Medications associated with the onset of tardive dyskinesia christine b. hunter, rn, christopher kenney, md, anthony davidson, bs, and joseph
Medications Associated with the Onset of Tardive Dyskinesia
Christine B. Hunter, RN, Christopher Kenney, MD, Nicte Mejia, MD, Anthony Davidson, BS, and Joseph Jankovic, MD
Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
FIGURE 3. Drugs Associated with Tardive Dyskinesia
TABLE 2. Medications with the potential to cause TD
FIGURE 1. Tardive Syndromes Present in 440 Patients
Chlorpromazine (e.g. Thorazine)
To define the offending drugs associated with
Triflupromazine (e.g. Vesprin)
In long-term studies, the incidence of TD due to first-
Thioridazine (e.g. Mellaril)
the occurrence of tardive syndromes in patients referred to a
generation antipsychotics was reported to be 5% per year
Mesoridazine (e.g. Serentil)
movement disorders clinic. BACKGROUND:
Trifluoperazine (e.g. Stelazine)
in adults and 25-30% in elderly patients, while the incidence
dyskinesia (TD), a hyperkinetic movement disorder causally
of TD due to second-generation antipsychotics was 0% in
related to dopamine receptor blocking drugs (DRBD), is a
children and 6.8% in the mixed adult and elderly population
Perphenazine (e.g. Trilafon)
well-recognized iatrogenic disorder. Although published
Fluphenazine (e.g. Prolixin)
[Correll, 2004; Pierre, 2005]. Although atypical
reports on TD mainly focus on patients who have been
antipsychotics may be better alternative medications with
exposed to DRBD used as anti-psychotics, these medications
less risk of causing TD, the risk of TD may increase with
are also used to treat a wide array of medical, chiefly
Chlorprothixene (e.g. Tarctan)
chronic use of these drugs, similar to the typical
gastrointestinal, conditions. METHODS:
A retrospective chart
Thiothixene (e.g. Navane)
neuroleptics [Tarsy and Baldessarini, 2006]. TD may have
review was performed on subjects evaluated for TD in the
Haloperidol (e.g. Haldol)
not only medical, but also legal implications. Although
Movement Disorders Clinic at Baylor College of Medicine.
Droperidol (e.g. Inapsine)
avoiding DRBD is the best approach to minimizing this risk,
We report data on 434 patients listed in our
Pimozide (e.g. Orap)
physicians must be able to recognize the early symptoms
database for whom we have detailed clinical information. The
Loxapine (e.g. Loxitane)
and signs of TD in patients exposed to DRBD and provide
patients (334 female, 77.0%), had a mean age of 63.8 ±14.8
Clozapine (e.g. Clozaril)
appropriate management. When a patient develops TD,
years at their initial evaluation. A causal DRBD was well
Quetiapine (e.g. Seroquel)
withdrawal of the offending drug should be the first
defined in 411 (94.7%) patients. The most common
Olanzapine (e.g. Zyprexa)
TABLE 3. Demographic and clinical characteristics of 434
management strategy. If this strategy fails, various
medications associated with the onset of TD were haloperidol
Risperidone (e.g. Risperdal)
Ziprasidone (e.g. Geodon)
pharmacological treatments may be considered, including
combination of Amitriptyline and Perphenazine (N=85, 8.2%),
Iloperidone (e.g. Zomaril)
TBZ, a monoamine-depleting drug by inhibiting the central
and thioridazine (N=72, 6.9%) [Figure 2]. CONCLUSIONS:
Metoclopramide (e.g. Reglan)
vesicular monoamine transporter type 2 [Kenney and
100 (23.0%) male; 334
TD, a feared and common side effect of DRBD treatment,
Jankovic, 2006]. More research is needed to develop new
1. Blanchet PJ, Abdillahi O, Beauvais C, Rompre PH, Lavigne GJ.
may be caused by multiple treatment agents other than anti-
medications that, without dopamine receptor antagonism,
Mean Age at initial
Prevalence of spontaneous oral dyskinesia in the elderly: a reappraisal.
are able to treat conditions in which DRBD are currently
63.8 years ± 14.8 (SD)
Mov Disord. 2004;19:892-6.
2. Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia
associated with second generation antipsychotics: a systematic review of
1-year studies. Am J Psychiatry 2004; 161:414-425.
Molindone (e.g. Moban)
3. Ganzini L, Casey DE, Hoffman WF, McCall AL. The prevalence of
Aripiprazole (e.g. Abilify)
metoclopramide-induced tardive dyskinesia and acute extrapyramidal
Tardive dyskinesia (TD), a hyperkinetic movement disorder
Amoxapine (e.g. Asendin)
movement disorders. Arch Intern Med 1993;153:1469-1475.
temporally and causally related to exposure to dopamine
4. Fernandez HH, Friedman JH. Classification and treatment of tardive
Flunarizine (e.g. Sibelium)
In this review of 434 patients referred to a movement
syndromes. The Neurologist 2003; 9:16-27.
receptor blocking drugs (DRBD), also referred to as
Cinnarizine (e.g. Stugeron)
Primary TD Type
disorders clinic with prior history of exposure to DRBD, the
5. Jankovic J. Tardive syndromes and other drug-induced movement
neuroleptics, is a well-recognized iatrogenic condition
most common medications associated with the onset of TD
disorders. Clinical neuropharmacology 1995;18:197-214.
particularly in adults [Stacy and Jankovic, 1991; Rodnitzky,
6. Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic
were were haloperidol (N=191, 18.4%), metoclopramide
2005] as well as in children including infants [Mejia and
movement disorders. Expert Rev Neurotherapeutics 2006;6:7-17.
(N=171, 16.5%), the combination of amitriptyline and
7. Marchand WR, Dilda V. New models of frontal-subcortical skeletomotor
Jankovic, 2005]. Although the literature on TD mainly focuses
perphenazine (N=85, 8.2%), and thioridazine (N=72, 6.9%).
circuit pathology in tardive dyskinesia. Neuroscientist 2006 Jun;12(3):186-
on patients who have been exposed to DRBD used as anti-
Prospective longitudinal studies are needed to confirm
psychotics, these medications are also used to treat a wide
8. Mejia NI, Jankovic J. Metoclopramide-induced tardive dyskinesia in an
whether atypical neuroleptics have a lower risk for TD than
array of medical, chiefly gastrointestinal, conditions [Tonini,
A retrospective chart review was performed on subjects evaluated
≥ 1 TD syndrome
infant. Mov Disord 2005; 20:86-89.
the tradional typical neuroleptics.
9. Mejia N, Jankovic J. Tardive dyskinesia and withdrawal emergent in
2004; Paulson, 2005; Pasricha et al, 2006] [Table 1]. Most of the
for TD in the Movement Disorders Clinic at Baylor College of
children. Arch Dis Child 2007 (in press).
drugs that cause TD are DRBD that block dopamine D2
Medicine. We included patients who: 1) exhibited a hyperkinetic
10. Miller LG, Jankovic J. Metoclopramide-induced movement disorders.
receptors, but other classes of drugs have the potential to cause
movement disorder, 2) had a documented exposure to one or more
Arch Int Med 1989;149:2386-2392.
11. Noyes K, Liu H, Holloway RG. What is the risk of developing
TD [Table 2, Table 3]. The reported frequency of TD in patients
DRBD for at least 3 months before the onset of symptoms (shorter
FIGURE 2. Medications Associated with the onset of TD
parkinsonism following neuroleptic use? Neurology 2006;66:941-3.
treated with DRBD has varied greatly, with an average at
exposure time to DRBD was accepted if this was clearly related to
12. Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J. Drug Insight: from
around 25% of exposed adults, and half that frequency in
the development of TD), and 3) the hyperkinetic movement disorder
disturbed motility to disordered movement-a review of the clinical benefits
Despite the recognition of TD more than a half of century
children [Stacy and Jankovic, 1991; Mejia and Jankovic, 2007].
and medicolegal risks of metoclopramide. Nat Clin Pract Gastroenterol
persisted for at least one month after stopping the offending DRBD
ago, the pathophysiology of this iatrogenic disorder is still
Risk factors associated with the development of TD include
[Jankovic, 1995]. We excluded patients with drug-induced
not well understood [Marchand and Dilda, 2006]. Although
13. Paulson GW. Historical comments on tardive dyskinesia: a
advanced age, female gender, and total cumulative drug
parkinsonism [Noyes et al, 2006]. Demographic and clinical data
neurologist’s perspective. J Clin Psychiatry 2005;66:260-264.
