
Bergen et al. 1992; Kane 1995). Roughly 50 percent of
patients have recurrent symptoms with neither marked
progression nor extended remission. Although estimates
vary among studies, many suggest that roughly 10 to 30
percent will have a reduction in movements or full remission, and another 10 to 30 percent will show some degree
of worsening. These data suggest that, for many patients,
continued treatment with neuroleptics after the development of TD is a reasonable option.
Risk factors have been examined in an attempt to
identify which patients will likely show progression or
persistence of TD with continued treatment. In general,
these factors are similar to the risk factors for developing
TD (however, see Kane 1995). They include age (Smith
and Baldessarini 1980), gender, and exposure to anticholinergic agents. Increasing age has been associated
with fewer spontaneous remissions while on medication
and less improvement after medications are withdrawn.
Regarding the effect of gender, the literature is divided.
Many suggest that female gender is associated with increased risk and persistence, although the opposite has also
been found (Bergen et al. 1992; Yassa and Jeste 1992;
Yassa and Nair 1992). Other risk factors include duration
of exposure to neuroleptics, diagnosis (worse with organic
brain syndromes and affective disorders), duration of TD
(Gardos and Cole 1983; Casey and Gerlach 1986; Glazer
et al. 1991; Bergen et al. 1992; Yassa and Nair 1992), and
frequent on-off manipulations (Kane 1995). Overall, these
data suggest that efforts to reduce or discontinue neuroleptics might be directed toward those at greater risk.
Neuroleptic Withdrawal. Although continued neuroleptic treatment may be the safest course for many
patients with TD, such as those with a lower risk profile,
this continuation must be weighed against the potential
benefits of withdrawal. Indeed, many experts (American
Psychiatric Association Task Force 1992) recommend
neuroleptic withdrawal, with the critical caveat that it
should be done only in patients who can tolerate it. In the
first several weeks after withdrawal, TD often worsens
Natural Course of TD. Data from several long-term
studies indicate that progression from mild to severe TD, if
it does occur, happens only in a small percentage of cases
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(Andreassen and Jorgensen 1994), reduce dyskinesia
scores in animals treated with long-term haloperidol
decanoate. Vitamin E has also been shown to attenuate the
development of D 2 supersensitivity (Gattaz et al. 1993),
likely an important step in the genesis of TD. Clinical
studies in humans have typically found that vitamin E
reduces the severity of preexisting TD (see below). These
observations suggest that prophylactic treatment with vitamin E (1,200 to 2,000 IU/day) could reduce the risk of
developing TD. Although no human studies are available
to support this strategy, long-term use of vitamin E has little risk. Lithium has also been suggested to reduce the
incidence of TD (Cole et al. 1984), although recent data
are conflicting (Kane et al. 1986; Ghadirian et al. 1996),
and the routine use of lithium for TD prevention is uncommon.
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Treatment of Tardive Dyskinesia
(Gardos et al. 1984; Dixon et al. 1993). For example,
Gardos et al. (1984) withdrew neuroleptics from 33
patients and noted significant increases in dyskinesia
severity and dysphoria in 33 percent, resulting in their
early removal from the study. Glazer et al. (1989) withdrew neuroleptics for 3 weeks in 19 patients and noted a
relapse of psychosis in 26 percent and TD worsening in
53 percent. The magnitude of TD exacerbation in this
study is unclear.
After the withdrawal of neuroleptics, TD does seem
to improve over the long term despite early exacerbation.
In a comprehensive review of 20 studies, Jeste and Wyatt
(1979) reported that 36 percent of patients withdrawn
from neuroleptics showed improvement. Additional studies tend to support their conclusion. Jus and colleagues
(1979) found improvement in 49 of 62 patients by slowly
tapering neuroleptics over 4 years. Improvement has been
seen up to 5 years after the cessation of treatment
(Klawans et al. 1984). In a mostly nonpsychotic patient
group, Fahn (1985) reported improvement in 13 of 22
patients over a 2- to 4-year period. The 22 patients in the
Fahn (1985) study had concurrent treatment with reserpine or tetrabenazine. In contrast, Glazer and colleagues
(1990) followed 49 patients for an average of 40 weeks
after the discontinuation of neuroleptics. Complete remission was rare (2%), and dyskinesia severity decreased in
only 20 percent. The rate of psychosis relapse for patients
with schizophrenia approached 50 percent (Glazer et al.
1984, 1990). One difficulty with drawing conclusions
from these studies is that many were unblinded or not
well controlled. Nevertheless, they suggest that neuroleptic withdrawal is risky but can result in long-term remission of TD in some patients (see also Casey and Gerlach
1986).
The degree of improvement during withdrawal may
be related to the same risk factors associated with the
development of TD and with improvement during continued treatment. These factors include age, with patients
over 65 (Smith and Baldessarini 1980) showing little
improvement; organic brain damage; number of extended
medication-free periods; and length of neuroleptic treatment (Jeste and Wyatt 1979). If drug withdrawal is
attempted, very gradual tapering seems less likely to
worsen psychosis. A variation of this strategy is an initial
increase in neuroleptic dose to suppress TD, the very gradual withdrawal (e.g., 10% per month). This strategy has
worked in several cases of moderate to severe TD with
dystonic features (Kleinman, personal communication,
May 1996) but has not been studied in controlled trials.
Although withdrawal should be considered, many
patients will not be able to tolerate this approach. The
risks associated with neuroleptic withdrawal include psy-
chotic decompensation (Gilbert et al. 1995) and an
increased likelihood of injury to self or others. Furthermore, untreated patients with schizophrenia may have a
worse long-term prognosis than patients treated with neuroleptics (Wyatt 1991). Over the long term, some patients
initially withdrawn from neuroleptics have actually ended
up receiving higher total doses of neuroleptics to cope
with symptom exacerbation (Johnson et al. 1983). Many
factors figure in predicting the success of neuroleptic
withdrawal, such as a history of dangerous behavior, current stressors, the living and working environments, and
family relationships.
Who Needs Suppressive Therapy? In our experience,
suppressive therapy should be considered if TD poses
health risks, impairs function, or is otherwise bothersome
to the patient, for example, if it creates problems with
breathing, eating, walking, or sleeping. Many patients
with moderate to severe TD are not aware of their symptoms. Furthermore, a moderate or severe rating on an item
of the AIMS scale does not necessarily mean a patient is
functionally impaired or disfigured. Suppression in some
cases may not be worth the risk. Assessment by an occupational or physical therapist can sometimes give insight
into functional impairment and may suggest nondrug
strategies to cope with disabilities.
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Switching to Atypical Neuroleptics. In lieu of typical
neuroleptics, alternate therapeutic agents can be considered. Most important, one must consider switching
patients to an atypical neuroleptic. These medications
offer the advantage of clear antipsychotic efficacy and the
significant possibility of reduced TD liability, so it is reasonable to conclude that patients with TD will have a
greater likelihood of TD remission on atypical neuroleptics. Unfortunately, this conclusion has not been demonstrated clearly in clinical studies and remains conjectural.
As a result, one must clearly delineate the benefits and
risks to patients of the use of atypical neuroleptics. In particular the possible benefits of TD reduction from clozapine may not be worth the risk of sedation, seizures, or
agranulocytosis for many patients. The fact that some
patients do better on typical agents than they do on clozapine or risperidone is also a consideration.
Although a feeling of therapeutic nihilism may creep
in regarding patients with TD who require continued
treatment with typical neuroleptics, one action that could
benefit them is to ensure adherence (limiting drug-free
periods) and to vigorously treat substance abuse disorders.
Anecdotal reports suggest that patients who abuse such
stimulants as cocaine may develop more severe TD symptoms.
Schizophrenia Bulletin, Vol. 23, No. 4,1997
M.F. Egan et al.
