Is second-generation antipsychotic-induced hyperprolactinemia due to biologically active prolactin or to biologically inactive macroprolactin? Results from a prospective study.

Sir: Hyperprolactinemia is of particular concern with antipsychotic medication, as symptoms associated with high prolactin levels, e.g., sexual dysfunction, can have a negative impact on the patient’s adherence to treatment, and has significant implications for the short-term and long-term health of patients. In general, second-generation antipsychotics (SGAs) produce lower increases in prolactin levels than first-generation antipsychotics due to the differences in these drugs’ binding affinity for the dopamine D2 receptor. 1,2 Particularly, olanzapine, quetiapine, and clozapine have been shown to produce no significant or sustained increase in prolactin. Conversely, SGAs that have been associated with increases in prolactin levels are amisulpride, zotepine, and risperidone. Besides monomeric prolactin, which accounts for approximately 85% of total prolactin in normal sera, higher-molecularweight variants of prolactin are known. Macroprolactin, which in the majority of cases consists of antigen-antibody complexes of monomeric prolactin and immunoglobulin G, contributes less than 1% to circulating prolactin levels. However, in some patients with supraphysiologic prolactin levels, macroprolactin was demonstrated to be the predominant form without eliciting the classical signs and symptoms of the hyperprolactinemic syndrome. Commonly used immunoassays for prolactin measurement fail to differentiate between biologically active monomeric prolactin and macroprolactin because of the assays’ variable degree of reactivity with macroprolactin. Conservative estimates suggest that the presence of macroprolactin leads to misdiagnosis in as many as 10% of all reported instances of biochemical hyperprolactinemia. In this prospective study, we investigated whether SGA treatment–induced hyperprolactinemia might be the result of an increase in macroprolactin levels in order to allow for better differentiation between symptoms caused by the antipsychotic agent and those that are disease related.