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Side effects of antipsychotic drugs
Avoiding and minimizing their impact in elderly patients
Bruce L. Saltz, MD Margaret G. Woerner, PhD; Delbert G. Robinson, MD; John M. Kane, MD
(Postgraduate Medicine 2000, Volume 107, No. 2)
PREVIEW
Clearly, the use of antipsychotic can be extremely helpful in elderly patients to reduce psychotic symptoms and agitation. However, these drugs may produce serious side effects, such as Parkinsonism, akathisia, dystonia, and tar dive dyskinesias, that can range in intensity from mild to severe. In this article, the authors describe how to use antipsychotic agents in the most careful fashion possible.
Antipsychotic drugs are widely used in facilities for the elderly and in general hospitals to treat older patients who have behavioral problems. More than 20 of these drugs have been introduced to the United States since the early 1950s. Agents in use through the 1980s are referred to as typical (also standard or first generation) antipsychotic drugs. Newer agents developed in the 1990s are called atypical (also novel or new generation) drugs. Typical agents include both low and high potency formulations (table 1).
Regardless of whether a patient is receiving typical (either low or high potency) or atypical antipsychotic drugs, thorough medical evaluation is important to identify, if possible, the cause of psychosis and of any abnormal motor activity that may be present.
Typical antipsychotic drugs
Chlorpromazine hydrochloride (Thorazine), which is seldom used today, was the first antipsychotic agent. It and other low-potency agents, such as thioridazine hydrochloride (Mellaril), often are not well tolerated by older patients because of anticholinergic side effects. In addition, these agents are quite sedating; in fact, in the 1960s and early 1970s, low-potency drugs were sometimes used in sedative hypnotics. However, with increased recognition of their serious side effects, they are no longer used for this purpose. High potency agents, such as haloperidol (Haldol), are less anticholinergic and less sedating, but they are more likely to cause parkinsonism and dystonia. The most commonly used antipsychotic regimen in the elderly is low doses of high potency agents.
Atypical antipsychotic drugs
Clozapine (Clozaril) was the first new-generation antipsychotic agent. It is often effective in patients who do not respond to typical agents. Although clozapine rarely produces motor side effects, it has the potential to cause agranulocytosis, increase heart rate, and lower the seizure threshold, so its use as first-line therapy is restricted. Therefore, a search was undertaken for similar compounds that did not cause serious side effects. Three additional new generation drugs are now available: risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine fumarate (Seroquel). A fourth, ziprasidone, is undergoing development.
These newer atypical antipsychotic agents do not cause agranulocytosis, but they have not yet shown the unique therapeutic efficacy of clozapine. They usually cause fewer parkinsonian symptoms than the typical agents when given in doses at the lower end of their therapeutic range. Therefore, atypical antipsychotic agents may have a role in treatment of psychosis or agitation in patients with idiopathic Parkinson's disease. The extent to which these newer drugs produce tardive dykinesia (TD) is still under investigation.
Nonmotor side effects
Elderly people are sensitive to several of the serious nonmotor side effects that can result from use of antipsychotic agents, including sedation, orthostatic hypotension, changes in heart rate and rhythm, incontinence, and reduced appetite. In addition, the elderly are especially sensitive to anticolinergic effects (eg, constipation, blurred vision, dry mouth, urinary retention). Antipsychotic drugs can produce cognitive deficits; because many older adults already have such problems, it is important to check for pre-existing cognitive deficits before starting therapy.
Neuroleptic malignant syndrome is a rare but potentially fatal side effect of antipsychotic drug treatment. Unlike many other adverse reactions to these drugs, the syndrome affects olds and young adults equally. Signs include muscle rigidity, unstable heart rate and blood pressure, diaphoresis and dehydration, hyperthermia, and a high creatine kinase level. Patients usually have leukocytosis and oftern delirium. Myoglobinuria occurs often and can cause renal insufficiency.
