Medication-induced movement disorder occurs due to treatment with antipsychotic medications. Most medication-induced movement disorders are caused by medications that block the action of dop-amine , a neurotransmitter that allows communication between two neurons to take place and that is necessary for coordination of movements of different parts of the body. When the receptor where dopamine is supposed to bind is blocked, certain movement-related side effects occur. All of the medications that block dopamine receptors are called neuroleptics.

Neuroleptics include both conventional or typical antipsychotic agents, such as chlorpromazine (Thor-azine), haloperidol (Haldol), and fluphenazine (Prolixin), as well as the newer, or atypical, antipsychotic agents such as clozapine (Clozaril), risperidone (Ris-perdal), olanzapine (Zyprexa), and quetiapine (Sero-quel). In general, the newer, atypical antipsychotics appear to have a lower likelihood to cause movement disorders than the older, typical medications. Other neuroleptics include certain drugs used in the treatment of physical symptoms such as nausea, and include prochlorperazine, promethazine, and meto-clopramide, as well as amoxapine (Asendin), which is marketed as an antidepressant.

There are other medications, however, that do not block dopamine action but still cause movement disorders. They are not referred to as neuroleptics, and they include lithium carbonate , valproic acid and a

class of drugs called selective serotonin reuptake inhibitors (SSRIs ). The disorder caused by these medications is called medication-induced postural tremor.

All of the disorders caused by neuroleptics, which include antipsychotics and other medications that block dopamine, as well as disorders caused by non-neuroleptic medications, are collectively referred to as medication-induced movement disorders.

Description

Neuroleptics

Medication-induced movement disorders caused by neuroleptics are divided into three time periods. The early-onset type, which usually occurs within the first seven days of treatment with neuroleptics, is known as neuroleptic-induced acute dystonia. Neuroleptic-induced acute dystonia is characterized by abnormal contractions of various muscle groups resulting in spasm and/or twisting of the head, neck, jaw, lips, tongue, and eye muscles as well as abnormal movements and postures of the limbs and the trunk.

The intermediate-onset types of movement disorders associated with the use of neuroleptics usually develop within the first three months of treatment. They are known as neuroleptic-induced Parkinsonism and neuroleptic-induced akathisia. Neuroleptic-induced Parkinsonism is associated with difficulty initiating movements. Once movements are initiated, they are very slow. Other characteristics of neuroleptic-induced Parkinsonism are tremor and rigidity in muscles. Neuroleptic-induced akathisia is associated with uncontrollable restlessness that may involve compulsive foot tapping, pacing, and a sense of inner tension.

The late-onset type of neuroleptic-related movement disorder is known as neuroleptic-induced tardive dyskinesia and the onset is usually seen many months to years after starting the neuroleptic treatment. Neuroleptic-induced tardive dyskinesia involves grotesque, repetitive, and involuntary movements. They are usually seen in the mouth and face.

A movement disorder that can occur at any time during the course of neuroleptic treatment is known as neuroleptic malignant syndrome. It is a serious condition and is characterized by changes in consciousness, ranging from agitation to coma. The patient may experience high fever, and increases in blood pressure and heart rate, as well as severe muscular rigidity.

Non-neuroleptics

All of the movement disorders mentioned above are related to the use of neuroleptic medications. However, other drugs, such as lithium, valproic acid, iso-proterenol, amphetamine, theophylline, as well as a class of drugs known as tricyclic antidepressants, may also cause a movement disorder that is mainly characterized by postural tremor, a rhythmic alteration in movement. Lithium-induced tremor may take the form of twitching in the arms and legs.

Causes and symptoms

Causes

Neuroleptic-induced movement disorders are caused because the actions of dopamine are blocked. Dopamine is a neurotransmitter necessary for coordination of movements of different parts of the body.

Other medications, which are not classified as neuroleptics, block the action of other neurotransmit-ters as well as dopamine. However, because they essentially block the action of dopamine, they cause similar unwanted effects associated with movements.

Symptoms

Neuroleptic-induced acute dystonia is associated with primarily abnormal postures and muscular spasms. They are usually characterized by abnormal positioning of the head and neck in relation to the body, spasms of the jaw muscles, impaired swallowing, speaking or breathing, thickened or slurred speech due to a slow movement of the tongue, tongue protrusion or tongue dysfunction, eyes deviated up, down, or sideways, and abnormal positioning of the limbs or trunk. Patients experience pain and cramps in the affected muscles. In addition, many patients experiencing dystonia due to the neuroleptic treatment also experience fear and anxiety . This is especially present in patients who are not aware of the possibility of developing dystonia and who mistakenly associate these side effects as part of their mental illness.

