Clozapine: A new antipsychotic drug

Clozapine:A New Antipsychotic Drug Diane Hamilton

Clozapine is a new antipsychotic drug that displays antipsychotic efficacy of the classic neuroleptics without the associated extrapyramidal side effects. This article briefly reviews the action and use of clozapine in order to help nurse clinicians become familiar with the drug usage. Clozapine is present@ in use only in cllnical trials, but la expected to be marketed by Sandoz Pharmaceutical

Corporation (Hanover, NJ) in 1990. 0 1990 by W.B. Saunders Company.

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N THE LAST TWO decades, a new series of antipsychotic agents belonging to the dibenzodiazepines was introduced. These drugs include loxapine, metiapine, and clozapine. Loxapine and metiapine are classic neuroleptics, in that they have both antipsychotic properties and a tendency to produce extrapyramidal side effects, such as dyskinetic movements and tardive dystonia and dyskinesia. The clinical trials using clozapine, however, suggest that this drug displays antipsychotic efficacy without associated clinical involvement of the extrapyramidal system. The lack of extrapyramidal side effects with clozapine stimulated European researchers in the 1970s to speculate that the availability of the drug would represent a major innovation in the treatment of schizophrenia. When patients receiving clozapine developed a high rate of agranulocytosis, the researchers’ hope vanished. Studies of patients receiving clozapine suggested that the overall incidence of agranulocytosis was 1 to 2:100, which is 10 to 20 times greater than that of typical neuroleptic agents. Because of the toxicity, clozapine has been generally unavailable in the United States except under humanitarian protocols or strictly monitored investigations (Simpson & Varga, 1974; Chapelle et al., 1977; Small et al., 1987). Despite its toxicity, the potential for the efficacy From the Department of Psychiatry, Medical University of South Carolina, Charleston. Address reprint requests to Diane Hamilton, R.N., Ph.D., Department of Psychiatry, Medical University of South Carolina. 171 Ash1e.uAve., Charleston, SC 29425. 0 1990 by W.B. sunders Company. 0883~9417/90/0404-0008$3.00ool0

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of clozapine without the discomfort that results from akathesia, akinesia, and tardive dyskinesia encouraged researchers to approach the Federal Drug Administration (FDA) and Sandoz Pharmaceutical Corporation (Hanover, NJ), the manufacturer of clozapine, to permit a multicenter clinical trial in treatment-resistant schizophrenics (Meltzer, 1988). Three hundred patients with a mean age of 35, a mean of nine previous admissions, and a mean duration of 6 years’ hospitalization were studied across the United States. All patients had shown no previous improvement to high doses of at least three neuroleptic drugs, had evidenced no remission the previous 2.5 years, and had demonstrated severe psychotic symptoms at the time of entry into the study. Initially, all study patients were treated with haloperidol (60 mg/day) plus an anticholinergic to decrease extrapyramidal side effects. After 6 weeks only three patients (1%) had improved. The remaining patients were medication-free for 1 week and then randomly assigned to a clozapine treatment group or a chlorpromazine treatment group for 6 weeks. The results of the study indicated that the clozapine-treated patients had a decrease of delusions, hallucinations, and paranoia, while only 4% of the chlorpromazinetreated patients showed improvement of these symptoms (Kane, Honigfeld, & Singer, 1989). Similar studies comparing the efficacy of clozapine with chlorpromazine in the treatment of schizophrenics (Chouinard et al., 1976; Shopsin et al., 1979; Lindstrom, 1987; Small et al., 1987; Gudelsky et al., 1987) as well as studies exploring the effects of clozapine in the treatment of tardive dyskinesia (Gerbino et al., 1988) suggest that clozapine improves schizophrenic symptoms, does

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not produce extrapyramidal side effects, and ameliorates symptoms of tardive dyskinesia. Although the research results suggest that clozapine may alter the treatment and outcome of schizophrenia, the potential for fatal side effects raises practical and ethical issues concerning the drug. Thus, psychiatric nurse practitioners should become familiar with clozapine, which will soon become available to physicians and hospitals in the United States. MECHANISM OF ACTION