However, none of these findings is pathognomonic for neuroleptic malignant syndrome, so careful workup is needed in any patient taking antipsychotic drugs who has any of these signs.
Medical workup for neuroleptic malignant syndrome should consist of a thorough physical examination, complete blood cell count with differential, sedimentation rate and thyroid hormone measurements, serum chemistry profile (including serum and urinary copper levels), and brain magnetic resonance imaging if intracranial disease is suspected. Any indication of neuroleptic malignant syndrome requires immediate discontinuation of antipsychotic drugs and consultation with an expert.
Reversible neuromotor side effects
Common neuromotor side effects of antipsychotic drugs (table 2) can be grouped into two basic categories: reversible effects, which usually disappear after the dose is lowered or the drug is discontinued, and potentially irreversible effects, which may persist even after discontinuation of drug therapy. As a general rule, reversible side effects appear first.
Parkinsonism
Drug-induced parkinsonism, which develops in about 40% of older adults treated with typical antipsychotic drugs, is often indistinguishable from idiopathic Parkinson's disease. It can occur in patients given very low doses and once it develops, it usually does not abate without dose reduction or Parkinson's disease therapy. Drug-induced parkinsonism causes uncomfortable symptoms, contributes to falls in the elderly, and may increase social isolation by decreasing mobility. In addition, it can make management of the underlying illness more difficult.
Signs of drug-induced parkinsonism are the same as those of idiopathic Parkinson's disease: tremor, rigidity of muscle tone expressed predominantly as difficulty in flexion and extension of major joints, reduction in and slowness of speech and movement accompanied by a general loss of spontaneity (sometimes resembling depression), increased salivation and drooling, micrographia, and seborrhea.
Parkinsonian tremor may occur at rest or during action. It disappears with sleep and worsens with stress and anxiety. Pill rolling movements of the hand are common. Lithium-induced tremor or the motor disturbance of thyroid or liver disease (usually called asterixis) is sometimes difficult to differentiate from parkinsonian tremor; however, tremor caused by these other disorders usually oscillates at a slightly faster frequency than parkinsonian tremor. The tremor of cerebellar disease, because it is often absent at rest and is more coarse, is usually relatively easy to distinguish from parkinsonian tremor.
In parkinsonian rigidity, affected muscles are continuously firm and tense, even when patients appear quiet and relaxed. The best technique for eliciting rigidity is testing for passive range of motion. Examination reveals increased resistance to passive movement throughout the range of motion of the effected limb. Sometimes ratchetlike resistance (ie, cogwheel rigidity) is also found. Other signs of rigidity include stiff gait, difficulty initiating motion or turning, and slow and inaudible arm dropn. To test arm drop, have patients hold their arms straight out to the sides, parallel to the ground. Tell them to drop their arms to their sides. In patients with rigidity, the arms descend slowly and do not make the slapping sound against the thighs that this maneuver normally makes.
Rigidity and akinesia (ie, lack of movement) of parkinsonism can occur concurrently or independently. Movement and speech may be slow or infrequent. In severe cases, patients may have reduced shifting of body positions or posture, and in extreme cases, they may be completely immobile for long periods of time. Sometimes, depression is difficult to differentiate from the akinesia of parkinsonism. Therefore, patients should be asked about mood and features that often characterize depression (eg, decreased appetite, sleeping problems, decreased interest in pleasurable activities, suicidal ideation).
Patients should always be evaluated for idiopathic Parkinson's disease before antipsychotic drugs are prescribed. Some patients with features of idiopathic Parkinson's disease need antipsychotic therapy for psychosis or behavioral disturbances. Before such therapy is undertaken, consultation with a specialist in psychiatry or neurology is usually a good idea.
Akathisia should be carefully discerned from agitation. Increasing the antipsychotic drug dose in an erroneous attempt to control agitation exacerbates akathisia.