Neuroleptic-induced Parkinsonism includes rigidity, tremor, and bradykinesia (slow movements). The tremor is a rhythmic, three- to six-cycle-per-second motion that is present at rest. The tremor can affect the limbs, head, mouth, or lips. Rigidity signifies the degree of tension present in the muscle. It can be either continuous or intermittent in the affected limbs or joints. Bradykinesia includes decreased arm movements related to walking, as well as difficulty initiating movement. Drooling may occur due to a decrease in phar-yngeal motor activity. People experiencing neuroleptic-induced akathisia usually feel anxious, agitated, and unable to relax. They also may pace, rock while sitting and standing, and often rapidly alternate between sitting and standing.

Neuroleptic-induced tardive dyskinesia manifests itself in involuntary movements of the tongue, jaw, trunk, or extremities. It occurs most commonly in patients who have taken older antipsychotic medications for many years, although the condition may appear earlier than that (after one year of treatment with neuroleptics, or even earlier than that, especially in elderly people). The movements can be rapid and jerky, slow and continual, or rhythmic in nature. Over three-fourths of the individuals with neuroleptic-induced tardive dyskinesia have abnormal movements of the face and the mouth. This may include licking, sucking or smacking of the lips, chewing movements, jaw deviations, grimacing, grunting and other peculiar sounds, or brow furrowing. About one-half of patients with tardive dyskinesia have abnormal limb movements, while about one-quarter have disposition of the trunk.

The basic features of neuroleptic malignant syndrome is the development of high fever and severe muscle rigidity. These can be accompanied by tremor, changes in level of consciousness ranging from confusion to coma, increased heart rate and blood pressure. The fever can be mildly elevated (99-100°F) or severe (106°F). Neuroleptic malignant syndrome can be fatal in some cases, while it is relatively benign in others. There are no known predictors of neuroleptic malignant syndrome. However, it usually develops four weeks after starting neuroleptics, and about two-thirds of cases develop within the first week of treatment. A very small number of patients develop neuroleptic malignant syndrome many months after taking the neuroleptic.

Medication-induced postural tremor is characterized by a regular, rhythmic oscillation of hands and fingers, head, mouth, or tongue. The frequency of the tremor ranges from eight to 12 cycles per second. These are most easily observed when the affected part is in a sustained position (for example if hands are outstretched or the mouth is held open).

Demographics

Neuroleptic-induced acute dystonia occurs most commonly in young males. It is far less likely to occur with the newer medications known as atypical neuroleptic medications, such as clozapine, risperidone, olanzapine, and quetiapine. The possibility of neuroleptic-induced acute dystonia occurring with these atypical medications is less than 5%. The possibility of this side effect occurring with the conventional or typical neuroleptics is about 15-20%. The incidence is inversely correlated with age, meaning that younger persons are more likely to experience dystonia.

Neuroleptic-induced Parkinsonism is directly correlated with age. This means that older patients are more likely to experience this effect. It occurs in about 30% of patients. Neuroleptic-induced acute akathisia is not related to age and occurs in about 20% of patients being treated with neuroleptics.

The incidence of neuroleptic-induced tardive dyskinesia is related to total lifetime of treatment with antipsychotics. The cumulative incidence is about 5% per year of therapy. This essentially means that there is a 50% chance of developing tardive dyskinesia with 10 years of treatment with neuroleptics.

The incidence of neuroleptic malignant syndrome is about 0.5%. This condition is fatal in about 20 to 30% of cases.

Most available information on medication-induced postural tremor is about lithium-induced tremor. The prevalence of this condition is about 40%.

Diagnosis

People taking antipsychotic medications and other medications that block dopamine action must be regularly evaluated by a physician to monitor for medication-induced movement disorders. In order for these conditions to be officially diagnosed, certain criteria must be met.

Neuroleptic-induced acute dystonia must have one or more of the following developed in association with the use of neuroleptic: abnormal positioning of the head and neck in relation to the body, spasms of the jaw muscles, impaired swallowing, thickened or slurred speech, tongue protrusion or dysfunction, eyes deviated up, down, or sideways, or abnormal positioning of limbs or trunk. These symptoms need to have developed within seven days of starting the neuro-leptic medication. Moreover, the symptoms cannot be associated with an underlying mental disorder, and they can’t be due to a medication other than a neuro-leptic. Dystonia due to neuroleptics needs to be distinguished from dystonia due to neuroleptic malignant syndrome.

