Extrapyramidal Symptoms

Although antipsychotic drugs often are effective, almost all are associated with adverse effects. The most important adverse effects associated with antipsychotic drugs include EPS, some of which may be irreversible. EPS include parkinsonian syndrome, akathisia, dystonia, neuroleptic malignant syndrome, and TD.

TD (abnormal involuntary movements) may be progressive and irreversible, even after the drug is discontinued. It is characterized by rhythmic involuntary movement of the tongue, face, mouth, or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). These may be accompanied by involuntary movements of the extremities. TD has been the major limitation of first-generation antipsychotics because symptoms of TD can be disabling, preventing the patient from returning to society, even after the schizophrenia is controlled.

Neuroleptic malignant syndrome (NMS): Symptoms usually occur weeks after initiation of treatment with antipsychotics. NMS is an idiosyncratic reaction to an antipsychotic or neuroleptic drug; symptoms typically develop over a period of hours to days, and the condition is life threatening. Major symptoms include fever, catatonic stupor, muscle rigidity, autonomic instability, tachycardia, delirium, and myoglobinemia.

Parkinsonian symptoms typically occur more commonly in the elderly and with higher-potency antipsychotics, except risperidone. Symptoms include masked facies, tremor, bradykinesia, rigidity, cogwheeling, drooling, and festination.

Akathisia may be difficult to differentiate from anxiety because the two appear to be so similar. Symptoms include an intensely unpleasant need to move, restlessness, and agitation. Because of the discomfort that is felt, akathisia is often a big factor in noncompliance regarding medications.

Acute dystonia: Symptoms include muscular rigidity, usually of the tongue, neck, face, or trunk. It is most likely to occur within the first week of antipsychotic drug treatment. Acute dystonia can be frightening, extremely uncomfortable, and life threatening if laryngeal dystonia occurs.

Therapeutic Overview

It is important to understand that psychosis is not a disease. Psychosis is the term that is used to describe a general symptom complex in which gross impairment of reality is demonstrated. It has many causes—both organic and psychiatric. Box 49-1 lists symptoms that are commonly associated with the presentation of a clinical psychosis. Table 49-1 shows the most common medical disorders that may present with psychiatric symptoms, but not all of these represent psychotic symptoms. A large number of diverse and even common medications can cause psychotic symptoms (Table 49-2). Table 49-3 lists different psychiatric disorders that may present with psychosis. Therefore, it is difficult to talk about treating the general symptoms of psychosis; it is more productive to talk about specific psychotic disorders such as schizophrenia.

Many elderly patients are particularly vulnerable to the development of psychotic symptoms. The confluence of medical disorders, psychiatric disorders, and medications may easily provoke psychotic symptoms, particularly when patients move from an unfamiliar environment to a strange setting, or when a change disturbs the tenuous balance they are maintaining while coping with medical and psychiatric problems. Geriatric patients with dementia may exhibit behavioral and psychologic symptoms, which may or may not represent psychosis. These symptoms commonly include agitation, physical aggression, delusions, and hallucinations. Other behaviors, such as refusing personal care, being unable to communicate or perform daily activities, wandering, being restless, and participating in self-destructive acts, may require the use of some of these medications, sometimes for brief intervals. Research has demonstrated that the risk of developing metabolic syndrome in children and adolescents increases sharply after 3 to 12 months of antipsychotic treatment.

Mechanism of Action

The exact mechanism of antipsychotic drug action is unknown. These drugs are thought to work by blocking postsynaptic dopamine receptors in the hypothalamus, basal ganglia, limbic system, brainstem, and medulla, and to some extent serotonin receptors. Much work has been done to elucidate which receptors each drug affects. How this receptor blocking causes specific changes in behavior and cognition is not known. See Table 49-4 for specific neurotransmitter-receptor blocking actions of individual medications. Each neurotransmitter is associated with specific side effects. However, the correlation between the two is not completely understood. A very complicated and overlapping set of mechanisms interact to produce a wide variety of effects. Another complication is that these drugs produce different effects from patient to patient. Most cause sedation in some people and agitation in others (Box 49-2). Some antipsychotic drugs cause metabolic side effects such as obesity and diabetes by activating the SMAD3 protein, which plays a role in the transforming growth factor beta pathway—a cellular mechanism responsible for inflammation and insulin signaling, among other processes.

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