The antipsychotics have the capacity to sedate, tranquilize, blunt emotional expression, attenuate aggressive and impulsive behavior, and cause disinterest in the environment and lack of initiative. Unique features of the drugs are that higher intellectual functions are left relatively intact and yet they act to specifically ameliorate the agitation and bizarre behavior and thinking of psychotic patients. Unfortunately no antipsychotic medication currently available even approaches what an ideal drug in this group should be. Virtually all have prominent anticholinergic side effects and produce a wide variety of dystonias and extrapyramidal symptoms. Of greater concern is the fact that these agents cause tardive dyskinesia, a seriously disabling movement disorder that is often irreversible. Nonetheless, the antipsychotics, primarily used in schizophrenia, have reduced enormously the patient populations in mental hospitals and have allowed for maintenance in the community of chronic mentally ill patients who before the advent of neuroleptics would have been lifelong residents of hospitals.
Mechanism of action of the antipsychotics With few exceptions, antipsychotics have notable effects on the brain’s dopaminergic neurotransmitter system. Specifically, antipsychotics antagonize the effects of the neurotransmitter dopamine in the basal ganglia and in the limbic portions of the forebrain. Since one of the central characteristics of neuroleptics is their capacity to block dopaminergic neurotransmission, this has led researchers to postulate that abnormalities in the CNS dopaminergic neurotransmitter systems are one of the central underlying pathophysiologic mechanisms in the etiology of schizophrenia. While specific aspects of the brain mechanism(s) by which the antipsychotics mediate their effects have been well-established, the full and detailed understanding of how these drugs actually work is not yet available.
Clinical conditions in which the antipsychotic medications are used Because the risk of tardive dyskinesia is significant, antipsychotics should only be used when necessary and in those conditions for which they are the drug of choice. Antipsychotics are drugs of choice in the treatment of schizophrenic disorders, in combination with lithium for acute manic episodes, and in combination with antidepressants for psychotic and agitated depressions. They are also used in Tourette’s syndrome and Huntington’s disease. There is a relatively narrow spectrum of mental disorders for which the antipsychotics should be used, although these disorders, in terms of sheer numbers of patients, make up a significant majority of patients with serious and chronic mental illness.
Clinical use of the antipsychotics
Chlorpromazine, one of the first drugs of this class developed, is the prototype antipsychotic drug and is the potency standard for the others. Dose equivalency for the antipsychotics is calculated on a ratio of the effect of that particular drug compared to the effect of 100 mg of chlorpromazine. For example, 5 mg of trifluoperazine or 2 mg of haloperidol is equivalent in potency to 100 mg of chlorpromazine. Using this ratio as a reference point, acutely psychotic patients usually require an accumulated dose of 500 to 800 mg orally of a chlorpromazine equivalent during the first 24 to 36 h. Following control of the acute agitation, the oral dose is increased over the next week to the chlorpromazine equivalent of between 600 and 1500 mg a day in divided doses. It is uncommon for therapeutic benefits to be measurably increased by exceeding the daily dose equivalent of 1500 mg of chlorpromazine, although it may be necessary to go to two and three times this level in some patients.
Schizophrenia is a chronic disorder and patients need long-term maintenance on antipsychotics to prevent relapse. In controlled studies as many as 60 percent of schizophrenics relapse within 6 months after discontinuing drug therapy. Patients are maintained on the lowest dose possible that will prevent reemergence of symptoms. This is usually in the range of 20 percent of the peak dose level needed to ameliorate the acute phase of the psychotic symptoms. Compliance is difficult to achieve in this chronically disordered group of patients, and it is often therapeutically advantageous for the clinician to use parenteral long-acting fluphenazine enanthate or decanoate, which can be administered by injection every week or two. Previously it was recommended that drug holidays be used, but this has not prevented tardive dyskinesia and there are few if any advantages to this technique, which is now rarely used.
Side effects and interactions with other drugs Initially patients are sedated, lethargic, and drowsy, but within days they develop tolerance to these effects. All of the antipsychotics have anticholinergic action, which may produce dry mouth, cycloplegia, postural hypotension, constipation, and urinary retention. Obstructive jaundice, retinal pigmentation, lenticular opacities, skin pigmentation and hypersensitivity to sunlight, and male impotence are also side effects seen with antipsychotics.
It is the extrapyramidal side effects that are the most bothersome. During the first five days of treatment patients may develop acute muscular dystonic reactions but the extrapyramidal Parkinson-like syndrome is the most common. Both the dystonias and the parkinsonism respond well to antiparkinsonian medications (benztropine mesylate, 1 to 2 mg bid or tid; trihexyphenidyl, 2 to 5 mg bid or tid, etc.). Another common side effect is akathisia, a motor restlessness in which patients feel compelled to move their extremities and to move about. It is not uncommon to mistake akathisia for psychotic agitation and increase the antipsychotic dose, exacerbating the problem. Akathisia may respond to antiparkinsonian agents but more often requires decreasing the dose of the antipsychotic. It is rarely necessary to continue antiparkinsonian drug treatment beyond the first 3 months of antipsychotic maintenance.
The most serious side effect of the antipsychotics is tardive dyskinesia, which has been seen with virtually every neuroleptic. The specter of tardive dyskinesia has altered the risk/benefit ratio of the antipsychotics so that exposure to these drugs should be reserved for those disorders in which these compounds are clearly the drugs of choice. Usually the symptoms of tardive dyskinesia appear late and consist of involuntary, repetitive movements of the lips, tongue (tongue thrusting, lip smacking, etc.) and not infrequently, of the extremities and trunk. Patients over 60 and those with preexisting CNS pathology are at a higher risk for this disorder, but no other risk factors have been identified. Further, no method of prevention or effective treatment for this frequently irreversible disorder has been developed. Mild to moderate tardive dyskinesia has been found in 10 to 20 percent of chronically hospitalized schizophrenics.
The malignant neuroleptic syndrome, a rare complication of neuroleptic drugs.
Newer antipsychotic drugs The newer antipsychotic drugs offer, at best, only slight improvements in the side effect profile over the older drugs and achieve little or no improvement in clinical effectiveness. Two of the more promising new antipsychotics are clozapine and sulpiride, but they are not routinely available in the United States. Each has a different molecular structure from the other neuroleptics, which may herald the development of new classes of safer and better antipsychotics.