Parkinson Current Topics
Drug-Induced & Tardive Movement Disorders
by Gwen M. Vernon
Several have postulated that their diagnosis with Parkinson's was preceded by adverse effects from taking different medications earlier in life.
This work is presented for education and research.
Lynn Schmidt-Speed.Section Editor
Knowledge of pharmacology is important to neuroscience nurses. Pharmacology Update is presented as a regular feature. Drug-induced movement disorders are discussed in this issue.
Questions or comments about this article may be directed to:-
Gwyn M. Vernon RN.MS, The Graduate Hospital, Parkinson's Disease and Movement Disorder Center, 1500 Lombard Street, Suite 900, Philadelphia, Pennsylvania 19146. (She is the coordinator).
Copyright American Association of Neuroscience Nurses 0047 2603/91/2303-0153 $1.25
J Neuroscience Nursing 1991; 23(3):183-187.
Drug-induced movement disorders and tardive syndromes present a unique challenge for neuroscience practitioners. Our understanding of the patho-physiology of these iatrogenic problems has developed mainly through clinical observations, while treatment and prognosis in most cases are complex and less than optimal. This article discusses drug-induced and tardive movement disorders, risk factors, management and nursing implications.
Movement disorders secondary to pharmacological agents represent a large number of extrapyramidal disorders seen by neurologists and psychiatrists in the outpatient setting.
Involuntary movements, including tremor, chorea, athetosis, dyskinesias, dystonia, myoclonus, tics, ballismus and akathisia, may be symptoms of primary neurologic disease or occur secondary to pharmacotherapy (Table 1). Drug-induced abnormal movement syndromes have been recognized since the 1950s, following the introduction of chlorpromazine (Thorazine) to treat schizophrenia.
The risk of developing a drug-induced movement disorder begins at the onset of treatment with an offending agent. Drug-induced syndromes may develop acutely, within hours or a few days, or sub-acutely, over several weeks. Yet others may develop after prolonged exposure to an offending agent. When a movement disorder develops six months or longer after exposure, the term "tardive" is used, implying a late or delayed onset.
Most of our understanding of the patho-physiology of movement disorders has developed from clinical observations of response to pharmacotherapy. Tardive syndromes appear to originate from drug effects on the striatal dopaminergic system. Five classes of drugs are known to affect central dopaminergic systems: [5,15
Tremor Rhythmic. oscillatory movement categorized
according to its relationship to activity or
Chorea Irregular, unpredictable brief jerky movements
Athetosis Slow, writhing movements of distal parts of
Dyskinesias Recessive abnormal involuntary movements
Dystonia Slow sustained, posturing or contractions of a
muscle or group of muscles
Myoclonus Rapid, brief shock-like muscle jerks
Tic Repetitive. irregular stereotype movements or
Bellismus Wild flinging or throwing movements
Akathisia Subjective sensation of restlessness often
associated with inability to keep still. Easily
confused with psychiatric symptoms such as
agitation, hyperactivity and anxiety
* Central stimulants that act as indirect dopamine
agonists such as amphetamine
* Levodopa, a precursor of dopamine
* Direct dopamine agonists such as bromocriptine
* Presynaptic dopamine antagonists (dopamine depleting
agents) such as reserpine
* Neuroleptics such as haloperidol (Haldol) or chlorpromazine (Thorazine), and other medications such as metoclopramide (Reglan) which antagonize or block central dopamine receptors
By far the most common cause of drug-induced and tardive syndromes are those that block or antagonize dopamine receptors, usually the neuroleptics.
Prognosis for the patient with a drug-induced movement disorder ranges from complete recovery to chronic, persistent movements, often resistant to therapy. Tragically, many patients develop these syndromes after insufficient consideration of the ever present danger of this adverse effect.
Neuroleptics and other drugs known to commonly cause movement disorders (Table 2) should be used cautiously and reserved for situations where the benefits outweigh the risks. Even then, short-term therapy of minimal therapeutic dosages should he the strategy employed.
While drug-induced and tardive syndromes can present with any of the involuntary movements; parkinsonism, dyskinesias and dystonia tend to be the most common.
Drug-induced and tardive parkinsonism resemble idiopathic parkinsonism, and are therefore characterized by tremor, rigidity and most commonly an extreme paucity of movement called akinesia. Ironically, tardive parkinsonism was recognized as a reserpine induced akinesia prior to our understanding of the importance of dopamine deficiency to the manifestations of idiopathic parkinsonism. Today, neuroleptic induced parkinsonism is the second leading cause of parkinsonism symptomatology following idiopathic Parkinson's disease.
The mechanism of tardive parkinsonism appears to be the drug-induced opposition or blockade of striatal dopamine receptors. This results in a subsequent imbalance in the normal acetylcholine-dopamine relationship.
