Neuroleptic-induced hyperprolactinemia
Introduction
Schizophrenia is a severe psychiatric disorder, with an onset usually in early adulthood, that causes prolonged disability in affected persons. Antipsychotic drug therapy, which often must be taken throughout the person's life, remains the cornerstone of treatment for patients with schizophrenia. New drugs developed for treating schizophrenia offer (1) improved efficacy, (2) the potential to treat a broader spectrum of symptoms, and (3) reduction of side effects, primarily by minimizing acute and chronic neurological movement disorders.
Some, but not all, of the marketed novel antipsychotic drugs have minimal effects on serum prolactin levels. However, the clinical implications of the variable propensity of these drugs to induce hyperprolactinemia have received limited attention. This paper reviews the side effects of hyperprolactinemia and discusses management options, given the availability of prolactin-sparing antipsychotic drugs.
Prolactin is an anterior pituitary peptide hormone that has a major role in preparing the breast for lactation and maintenance of lactation. This hormone thus has great physiological importance during pregnancy and breast-feeding (Corenblum, 1990; Melmed, 1995). At other times, the secretion of prolactin is mainly inhibited by the hypothalamus, with the neurotransmitter dopamine secreted into the pituitary portal venous system acting as the primary prolactin inhibitory factor. Control of prolactin release is in fact complex, with many physiologic and neuroendocrine factors involved (Melmed, 1995). Traditional neuroleptics are thought to elevate prolactin levels primarily by dopamine blockade at the level of the pituitary (Rubin, 1987). Whether manipulation of serotonin pathways and receptors by the atypical antipsychotics contributes to their variable effect on prolactin is unclear. Possible mechanisms involved in the differential effects of the new atypical antipsychotics on prolactin secretion are discussed by Petty in this journal.
Neuroleptic-induced hyperprolactinemia (NIHP) has been a `cost' of traditional antipsychotic therapy. Because all of the traditional neuroleptics are capable of elevating serum prolactin (Rubin, 1987), clinicians have had to accept the implications of NIHP coupled with the antipsychotic's efficacy. In contrast, the new generation of atypical antipsychotics has variable tendencies to induce hyperprolactinemia. Clozapine (Meltzer et al., 1970), olanzapine (Beasley et al., 1996a; Beasley et al., 1996b; Crawford et al., 1997; Tollefson et al., 1997), and quetiapine (Arvanitis and Miller, 1997) have been reported to produce little or no clinically significant prolactin elevation. In contrast, risperidone is comparable to typical neuroleptics in its proclivity to raise serum prolactin (American Psychiatric Association, 1997). With the introduction of the new, more highly selective mesolimbic and mesocortical dopamine-blocking, prolactin-sparing antipsychotic drugs, NIHP may now be prevented or minimized. Given this possibility, it becomes more important than ever that clinicians understand both the short- and long-term side effects of hyperprolactinemia and current management approaches.
Section snippets
Side effects of hyperprolactinemia
Hyperprolactinemia has both direct actions on the brain and indirect effects via suppression of sex hormones (Corenblum, 1990; Melmed, 1995). Of greatest concern with hyperprolactinemia is the possibility of developing hypogonadism (i.e. estrogen deficiency in women and testosterone deficiency in men), because this condition can produce significant morbidity (Vance, 1997; Corenblum, 1993, Corenblum, 1997). It has not been routine psychiatric practice to systematically monitor for side effects
Breast cancer
Although most past studies have not supported a link between neuroleptic drugs and the subsequent development of breast cancer (Wagner and Mantal, 1978; Katz et al., 1967; Mortensen, 1989; Mortensen, 1994; Overall, 1978), a recent study (Halbreich et al., 1996) that has been criticized on methodological grounds (Goodwin, 1997; Torrey, 1997; Mortensen, 1997) did show an increased incidence of breast cancer in a small sample of neuroleptic-treated women. Product labeling of prolactin-elevating
Treatment of NIHP
It is essential to monitor for the known side effects of hyperprolactinemia discussed in this paper (see Table 1), recognizing that there is individual variability in (1) end-organ susceptibility to elevated prolactin levels and (2) the length of time for side effects to occur. If side effects do occur and are detected, reduction of the neuroleptic dose has been the treatment of choice. If that is not possible, then treatment with amantadine or bromocriptine has been advised (Marken et al., 1992
Conclusion
The onset of schizophrenia typically occurs during adolescence to the mid-20s. Because persons who have received long-term treatment with neuroleptics have aged and are thus at higher risk for the development of breast cancer, osteoporosis, and heart disease, continuing to study the interaction of age and chronic use of psychotropic drugs is important. The safety record of the neuroleptics is in fact good. Although more research is needed, the known benefits of neuroleptics clearly outweigh the
Acknowledgements
The authors wish to acknowledge the assistance of Dr. B. Corenblum, Professor of Endocrinology, University of Calgary, with this manuscript.
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