0022-5347/92/1483-0876$03.00/0 Vol. 148, 876-877, September 1992

THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.

Printed in U.S.A.

CLOZAPINE-INDUCED PRIAPISM SCOTT I. ROSEN

PHILIP M. HANNO

AND

From the Department of Urology, Temple University School of Medicine, Philadelphia, Pennsylvania

ABSTRACT

Priapism may be a side effect of certain medications. We present a case of priapism associated with the nonphenothiazine antipsychotic drug clozapine. The possible mechanism for the druginduced priapism is discussed. KEY WORDS:

penis, penile erection, priapism

Medication side effects are among the many causes of priapism. The medications most frequently associated with this condition are psychotropic medications, usually antipsychotic drugs, 1-7 and more recently the antidepressant trazodone, 5·8·9 as well as antihypertensive medications, such as hydralazine, guanethidine and prazosin. 5·10- 12 Among the antipsychotic medications associated with priapism the phenothiazines, especially chlorpromazine and thioridazine, are the most commonly implicated.13 Priapism also has been reported with the nonphenothiazine antipsychotics thiothixene and molindone hydrochloride. 7 Clozapine is a nonphenothiazine antipsychotic drug indicated for the treatment of schizophrenic patients who fail to respond to ·standard antipsychotic drug therapy. Clozapine entered phase 1 testing in the United States in 1972 but trials were suspended in 1975 after cases of agranulocytosis were reported. It was not until Food and Drug Administration approval in 1989 that clozapine became widely available in the United States. We report a case ofpriapism seen after clozapine use. Since this case 2 others have been reported to the Food and Drug Administration. 14 However, to date neither case has appeared in the literature. CASE REPORT

A 32-year-old man with a history of schizophrenia, mental retardation and seizure disorder was evaluated in the emergency department for a painful erection 2 days in duration. The antipsychotic medication had been switched to clozapine 27 days previously. The clozapine dosage was on a schedule of •slowly increasing increments and the last dose was 250 mg. on the morning of admission to the hospital. The other medications included haloperidol and phenobarbital, both of which he had been taking for many years. He had no history of sickle cell disease and no known prior episodes of prolonged penile erection. Physical examination was significant only for priapism, with erect, firm corpora cavernosa, and a flaccid corpus spongiosum and glans. He was initially treated with intracorporeal epinephrine injection and then corporeal irrigation with only transient and partial detumescence. A cavernosal glandular shunt with a biopsy needle (Winter procedure) as well as repeat epinephrine injection resulted in partial detumescence. However, by the following morning the phallus was again rigid and erect. At operation percutaneous corporeal irrigation was limited by marked corporeal congestion and fibrosis. A more extensive cavernosal glandular shunt (El-Ghorab procedure) revealed "crank-case oil" venous efflux. Upon completion, the penis was only mildly turgid without erection. Upon discharge from the hospital the penis was tumescent but not fully erect. Currently, the corporeal bodies are firm due to marked fibrosis but the penis is not erect or painful. As far as we can determine the patient is impotent. Accepted for publication February 28, 1992.

DISCUSSION

Clozapine is an atypical antipsychotic drug indicated for the management of refractory schizophrenic patients. We report a case of priapism following clozapine use. Two additional cases recently have been reported to the Food and Drug Administration but neither has yet appeared in the literature. 14 The precise mechanism of drug-induced priapism is not completely understood. In a review of the literature one can conclude that the most likely mechanism stems from the antagonistic activity at a-adrenergic receptor sites. 1·2• 4 - 7,10·12 a-Adrenergic blocking action is a common denominator among many drugs implicated in causing priapism, including the phenothiazine and nonphenothiazine antipsychotics, guanethidine, prazosin and trazodone. Clozapine is similarly an adrenergic antagonist. As do other antipsychotic drugs, clozapine has antagonistic activity at dopaminergic, adrenergic, cholinergic, histaminergic and serotonergic receptors. Despite the many differing effects of antipsychotics, most investigators cite the antiadrenergic effect as the most important in causing priapism. a-Adrenergic blockade could cause priapism by favoring erection, which is parasympathetically mediated, and by inhibiting the sympathetically mediated detumescence. 10 The rich innervation of the corpora cavernosa by adrenergic fibers is related to vasoconstriction and maintaining the penis in the detumescent state. Prolonged erections have been produced by intracorporeal injections of relatively nonspecific a-adrenergic blockers, such as phenoxybenzamine and phentolamine. 12 There are also other generally less accepted explanations of priapism caused by psychotropic medications. Some physicians suggest that priapism associated with psychotropic medications is related to a-adrenergic antagonism in the absence of adequate anticholinergic activity. 12·15 ·16 This theory stems from reports of anticholinergic agents, such as diphenhydramine and benztropine, as treatment for priapism caused by psychotropic drugs. 15 ·16 As examples of this balance between antiadrenergic and anticholinergic effects, the phenothiazine chlorpromazine and the antidepressant trazodone have significant antiadrenergic side effects but much weaker anticholinergic effects. However, other phenothiazines associated with priapism, as well as clozapine, have strong anticholinergic effects, thus, directly opposing this theory. An explanation for this discrepancy is that, while clozapine has strong central anticholinergic activity, much of its peripheral anticholinergic activity may be antagonized by the strong peripheral a-receptor-blocking properties.17 An older theory proposed by Hinman suggested that priapism may be caused by the central nervous system effects of psychotropic drugs. 18 Prolonged stimulation of psychic centers by these drugs may lead' to persistent erection resulting in priapism. The 3 to 4-week delay in onset of priapism after beginning clozapine therapy in our patient is consistent with the literature and not unusual, especially since the full daily dose of clozapine was not reached until at least 2 to 3 weeks after starting the slowly increasing dosage titration schedule. In the many reports