most drugs with the potential to cause TD belong to the
exposure [Woerner et al, 1998; van Os et al, 1997; Fernandez
14. Pierre JM. Extrapyramidal symptoms with atypical antipsychotics :
were ascertained. We also searched for information about dose,
antipsychotic family of drugs (phenothiazines,
incidence, prevention and management. Drug Saf. 2005;28:191-208.
treatment duration, and drug free intervals.
thioxanthenes, butyrophenones, etc), other medications for
15. Putnam PE, Orenstein SR, Wessel HB, Stowe RM. Tardive dyskinesia
associated with use of metoclopramide in a child. J Pediatr 1992;121:983-
non-psychiatric-related problems, such as metoclopramide
TABLE 1. Some conditions that may require DRBD therapy
(substituted benzamide), are also DRBD and have the ability
16. Rodnitzky RL. Drug-induced movement disorders in children and
to cause TD. Metoclopramide seems to be one of the most
adolescents. Expert Opin Drug Saf. 2005;4:91-102.
common causes of TD in adults. A previous review of 131
17. Stacy M, Jankovic J. Tardive dyskinesia. Current Opinion in Neurology
and Neurosurgery 1991;4:343-349.
We report data on 434 TD patients listed in our database for whom
patients with drug-induced movement disorders at our
18. Tarsy D, Baldessarini RJ. Epidemiology of tardive dyskinesia: is risk
we have detailed clinical information. Patients, 334 female (77.0%),
institution found this DRBD to be the TD causative agent for
declining with modern antipsychotics? Mov Disord 2006;21:589-98.
had a mean age of 63.8 ± 14.8 years at their initial evaluation. Of the
12% (N= 16) of patients; all of whom had been exposed to
19. Tonini M, Cipollina L, Poluzzi E, Crema F, Corazza GR, De Ponti F.
434 patients, the majority presented with orolingual stereotypy
Review article: clinical implications of enteric and central D2 receptor
metoclopramide doses between 20 and 40 mg/day [Miller
blockade by antidopaminergic gastrointestinal prokinetics. Aliment
(N=198, 45.0%), dystonia (N= 165, 37.5%), or other stereotopies
and Jankovic, 1989]. Another study of metoclopramide-
Pharmacol Ther. 2004;19:379-390.
(N=159, 36.1%) [Figure 1]. The most frequent phenomenology that
treated adult patients reported that 29% (n=15) met criteria
20. van Os J, Fahy T, Jones P, et al. Tardive dyskinesia: who is at risk?
Acta Psychiatr Scand. 1997; 96:206-216.
patients exhibited, alone or in combination with other TS, were
for TD, compared with 17.6% (n= 9) of metoclopramide non-
21. Woerner MG, Alvir JM, Saltz BL, Lieberman JA, Kane JM. Prospective
orolingual stereotypies (N=292, 28.2%), dystonia (N=256, 24.7%),
users (P = 0.08) [Ganzini et al, 1993]. Although we believe
study of tardive dyskinesia in the elderly: rates and risk factors. Am J
and other stereotypies (N= 253, 24.4%). A specific causal DRBD
that metoclopramide is also an important cause of TD in
Psychiatry 1998; 155:1521-1528.
was defined for 411 (94.7%) patients. The most common
22. Wonodi I, Helene MA, Cassady SL, Sherr JD, Avila MT, Thaker GK.
children, it seems to be under-recognized; only two children
Ethnicity and the course of tardive dyskinesia in outpatients presenting to
medications associated with the onset of TD were haloperidol
with metoclopramide-induced TD are reported in the
the motor disorders clinic at the Maryland Psychiatric Research Center. J
(N=191, 18.4%), metoclopramide (N=171, 16.5%), the combination of
literature [Putnam et al, 1992; Mejia and Jankovic, 2005a].
Clin Psychopharmacol 2004; 24: 592-598.
Amitriptyline and Perphenazine (N=85, 8.2%), and thioridazine
(N=72, 6.9%) [Figure 2].
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