Dopamine Supersensitivity. The dopamine supersensitivity hypothesis of TD was first proposed in 1970 by
Klawans et al. Based on the similarity between L-dopainduced dyskinesias and TD, he suggested that chronic
neuroleptic treatment produced supersensitive striatal
dopamine receptors, similar to denervation-induced supersensitivity found in peripheral muscles. Since then,
dopamine supersensitivity has been an important theoretical construct guiding TD research. Several inconsistencies, however, suggest that it cannot explain entirely the
pathogenesis of TD. First, supersensitivity occurs within 2
to 4 weeks of initiating neuroleptic treatment, whereas TD
develops after long-term use. Second, in animal studies,
most subjects develop supersensitivity, in contrast to only
the minority of patients who develop TD. Finally, supersensitivity disappears within weeks after neuroleptics are
withdrawn, whereas TD can persist for months and years.
The original version of this idea has been supplanted with
the notion that D 2 supersensitivity may be a necessary
first step in a path that ultimately leads to the development
of TD. Interestingly, clozapine does not induce D 2 supersensitivity at standard doses.
A variety of risk factors for severe TD have been
examined, such as number of medication-free periods
(Yassa et al. 1990; but see Gardos et al. 1987); however, it
is difficult to predict who will develop this condition.
Anecdotal reports suggest that severe TD comes on
quickly, developing over the course of several months,
rather than being the result of a relentlessly progressive
process that develops over a long period of time with continued neuroleptic exposure. Several authors have noted
that increased blinking or blepharospasm may be a prodromal symptom (Gardos et al. 1987; Wojcik et al. 1991).
Yet, certainly many patients with increased blinking do
not go on to develop severe TD. Treatment of severe TD,
as with less pronounced forms, often requires continued
neuroleptic treatment with the serial addition of a variety
of suppressive agents.
A related idea implicates the balance between acetylcholine and dopamine and is supported, for example, by
the observation that Parkinsonian symptoms are alleviated
by dopamine agonists or cholinergic antagonists. Higher
doses of dopamine agonists can also induce dyskinesias.
If dopamine and acetylcholine work in the opposite direction, then cholinergic agonists could alleviate dyskinesias.
Although this idea has been heuristically useful, cholinergic potentiation as a treatment for TD has been largely
unsuccessful.
GABA Depletion. As a result of deficiencies in the
dopamine supersensitivity hypothesis, considerable attention has been focused on the GABA system (Mao et al.
1977; Gale 1980; Fibiger and Lloyd 1989). Several studies point to decreased GABA turnover or increased
GABA binding sites in one or more areas of the basal
ganglia in rodents and primates after chronic neuroleptic
treatment. This reduction in turnover is most prominent in
animals that have dyskinesias (Gunne et al. 1984).
Anderson and colleagues (1989), in a very small human
postmortem study, found a significant decrease in subthalamic glutamic acid decarboxylase activity—the rate-limiting enzyme in the metabolic pathway for GABA—in
patients with TD compared with non-TD patients. Other
attempts to assess GABAergic neurotransmission in living
patients have also suggested that individuals with TD
have particular abnormalities (Thaker et al. 1987, 1988).
GABAergic neurons play a central role in the subcortical
regions that generate abnormal movements. Further study
Pathophysiology of TD
Several comprehensive reviews (Jeste and Wyatt 1982a,
19826; Jeste et al. 1988) have surveyed most of the published data on the treatment of TD from the 1970s and
1980s. In general, the goal of most studies was to demonstrate short-term reduction or suppression of dyskinetic
symptoms.
There are no empirically validated guidelines to follow
when choosing a suppressive agent. In general, therapeutic
trials have attempted to manipulate one of the following
neurotransmitter systems: dopamine, gamma-amino-butyric
acid (GABA), acetylcholine, norepinephrine, and serotonin. These systems have received the most attention, in
part due to theories about the pathophysiology of TD.
Although an extensive review of this topic is beyond the
scope of this article, a brief description of leading ideas
may be instructive.
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Patients with moderate to severe TD are the most
likely candidates for supressive treatment. Severe TD is
most common in younger men (under age 40) and older
women (over 65) and often has a component of dystonia.
A variety of functional problems can be produced by
severe TD, depending on the area of the body that is
affected. For example, truncal TD can interfere with walking, sitting, and even sleeping, although TD disappears for
the most part once a patient is able to fall asleep.
Orofacial dyskinesia can be particularly disfiguring,
sometimes interfering with eating and adequate nutrition,
and has been linked to reduced life expectancy
(McClelland et al. 1986). Respiratory dyskinesia, often
overlooked, can produce a variety of respiratory signs and
symptoms, including irregular respiratory rate, tachypnea,
and grunting (Chiu et al. 1991; Nishikawa et al. 1992).
Patients with severe TD are at risk for aspiration.
Treatment of Tardive Dyskinesia
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
of this system has led to more detailed notions of which
components may be abnormal.
Substantia
Nigra
Thalamus
Excitatory corticostriatal projections regulate striatal outflow.
Dopamine projections from the substantia nigra, pars compacta,
modulate striatal neuronal activity via dopamine D1 and D 2 receptors. These receptors seem to be segregated into the two major
striatal outflow tracts: the D2-mediated striatopallidal or "indirect"
loop and the D.,-mediated striatonigral or "direct" loop. These
loops ultimately terminate in the globus pallidus, interna, and the
substantia nigra, pars reticulata. These two regions modulate thalamic activity via gamma-amino-birtyric acid (GABA)ergic inhibitory
projections. ACH = acetylcholine; ENK = enkephalin; SP = substance; DYN = dynorphin.
Striatal Dysregulation. Studies on the basal ganglia
and movement disorders suggest that the final common
pathway for dyskinesias is increased activation of the D,mediated striatonigral (or "direct") pathway (Albin et al.
1989; Crossman 1990; DeLong 1990). These medium
spiny striatal neurons are primarily GABAergic but also
use several neuropeptides as cotransmitters, including
substance P and dynorphin. The direct pathway inhibits
neurons in the substantia nigra, pars reticulata, and its
associated nucleus, the internal segment of the globus pallidus (figure 1). These areas, in turn, project to the thalamus, which is thought to act as a filter for cortical input.
The classical theory is that increased inhibition of the
inhibitory GABAergic nigral/pallidal outflow produces a
net increase (or loss of inhibition) of thalamocortical projections. The other major outflow tract from the striatum
(Albin et al. 1989; Crossman 1990; DeLong 1990), the
D2-mediated striatopallidal (or "indirect") loop, may also
play a role. The medium spiny neurons of this pathway
are also GABAergic and use the neuropeptide enkephalin
as a cotransmitter. Increased activity of this pathway,
which results from blockade of the inhibitory D 2 receptors, may facilitate the expression of D : overactivation
(Egan et al. 1994). Indeed, animal studies suggest that
haloperidol increases D] agonist-induced dyskinetic
mouth movements in rodents.