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of drug-induced priapism in the literature the onset ofpriapism after beginning drug therapy ranges from as rapid as 2 hours to as long as several months. There are a number of cases of phenothiazine-induced priapism occurring 3 weeks or longer after the start of drug therapy. 1· 4, 7 In summary, priapism is a urological emergency and must be treated immediately. Surgical management is required in most cases of drug-induced priapism.7 Despite prompt intervention, impotence may still result. Clozapine must be added to the list of medications associated with priapism. As with other antipsychotic drugs, a-adrenergic blockade is the most plausible mechanism of action. However, further investigation is clearly needed.

6. 7.

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9. 10.

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ADDENDUM

Since acceptance of this article, another case was reported in the January 1992 issue of this Journal. REFERENCES 1. Dorman, B. W. and Schmidt, J. D.: Association of priapism in

phenothiazine therapy. J. Urol., lH:l: 51, 1976. 2. Gottlieb, J, I. and Lustberg, T.: Phenothiazine-induced priapism: a case report. Amer. J. Psychiat., 134: 1445, 1977. 3. Griffith, S. R. and Zil, J. S.: Priapism in a patient receiving antipsychotic therapy. Psychosomatics, 25: 629, 1984. 4. Kogeorgos, J. and de Alwis, C.: Priapism and psychotropic medication. Brit. J. Psychiat., 149: 241, 1986. 5. Abber, J.C., Lue, T. F., Luo, J.-A., Juenemann, K.-P. and Tanagho,

12. 13. 14. 15. 16. 17.

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E. A.: Priapism induced by chlorpromazine and trazodone: mechanism of action. J. Urol., 137: 1039, 1987. Gold, D. D., Jr. and Justino, J. D.: "Bicycle kickstand" phenomenon: prolonged erections associated with antipsychotic agents. South. Med. J., 81: 792, 1988. Chan, J., Alldredge, B. K. and Baskin, L. S.: Perphenazine-induced priapism. DICP, 24: 246, 1990. Carson, C. C., III and Mino, R. D.: Priapism associated with trazodone therapy. J. Urol., 139: 369, 1988. Hanno, P. M., Lopez, R. and Wein, A. J.: Trazodone-induced priapism. Brit. J. Urol., 61: 94, 1988. Robbins, D, N., Crawford, E. D. and Lackner, L. H.: Priapism secondary to prazosin overdose. J. Urol., 130: 975, 1983. Siegel, S., Streem, S. B. and Steinmuller, D. R.: Prazosin-induced priapism. Pathogenic and therapeutic implications. Brit. J. Uroi., 61: 165, 1988. Segraves, R. T.: Effects of psychotropic drugs on human erection and ejaculation. Arch. Gen. Psychiat., 46: 275, 1989. Mitchell, J.E. and Popkin, M. K.: Antipsychotic drug therapy and sexual dysfunction in men. Amer. J. Psychiat., 139: 633, 1982. Sandoz Pharmaceuticals Corp.: Personal communication. Greenberg, W. M.: Mechanism of neuroleptic-associated priapism. Amer. J. Psychiat., 145: 393, 1988. Fishbain, D. A.: Priapism associated with trazodone therapy. Letter to the Editor. J. Ural., 142: 831, 1989. Ereshefsky, L., Watanabe, M. D. and Tran-Johnson, T. K.: Clozapine: an atypical antipsychotic agent. Clin. Pharm., 8: 691, 1989. Hinman, F., Jr.: Priapism: reasons for failure of therapy. J. Urol., 83: 420, 1960.

Clozapine-induced priapism.

Priapism may be a side effect of certain medications. We present a case of priapism associated with the nonphenothiazine antipsychotic drug clozapine...
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