There is a debate as to the biological basis for clozapine’s difference from typical neuroleptics. Researchers originally believed that the potent anticholinergic properties accounted for the low extrapyramidal side effects, but recently, researchers have speculated that a selective effect on mesolimbit dopamine neurons may account for its typical profile (Farde, 1988). While the exact mechanism of clozapine is still unknown, clozapine does block pituitary and hypothalamic dopamine receptors and affect striatal dopamine receptors. Researchers are testing the hypothesis that clozapine may be an antagonist of cortisol serotonin (5HT) receptors, thereby decreasing basal cortisol levels (Altar et al., 1986). While much research remains to be accomplished to answer specific questions regarding its mechanism of action, clozapine does have distinctive antipsychotic, extrapyramidal, and neuroendocrine actions. ROUTE AND DOSE

The therapeutic dose of clozapine ranges from 50 mg (in children and the elderly) to 800 mg daily. Clinical trials have shown that most patients respond to 200 to 600 mg daily with doses divided at intervals of 4 to 6 hours. Because clozapine is quite sedating, some investigators give low doses during the daytime and the bulk of the daily dose in the evening, while others give the whole dose in the evening (Ayd, 1974; Marder, 1988). As is true for the neuroleptics, the higher the dose, the greater the risk of side effects. Therefore, some clinicians initiate treatment with a daily dose of 50 to 100 mg by increments of 50 mg until the optimal therapeutic dosage is achieved. While clozapine may be given orally or intramuscularly, the rapid and complete absorption of oral clozapine makes the oral route preferred if patient compliance is present.

CLINICAL IMPLICATIONS

Early investigators (Gross & Langman, 1968) administered clozapine to refractory hospitalized schizophrenic patients. The symptoms common to chronic schizophrenia improved significantly. Symptoms such as withdrawal, posturing, paranoia, thought disturbance, blunted affect and hostility diminish with the use of clozapine. Recent investigations (Honigfeld et al., 1984) validate the earlier findings of the clinical efficacy of psychotic symptoms with refractory schizophrenic patients. It is important to realize that clozapine is far from a miracle drug. In a chlorpromazine-clozapine comparison study (Fischer-Cornelssen, 1976), only 47% of clozapine patients were discharged and only 5 1% were capable of employment. Similarly, in a haloperidol-clozapine comparison study (Fischer-Comelssen, 1976) clozapine had a therapeutic benefit in 31% of patients, although none were fit either for discharge or employment. Despite the limitations of clozapine in terms of dramatic improvement, the drug may reverse the sense of hopelessness that often accompanies the care of refractory schizophrenics. Psychotic patients with florid symptoms such as violence, hallucinations, delusions, or ritualistic posturing do respond to clozapine. With psychotic symptoms under control, the rehabilitation of refractory schizophrenics becomes a possibility as patients require education in socialization and self-care activities to accommodate deficits from years of institutionalization. SIDE EFFECTS The most serious side effect of clozapine is agranulocytosis. During the early clinical trials of clozapine, what could be called an epidemic of agranulocytosis resulted in 12 deaths. While side effects from drugs are expected, both the incidence and the severity of agranulocytosis made the widespread use of clozapine suspect. Although agranulocytosis remains as clozapine’s most serious side effect, several studies (Marden dz Van Putten, 1988) suggest that careful hematological monitoring (twice a week) can decrease the danger of agranulocytosis. Patients receiving clozapine also may suffer from sedation, hypersalivation, tachycardia, and hypotension. These symptoms usually appear soon after therapy is initiated and with the

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exception of hypersalivation tend to abate within 10 to 20 days even though clozapine therapy is continued. Patients may also complain of hypothermia. The onset of this reaction most often appears between treatment day 10 and 15. It is usually mild, lasts 5 to 7 days and spontaneously recedes without discontinuation of the drug. Less frequently reported side effects of clozapine are weakness, dry mouth, headache, nausea, impotence, and pruritus. Most of these symptoms occur when the dose exceeds 150 mg/day . In addition to these more minor side effects, clozapine may lower the seizure threshold, especially with epileptics and in patients with organic brain disorder (Ayd, 1974; Simpson et al., 1974; Marden & Van Putten, 1988). WHO SHOULD RECEIVE CLOZAPINE?