While parkinsonism may begin within several days of treatment, it usually follows a more delayed or subacute onset with 90% of cases evidenced within three months. Women appear to have a higher incidence than men. Overall the incidence of developing a drug-induced parkinsonism ranges from 5-60% depending on the type of neuroleptic employed.
Drug-induced parkinsonism appears dependent on two variables, drug type and dosage. The relative dopamine receptor blocking activity varies between offending agents, however all patients have the potential for developing tardive parkinsonism if dosages are continually escalated.
Additionally, research supports the hypothesis there may be subclinical deficits in the dopaminergic system related to normal aging or even preclinical Parkinson's disease which may contribute a significant risk for developing tardive parkinsonism.[1,8]
When drug-induced parkinsonism occurs, the offending medication should be reduced, withdrawn or changed to an agent with a lower propensity for causing this adverse effect. However, this plan is not always feasible because of the underlying psychiatric or medical illness. Anticholinergics, or more commonly, amantadine (Symmetrel) are used to treat symptoms in cases where drug reduction, withdrawal or alternative therapy fail. Routine use of anticholinergics in patients receiving neuroleptics is not suggested as prophylaxis as there is evidence anticholinergics may reduce therapeutic efficacy of neuroleptics.
Moreover, adverse effects of anticholinergics such as hallucinations and confusion may exacerbate underlying psychiatric symptoms.
Following the introduction of chlorpromazine (Thorazine) in 1952, several researchers began to describe a complicated movement disorder following exposure to this drug. Lipsmacking, facial and lingual masticatory movements, trunk rocking and restless foot movements were some of the movements described.
Faurbye and his colleagues coined the term tardive dyskinesia and described it as a syndrome of abnormal movements following at least six months and often many years of neuroleptic therapy, hence, tardive or late onset. Today, tardive dyskinesia is characterized by choreiform movements of the mouth, tongue, face, arms, legs and body, in order of decreasing frequency.
Risk factors for developing tardive dyskinesia include:
* chronic neuroleptic therapy especially polypharmacy
* age greater than 40 years
* chronic schizophrenia
* Females are more commonly affected than males.
Institutionalization is included as a risk factor because of long-term, high dose neuroleptic therapy frequently employed in chronic care facilities.
Indiscriminate use of anticholinergics may also increase a patient's risk for developing tardive dyskinesia by blocking the cholinergic system and thereby
enhancing dopamine hence creating a neurotransmitter imbalance.
Onset of tardive dyskinesia may be insidious or emerge as neuroleptics are being reduced or discontinued. This pattern theoretically is related to denervation-hypersensitivity phenomenon. It appears with prolonged receptor blockade by a neuroleptic, the receptors rebound, becoming supersensitized. Medication non-compliance such as running out of a prescription or undergoing sudden drug withdrawals and resumptions are a common cause of this denervation-hypersensitivity rebound phenomenon.
The best treatment for tardive dyskinesia is prevention. The indication for long-term neuroleptics must be well established and continually re-evaluated, with alternatives considered. Once tardive dyskinesia presents, a gradual reduction of the neuroleptic should be attempted in hopes of a spontaneous remission. Overall 60% of persons may improve, however it may take two or more years for a remission to occur.
Drug interventions for persistent dyskinesias include low doses of benzodiazepines, dopamine antagonists and other dopamine depleting agents such as reserpine and tetrabenazine.
Frequently, patients prefer the neuroleptic be resumed as the effectiveness of other agents is often insufficient to bring a satisfactory level of relief from the abnormal involuntary movements. At best, the prognosis for patients with tardive dyskinesia is poor. Emphasis must be placed on prevention, appropriate use of antipsychotics and early recognition of this phenomenon.