Akathisia
This condition is common and should always be considered when evaluating agitated or restless older adults. Akathisia is characterized by motor restlessness accompanied by a feeling of inner restlessness (sometimes described as anxiety), an urge to move, and an inability to sit still. Patients often describe themselves as "jumping out of their skin." In severe cases, patients may pace or continuously move their feet and legs.
Akathisia should be carefully discerned from agitation, because increasing the dose of antipsychotic medication in an erroneous attempt to control agitation exacerbates akathisia. Usually, akathisia gets worse when the antipsychotic dose is raised and improves when the dose is lowered, whereas agitation may worsen with dose reduction.
Potentially irreversible neuromotor side effects
Patients may have reversible and irreversible neuromotor side effects simultaneously. In the elderly, irreversible side effects may occur after only a few weeks of antipsychotic treatment. Acute dystonia is often reversible but is much more rare in the elderly than in younger patients; dystonia that develops later in the course of therapy is less often reversible. TD develops more rapidly in the elderly than in younger patients, and it is more likely to be irreversible in the elderly.
Dystonia
Typified by sustained contraction of muscles, dystonia usually causes twisting postures and may be visible only when the patient is moving. Neck and arm muscles are most commonly affected, but a painful condition involving the eye muscles may also occur. In this condition, called oculogyric crisis, the patient's eyes may rotate upward or to the side and remain fixed in that position for lenghthy periods of time (often seconds to minutes, but occasionally a few hours if not treated).
Dystonia may occur when antipsychotic treatment has just begun, or it may appear after prolonged treatment. Acute dystonia is much more rare in the elderly than in the younger patients, but if it occurs, it requires immediate treatment.
Tardive dyskinesia
Patients with TD have involuntary movements, most often of the muscles of the face, mouth, and tongue. Orofacial movements are almost always present in elderly patients with TD and are the only dyskinesia in about 40% of these patients. Distinguishing TD from movements related to tooth or denture problems can be difficult in patients with orofacial movements only. In addition, about 5% of elderly patients have spontaneous orofacial dyskinesias that is not related to drug exposure, and much higher percentages with neurologic disorders have orofacial movements.
TD may also affect the arms, fingers, legs, and toes. The most common TD manifestations in the upper extremities are finger movements. Common TD movements of the lower extremities include stamping, ankle rotation, and toe movements. TD movements of the neck and trunk are rare but can be very disabling. In severe cases of TD, the whole body may be involved. Very rarely, the muscles that control breathing and swallowing are affected. Involvement of respiratory muscles produces sudden, forced, audible inspiration and expiration or grunting.
Choreiform movements are most common, but choreoathetoid, ballistic, dystonic, and ticlike movements are also seen. Movements of TD may resemble those of other disorders (eg, antiparkinsonian- or psychostimulant-induced dyskinesias, Huntington's chorea), but additional characteristics of the other conditions are usually absent in patients with TD (eg, the dementia of Huntington's chorea).
TD develops in older patients about three to five times faster than in younger patients. In young adults, TD develops in about 5% after 1 year of antipsychotic treatment and in about 15% after 3 years of treatment. In striking contrast, in elderly patients, TD develops in about 25% after 1 year of treatment and in about 53% after 3 years of treatment. In older patients, TD movements may be more severe and more likely to persist after antipsychotic drugs are discontinued.
Fortunately, in most cases, abnormal movements are mild and not profoundly disabling; some affected patients are not even aware of their movements. Most abnormal involuntary movements can be consciously suppressed for brief periods. They often disappear during sleep and increase with anxiety or activation techniques during examination. Severe cases in which TD interferes with a patient's mobility are rare, although embarrassment about the unusual movements may lead to social withdrawal and isolation in some patients. There is no way to predict which patients will have the mild form and which will have a severe form of TD.