Although the hypothesis that TD is a result of such
alterations in basal ganglia physiology remains unproved,
it suggests that a variety of neurotransmitters and receptors could play a role; for example, Dj and D 2 receptors,
cholecystokinin (CCK), neurotensin, GABA, Af-methyl-Daspartate receptors, and opiate receptors (mu, kappa, and
possibly delta). Drugs targeting these transmitter systems
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Neurotoxicity. The idea that long-term neuroleptic
treatment may have a toxic effect on the brain has led to
many studies of evidence of neuronal injury. The neurotoxicity hypothesis is particularly engaging given the persistence of TD in some cases and the similarity between
TD and degenerative diseases of the basal ganglia, such as
Huntington's. Unfortunately, most postmortem studies in
animals and patients exposed to long-term neuroleptic
treatment have been inconsistent or have suffered from
methodological problems (Christensen et al. 1970;
Pakkenberg et al. 1973; Pakkenberg and Fog 1974; Colon
1975; Gerlach 1975; Fog et al. 1976; Jellinger 1977;
Nielsen and Lyon 1978). Neuroleptics could produce
more subtle damage, however, through mechanisms other
than simple neuronal degeneration. Dopamine is metabolized by monoamine oxidase to dihydroxyphenylacetic
acid (and then homovanillic acid). A byproduct of this
reaction is hydrogen peroxide, a potent oxidant. It has
been hypothesized that hydrogen peroxide could generate
a cascade of free radicals that react with proteins, lipids,
and other cellular constituents, ultimately leading to significant neuronal dysfunction. Indeed, several groups have
found evidence suggesting that free radical formation may
occur both in rodents and humans treated with neuroleptics (e.g., Pai et al. 1994). Although stronger evidence is
clearly required, this hypothesis has led to trials of antioxidants as a treatment for TD.
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
M.F. Egan et al.
may affect TD symptoms. Unfortunately, animal studies
using such agents have generally been inconclusive, and
human studies are limited.
Suppressive Therapies for TD
Typical Antipsychotics. Neuroleptics themselves may
be effective to some degree in suppressing TD. A 1979
review of 50 studies, totaling 501 patients, found that 67
percent showed clinical improvement with neuroleptic
suppression, the highest improvement rate of any suppressive strategy (Jeste and Wyatt 1979). However, a more
recent review (Jeste et al. 1988) suggested a lower rate of
response. Suppressive effects are most pronounced in
short-term studies (Doongaji et al. 1982; Jeste and Wyatt
1982a; Perenyi et al. 1985; American Psychiatric
Association Task Force 1992), although some well-controlled studies have found that suppression is often minimal (e.g., Lieberman et al. 1988a, 19886). The therapeutic
efficacy of long-term (more than 8 weeks) suppression is
unclear, in part due to problems with study design. Most
studies have first withdrawn patients from neuroleptics
and then compared changes between neuroleptic and
placebo treatment (Roxburgh 1970; Singer and Cheng
1971; Kazamatsuri et al. 1912b, 1973; Glazer and Hafez
1990). This design may be a better measure of the neuroleptics' ability to suppress withdrawal dyskinesias than
persistent TD. Other studies were either unblinded or did
not use appropriate control groups (Roxburgh 1970;
Curran 1973; Jus et al. 1979; Smith and Kiloh 1979). Of
three particularly well-controlled studies, two found significant long-term suppression (Frangos and
Christodoulides 1975; Gerlach and Casey 1983), while
the third did not (Korsgaard et al. 1984). A fourth study
using depot neuroleptics showed brief improvement (i.e.,
1-2 days) along with increased blood levels immediately
after drug injection in 4 of 6 patients (Barnes and Wiles
1983). Although these findings are suggestive, the safety
and efficacy of increased neuroleptic dose for long-term
suppression remain questionable.
A primary concern with using higher neuroleptic
doses for suppression is the potential that TD could
become worse. Nevertheless, in severe cases with life-
Atypical Neuroleptics. In addition to their use as drugs
with lower TD liability, atypical neuroleptics, particularly
clozapine, have also been tried as suppressive agents.
Although early experience with clozapine was generally
disappointing (Gerlach et al. 1974; Gerlach and
Simmelsgaard 1978; Caine et al. 1979), more recent studies have been mixed (Lieberman et al. 1991). A description of published reports provided in table 1 includes 16
clozapine studies—7 case reports, 4 open trials, 1 single
blind, and 4 double-blind, controlled, or crossover studies.
All seven case reports, not surprisingly, found improvement: two described rapid TD suppression (Carroll et al.
1977; Meltzer and Luchins 1984), and four observed dramatic responses only after months or years (Lamberti and
Bellnier 1993; Friedman 1994; Trugman et al. 1994;
Levkovitch et al. 1995). Four open, uncontrolled trials
(Cole et al. 1980; Gerbino et al. 1980; Small et al. 1987;
Lieberman et al. 1991) also found beneficial effects with
clozapine. The most significant results were observed
after at least 4 weeks of treatment and for patients with
severe TD and tardive dystonia (Carroll et al. 1977;
Meltzer and Luchins 1984; Lieberman et al. 1991). In
most cases, TD symptoms returned to baseline after the
discontinuation of clozapine (Cole et al. 1980; Gerbino et
al. 1980; Small et al. 1987; Lieberman et al. 1991), which
suggests that TD was suppressed.
Of four double-blind, controlled or double-blind,
crossover studies, two found significant improvement
with clozapine (Simpson et al. 1978; Tamminga et al.
1994). In both positive studies, clozapine was administered for 22 to 52 weeks. In contrast, the negative studies
lasted only 3 to 5 weeks. The study by Tamminga et al.
(1994) was particularly lengthy and included a control
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The competing theories on TD have led to clinical trials
of a wide variety of medications. None has been successful in the majority of patients. As a result, one may have
to try several medications in series before finding one
with some utility. In general, selection is guided by a benefits-risk analysis, success in prior studies, potential side
effects of the suppressing agent, and interactions with
other medications.
threatening complications, increasing the dose many be the
only maneuver that will help. Higher potency neuroleptics,
such as haloperidol, may be more effective in suppressing
movements than those of lower potency, such as molindone. In patients with withdrawal TD, Glazer and colleagues (1985a) were able to suppress symptoms in 66
percent of those using haloperidol versus only 39 percent
of those using molindone. If withdrawal dyskinesias are
similar pharmacologically to persistent dyskinesias, they
may also be suppressed more effectively by high-potency
neuroleptics. Giving medications in divided doses
throughout the day has also been helpful in masking symptoms of TD. In a variation of this strategy, we have seen
improvement in several patients after stopping neuroleptic
treatment for several weeks, then restarting it at a lower
dose. This strategy has not been studied under controlled
conditions, however, and the two patients who improved
had a marked Parkinsonian tremor in addition to TD.
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Treatment of Tardive Dyskinesia
Table 1. Studies of the effect of atypical neuroleptics on tardive dyskinesia
Design
Duration
Maximum dose
Gerlachetal. (1974)
Clozapine
Double-blind, crossover
3 weeks
225 mg/day
No significant effect
Caineetal. (1979)
Clozapine
Double-blind, placebocontrolled
3-5 weeks
425 mg/day
No significant effect
Geriach and
Simmelsgaard (1978)
Clozapine
Crossover
4 weeks
62.5 mg/day
No significant effect
Carroll et al. (1977)
Clozapine
Case report
18 days
1,000 mg/day Significant improvement
Simpson etal. (1978)
Clozapine
Single-blind, placebocontrolled, double
crossover
22 weeks
523-775
mg/day
Significant improvement
Coleetal. (1980)
Clozapine
Open, uncontrolled
Up to 12
weeks or
more
100-500
mg/day
Significant improvement,
mainly after > 12 weeks
Gerbinoetal. (1980)
Clozapine
Open
4 weeks
and 12
months
4 weeks: 650 Significant improvement
mg/day; 12
at both times
months: down
to 50% of initial
dose
Meltzer and Luchins
(1984)
Clozapine
Case report
2 weeks
900 mg/day
Significant improvement
Small etal. (1987)
Clozapine
Open, uncontrolled
7 weeks
340 mg/day
Significant improvement
in only 7 of 19 patients
Van Putten et al.
(1990)
Clozapine
Case report
14 weeks
250 mg/day
Significant improvement
Lieberman et al.