Syndrome Drugs responsible
Postural tremor Sympathomimetica ++
Lithium carbonate ++
Thyroid hormone ++
Sodium valproate ++
Hypoglycemic agent ++
Alcohol withdrawal ++
Cyclosporin A +
Acute dystonic APDs ++
reactions Metoclopramid ++
Mefenamic acid +/-
Flunarizine and cinnarizine +/-
Akathisia APDs ++
Levodopa & DA agonists (3,4) +
Flunarizine and cinnarizine +/-
Parkinsonism APDs ++
Flunarizine and cinnarizine +/-
Alcohol withdrawal +
MPTP (2) +
Other toxins (Mn, Carbon disulfide
Cytosine arabinoside +/-
Chorea,including APDs ++
tardive Metoclopramide ++
dyskinesis and Levodopa ++
orofacial Direct DA agonists (3) ++
dyskinesia Indirect DA Agoniets and other
Catecholaminergic Drugs (4) ++
Oral Contraceptives +
Phenytonin (T) +
Carbamazepine (T) +/-
Phenobarbital (T) +/-
Lithium (T) +/-
MAO Inhibitors +/-
Tricyclic antidepressants +/-
Alcohol withdrawal +/-
Toluene (glue) snifling +/-
Flunarizine and cinnarizine +/-
Dystonia, APDs ++
including Metoclopramide ++
tardive Levodopa ++
dystonia Direct DA agonists (3) +
(excluding acute Phenytoin (T) +
dystonic Carbamazepine (T) +/-
reactions) Flunarizine and cinnarizine +/-
Neuroleptic APDs +
malignant Tetrabenazine + AMPT +/-
syndrome Withdrawal of antiparkinsonian
drugs in Parkinson's disease +/-
Tics (simple and Levodopa +
complex), Direct PA agonists +
including Indirect PA agonists ++
aggravation of APDs +
pre-existing tic Carbamazepine +/-
Myoclonus Levodopa (T) ++
Anticonvulsants (5) (T) ++
Tricyclic antidepressants ++
Asterixis Anticonvulsants (5) (T) ++
Hepatotoxins (T) ++
Respiratory Depressants (T) ++
Others (6) (T) ++
++ = Well documented common or not infrequent
+ = Relatively well documented; uncommon
+/- = Not well documented or only sma11 number of cases in literature
T = Usually other evidence of drug toxicity present (including serum drug levels)
DA = Dopamine
1. APDs=antipsychotic drugs
3. Includes: Apomorphine, Bromocriptine, Lisuride,
4. Includes: Amphetamines, Methylphenidate, Amantadine,
Pemoline, Fenfluramine, Nomifensine
5. Includes most categories of anticonvulsant drugs
6. Includes wide variety of other drugs capable of causing
From Weiner WJ, Lang AE. Pages 600-602: Movement Disorders: A Comprehensive Survey. Futura Publishing Co., 1989. Reprinted with permission.
Tardive dystonia, resembling idiopathic torsion dystonia, is characterized by contorting posture(s) of a muscle or muscle groups. Tardive dystonia commonly affects the face or neck, but may also involve the leg or trunk. Other drug-induced movement disorders including tardive dyskinesia, akathisia (a subjective sensation of restlessness) or myoclonus may accompany tardive dystonia, and have led many researchers to classify tardive dystonia as a variant of tardive dyskinesia. Unlike tardive dyskinesia, tardive dystonia is seen in children as well as adults. As many as 2% of psychiatric inpatients have been noted to have features of tardive dystonia.
There are no known biochemical changes in idiopathic dystonia. However, it has been postulated through pharmacologic observation an alteration may exist in the cholinergic system.
Clinically, patients with tardive dystonia often respond to dopamine-depleting drugs or antagonists. However, if ineffective, patients should be offered trials of the pharmacological therapy used in patients with primary idiopathic dystonia.
Infrequent Drug-Induced Syndromes
Two other syndromes, although infrequently seen, warrant consideration because of their potential morbidity and mortality: acute dystonic reactions and neuroleptic malignant syndrome.
Acute dystonic reactions have been associated with all neuroleptics. Swett found an incidence of acute dystonic reactions in 10.1% of patients studied on a variety of antipsychotic drugs; males under the age of 30 were most commonly affected. Acute dystonic reactions are frequently seen in the psychiatric setting, or bring patients in the community to the emergency room within hours or a few days after the initiation of therapy with a neuroleptic, metoclopramide (Reglan) or other potential drugs. Like idiopathic and tardive dystonia, the pathophysiology of acute dystonic reactions remains obscure.
Treatment for acute dystonic reactions includes withdrawal of the offending agent and parenteral infusion of an anticholinergic or antihistamine such as benztropine (Cogentin) or diphenhydramine (Benadryl) followed by oral anticholinergic therapy every 4-6 hours for the next 24-48 hours.
Neuroleptic malignant syndrome is the least common of the extrapyramidal adverse effects of neuroleptic drugs, but the most dangerous.
Idiosyncratic reactions including fever, severe rigidity, tremor, autonomic instability and obtundation lead to pulmonary embolism, myocardial infarction and disseminated intravascular coagulation. Death occurs in 20-80% of the cases while gradual spontaneous resolution over 2 weeks occurs in the remainder.
Infrequently, patients continue to exhibit involuntary movements including dyskinesia or parkinsonism upon recovery from the acute phase.
The pathological mechanism of neuroleptic malignant syndrome is uncertain, however, it is thought the neuroleptic blocking effects on striatal dopamine receptors result in severe rigidity and excessive heat production from severe muscle contraction.
Additionally, thermo-regulatory function maybe altered by central effects of the neuroleptics.
Life supporting care including provision of fluids and electrolytes, cooling and artificial ventilation may be required. Dopamine agonists and direct acting skeletal muscle relaxants such as dantrolene sodium have been used with fair to good results.
Nurses in many settings are exposed to patients at risk for, or who suffer from drug-induced and tardive syndromes. Prevention of these complications is the best treatment.