Patients who have drug-induced parkinsonism early in treatment for depressive disorders are more vulnerable to TD. Patients treated with antipsychotic drugs for prolonged periods and at higher dosages are also at increased risk. In particular, elderly patients who were treated with electroconvulsive therapy or have a history of alcohol abuse or diabetes are at increased risk of TD.
Prevention and treatment
Prevention is always the first strategy in managing side effects of antipsychotic drugs. In fact, it is the only strategy in management of TD, since no treatment has proved effective. General principles of prevention may be recalled with use of mnemonic CARE (see box above).
What can be done once drug induced parkinsonism, akathisia, or dystonia has developed? These side effects have different treatments, but all share the need to first reevaluate therapy and lower the dose or, if possible, discontinue the antipsychotic agent altogether. An alternative is to try one of the newer antipsychotic drugs, such as risperdone, olanzapine, or quetiapine. The new agents may cause fewer side effects than earlier agents, but they have their own side effects and are much more expensive. Consultation with a psychopharmacology may be a good idea when switching to a newer agent.
Drug-induced parkinsonism
In patients with drug-induced parkinsonism who do not respond to dose reduction or switching to another antipsychotic, treatment with an anticholinergic medication is usually effective. Benztropine mesylate (Cogentin) is the most commonly prescribed of these agents. They should be used sparingly and for as short a time as possible, because they may cause memory problems, increased heart rate, blurred vision, constipation, and urinary retention in older people. Although levodopa-carbidopa in the form of Sinemet is the standard agent given for the idiopathic Parkinson's disease, it is not used in drug-induced parkinsonism because of its potential for causing hallucinations, delusions, and dyskinesias.
Akathisia
In patients with signs of akathisia, treatment with a benzodiazepinesuch as lorazepam (Ativan), low-dose propranolol hydrochloride (inderal), or the alpha-adrenergic drug clonidine hydrochloride (Catapres) is often effective. Initial treatment should be for 5 to10 days, and the dose should then be reduced if possible. However, some patients may need ongoing akathisia therapy for the duration of antipsychotic treatment.
Akathisia medications can have adverse effects in older people (eg, gait instability, confusion, addiction potential in the case of benzodiazepines), so changing the antipsychotic drug or reducing the dose is still the best long term management strategy.
Acute dystonic reactions require immediate attention and usually respond to an anticholinergic drug.
Dystonic reactions
Acute dystonic reactions require immediate attention and usually respond to an anticholinergic drug, such as benztropine or diphenhydramine. Intramuscular administration is sometimes required. When the acute dystonic episode is under control, the antipsychotic medication should be changed or the dose lowered. Oral anticholinergic therapy is sometimes required during adjustment of the antipsychotic agent.
Tardive dyskinesia
Although some compounds have been reported to be potentially therapeutic in TD, none has demonstrated effectiveness in controlled trials. Vitamin E, for example, initially seemed promising, but a recent study indicates that it may be no more beneficial than placebo.
The newer antipsychotic agents (ie, risperidone, olanzapine, and quetiapine) may have less potential to cause TD than the older drugs. Whether these agents should supplant the earlier ones as first-line therapy will become clearer as more is learned about use of these compounds in geriatric populations. Clozapine is unique among antipsychotic drugs in having very low or no risk of causing TD, but its adverse-effect profile severely resists its use in the elderly.
Lowering or discontinuing the anti psychotic drug should probably be attempted if TD movements develop, even though this change may make the movements worse, at least temporarily. TD is most likely to be first observed when the dose is lowered or the antiopsychotic drug is stopped, because antipsychotic drugs, which cause TD, may also suppress TD movements. In very severe cases, raising the dose to suppress the movements may be necessary. If the patient is taking a low-potency drug, switching to a less anticholinergic high-potency agent may be the best strategy for suppressing TD movements.
If a patient with TD still needs antipsychotic therapy for behavioral control, consider using one of the atypical drugs, although as yet, few data are available about their effects on preexisting TD.
