Medications Associated with the Onset of Tardive Dyskinesia Nicte I. Mejia, M.D., Kevin Dat Vuong, M.A., Christine B. Hunter, R.N., and Joseph Jankovic, M.D.
Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas
ABSTRACT RESULTS Figure 2. Medications associated with the onset of TD in 89 patients. CONCLUSIONS Table 2. Medications with the potential to cause TD. Medication class Examples OBJECTIVE: To define the offending drugs associated with the occurrence Phenothiazines
A total of 116 TD patients currently treated with TBZ were listed in the TBZ
• Atypical antipsychotics may be better alternative medications with less
of tardive syndromes (TS). BACKGROUND: Tardive dyskinesia (TD), a
database. We report data on 89 (76.7%) of them, for whom we have
risk of causing TD and should be considered whenever possible. In long-
hyperkinetic movement disorder causally related to exposure to dopamine
complete clinical information. Patients, 74 female (83.1%), aged 62.3 ± 13.9
term studies, the incidence of TD due to first-generation antipsychotics
receptor blocking drugs (DRBD), is a well-recognized iatrogenic condition.
years at their initial evaluation, and had a mean age of TD onset at 58.6 ±
was reported to be 5% per year in adults and 25-30% in elderly patients,
Although the published reports on TD mainly focus on patients who have
14.1 years. The most frequent phenomenology that patients exhibited, alone
while the incidence of TD due to second-generation antipsychotics was 0%
been exposed to DRBD used as anti-psychotics, these medications are also
or in combination with other TS, were stereotypies (N= 69, 77.5%), dystonia
in children and 6.8% in the mixed adult and elderly population [Correll,
used to treat a wide array of medical, chiefly gastrointestinal, conditions.
(N= 38, 42.6%), and akathisia (N= 11, 12.3%) [Figure 1]. A specific causal
METHODS: A retrospective chart review was performed on subjects
DRBD was defined for 81 (91.0%) patients. The most common medications
evaluated for TD in the Movement Disorders Clinic at Baylor College of
associated with the onset of TD were metoclopramide (N= 23, 25.8%),
• TD may have not only medical, but also legal implications. Although
Medicine who were enrolled in our trial of tetrabenazine (TBZ). Demographic
haloperidol (N= 9, 10.1%), the combination of amitriptyline and perphenazine
avoiding DRBD is the best approach to minimizing this risk, physicians
and clinical data were ascertained. RESULTS: A total of 116 patients with Thioxanthenes
(N= 9, 10.1%), and risperidone (N= 7, 7.9%) [Figure 2].
must be able to recognize the early symptoms and signs of TD in patients
TD currently treated with TBZ; we report data on 89 (76.7%) for whom we
exposed to DRBD and provide appropriate management. When a patient
have complete clinical information. The patients, 74 female (83.1%), aged
develops TD, withdrawal of the offending drug should be the first
62.3 ±13.9 years at their initial evaluation, had a mean age of TD onset at
management strategy. If this strategy fails, various pharmacological
58.6 ± 14.1 years. A causal DRBD was well defined in 81 (91.0%) patients.
Butyrophenones
treatments may be considered, including TBZ, a monoamine-depleting
The most common drugs associated with the onset of TD were
drug by inhibiting the central vesicular monoamine transporter type 2
metoclopramide (N= 23, 25.8%), haloperidol (N= 9, 10.1%), and the
Table 3. Demographic and clinical characteristics of 89 TD patients. Diphenylbutylpiperidine
[Jankovic and Beach, 1997; Vuong et al, 2004].
Dibenzazepine CONCLUSION: TD, a feared and common side effect of DRBD treatment, Characteristics
• More research is needed to develop new medications that, without
may be caused by multiple treatment agents other than anti-psychotic
Dibenzodiazepine
dopamine receptor antagonism, are able to treat conditions in which DRBD
Thienobenzodiazepine Pyrimidinone Benzisothiazole INTRODUCTION CONCLUSIONS REFERENCES Benzisoxazole Substituted benzamides
Tardive dyskinesia (TD), a hyperkinetic movement disorder temporarily and
DRBD indication
Correll CU, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second generation
• Although most drugs with the potential to cause TD belong to the
antipsychotics: a systematic review of 1-year studies. Am J Psychiatry 2004; 161:414-425.
causally related to exposure to dopamine receptor blocking drugs (DRBD),
antipsychotic family of drugs (phenothiazines, thioxanthenes,
Fernandez HH, Friedman JH. Classification and treatment of tardive syndromes. The Neurologist 2003;
also referred to as neuroleptics, is a well-recognized iatrogenic condition
butyrophenones, etc), other medications for non-psychiatric-related
Ganzini L, Casey DE, Hoffman WF, McCall AL. The prevalence of metoclopramide-induced tardive
particularly in adults [Stacy and Jankovic, 1991; Rodnitzky, 2005] as well as
problems, such as metoclopramide (substituted benzamide), are also DRBD
dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med 1993;153:1469-1475.
in children, including infants [Mejia and Jankovic, 2005a]. Although the
and have the ability to cause TD.
Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement disorders.
literature on TD mainly focuses on patients who have been exposed to
Jankovic J. Tardive syndromes and other drug-induced movement disorders. Clinical
DRBD used as anti-psychotics, these medications are also used to treat a
• Metoclopramide seems to be one of the most common causes of TD in
Mejia NI and Jankovic J. Tardive dyskinesia and withdrawal emergent syndrome in children. 2005b
wide array of medical, chiefly gastrointestinal, conditions [Tonini, 2004;
Indolones adults. A previous review of 131 patients with drug-induced movement
Paulson, 2005] [Table 1]. Most of the drugs that cause TD are DRBD that
Mejia NI, Jankovic J. Metoclopramide-induced tardive dyskinesia in an infant. Mov Disord 2005; 20:86-
Quinolinone
disorders at our institution found this DRBD to be the TD causative agent for
block dopamine D2 receptors, but other classes of drugs have the potential
Tricyclic
12% (N= 16) of patients; all of whom had been exposed to metoclopramide
Miller LG, Jankovic J. Metoclopramide-induced movement disorders. Arch Int Med 1989;149:2386-
to cause TD [Table 2]. The reported frequency of TD in patients treated with
doses between 20 and 40 mg/day [Miller and Jankovic, 1989]. Another study
Calcium channel blockers
Paulson GW. Historical comments on tardive dyskinesia: a neurologist’s perspective. J Clin Psychiatry
DRBD has varied greatly, with an average at around 25% of exposed adults,
Figure 1. TS presented in 89 patients*.
of metoclopramide-treated adult patients reported that 29% (n=15) met
and half that frequency in children [Stacy and Jankovic, 1991; Mejia and
criteria for TD, compared with 17.6% (n= 9) of metoclopramide non-users (P
Putnam PE, Orenstein SR, Wessel HB, Stowe RM. Tardive dyskinesia associated with use of metoclopramide in a child. J Pediatr 1992;121:983-985.
Jankovic, 2005b]. Risk factors associated with the development of TD
N-acetyl-4-
Rodnitzky RL. Drug-induced movement disorders in children and adolescents. Expert Opin Drug Saf.
include advanced age, female gender, and total cumulative drug exposure
methoxytryptamine
Stacy M, Jankovic J. Tardive dyskinesia. Current Opinion in Neurology and Neurosurgery 1991;4:343-
[Woerner et al, 1998; van Os et al, 1997; Fernandez et al, 2003; Wonodi et
•Although we believe that metoclopramide is also an important cause of TD
in children, it seems to be under-recognized; only two children with
Tonini M, Cipollina L, Poluzzi E, Crema F, Corazza GR, De Ponti F. Review article: clinical implications
of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics. Aliment
metoclopramide-induced TD are reported in the literature [Putnam et al,
van Os J, Fahy T, Jones P, et al. Tardive dyskinesia: who is at risk? Acta Psychiatr Scand. 1997;
Table 1. Conditions and procedures that may require DRBD therapy. METHODS
1992; Mejia and Jankovic, 2005a]. More prospective or retrospective cohort studies are needed to determine the true prevalence of metoclopramide
Vuong K, Hunter CB, Mejia N, Jankovic J. Safety and efficacy of tetrabenazine in childhood
hyperkinetic movement disorders. Mov Disord 2004;19(Suppl 9):S422. Gastrointestinal
Nausea, vomiting, GERD, diabetic gastroparesis;
A retrospective chart review was performed on subjects evaluated for
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the elderly: rates and risk factors. Am J Psychiatry 1998; 155:1521-1528.
TD in the Movement Disorders Clinic at Baylor College of Medicine
Wonodi I, Helene MA, Cassady SL, Sherr JD, Avila MT, Thaker GK. Ethnicity and the course of tardive
who were enrolled in the compassionate protocol of TBZ under a
dyskinesia in outpatients presenting to the motor disorders clinic at the Maryland Psychiatric Research Center. J Clin Psychopharmacol 2004; 24: 592-598. Psychiatric
Anxiety, depression, schizophrenia, bipolar
Claimed Investigational Exemption for a New Drug (IND) awarded to
one of the authors (JJ) in 1979. We included patients who: 1) exhibited a hyperkinetic movement disorder, 2) had a documented
Neurological
Tourette syndrome, migraines, epilepsy.
exposure to one or more DRBD for at least 3 months before the onset
Menopausal symptoms, labyrinthine disorders,
of symptoms (shorter exposure time to DRBD was accepted if this
peripheral and cerebral vascular disorders,
was clearly related to the development of TD), and 3) the hyperkinetic
dermatological problems; anesthesia.
movement disorder persisted for at least one month after stopping the
* > 1 TS was presented by 26 (29.2%) patients.
offending DRBD [Jankovic, 1995]. Demographic and clinical data were ascertained. We attempted to not only identify the causal DRBD in all TD cases, but also searched for information about dose, treatment duration, and drug free intervals, but this data was often lacking or not available.
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Medications Associated with the Onset of Tardive Dyskinesia