(1991)
Clozapine
Open, uncontrolled
36 months
486 mg/day
(average
daily dose at
endpoint)
At least 50% improvement in 43% of patients
Lambert and Bellnier
(1993)
Clozapine
Case report
11 months
300 mg/day
Significant improvement
Friedman (1994)
Clozapine
Case report
> 3 years
350-500
mg/day
Significant improvement
Tamminga et al.
(1994)
Clozapine
Double-blind
controlled,
randomized, noncrossover
12 months
293.8±171.9 Significant improvement
mg/day
(average daily
dose at endpoint)
Trugmanetal. (1994)
Clozapine
Case report
4 years
625 mg/day
Significant improvement
Levkovitch etal. (1995)
Clozapine
Case report
48 months
450-550
mg/day
Significant improvement
Meco etal. (1989)
Risperidone
Crossover,
placebo-controlled
4 weeks
6 mg/day
No significant effect
Kopala and Honer
(1994)
Risperidone
Case report
4 weeks
4 mg/day
Significant improvement
Chouinard(1995)
Risperidone
Double-blind,
parallel
8 weeks
6-16 mg/day
Significant improvement
Reference
Drug
clozapine, lack of appropriate controls, and inconsistent
patient followup. Two noteworthy trends are that a long
duration of treatment is needed and that dystonic features
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group of 32 patients treated with haloperidol during a 12month blind treatment period. Comparison of the different
studies is complicated by the use of different doses of
Outcome
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
M.F. Egan et al.
Dopamine Agonists. In animal studies, dopamine agonists downregulate dopamine receptors and theoretically
could be useful in TD. A major drawback is that they can
initially exacerbate both TD and psychotic symptoms.
Direct (apomorphine and bromocriptine) and indirect
(amantadine and levodopa) dopamine agonists have been
tried in humans. Some positive case reports or singleblind studies have been published, but most double-blind
studies show little improvement (Jeste et al. 1988; Lieberman et al. 1989). One exception is a recent report of 35
inpatients with severe orofacial TD who showed marked
improvement on L-dopa after 3 months. Symptoms
returned when L-dopa was discontinued and again
responded when treatment was restarted (Ludatscher
1989). This study, which suffers from several methodological shortcomings, needs to be replicated in a doubleblind, crossover study but is encouraging nonetheless.
Dopamine autoreceptor agonists—for example, n-Npropyl-3-(3-hydroxyphenyl)piperidine (3-PPP)—decrease
the release of dopamine and present another possible
mechanism to treat TD. 3-PPP has been shown to improve
TD in monkeys (Kovacic et al. 1988), but it has not been
tried in humans. In low doses, apomorphine is an autoreceptor agonist, whereas in high doses it is a postsynaptic
receptor agonist. Theoretically, low doses should decrease
Dopamine Depleters. Medications that work primarily
by reducing or depleting presynaptic stores of dopamine
have sometimes been helpful in reducing TD severity.
Dopamine depleters act by several different mechanisms.
Reserpine and tetrabenazine (not available in the United
States) disrupt the storage of dopamine in presynaptic
vesicles. Alpha-methyldopa reduces dopamine synthesis
by competitive inhibition of dopa decarboxylase and the
formation of a false neurotransmitter. Alpha-methyl-paratyrosine (AMPT) also reduces dopamine (and norepinephrine) synthesis via its actions on tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis.
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Studies of dopamine-depleting medications suggest
that they may alleviate symptoms in up to 50 percent of
patients with TD. For example, using reserpine, Huang et
al. (1981) found at least 50 percent improvement in 5 of
10 patients, whereas Fahn (1985) showed improvement in
8 of 17 patients who were not taking neuroleptics.
Nasrallah et al. (1986) found improvement in 5 of 10
patients in a 4-week, double-blind study using AMPT;
only patients who remained on neuroleptics in addition to
AMPT improved. Although not all studies have found this
degree of success (Lang and Marsden 1982), previous
reviews of both uncontrolled case reports and controlled
studies support the 50 percent estimate (Jeste and Wyatt
1979; Jeste et al. 1988). For example, a review of five
studies performed from 1961 to 1977 found that tetrabenazine improved TD in 29 of 42 patients. In the same
review, 17 of 38 patients from another five reports
improved on reserpine, and 18 of 32 improved on AMPT
(Jeste and Wyatt 1979). Although larger, well-controlled
studies are needed to validate these findings, the limited
available data support the use of dopamine-depleting
medications for TD suppression. Unfortunately, side
effects, including hypotension (reserpine, alpha-methyldopa), impotence, and depression, as well as Parkinsonism and akathisia, often limit their use. Depression, a
relatively frequent side effect, has been treated successfully with concurrent antidepressant administration.
may be more responsive than dyskinetic ones (Lieberman
et al. 1991). The mixed results in controlled studies suggest that further investigations of clozapine's suppressive
properties are warranted.
If clozapine is shown to have therapeutic effects in
TD, several mechanisms could play a role. An early acute
response to clozapine suggests a suppressive effect similar
to classical neuroleptics. Longer-term improvement could
be due to a passive mechanism in which dyskinetic movements improve over time in the absence of the offending
agent. A third possibility is that clozapine has an active,
not simply suppressive, therapeutic effect on dyskinetic
movements.
Little is known about the effect of risperidone on TD.
An early, controlled study (see table 1) found no evidence
of suppression (Meco et al. 1989). More recently, a case
report found suppression of severe TD with risperidone
(Kopala and Honer 1994), and more convincingly, the
Canadian Multicenter Risperidone Study showed an antidyskinetic effect in a double-blind, placebo-controlled
trial (Chouinard 1995). Thus, risperidone could be useful
as a suppressive medication, although since it may also
induce TD (Buzan 1996; Daniel et al. 1996; Woerner et al.
1996), the risk of long-term exacerbation is unknown.
The development of new atypical antipsychotics may
provide alternatives for the treatment of TD. Olanzapine,
sertindole, seroquel, and ziprasidone have been shown to
be efficacious for the treatment of psychosis and to produce fewer EPS than traditional neuroleptics (Seeger et al.
1995; Beasley et al. 1996; Borison et al. 1996; Schulz et
al. 1996; Tollefson et al. 1996). Like clozapine, these
drugs are more effective in blocking the 5-hydroxytryptamine 2 (5-HTj) than the D 2 receptor site. In contrast to
clozapine, however, all are relatively potent D 2 antagonists. The finding that clozapine is associated with a lower
incidence of TD (Casey 1989) and may suppress TD suggests that there are important advantages to using clozapinelike medications with selectivity for the 5-HT2 receptor. However, it is unclear whether these putative atypical
neuroleptics will be effective in suppressing TD.
Treatment of Tardive Dyskinesia
Schizophrenia Bulletin, 'Vol. 23, No. 4, 1997
dopamine release and improve symptoms of TD, whereas
high doses should do the opposite. Paradoxically, one
study showed that high doses, up to 6.0 mg, reduced TD
movements (Smith et al. 1977). The usefulness of apomorphine may be limited by such side effects as nausea
and vomiting at therapeutic doses.
Anticholinergics. As mentioned above, dopamine and
acetylcholine seem to have opposite effects on behaviors
mediated by the striatum. One could predict that anticholinergics would make TD worse. Although this effect
has been found in some reports (Klawans 1973), others
have found either no change (Wirshing et al. 1989) or even
improvement in TD with anticholinergics. For example, in
an acute challenge study using intravenous administration,
Lieberman and colleagues (1988a, 1988f>) showed that
benztropine tended to decrease movements, whereas
physostigmine worsened them (see also Moore and
Bowers 1980). This finding suggests that dopamine and
acetylcholine are not simply functional antagonists in the
basal ganglia. In general, however, most data indicate that
Cholinergics. Just as anticholinergics theoretically
should worsen TD, cholinergic agonists should improve
it. Numerous studies conducted primarily in the 1970s
with several acetylcholine precursors generally yielded
disappointing results (Jeste and Wyatt 1979, 1982a).