Summary
Antipsychotic drugs are very useful in treatment of psychosis and severe agitation in the elderly. Their use for other behavioral problems is contraindicated. Antipsychotics have many potential side effects (eg, sedation, cardiovascular effects, incontinence,
anticolinergic effects, reduced appetite, such motor disturbances as drug-induced parkinsonism, akathisia, dystonia, TD).
Prevention, by using the minimum dose and duration of treatment possible, is the key to managing motor side effects. If prevention fails, drug-induced parkinsonism and dystonia may improve with use of anticholinergics, and akathisia may improve with use of benzodiazepines or low-dose propranolol. There is no proven treatment for TD, which is most likely to be observed during dose reduction or after discontinuation of antipsychotic drugs.
Compared with older agents, newer antipsychotic drugs are less likely to cause parkinsonism, akathisia, and dystonia and may cause TD less often. More research is needed to clarify use of the new drugs in the elderly. PGM
Adapted from a video tape entitled "Recognizing and Managing Antipsychotic Drug Side Effects" that was jointly sponsored by Mental Health Advocates, Inc, Boca Raton, Florida, and Long Island Jewish Medical Center, New Hyde Park, New York. This project was funded by a grant from the National Institutes of Health (Institute on Aging) under No. IR43AG13785-01A1. Earn CME credit on the web. www.postgradmed.com
References
1. Harrington C, Tompkins C, Curtis M, et al. Psychotropic drug use in long term care facilities: a review of the literature. Gerontologist 1992;32(6):822-33
2. Salzman C. Treatment of agitation in the elderly. In Meltzer HY, ed. Psychopharmacology: the third generation on progress. New York: Raven Press, 1987:1167
3. Kane JM, Woerner MG, Pollack S, et al. Does clozapine cause tardive dyskinesia? J Clin Psychiatry 1993;54 (Sep):327-30
4. Saltz BL, Woerner MG, Lieberman JA, et al. Development of drug induced parkinsonism in elderly individuals receiving neuroleptics for the first time. International Congree on Schizophrenia Research. Tuscon, Arizona: 1990 Apr
5. Barnes TR. The present status of tardive dyskinesia and akathisia in the treatment of schizophrenia. Psychiatric Developments 1987;4:301-19
6. Burke RE, Fahn S, Marsden CD, et al. Validity and reliability of a rating scale for the primary torsion dystonias. Neurology 1985;35:73-7
7. Delwaide PJ, Desseilles M. Spontaneous buccolinguofacial dyskinesias in the elderly. Acta Neurol Scand 1977;56(3):256-62
8. Brandon S, McClelland HA, Protheroe C. A study of facial dyskinesia in a mental hospital population. Br J Psychiatry 1971;118:171-84
9. Woerner MG, ALvir JM, Saltz BL, et al. Prospective study of tardive dyskinesia in the elderly: rates and risk factors. Am J Psychiatry 1998;155(11):1521-8
10. Jeste DV, Caligiuri MP, Paulsen JS, et al. Risk of tardive dyskinesia in older patients: a prospective longitudinal study 266 outpatients. Arch Gen Psychiatry 1995;52(Sep):756-65.
11. Mental Health Advocates. Recognizing and managing antipsychotic drug side effects (a videotape-based educational program). Boca Raton, Florida: Mental Health Advocates Inc, 1998
12. Adler L, Angrist B, Peselow E, et al. Noradrenergic mechanisms in akathisia: treatment with propranolol and clonidine. Psychopharmacol Bull 1987;23(1):21-5
13. Nishikawa T, Tanaka M, Tsuda A, et al. Clonidine therapy for tardive dyskinesia and related syndromes. Clin Neuropharmacol 1984;7(3):239-45
14. Tollefson GD, Beasley CM Jr, Tamura RN, et al. Blind, controlled, long-term study of the comparative incidence treatment-emergent tardive dyskinesia with olanzapine or haloperidol. Am J Psychiatry 1997;154(Sep):1248-54
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