Are high levels of prolactin and gynecomastia reversible side-effects of risperidone (Risperdal) tr

Fråga: Are high levels of prolactin and gynecomastia reversible side-effects of risperidone (Risperdal) treatment although it is continued? Is the risk equal for all neuroleptics or is switching to quetiapine (Seroquel) rational considering this side-effect?

The question concerns a 29-year-old man who is treated with oral Risperdal in monotherapy for schizophrenia. The dose has been 6-8 mg/d for a long time and the problems with gynecomasty began 6 years ago, which was after the treatment was started. S-prolactin is 32 ug/mL (reference value 3-17 ug/mL) and he is currently being investigated by the endocrine department for suspected SIADH. No plasma levels of risperidone have been measured as far as the questioner knows.

Sammanfattning: There is documentation of an increased risk of hyperprolactinemia during treatment with risperidone in a dose-dependent manner and it may probably be sustained if treatment is continued with an unchanged dose and if no dopamine agonist is added. Gynecomastia of long duration may never resolve even though the cause is corrected. The risk of hyperprolactinemia with quetiapine is probably less, but there is less data in general for this drug. If it is clinically suitable, a switch to quetiapine is rational in this aspect. Clozapine is the atypical antipsychotic drug which has the most documentation of a very low or even nonexistent risk of hyperprolactinemia.

Svar: The mechanism of increased prolactin levels due to treatment with neuroleptics is thought to be antagonism of D2-receptors on lactotrophs in the anterior pituitary. Dopamine inhibits secretion of prolactin from these cells (1) and it is a dose-dependent side effect (2). Both risperidone and quetiapine are atypical neuroleptics. Risperidone acts as an antagonist on dopaminergic D2-receptors and on serotonergic 5-HT2-receptors. The antipsychotic effect of D2-antagonism is modulated by the serotonergic system (3). Quetiapine is an antagonist of dopaminergic D2-receptors, serotonergic 5-HT2-receptors and dopaminergic D1-receptors. Both substances are antagonists of several other receptors as well (3, 4). Considering the mechanism, especially conventional antipsychotics would therefore have a risk of this side effect. However, risperidone has been found to cause hyperprolactinemia and related symptoms to at least a similar extent as haloperidol, possibly because of a contributive effect of the active metabolite 9-hydroxyrisperidone (5). The risk of hyperprolactinemia with risperidone has been previously discussed in documents in the Drugline database (6,7,8,9,10). The level of hyperprolactinemia due to treatment with neuroleptics is usually lower than when the cause is a prolactinoma (1). Other reasons for the increased level are possible but the moderately increased value in the present case is not incompatible with the cause being the neuroleptic treatment. Neuroleptic induced hyperprolactinemia may cause several symptoms in spite of the often moderate levels including sexual disturbances, infertility, galactorrhea, gynecomastia and in the long term osteoporosis and cardiovascular disease (5). Gynecomastia of long duration, as in the present case, may never resolve even though the cause is corrected because of fibrosis (11).

In previous documents in the Drugline database, clozapine and olanzapine have been suggested as alternatives when this side effect occurs during risperidone treatment (7, 10). Regarding quetiapine there is less documentation. A few cases of suspected increase in prolactin levels due to treatment with quetiapine were found in 2004 when a case was reported to the regional adverse drug reactions monitoring centre and to Karolic. In this Drugline document it is concluded that quetiapine does not usually cause hyperprolactinemia and that it is less prone to cause prolactin elevation than conventional antipsychotics (12). An updated search revealed a new study of quetiapine and risperidone treatment and hyperprolactinemia. The patients were boys with a mean age of 13 years. A dose relationship between quetiapine and prolactin levels was found (p=0.008). The study was made without measuring the prolactin levels before treatment was started, but 4 of the 20 boys who were treated with quetiapine for at least 6 weeks before blood was sampled were found to have levels above the upper limit of normal. A dose relationship was also found for risperidone treatment and prolactin increase (p=0.002). Some of the boys had elevated prolactin values two years after starting treatment, suggesting that the effect is at least sometimes not transient (3). Treatment with bromocriptine has been suggested as an alternative, but there is a risk of worsening the psychotic illness if this is tried (13). The only report in the Swedish adverse drug reactions register of hyperprolactinemia as a side effect of quetiapine is the above mentioned from 2004, out of a total of only 29 reports, and because of lack of dechallenge and sparse documentation in the literature the cause relationship was evaluated as unclassifiable. There are three reports of hyperprolactinemia, out of 185 in total, in the same register for olanzapine and the cause relationship was evaluated as at least possible in all those cases. For clozapine there is only one report, evaluated to the cause relationship as at least possible, in the Swedish adverse drug reactions register out of a total of 437 reports (14). It has been questioned whether clozapine may increase the prolactin levels at all (2). When comparing the number of reports in the WHO register of reported side-effects (15), which have not been evaluated as to the cause relationship, there are only 27 reports of hyperprolactinemia for clozapine (43739 reports in total), 20 for quetiapine (5178 reports in total), 117 for olanzapine (15794 reports in total) and 880 for risperidone (total number of reports not known).

Regarding SIADH, it is not clear whether it can be a side-effect of risperidone because it has been reported more often also in schizophrenic patients not taking neuroleptics than in the general population (16). An updated search of this side-effect for risperidone, quetiapine, olanzapine and clozapine resulted in no additional information. Stevens JR, Kymissis PI, Baker AJ. Elevated prolactin levels in male youths treated with risperidone and quetiapine. J Child Adolesc Psychopharmacol 2005;15(6):893-900.

Barnes TRE, editor. Antipsychotic drugs and their side-effects. London: Academic Press; 1993. p 22-23, 29.
Risperdal. Summary of product characteristics (SPC). Janssen-Cilag AB (cited 2006-09-29)
Seroquel. Summary of product characteristics (SPC). Astra-Zeneca AB (cited 2006-09-29)

Melkersson K. Differences in prolactin elevation and related symptoms of atypical antipsychotics in schizophrenic patients. J Clin Psychiatry 2005;66(6):761-767.

Drugline no 22449 (year 2004)
Drugline no 20194 (year 2003)
8 . Drugline no 18868 (year 2002)
Drugline no 18957 (year 2002)
Drugline no 17356 (year 2000)

Wilson JD, Foster DW, Kronenberg HM, Reed Larsen P (eds). Williams textbook of endocrinology. 9th ed. Philadelphia: WB Saunders; 1998. p 885. Drugline no 21487 (year 2004) Halbreich U, Kahn LS. Hyperprolactinemia and schizophrenia: mechanisms and clinical aspects. J Psychiatr Pract 2003;9(5):344-353 Swedis (The Swedish Drug Information System) cited 2006-09-29 Vigibase (WHOs adverse drug reactions database) cited 2006-09-29 Drugline no 15594 (year 1998)