These agents include deanol, choline, and lecithin, a naturally occurring precursor of choline. One difficulty with
interpreting these negative findings is the issue of how
such drugs like deanol actually boost central cholinergic
neurotransmission. Physostigmine, a centrally acting
cholinesterase inhibitor, has been used to investigate the
pharmacology of TD, with mixed results (Lieberman et al.
1988a, 19886; Yagi et al. 1989). An encouraging preliminary study using the cholinergic releasing agent
meclofenoxate found improvement in 5 of 11 patients
(Izumi et al. 1986). Tacrine (or THA) is a recently
released cholinesterase inhibitor primarily used for the
treatment of Alzheimer's disease. Although this agent is
clearly effective in boosting central acetylcholine neurotransmission, we are not aware of studies of its use
involving TD. While future experience may alter this surprising omission, cholinergic agents do not currently play
a significant role in the treatment of TD.
GABA Agonists. A variety of experimental and commercially available GABA agonists have been used to
treat TD, some with significant success. Jeste and Wyatt's
review (1982a) described 19 studies totaling 204 patients,
with 54 percent having greater than 50 percent improvement, making GABA agonists the most effective nonneuroleptic class of drugs reviewed. In a 1988 review of nine
additional studies, the efficacy of GABA agonists fell to
about 30 percent (Jeste et al. 1988). In contrast, a selective review of the effects of benzodiazepines by Thaker et
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Noradrenergic Antagonists. Although noradrenergic
innervation of basal ganglia structures is sparse and limited primarily to the thalamus, noradrenergic agents have
been used to treat TD. The beta-adrenergic antagonist,
propranolol, has been reported in open studies to partially
suppress TD in 11 of 15 patients (Jeste and Wyatt 19826).
In a double-blind study of four patients, two improved
with long-term treatment (Schrodt et al. 1982). Unfortunately, no larger or more recent studies are available,
and it is unclear whether or not propranolol's suppressive
effect is due to increased neuroleptic blood levels. In contrast, pindolol, another beta blocker, was unsuccessful in
suppressing TD in a small placebo-controlled study
(Greendyke et al. 1988). Clonidine, an alpha2 agonist,
decreases the release of norepinephrine by autoreceptor
stimulation and has been reported to have antidyskinetic
properties in a majority of patients (Freedman et al. 1982;
Nishikawa et al. 1984; Browne et al. 1986). Clonidine
may also have antipsychotic properties (Freedman et al.
1982) and has relatively few side effects (hypotension,
sedation). Other noradrenergic antagonists with apparent
suppressive effects are disulfiram (Jeste et al. 1986) and
fusaric acid, both dopamine beta-hydroxylase inhibitors.
Oxypertine depletes norepinephrine and dopamine and
may also improve dyskinesias (Soni et al. 1984).
Unfortunately, this line of treatment has not been pursued
in large well-controlled studies. At the present time, noradrenergic antagonists, particularly clonidine, seem to be
relatively safe and somewhat effective as suppressive
agents.
long-term treatment with anticholinergics either does not
help or may actually worsen TD (Jeste and Wyatt 1982a,
19826; Friis et al. 1983), and their discontinuation may be
helpful in up to 60 percent of patients (Jeste et al. 1988;
Yassa 1988). An important exception is tardive dystonia,
which may markedly improve with moderate to high doses
(20 mg/day and higher) of anticholinergics such as trihexyphenidyl (Artane) (Burke et al. 1982; Fahn 1983).
Anticholinergics have been also hypothesized to predispose patients to develop TD (Klawans 1976), although
this has been disputed (Yassa 1988). The issue may be
that patients exhibiting acute EPS, who are more likely to
be treated with anticholinergics, are more susceptible to
TD than patients who do not exhibit acute EPS (Keepers
and Casey 1991). Despite such theoretical considerations,
for many patients anticholinergics remain useful for acute
EPS.
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
M.F. Egan et al.
al. 1978). Baclofen seems to act primarily on GABA B
receptors, which may not be as important in TD.
In summary, among GABA agonists, benzodiazepines have been the most effective in clinical studies for
suppressing TD. On average, 58 percent of patients in
open studies and 43 percent in double-blind studies have
improved (Gardos and Cole 1995). Thus, clonazepam and
diazepam are important therapeutic options in treating
TD. Valproate and baclofen are probably less effective
and cannot be strongly endorsed. Newer agents, such as
gabapentin, have not been employed in controlled studies.
Antioxidants. One of the more interesting new treatments for TD is vitamin E, an antioxidant and free radical
scavenger. The use of this compound was originally motivated by the notion that neuroleptics produce toxic free
radicals that can cause neuronal dysfunction or cell death.
In table 2, eleven double-blind, placebo-controlled studies
have examined the effects of vitamin E (Lohr and
Caligiuri 1996). Of these, three reported no evidence of a
therapeutic effect (Schmidt et al. 1991; Shriqui et al.
1992; Lam et al. 1994). These negative studies were either
brief (2 weeks), included older patients, or studied
patients with a relatively long duration of TD. In contrast,
the other eight studies found some evidence of reduced
TD severity with doses ranging from 1,200 to 1,600 IU
for 4 to 12 weeks. Vitamin E's effects have been most
pronounced in patients with relatively recent onset (e.g.,
within 5 years) (Egan et al. 1992; Adler et al. 1993; Lohr
and Caligiuri 1996). Overall, improvement in positive
studies has ranged from 18.5 to 43 percent. In addition,
several open trials or case reports have also found evidence for vitamin E's therapeutic effects in TD or tardive
dystonia (Spivak et al. 1992; Peet et al. 1993; Coupland
and Nutt 1995). An ongoing large, multicenter study
funded by the Department of Veterans Affairs may help
clarify issues about therapeutic efficacy and subpopulations that respond favorably.
The most-studied commercially available GABA
agonists are valproate, diazepam, clonazepam, and
baclofen. A 1979 review described three studies using valproate that had mixed results (Jeste and Wyatt 1979).
Since then, three additional reports were not encouraging.
In one, 3 of 6 patients improved (Friis et al. 1983),
whereas in a second, none of 10 improved (Nasrallah et
al. 1986). In the third, a well-controlled, double-blind
study, 33 patients treated for 6 weeks with valproate were
not significantly different from 29 patients treated with
placebo (Fisk and York 1987). Diazepam, in contrast, has
been more effective. Four studies before 1979 reported
improvement in 26 of 29 patients on diazepam (Jeste and
Wyatt 1979). More recently, in a single-blind study,
diazepam was again effective in 11 of 20 patients (Singh
et al. 1983). One drawback of diazepam is that it can be
habit forming or cause sedation, depression, or, less commonly, impulsiveness and belligerence. Clonazepam is an
effective alternative. Two open studies found markedly
different results, with 42 of 42 patients benefiting in one
(O'Flannagan 1975) but only 2 of 18 improving in the
other (Sedman 1976). In a more recent, well-controlled,
double-blind study by Thaker et al. (1990), suppression
was observed in 26.5 percent of patients with choreoathetosis and 41.5 percent of patients with dystonia.
Tolerance can develop to clonazepam's therapeutic
effects, but it may be overcome by a brief withdrawal
period (Thaker et al. 1990). In a selective review of eight
studies with baclofen, Glazer et al. (1985&) noted only
two that showed significant results. In one study, 75 percent of 20 patients improved on 15 to 60 mg per day
(Korsgaard 1976), whereas in the second study, TD ratings were reduced by 40 percent in 18 patients (Gerlach et
Despite the positive data regarding vitamin E, several
caveats are indicated. First, a therapeutic effect of vitamin
E does not necessarily validate the free-radical hypothesis
of TD. Vitamin E may have other neurobiological effects,
such as reducing D 2 supersensitivity (Gattaz et al. 1993)
or altering monoamine metabolism (Jackson-Lewis et al.