The chronic schizophrenic patients in state and veterans’ hospitals would appear to be the most natural candidates for a trial of clozapine. Often these patients are refractory to neuroleptics and remain severely symptomatic. Inpatient hospital units generally provide a safe environment in which clozapine can be administered safely. Since clozapine treatment requires careful monitoring of both blood counts and clinical response, the safety of using clozapine for outpatients should be considered carefully by the treatment team (Marder & Van Putten, 1988). Patients with severe tardive dyskinesia or extrapyramidal sensitivity may also be considered for a clozapine trial. Clinical reports suggest that clozapine causes minimal or no extrapyramidal side effects and may repress tardive dyskinesia (Gerbino, Shopsin & Collora, 1980; Small et al., 1987). NURSING RESPONSE

Clozapine may be an important medication because study results thus far suggest that schizophrenia may be a treatable disease using drugs that have a different mechanism of action. Yet, as with many scientific and technological advances throughout history, the use of clozapine has nursing implications. While administering clozapine, the nurse should consider the information below. Management of Neuroleptic-Free Patients

Generally, patients are prepared for clozapine administration with a wash-out period in which no

neuroleptic medications are given. During this wash-out period, which lasts 7 to 10 days, patients may display hostile, aggressive behavior. If possible, it is most effective to begin the wash-out period 3 to 4 days after admission to enable the nurse to establish a relationship with the patient and obtain behavioral data. When neuroleptics are discontinued, the patient often regresses and requires intensive nursing care. Hostile or agressive behavior must be managed for the safety of the patient, her or his copatients, and the staff. Room programs in which the patient is restricted to her or his room for 30 to 55 minutes each hour may help to decrease stimuli and limit outbursts. The time period of room restriction (i.e., 30 minutes in, 30 minutes out) can be altered to accommodate the patient’s ability for self-control. If a room program is unsuccessful, low doses of a benzodiazepine, seclusion, one-to-one, or restraints may be required to ensure the patient’s safety and comfort. Prevention of Potentially Fatal Side Effects

Patients receiving clozapine should be observed for seizures and agranulocytosis. It is imperative that the nurse monitor the hematological studies twice weekly. It is wise for nurses to discuss white blood cell (WBC) count and differential results during shift report to emphasize the importance, as well as to disseminate test results. A declining WBC count should be reported to the physician and documented on the chart. Patients receiving clozapine should be placed on seizure precautions, ensuring the availability of airway equipment. Should seizures occur, safety precautions such as the padding of bed rails and the monitoring of airway maintenance can be initiated by the nurse. Management of Side Efsects

Hypotension is best managed by frequent (three times a day) orthostatic vital sign monitoring. Blood pressure and pulse should be taken with the patient in a prone position. After 1 to 2 minutes the vital signs are repeated while the patient is in a sitting position. Both sets of vital signs must be documented. If the difference in readings exceeds 20 points, the patient is considered hypotensive. Hypersalivation usually can be managed by lowdose anticholinergics, although if severe, suction may be necessary. Other side effects are generally managed by common nursing interventions. For instance, hypothermia requires that the nurse mon-

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itor the environmental temperature, provide blankets and dress the patient warmly; pruritus can be managed with cool water baths or calamine lotion; nausea can be diminished with crackers or deep breathing. Rehabilitation or Discharge Planning

While the discipline of medicine is hopeful that clozapine will offer treatment-resistant schizophrenics a therapeutic option, the potential effectiveness of the drug creates a challenge for nursing. Refractory schizophrenic patients will require the teaching of self-care skills, activities of living, socialization, and problem-solving. Although the outcome of clozapine treatment varies, most patients are able to function at a higher level than before treatment. The literature suggests that few patients are discharged, but it has been the author’s experience that posttreatment clozapine patients are capable of halfway house placement or sheltered living with adequate planning, teaching, and support. CONCLUSIONS

