Individuals with schizophrenia who are not taking antipsychotics do not appear to have elevated prolactin levels (Kuruvilla et al. 1992). Drugs with dopamine antagonist effects may result in prolactin elevation, and it is clear that the magnitude of hyperprolactinemia varies among the available an-tipsychotic medications, generally in proportion to the potency of D2 antagonism. Prolactin elevation is greatest during treatment with typical antipsychotics and the atypical antipsychotic risperidone (Caracci and Ananthamoorthay 1999; David et al. 2000; Kleinberg et al. 1999); the atypical antipsychotics quetiapine (Hamner et al. 1996), clozapine (Kane et al. 1981), and ziprasidone (Goff et al. 1998) are not associated with prolactin elevation. With olanzapine, transient modest elevations of prolactin occur with initial treatment, but prolactin levels appear to normalize after a few weeks and remain normal with chronic treatment (Crawford et al. 1997).
Special populations may be especially vulnerable to antipsychotic-induced hyperprolactinemia. Women are clearly more sensitive than men to the effects of antipsychotics on prolactin (Crawford et al. 1997; David et al. 2000; Kleinberg et al. 1999). In a 6-week study, 63% of haloperidol-treated men compared with 98% of haloperidol-treated women had a prolactin level above the upper limit of normal (Crawford et al. 1997). In addition, children and adolescents may be especially sensitive to the prolactin-elevating effects of antipsychotics. In one study 100% (10/10) of haloperidol-treated, 70% (7/10) of olanzapine-treated, but no (0/15) clozapine-treated children (mean age 14, range 9-19 years) had elevated prolactin (Wudarsky et al. 1999). Olanzapine levels correlated with prolactin levels, and one olanzapine-treated girl with a prolactin level above 90 ng/mL experienced treatment-emergent galactorrhea (Alfaro et al. 2002).
The most prominent theory for explaining differences in prolactin elevation with atypical antipsychotics relates to the variable ability of antipsychotics to cross the blood-brain barrier (Kapur et al. 2002). The pituitary gland sits outside the blood-brain barrier and is exposed to peripheral blood; the rest of the brain is protected by the blood-brain barrier. Higher peripheral blood levels of a drug are needed to achieve adequate central nervous system levels if the drug does not readily cross the blood-brain barrier. Thus, the pituitary gland is exposed to higher levels of antipsychotics that do not readily cross the blood-brain barrier than the rest of the brain. This theory is supported by the results of an animal study that found relatively high pituitary-to-striatal dopamine receptor binding ratios for risperidone compared with quetiapine and olanzapine, with prolactin elevation highly correlated to this ratio (Kapur et al. 2002). In addition, the finding that prolactin is transiently elevated for 2-4 hours following administration of atypical antipsychotics (Turrone et al. 2002) is consistent with this theory. Other theories proposed to explain the lower risk of extrapyramidal side effects, including high ratios of affinity for serotonin (5-HT2) to dopamine (D2) antagonism (Meltzer 1989) and "loose" dopamine receptor binding (Kapur and Seeman 2001), do not readily explain differences in the prolactin-elevating properties of anti-psychotics.
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