1991). Furthermore, several other drugs with antioxidant
properties (e.g., selegiline and coenzyme Q) have not
been effective in TD. Finally, in most cases, the effects of
vitamin E are fairly minor. Thus, although vitamin E
could be a reasonable addition to the therapeutic armamentarium, its beneficial effects seem to be limited. Case
reports have suggested an association between vitamin E
and thrombophlebitis in the elderly (Roberts 1981), but
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al. (1990) found that, in 15 reports involving a total of
158 patients, 83 percent of patients improved to some
degree. Although side effects, such as sedation, ataxia,
and addiction, may limit the use of many GABA agonists,
they have an important role, at least as second-line agents,
for the suppression of TD.
Experimental GABA agonists have produced mixed
results in clinical studies. For example, 4,5,6,7-tetrahydroisoxazolo-(5,4-c)pyridine-3-ol, a GABA A agonist
(Thaker et al. 1987), and gamma-vinyl-GABA, a GABAtransaminase inhibitor (Stahl et al. 1985), improved TD,
but only to a minor degree. Muscimol, another GABAA
agonist, produced a 45 percent reduction in seven patients
(Tamminga et al. 1979). Several reports suggested that
progabide, a mixed GABA A and GABAB agonist, may
have significant therapeutic effects, but more studies are
needed. Although the efficacy of these experimental
agents supports a role for GABA in the pathophysiology
of TD, they have limited clinical use.
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Treatment of Tardive Dyskinesia
Table 2. Studies of the effect of vitamin E on tardive dyskinesia (TD)
Reference
Maximum dose
Duration
ofTD
Design
Number of
patients
Outcome
1,200 IU
Double-blind,
crossover
2.6 ± 1.9 year
15
43% improvement
Elkashef et al. (1990)
1,200 IU
(4 weeks)
Double-blind,
crossover
3.8 ± 2.8 years
8
27% improvement
Schmidt et al. (1991)
1,200 mg
(2 weeks)
Double-blind,
crossover
10 patients > 1 yr;
9 patients < 1 yr
19
No overall effect
Eganetal. (1992)
1,600 IU
(6 weeks)
Double-blind,
crossover
5.9 ± 4.8 years
18
No overall effect; 9
patients with TD s 5
years showed 18.5%
improvement
Junker etal. (1992)
1,200 mg
Double-blind,
crossover
Not significant
16
Significant improvement
in patients over age 40
Shriqui etal. (1992)
1,200 IU
(6 weeks)
Double-blind,
crossover
"Long
duration"
27
No effect
Adleretal. (1993)
1,600 IU
(8-12 weeks)
Double-blind,
parallel
9 patients > 5
years; 4 patients
< 5 years
28
32% improvement on
vitamin E; patients with
TD < 5 years did better
(52% vs. 27%)
Aktaretal. (1993)
1,200 mg
(4 weeks)
DouWe-blind,
parallel
6.5 years
32
Greater improvement in
patients on vitamin E
(20%)
Dabirietal. (1994)
1,200 IU
(12 weeks)
Double-blind,
parallel
14 weeks
11
36% improvement
Lam etal. (1994)
1,200 IU
(4 weeks)
Double-blind,
crossover
Not
available
12
No difference; older
patients (mean age 61.8
years); long duration of
illness (> 20 years)
Lohr and Caligiuri
(1996)
1,600 IU
(2 months)
Double-blind,
parallel
11 months
35
24% improvement
plethora of anecdotes, only three double-blind, placebocontrolled or double-blind, crossover studies have been
published. Suppressive efficacy is most convincing for
nifedipine. Two open, one single-blind, and one doubleblind study all found significant improvement with
nifedipine. Data on verapamil are more limited; three case
reports (Barrow and Childs 1986; Buck and Harvey 1988;
Abad and Ovsiew 1993) and one single-blind, placebocontrolled study of nine patients (Reiter et al. 1989) found
that verapamil suppressed moderate to severe TD. Case
reports suggested that diltiazem may also have at least a
temporary suppressive effect (Ross et al. 1987; Falk et al.
1988). Similarly, an acute, single-dose, double-blind challenge study concluded that diltiazem suppressed TD (Leys
et al. 1988). In contrast, in a 3-week double-blind crossover study, diltiazem was no different from placebo
(Loonen et al. 1992).
this or other serious side effects have not been found in
well-controlled studies. Generally, vitamin E is safe, producing few side effects. Rarely, patients report abdominal
pain, headaches, muscle cramps, nausea, or fatigue.
Vitamin E may elevate triglycerides and cholesterol and
decrease thyroid indices, although it has not been reported
to cause hypothyroidism. These abnormalities and symptoms all disappear after its discontinuation. Vitamin E
may also interact with coumadin to prolong bleeding
time. Additional research is needed to establish the therapeutic efficacy of vitamin E.
Calcium Channel Blockers. Observations that calcium
channel blockers may help alleviate TD symptoms come
initially from case reports in the late 1980s (Barrow and
Childs 1986; Ross et al. 1987; Buck and Harvey 1988;
Falk et al. 1988) (see table 3). Unfortunately, despite the
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Lohretal. (1988)
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
M.F. Egan et al.
Table 3. Studies of the effect of calcium channel blockers on tardive dysklnesia
Drug
Reference
Duration 1Maximum dose
Design
Outcome
Nifedipine
Open
1-8
months
20-80
mg/day
Significant improvement
Nifedipine
Single-blind
7-14 days
60 mg/day
Significant improvement
Nifedipine
Open
6 weeks
60 mg/day
Significant improvement
Nifedipine
Double-blind, crossover
8 weeks
90 mg/day
Significant improvement
Barrow and Childs
(1986)
Buck and Harvey (1988)
Verapamil
Case report
Unspecified 320 mg/day
Significant improvement
Verapamil
Case report
6 months
320 mg/day
Significant improvement
Reiteretal. (1989)
Verapamil
Single-blind
2-5 days
160-320
mg/day
Significant improvement
Abad and Ovsiew (1993) Verapamil
Case report
1 week and 1 week: 240
> 1 month
mg/day; >1
month: 360
mg/day
Significant improvement
Rossetal. (1987)
Diltiazem
Case report
Few hours
to 3 weeks
120-240
mg/day
Significant improvement
Falketal. (1988)
Leysetal. (1988)
Diltiazem
Case report
25 weeks
240 mg/day
Temporary improvement
Diltiazem
Single-dose,
double-blind,
placebo-controlled
180
minutes
60 mg
Temporary improvement
up to 90 minutes
Adleretal. (1988)
Loonen etal. (1992)
Diltiazem
Single-blind
2-12 days
240 mg/day
No significant effect
Diltiazem
Randomized,
double-blind,
crossover
3 weeks
240 mg/day
No significant effect
Although the paucity of controlled, double-blind studies of calcium channel blockers limits conclusions about
their efficacy, several trends emerge from prior reports.
First, of the three, nifedipine may be the most effective
(Kushnir and Ratner 1989; Duncan et al. 1990; Stedman et
al. 1991). Second, regardless of the calcium channel
blocker used, there seems to be a dose-related response
(Adler et al. 1988; Kushnir and Ratner 1989; Reiter et al.
1989; Stedman et al. 1991). Third, older rather than
younger patients may respond better to nifedipine (Buck
and Harvey 1988; Kushnir and Ratner 1989).
Several mechanisms could be involved in the action
of calcium channel blockers. It may be due to trivial pharmacokinetic effects, as nifedipine has been shown to
increase plasma neuroleptic activity (Stedman et al.