While science has created new technology for the treatment of schizophrenia, the medical literature currently addresses neither the management nor the resources that may be required to rehabilitate the refractory schizophrenic patient. Psychiatric nurses should be aware of the side effects of clozapine in order to provide safe care for patients, In addition, nurses must consider the practical implications of managing aggressive schizophrenic patients during the wash-out period (i.e., staffing patterns) and throughout the intensive rehabilitation period that follows treatment with clozapine. REFERENCES Altar, CA. (1986). Typical and atypical antipsychotic occupancy of D, and S, receptors. Brain Research Biology, 16, 517-525. Ayd, F. (1974). Clozapine. International Drug Newsletter, 9. 5-12. Chapelle, A., Kari, C., & Nurman, M. (1977). Clozapine, chlorpromazine and placebo in acutely schizophrenic patients. Human Genetics, 37, 183-194. Chouinard, G., & Annable, L. (1976, May-June). Clozapine in the treatment of newly admitted schizophrenic patients. Jortrnol of Clinical Pharmacology, 289-237. Claghom, J., Honigfeld, G., Abzzuhab, F., Wang, R., Steinbrook, S., Juason, V., & Klerman, G. (1987). The risk and benefits of clozapine versus chlorpromazine. Journal of Clinical Pharmacology, 7(6), 377-383.

Collera, M. (1979). Clozapine, chlorpromazine and placebo in newly acute schizophrenics. Archives of General Psychinfry. 36, 657661. Crow, T. (1980). Molecular pathology in schizophrenia. Brirish Medical Journal, 280, 66-68. Farde, E.L. (1988). Central Da-dopamine receptor occupancy. Archives of General Psychiatry, 45, 7 1-76. Fisher-Comelssen, K., & Femer, U. (1976). An example of European multicenter trials. Psychopharmacology Rulletin, 12. 34-39. Gerbino, L., Shopsin, B., & Collera, M. (1988). Clozapine in the treatment of tardive dyskinesia. In W.E. Tann, R. Smith, V. Daers, & E. Domino (Eds.), Tardive dyskinesia: Research and treatment. New York, NY: Spectrum. Gerlach, J., Koppelhus, P., Helierg, E., & Monrad, A. (1974). Clozapine and haloperidol in a single blind crossover trial. Acta Psychiat Scandinavia, 50. 410-424. Gross, H., & Langman, E. (1968). Proceedings of the intemational congress. Excerpta Medici International Congress Services, No. 180, 477-480. Gudelsky, G., Koenig. J., & Simonvic, M. (1987). Differential effects of haloperidol, clozapine. fluperazine on tuberoinfundibuhu dopamine neurons and prolactin secretion in rats. Journal of Neurotransmitters, 68. 227-240. Honigfeld. G., Patison, J., & Singer, J. (1984). Clozapine: Antipsychotic activity in treatment resistant schizophrenia. Advances in Therapy, l(2), 77-97. Kane, J., & Cooper, T. (1981). Clozapine plasma and prolactin response. Ps.ychopharmacology, 75. 184- 187. Kane. J., Honigfeld. G., & Singer, J. (1988). Clozapine for treatment resistant schizophrenics. Archives of General Psychiatry. 45(9), 789-795. Lindstrom. L. (1987). The effects of long-term treatment with clozapine in schizophrenics. navia. II. 945950. Marder.

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Simpson, G., & Varga, E. (1974). Clozapine. Current Therapeutics and Research. 14(7), 679-686. Small, J.. Multstein, V., Marhenke, J.. & Hare, D. (1987). Treatment outcome with clozapine. Journal of Clinical Pharmacology, 48(7), 263-267. Small, J.. Multstein, V., Small, A., & Kellams, J. (1987). Computerized EEG profiles of clozapine in treatment resistant schizophrenics. Clinical Electroencephalopathy. J&3), 124-135.