Neuroleptic-induced Parkinsonism needs to have the triad of symptoms described above which include tremor, rigidity, and bradykinesia (slow movements). These symptoms cannot be related to a non-neuroleptic medication, or a psychiatric condition, such as Parkinson’s disease, Wilson’s disease, neuroleptic malignant syndrome, or substance withdrawal. Neuroleptic-induced akathisia is due to the use of a neuroleptic and not to anxiety, substance withdrawal or psychotic agitation. At least one of the symptoms of fidgety movements or swinging the legs, rocking from foot to foot while standing, pacing to relieve restlessness, or inability to sit and stand needs to be present. These symptoms must have developed within four weeks of initiating the therapy with neuroleptics.

Neuroleptic-induced tardive dyskinesia needs to include involuntary movements over a period of at least four weeks that manifest themselves as rapid and jerky, slow and continual, or rhythmic movements. The exposure to neuroleptics needs to be for at least three months, and the symptoms cannot be due to a neurologic condition, such as Huntington’s disease, Wilson’s disease, Sydenham’s (rheumatic) chorea, systemic lupus, or hyperthyroidism.

Neuroleptic malignant syndrome must include severe muscle rigidity and elevated temperature as well as at least two of the following symptoms: sweating, difficulty swallowing, tremor, incontinence, changes in level of consciousness, mutism, increased heart rate, elevated blood pressure, or laboratory evidence of muscle injury. These symptoms cannot be due to another substance or a medical condition, such as viral encephalitis, or mood disorder with catatonic features.

The criteria for diagnosing medication-induced postural tremor includes a development of tremor associated with the use of a medication other than a neuroleptic. The tremor cannot be due to a non-medication condition that was present prior to starting the medication and cannot continue to be present following discontinuation of the medication. These criteria are helpful in distinguishing the tremor due to medication use from the tremor due to anxiety, alcohol withdrawal, stress , or fatigue . The tremor must have a frequency between eight and 12 cycles per second, and the tremor must not be caused by neuroleptic-induced Parkinsonism.

Treatments

In an attempt to prevent acute dystonia from developing, physicians may prescribe a preventative medication along with the antipsychotic (see “Prevention,” below). Once neuroleptic-induced acute dystonia has appeared, however, there are several treatment options. A medication called benztropine in doses ranging from 1 mg to 8 mg is effective in reducing symptoms associated with dystonia. Most patients take 2 mg twice daily for seven days for prevention of dystonia at the time they are starting neuroleptic treatment. When benztropine therapy is initiated, the dose is slowly increased. Moreover, when discontinuing the treatment with benztropine, the dose should be slowly decreased to prevent the nausea and vomiting associated with abrupt withdrawal. Another medication that may be useful in treating neuroleptic-induced acute dystonia is called trihexyphenidyl . The doses can vary from 10 mg to 45 mg daily. Younger patients may respond better to the treatment with trihexyphenidyl because they can tolerate higher doses. The third pharmacological option is diphenhydramine (Benadryl). This medication can be taken for the period dystonic symptoms last. Another option may include switching the patient to one of the newer anti-psychotics, such as clozapine, risperidone, or olanza-pine, since each of these has a low incidence of causing dystonia.

There are a couple of ways to treat intermediate-onset movement disorders due to neuroleptics. Aman-tadine is a medication that is approved by the United States Food and Drug Administration for the treatment of Parkinsonian symptoms. Another helpful medication called propranolol comes from a class of drugs called beta blockers . Propranolol has been reported effective in the treatment of akathisia. The doses that are effective range from 20 mg to 100 mg daily. The response to propranolol is usually seen within the 24 hours of administration. Switching the patient to a newer or atypical antipsychotic, such as clozapine, or decreasing the dose of the current anti-psychotic sometimes helps the condition.

There are no effective treatments for tardive dyskinesia once it develops. Tardive dyskinesia is associated and strongly correlated with the cumulative dose of the antipsychotic during years of treatment. Hence, the key to tardive dyskinesia is prevention. If possible, a newer medication, such as clozapine or risperidone, which have only a few case reports of tardive dyskinesia, should be used whenever possible.

