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Medication-Induced Movement Disorders
Clinical Vignette
A 52-year-old Caucasian woman presented to a psychiatrist with her first manic episode. Patient had never been treated with any antipsychotic medication in her life. During the current episode, she was treated with aripiprazole 30 mg/day. During a follow-up visit 3 months later, the patient was found to have developed involuntary orofacial movements. She was not taking any other antipsychotic or antidopaminergic medications. The patient's psychiatrist immediately discontinued aripiprazole, but unfortunately involuntary movements persisted. Physical exam showed involuntary chewing movements of jaw, lip smacking, infrequent tongue protrusion, and twisting and side-to-side movement of the tongue. Her routine laboratory examinations (complete blood count, liver function test, and urine analysis), serum copper, ceruloplasmin, and thyroid-stimulating hormone levels were within normal limits. Computed tomography (CT) scan of head (without contrast) was negative for any acute changes. She was diagnosed with tardive dyskinesia (TD) and was then treated with various psychotropics including quetiapine, lamotrigine, and sodium valproate to control her mood symptoms. Unfortunately, TD symptoms persisted prompting initiation of tetrabenazine with subsequent improvement of tongue and lip movements.
There are a large number of pharmaceutical agents with the potential to cause a movement disorder ( Table 35.1 ). These medications primarily interfere with dopaminergic transmission within the basal ganglia (levodopa, dopamine agonists, dopamine receptor–blocking agents [DRBs]). Other classes of these movement disorder–inducing agents do not have as precisely defined biochemical mechanisms. These medications include central nervous system (CNS) stimulants, anticonvulsants, tricyclic antidepressants, and estrogens. From a clinical perspective, the medications most commonly responsible for iatrogenic movement disorders are the various neuroleptics and pharmacologic agents that block or stimulate dopamine receptors.
TABLE 35.1
Types of Drug-Induced Movement Disorders and Responsible Medications
| Syndrome | Responsible Medication |
|---|---|
| Postural tremor | Sympathomimetics Levodopa Amphetamines Bronchodilators Tricyclic antidepressants Lithium carbonate Caffeine Thyroid hormone Sodium valproate Antipsychotics Hypoglycemic agents Adrenocorticosteroids Alcohol withdrawal Amiodarone Cyclosporin A Others |
| Acute dystonic reactions | Antipsychotics Metoclopramide Antimalarial agents Tetrabenazine Diphenhydramine Mefenamic acid Oxatomide Flunarizine and cinnarizine |
| Akathisia | Antipsychotics Metoclopramide Reserpine Tetrabenazine Levodopa and dopamine agonists Flunarizine and cinnarizine Ethosuximide Methysergide |
| Parkinsonism | Antipsychotics Metoclopramide Reserpine Tetrabenazine Methyldopa Flunarizine and cinnarizine Lithium Phenytoin Captopril Alcohol withdrawal MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Other toxins (manganese, carbon disulfide, cyanide) Cytosine arabinoside |
| Chorea, including tardive and orofacial dyskinesia | Antipsychotics Metoclopramide Levodopa Direct dopamine agonists Indirect dopamine agonists and other catecholaminergic drugs Anticholinergics Antihistaminics Oral contraceptives Phenytoin Carbamazepine Ethosuximide Phenobarbital Lithium carbonate Methadone Benzodiazepines Monoamine oxidase inhibitors Tricyclic antidepressants Methyldopa Digoxin Alcohol withdrawal Toluene sniffing Flunarizine and cinnarizine |
| Dystonia, including tardive dystonia (excluding acute dystonic reactions) | Antipsychotics Metoclopramide Levodopa Direct dopamine agonists Phenytoin Carbamazepine Flunarizine and cinnarizine |
| Neuroleptic malignant syndrome | Antipsychotics Tetrabenazine with α-methyl- para -tyrosine Antiparkinsonian drugs withdrawal |
| Tics | Levodopa Direct dopamine agonists Antipsychotics Carbamazepine |
| Myoclonus | Levodopa Anticonvulsants Tricyclic antidepressants Antipsychotics |
| Asterixis | Anticonvulsants Levodopa Hepatotoxins Respiratory depressants |
The clinical temporal profile of drug-induced movement disorders can be acute, subacute, or chronic. Acute syndromes include dystonia, choreoathetosis, akathisia, and tics. Subacute syndromes include drug-induced parkinsonism and tremor. Chronic syndromes include levodopa-induced dyskinesias in Parkinson disease and tardive dyskinesia (TD). There is no direct evidence of precise CNS pathology predisposing to the development of drug-induced movement disorders. Because no precise pathoanatomic correlation or model is known, a primary biochemical mechanism is therefore the likely responsible pathophysiologic mechanism here.
Clinical Syndromes
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS) is a very unusual complication and is one of the most severe reactions to neuroleptic therapy. It has a relatively high incidence (0.5%–1%) considering the very large numbers of patients taking neuroleptic medication. Symptoms typically occur shortly after institution of neuroleptic therapy or at the time of initiating increased dosage. Young men are at higher risk than the general population. Pathogenesis is thought to involve both central and peripheral effects of dopamine receptor blockade.
Typically, NMS patients present with an acute onset of a severe movement disorder characterized by rigidity, tremor, and dystonia. There are often manifestations of very significant dysautonomic disturbances, including fever, diaphoresis, and cardiovascular/pulmonary dysfunction. Often the patients are stuporous, and a very intense concomitant myonecrosis usually accompanies the NMS; this leads to significant elevation of serum creatine kinase (usually >1000 IU/L) with its own innate risk of significant renal compromise. There is an associated leukocytosis. The fatality rate in NMS may reach as much as 20% because of the various associated complications, including dehydration, cardiac arrhythmias, pulmonary embolism, and renal failure. As soon as this clinical setting of NMS is recognized, it is very important to begin treatment. Medications that are frequently useful include levodopa, dopamine agonists, and the antispastic agent dantrolene.
Acute Dystonic Reactions
These very dramatic movement disorder syndromes usually develop within 5 days after initiation of various neuroleptic medications. This clinical picture typically presents very rapidly after initiation of the responsible therapeutic agent. The craniocervical region is the most commonly affected site. These patients are sometimes thought to have tetanus because the facial spasms may mimic the classic trismus with risus sardonicus ( Fig. 35.1 ).
Pathophysiologically, these disorders are related to a sudden imbalance between the striatal dopamine and cholinergic systems. Typically these disorders are diagnosed by their relatively acute resolution either spontaneously subsequent to drug withdrawal or more immediately by parenteral administration of an antihistamine, such as diphenhydramine, or sometimes anticholinergics.
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