Careful assessment of the need for antipsychotic treatment must be considered along with knowledge of the risk of a persistent, irreversible involuntary movement disorder evolving as a complication of neuroleptic therapy. Nurses are in a position to carefully discuss these risks and benefits with the medical team, patient and family.
Constant weekly monitoring for early detection of abnormal involuntary movements is an important role of the nurse. Education of the patient and family is of utmost importance, with emphasis placed on the goals of treatment, medication effects and potential adverse effects.
Compliance should be monitored and patients must be discouraged from sudden drug discontinuance, Additionally, comprehensive care including options such as day programs and counseling should be considered to assist in resolving or optimally managing psychiatric problems. Once a movement disorder develops, nurses must carefully monitor the patient, assess therapeutic alternatives
and provide reassurance and counseling for the patient and family.
Drug-induced and tardive movement disorders represent a large number of extrapyramidal disorders seen in neurologic practice. Iatrogenically induced, most commonly by neuroleptics, these disorders can be characterized by any abnormal body movement including tremor, chorea, athetosis, dyskinesias, dystonia, myoclonus, tics, ballismus or akathisia. Parkinsonism, dyskinesias and dystonia tend to be the most common. Management of patients with drug-induced or tardive syndromes is complex.
Prognosis is frequently poor as patients usually need the offending agent to manage their underlying psychiatric or medical problem. Neuroleptics and other drugs known commonly to cause movement disorders should be used cautiously and significant consideration of all risks and benefits measured
before initiating therapy.
The author wishes to thank Matthew B. Stern, MD, for useful comments in support of this article, and Rita Verrilli for her assistance in the preparation of the manuscript.
1. Ayd Fa: A survey of drug induced extrapyramidal reactions.
J Am Med Assoc 1961; 175:1054-1060.
2. Caroff SN: The neuroleptic malignant syndrome.
J Clin Psychiatry 1980; 41:79-83.
3. Chase TN, Shur JA, Gordon EK: Cerebrospinal fluid monoamine catabolites in induced extrapyramidal disorders. Neuropharmacology 1970; 9:265-275.
4. Faurbye A, Rasch PJ, Peterson PB, et al:
Neurological syndromes in pharmacotherapy of psychosis.
Acta Psychiatr Scand 1964 40:10-27.
5. Klawans HL: The pathophysiology a drug-induced movement disorders.
Pages 315-326 in: Parkinson's Disease and Movement Disorders,
Jankovic J, Tolosa E (editors).
Urban and Schwartzenberg. 1988.
6. Marsden CD: Is tardive dyskinesia a unique disorder?
Pages 64-71 in: Dyskinesia: Research and Treatment,
Casey DE, Chase TN, Christensen AV. Gerlach J (editors).
Springer Verlag 1985.
7. Marsden CD, Tarsy D, Baldessarini RJ:
Spontaneous and drug-induced movement disorders in psychotic patients.
Pages 219-226 in: Psychiatric Aspects of Neurologic Disease, Benson DF, Blumer D (editors). Grune and Statton, 1975.
8. Rajput A, Rozdilsky B, Hornykiewicz O et al:
Reversible drug-induced parkinsonism: Clinicopathologic study of two cases. Arch Neurol 1982; 39:644-646.
9. Rajput AH. Offord KP Beard CM et al:
Epidemiology of parkinsonism: Incidence, classification and mortality.
Ann Neurol 1984; 16:278-282.
10.Singh MM, Kay SR:
A comparative study of haloperidol and chlorpromazine in terms of clinical effect and therapeutic reversal with benztropine in schizophrenia. Theoretical implications for potency differences among neuroleptics. Psychopharmacologia 1975; 43:103-113.
11.Singh MM, Kay SR: A longitudinal therapeutic comparison between two prototypic neuroleptics (haloperidol and chlorpromazine) in matched groups of schizophrenics.
Non-therapeutic interactions with trihexyphenidyl.
Therapeutical implications for potency differences.
Psychopharmacologia 1975; 43:115-123.
12.Sweet C: Drug induced dystonia. Am J Psychiatry 1975; 132:532-534.
13.Tolosa E, Alom J: Drug induced dyskinesisas. Pages 327-347 in: Parkinson's Disease and Movement Disorders,
Jankovic J. Tolosa E (editors). Urban end Schwartzenberg 1988.
14.Van Praag HM, Ifoif J: Importance of dopamine metabolism for clinical effects and side effects of neuroleptics.
Am J Psychiatry 1976; 133:1171-1176.
15.Weiner WJ, Lang AE: Movement Disorders: A Comprehensive Survey.
Futura Publishing Company, Inc., 1989
16.Yassa R, Nair V, Dimitry R: Prevalence of tardive dystonia.
Acta Psychiatr Scand 1986; 73:629-633.
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Last updated 21 July 2020