1991). Alternatively, these drugs may exert therapeutic
effects by their actions on dopamine neurotransmission.
In animals, calcium channel antagonists have been
reported to block postsynaptic D 2 receptors and inhibit
presynaptic dopaminergic activity (Mena et al. 1995).
Single photon emission computed tomography studies
show that calcium channel blockers reduce [123]iodobenza-
mide (a D2 ligand) binding to D 2 receptors in the striatum,
suggesting a weak antidopaminergic effect (Brucke et al.
1995). Finally, calcium channel blockers exert several
indirect effects (Sabria et al. 1995), such as reducing noradrenergic activity, that could be related to the apparent
decrease in TD severity. Well-controlled clinical studies
and more data on the neurochemical effects are needed,
but the data to date suggest that these agents may be worth
considering for patients requiring TD suppression.
Serotonin. Preclinical studies have shown that serotonin modulates striatal dopamine release and could theoretically influence dyskinetic movements (Seibyl et al.
1989). There is increasing evidence that serotonergic
agents may affect TD in humans, although their efficacy
as suppressive agents is not clear. For example, buspirone,
a serotonin 5-HT1A partial agonist, has been observed to
suppress TD (Neppe 1989) and levodopa-induced dyskinesias (Kleedorfer et al. 1991). Subsequent reports, however, raise doubts about the utility of buspirone as a robust
suppressive agent. Of two open trials, one found that TD
improved in eight patients (Moss et al. 1993), while in the
596
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Kushnir and Ratner
(1989)
Duncan et al. (1990)
Stedman et al. (1991)
Suddathetal. (1991)
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Treatment of Tardive Dyskinesia
Botulinum Toxin. Advances in treating other movement disorders are often put to use to treat TD. This strategy has been particularly successful with the recent introduction of botulinum toxin to treat tardive dystonia.
597
Botulinum toxin (type A) blocks acetylcholine release at
the neuromuscular junction, producing a chemical denervation. The resulting focal muscle paralysis persists for up
to 3 or 4 months (Hughes 1994). Botulinum toxin injections have been used to treat blepharospasm, laryngeal
dystonia, hemifacial spasm, and torticollis. Patients
responsive to botulinum injections may also do well with
a newly described surgical procedure involving selective
peripheral denervation of the involved musculature
(Braun and Richter 1994).
Miscellaneous Therapeutic Agents. A variety of other
drugs and neurotransmitter systems have been implicated
in the physiology of dyskinetic movements and could theoretically play a role in the suppression of TD. However,
many potential therapeutic agents are described only in
case reports, small series, animal studies, or unblinded trials, making conclusions problematic. One particularly
interesting approach has been to use ceruletide, a CCK
analog. CCK is a neuropeptide coexpressed in dopaminergic neurons and seems to function as a neuromodular
in the striatum. It purportedly exhibits neurolepticlike
effects on dopamine receptors, metabolism, and behavior.
Ceruletide itself seems to inhibit some of the behavioral
effects of amphetamine, reduces striatal dopamine metabolism (Matsumoto et al. 1984), and blocks dyskinetic
mouth movements in an animal model of TD (Stoessl et
al. 1989). Ceruletide has been found to be beneficial in
one study of seven patients (Nishikawa et al. 1988) that
included several patients with severe TD. In a much larger
(n = 77) well-controlled, parallel study, long-lasting moderate to marked improvement was seen in 42.5 percent of
patients receiving the active drug compared with 9.1 percent improvement in the placebo group (Kojima et al.
1992). Although seemingly promising, one difficulty with
interpreting these data is that ceruletide is a peptide that,
administered peripherally, may not get into the brain in
appreciable amounts (Passaro et al. 1982). On the other
hand, peripherally administered ceruletide has been
shown to have central effects on dopamine neuronal activity (Skirboll et al. 1981) and on metabolism in rats
(Matsumoto et al. 1984).
Lithium is frequently mentioned in conjunction with
TD, although limited data on its effects are available.
Lithium seems to prevent dopamine supersensitivity in
rats when used with neuroleptics (Klawans et al. 1977). In
humans, epidemiological data suggest that when lithium
is added to neuroleptic treatment, the incidence of TD is
reduced (Kane 1995). In contrast, lithium has not been
successful as a suppressive agent (Gardos and Cole 1995).
Anecdotes of successful treatments with a panoply of
other, often unusual, interventions abound. A very low
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second, if anything, buspirone worsened TD in seven
patients (Brody et al. 1990). In a third open trial of 19
patients treated for 6 weeks, a nonsignificant 25 percent
reduction in TD severity was observed; haloperidol levels,
however, were significantly increased by 26 percent (Goff
et al. 1991). Paradoxically, buspirone has also been
reported to induce akathisia (Newton et al. 1986), dystonia
(Boylan 1990), and oral dyskinesia (Strauss 1988).
Buspirone's disparate effects could be attributed to neurotransmitter systems other than serotonin; it is weakly antidopaminergic with mixed D 2 agonist/antagonist properties,
and it reverses neuroleptic-induced D 2 supersensitivity in
rats (McMillan 1985). It is also a sigma receptor antagonist. Based on these few reports, routine use of buspirone
for TD suppression cannot be recommended. In patients
who have failed other modalities, however, it could be
considered.
Serotonin re-uptake inhibitors (SRIs) are a second
class of serotonergic medications that sometimes seem to
affect hyperkinetic disorders. Preclinical studies show
that SRIs reduce dopamine synthesis in a variety of brain
areas, including the striatum (Baldessarini and Marsh
1990). In monkeys, SRIs inhibit amphetamine-induced
repetitive movements and worsen neuroleptic-induced
Parkinsonism (Korsgaard et al. 1984). Furthermore, in
humans, SRIs have been noted to exacerbate Parkinsonian
symptoms (Bouchard et al. 1989). Theoretically, one
might expect SRIs to improve symptoms of TD.
Surprisingly, these medications seem to induce "oral
hyperkinesias" in monkeys (Korsgaard et al. 1984),
although it is difficult to know the relationship between
these movements and TD. Case reports have suggested
that SRIs might rarely produce TD in humans as well
(Budman and Bruun 1991; Stein 1991; Arya and Szabadi
1993). Finally, unpublished observations by Egan and
Daniel in 1991 of a double-blind, placebo-controlled trial
of fluvoxamine in patients with TD have not been impressive. These limited observations, although supporting a
role for serotonin in movement disorders, do not indicate
a prominent role for SRIs as suppressive medications.
If SRIs fail to improve TD, one might try the opposite strategy by using a serotonin antagonist. Two such
studies have noted some improvement with cyproheptadine (Goldman 1976; Kurata et al. 1977); a third found no
effect (Gardos and Cole 1978). In general, interventions
using the serotonin system have not been rewarding (but
see earlier discussion of clozapine).
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
M.F. Egan et al.
Other Experimental Approaches: Striatonigral Inhibition. Theoretically, attempts to reduce the Dj -mediated
striatonigral pathway should reduce hyperkinetic movements by increasing GABAergic projections from the substantia nigra to the thalamus. This increase, in turn, would
decrease thalamocortical activity and ultimately motor
activity (see figure 1). What is not clear, however, is how
to reduce striatonigral activity. One strategy from animal
behavioral work is to use Dj antagonists. Several investigators have looked at the role of Da antagonists in movement disorders and dyskinesia (e.g., see Boyce et al.
1990). Although no D] antagonist is currently available
for clinical use in the United States and controlled studies
are few, at least one trial of a mixed Dl and D 2 antagonist
elicited no better results than a more pure D2 antagonist in
suppressing TD (Lublin et al. 1991). Furthermore, despite
preclinical data from rats and primate studies (e.g., Boyce
et al. 1990; Nutt 1990) suggesting a role for Dj receptors
in L-dopa-induced dyskinesias, at least one study in
humans did not support this notion (Braun et al. 1987).
