Hyperprolactinaemia and Antipsychotic Therapy in Schizophrenia

Martina Hummer; Johannes Huber


Curr Med Res Opin. 2004;20(2) 

In This Article

Antipsychotics and Hyperprolactinaemia

The use of any class of drug that affects the hypothalamic dopamine system and/or pituitary dopamine receptors can result in elevated prolactin levels. One of the more important groups of drug within this class are the antipsychotics (dopamine antagonists), which are used in the treatment of schizophrenia.[25] Hyperprolactinaemia is thought to be caused by these agents blocking the D2 receptors on the lactrotroph cells and thus preventing inhibition of prolactin secretion. Furthermore, it has been suggested that the degree of elevation of prolactin correlates with the degree of occupation of D2 receptors in excess of 50%.[26]

Most studies have shown that conventional antipsychotics are associated with a two-to ten-fold increase in prolactin levels.[27,28] Twenty-seven schizophrenic patients treated with chlorpromazine, thioridazine or trifluoperazine experienced considerable increases in serum prolactin by 72 h post-dose (50-100 ng/ml).[27] In two double-blind, randomised studies, haloperidol produced a significantly (p < 0.001) larger increase in prolactin levels in schizophrenia patients than either placebo (72 vs 8% increase)[29] or olanzapine (17 vs 4 ng).[30]

The increase in prolactin that occurs through the use of conventional antipsychotics develops over the first week of treatment and remains elevated throughout the period of use. Once treatment stops, prolactin levels return to normal within 2-3 weeks.[31,32] It has been suggested that tolerance can develop in patients treated chronically with antipsychotics and that prolactin levels gradually decline with extended antipsychotic use.[33,34]

In general, second-generation antipsychotics produce lower increases in prolactin than conventional agents.[3] Some agents, including olanzapine,[29,35] quetiapine,[36,37] ziprasidone[38,39] and clozapine[40,41] have been shown to produce no significant or sustained increase in prolactin in adult patients. However, in adolescents (age 9-19 years) treated for childhood-onset schizophrenia or psychotic disorder, it has been shown that after 6 weeks of olanzapine treatment prolactin levels were increased beyond the upper limit of the normal range in 70% of patients. The authors concluded that further studies involving second-generation antipsychotics in adolescent patients, with longer observation intervals and bigger samples, were required.[42]

Second-generation antipsychotics that have been associated with increases in prolactin levels are amisulpride, zotepine and risperidone[43,44,45]. An analysis of double-blind studies of risperidone in schizophrenic patients showed that this drug dose-dependently increased prolactin concentrations in both men and women. However, the increase was not associated with the occurrence of adverse events.[43] Furthermore, a significant prolactin increase was observed in an open study in which patients were switched from haloperidol to risperidone.[46] In schizophrenia patients treated with amisulpride for 12 months, prolactin secretion was significantly increased over baseline after 1 month of high dosing (1000 mg/day) during the acute phase. Prolactin levels remained elevated above baseline for the 12-month dosing period but gradually declined during the maintenance phase (amisulpride 200-600mg/day).[44] However, a review of 11 studies, which involved a total of 1247 patients treated with amisulpride, concluded that the incidence of endocrine-related adverse events was similar for amisulpride, haloperidol, risperidone and placebo (Figure 3). Furthermore, the study concluded that the safety profile of amisulpride was comparable to that of risperidone and superior to conventional antipsychotics, including haloperidol.[47] Finally, Fleischhacker and colleagues[45] found increased prolactin levels investigating the efficacy of zotepine in the treatment of negative symptoms.

Incidence of endocrine-related adverse events in patients exposed to amisulpride, risperidone, haloperidol and placebo in (a) acute phase patients and (b) patients with prominent negative symptoms


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