KEY TERMS

Dystonia —A neurological disorder characterized by involuntary muscle spasms. The spasms can cause a painful twisting of the body and difficulty walking or moving.

Hyperthyroidism —Condition resulting from the thyroid glands secreting excessive thyroid hormone, causing increased basal metabolic rate, and causing an increased need for food to meet the demand of the metabolic activity; generally, however, weight loss results.

Neuroleptic —Another name for antipsychotic medications, such as haloperidol (Haldol) and chlorpro-mazine (Thorazine).

Neuroleptic malignant syndrome —An unusual but potentially serious complication that develops in some patients who have been treated with antipsychotic medications. NMS is characterized by changes in blood pressure, altered states of consciousness, rigid muscles, and fever. Untreated NMS can result in coma and death.

Neuroleptic-induced acute dystonia —A severe form of the neurological movement disorder caused by the use of neuroleptic drugs.

Neuroleptic-induced akathisia —Refers to the disorder characterized by a physical restlessness (the inability to sit still, for example), and manifested by excessive voluntary movements, as a result of the use of neuroleptic drugs; research indicates it is likely the most common of neuroleptic-induced movement disorders.

Neuroleptic-induced Parkinsonism —Symptoms similar to Parkinson’s disease that may appear in people taking neuroleptic (antipsychotic) medications. These symptoms include tremors in muscles and a shuffling gait.

Neuroleptic-induced tardive dyskinesia —A potentially irreversible neurological disorder caused by the use of antipsychotic/neuroleptic medications, with symptoms involving uncontrollable movement of various body parts.

Postural tremor —A continuous quiver that affects body posture and movement.

SLE (Systemic Lupus Erythematosus) —An autoimmune disease that leads to inflammation and damage to various body tissues and parts, including joints, skin, kidneys, heart, lungs, blood vessels, and brain.

Sydenham’s chorea —A serious manifestation of acute rheumatic fever that commonly occurs in children ages seven through 14, peaking at age eight. This disease of the central nervous system is characterized by emotional instability, purposeless movements, and muscular weakness. At its peak in the 1950s it occured in nearly 50% of the acute rheumatic fever cases, but by 2002 had subsided to a degree of less than 10% of the acute cases.

In many cases, if tardive dyskinesia is noticed early in a regular check-up with the physician, and if the medication causing the condition is stopped, the symptoms of tardive dyskinesia will subside. If the symptoms continue after the antipsychotic has been discontinued, the situation becomes difficult. Treatment will most likely involve movement disorder specialists and may or may not be successful. The medications reserpine and levodopa may be helpful for some patients.

The most common medications used to treat neuroleptic malignant syndrome are dantrolene, (a muscle relaxant that helps with the fever), bromocriptine, and amantadine.

In order to reduce medication-induced postural tremor, the lowest possible dose of the psychiatric drug should be used. Moreover, a medication from the beta blockers, such as propranolol, can be used to help with the symptoms.

Prognosis

The prognoses for the early- and intermediate-onset of movement disorders are very good, especially with the option of switching the patient to a newer antipsychotic such as clozapine.

The prognosis for the late-onset disorder called tar-dive dyskinesia is very poor. Once the condition occurs, it is essentially irreversible and is very difficult to treat.

Neuroleptic malignant syndrome is a serious condition. It is deadly in about 20 to 30% of patients. Those who survive have a good chance of recovering.

Medication-induced postural tremor is very well-controlled with propranolol, and hence the prognosis is good while the patient is being treated with the medication causing the movement disorder.

Prevention

To prevent acute dystonia, some physicians prescribe benztropine, diphenhydramine, or other medications that treat dystonia, at the outset of treatment with an older antipsychotic.

The most important component of neuroleptic-induced tardive dyskinesia is prevention. If conventional antipsychotics are used, the drug use, drug dose, and the duration of use therefore should be minimized.

In order to avoid medication-induced postural tremor, patients should limit the amount of caffeine consumption. Also, in order to minimize the amount of daytime tremor they should take the psychiatric drug at bedtime.

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revised. Washington, DC: American Psychiatric Association, 2000.

Lacy, Charles F. Drug Information Handbook. Lexi-Comp, Inc. 2002.

Kaplan, Harold. Comprehensive Textbook of Psychiatry. Williams and Wilkins, 1995.

Gilman, Alfred G. The Pharmacological Basis of Therapeutics. McGraw-Hill, 1996.