A second approach is to reduce neurotransmission of
the colocalized neuropeptides, in this case dynorphin and
substance P. In humans, several case reports suggest that
intravenous naloxone, a relatively nonspecific opioid receptor antagonist, reduces L-dopa-induced dyskinesias (Sandyk
and Snider 1986) and TD (Blum et al. 1984; see also
Lindenmayer et al. 1987). In contrast, naltrexone failed to
improve L-dopa-induced dyskinesias in Parkinsonian
patients (Rascol et al. 1994). Such case reports are suggestive, but more data are needed before the clinical utility or
feasibility of striatonigral inhibition is clear.
The use of suppressive agents is typically a highly
individualized process: one approach is outlined in table
4. However, this approach should be considered only a
proposal based on our experience. It has not been evaluated prospectively, and other experts may have differing
strategies. Furthermore, it may not be the best approach in
all circumstances. Many patients will have special needs
indicating that third- or fourth-line agents should be tried
first. Often, a trial of several drugs is needed before an
effective one is found. In our experience, success can
sometimes be achieved by patiently trying several agents,
one after another. This approach requires not only familiarity with the many strategies already described, but also
a strong working alliance with the patient.
Summary
Despite the promise of a new generation of neuroleptics
with reduced EPS, TD remains a vexing clinical issue.
Prevention is still an important approach; clinicians must
consider whether other treatments are more effective than
neuroleptics. This is particularly true for high-risk groups,
such as the elderly and patients with brain damage or diabetes. Switching to an atypical agent is becoming a com-
TD will remain a major public health issue in psychiatry at least for the near future. With better understanding
598
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mon first step, although the efficacy of this approach is
unclear (figure 1). If typical agents are needed, the dose
should be tapered to the lowest possible effective level.
Adding vitamin E to typical agents may also be worthwhile. For many patients, however, neuroleptics are
unavoidable for the treatment of chronic psychosis.
Fortunately, the incidence of severe TD is relatively
low. When TD does cause distress or disfigurement or
affects health or function adversely, suppressive agents
may be needed. Preliminary data suggest that atypical
neuroleptics may be useful in such cases, although more
data are needed. At present, many consider them to be a
first-line treatment for suppression. Clozapine is often
considered a second-line agent due to the complications
associated with its use. As a third step, suppression can be
tried using drugs that are fairly safe and have at least
some moderate record of success, including vitamin E,
calcium channel blockers, and adrenergic antagonists such
as clonidine. Medications that have more side effects or
risks but are probably more effective in the short term
include benzodiazepines and dopamine-depleting agents.
These fourth-line agents are sometimes used first by
movement disorder specialists when a rapid response is
needed. A fifth approach is to increase the dose of typical
neuroleptics in an attempt to achieve temporary suppression, followed by a gradual reduction. This strategy does
not always produce suppression and runs the theoretical
risk of producing long-term worsening. More experimental agents can be tried when other attempts fail: agents
such as cholinergic agonists (e.g., tacrine), dopamine agonists (e.g., amantadine), buspirone, GABA agonists (e.g.,
gabapentin), an SRI, cyproheptadine, opioid antagonists,
estrogen, steroids, or even ECT. When dystonia is a
prominent feature, specific therapeutic agents include
anticholinergics and, if sufficiently localized, botulinum
toxin injections.
dose of prednisolone, for example, surprisingly produced
a complete remission in two patients with severe TD
(Benecke et al. 1988). Estrogen replacement produced
marginal improvement in postmenopausal women (Glazer
et al. 1985c). The use of dentures and the correction of
other dental problems have been observed to markedly
reduce oral TD. Canes, braces, or biofeedback may offer
limited benefit in severe cases. Electroconvulsive therapy
(ECT) has had variable effects, with a few patients reportedly showing dramatic improvement (Hay et al. 1990).
Schizophrenia Bulletin, Vol. 23, No. 4, 1997
Treatment of Tardive Dyskinesia
Table 4.
Possible treatment approach to tardive dyskinesia (TD)
A. For mild to moderate TD that does not require suppression
1. Reevaluate need for antipsychotics; use other classes of medications when possible.
2. If an antipsychotic is required, switch to a putative atypical antipsychotic (olanzapine, risperidone, seroquel, sertindole).
3. If typical antipsychotics must be used, taper to lowest possible levels and follow for improvement in TD.
4. Add vitamin E to neuroleptic if TD persists. If no improvement in 3 months, discontinue vitamin E.
5. If symptoms progress, consider clozapine.
B. For suppression of moderate to severe TD
1. Switch to a putative atypical agent; begin with olanzapine. Increase dose until TD is suppressed or maximum dose is
reached. Gradually taper to lowest effective dose that suppresses psychosis and TD. Consider other putative atypical
agents (risperidone, seroquel, sertindole) if no response is seen to the first.
2. Switch to clozapine.
3. Add vitamin E to antipsychotic.
4. Add calcium channel blocker (e.g., nifedipine) to antipsychotic.
5. Add noradrenergic antagonist (e.g., clonidine) to antipsychotic.
6. Add benzodiazepine (e.g., clonazepam) to antipsychotic.12
7. Add dopamine depleter (e.g., reserpine) to antispychotic.1
8. Increase dose of typical antipsychotic until TD is suppressed, then very gradually taper dose.3
9. Try other possible suppressive agents3: cholinergic agonists (e.g., tacrine), dopamine agonists (e.g., amantadine),
buspirone, GABA agonist (e.g., gabapentin), an SRI, cyproheptadine, opioid antagonists, estrogen, steroids, ECT.
C. For suppression of tardive dystonia
1. Add anticholinergics (increase gradually to "high" doses).
2. Add vitamin E.
3. Add clonazepam.
4. Go to steps 1, 2, 4, 7, and 8 in part B.
5. Consider botulinum injections.
Note.—QABA . gamma-amtno-bytyric add; SRI = sertonln re-uptake Inhibitor, ECT = etectroconvulsive therapy.
'May be tried first particularly if rapid relief Is needed.
Be cautious when adding to clozapine due to case reports of respiratory depression.
'These therapies should be considered experimental. Although the other therapies have some supportfortheir efficacy In well-controlled studies, In general
these have less support Clear benefit and risk data may not be available.
2
of the mechanisms of action of atypical neuroleptics and
the physiology of the basal ganglia, continued improvements can be anticipated. As the new millennium dawns,
perhaps these advances will leave TD as a footnote in the
history of medicine.
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Albin, R.L.; Young, A.B.; and Penney, J.B. The functional
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Announcement
For further information, please contact:
The 16th Annual Therapeutic Activities & Psychosocial
Rehabilitation Conference entitled "Setting New Goals:
The Recreation and Rehabilitation Revolution" will be
held in Philadelphia, Pennsylvania, March 23-24, 1998.
The conference, sponsored by the Allegheny University of
the Health Sciences, focuses on the development of activity and psychosocial rehabilitation skills for client populations. The presentations will include program development
and experiential workshops.
TAL Conference, BHE
Allegheny University Health Sciences
3200 Henry Avenue
Philadelphia, PA 19129
Telephone: 215-842-4340
609
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Michael F. Egan, M.D., is Acting Branch Chief, Clinical
Research Services Branch, and Medical Director and Acting Chief Executive Officer; Jose Apud, M.D., Ph.D., is
Senior Staff Fellow, Neuropsychiatry Branch; and
Richard Jed Wyatt, M.D., is Chief, Neuropsychiatry
Branch, Intramural Research Program, National Institute
of Mental Health Neurosciences Research Center, St.
Elizabeths Hospital, Washington, DC.