Hyperprolactinemia: Monitoring children on long-term risperidone
How to address evidence of potential for developmental effects with sustained use.
Serum prolactin increased sharply in children treated with risperidone in the placebo-controlled trial. After 8 weeks, prolactin levels were 4 times higher with risperidone treatment than with placebo (39.0±19.2 ng/mL vs 10.1±8.8 ng/mL [P< 0.0001]). In the open-label risperidone continuation trial, prolactin levels remained significantly higher than at baseline but decreased over time to:
- 32.4±17.8 ng/mL in 43 children who remained in the study at 6 months (P< 0.0001)
- 25.3±15.6 ng/mL in 30 children who remained at 22 months (P< 0.0001).
In this study, a sharp rise in serum prolactin in the first 2 months trended down to the upper limit of normal at 22 months. None of the children showed known clinical manifestations of elevated prolactin, including gynecomastia, galactorrhea, or menstrual disturbance.
A double-blind, placebo-controlled trial by Hellings et al18 examined risperidone’s effect on aggression and self-injury in children, adolescents, and adults with mental retardation and pervasive developmental disorders. In a subset of 10 children and adolescents whose serum prolactin was measured during the trial, prolactin remained elevated during at least 26 weeks of risperidone treatment. Mean prolactin levels were:
- 13.2±8.6 ng/mL at baseline
- 31.0±11.6 ng/mL during acute risperidone therapy
- 37.9±10.4 ng/mL during maintenance therapy.
Clinical features. Higher risperidone dosages—rather than longer duration of use—appear more likely to cause symptomatic elevated serum prolactin. A case series of 3 adolescents with symptomatic prolactin elevation showed:
- gynecomastia and galactorrhea in 2 adolescent males age 17 and 18, receiving risperidone, 4 mg/d and 5 mg/d, respectively
- amenorrhea within 2 to 6 weeks of starting treatment in a female patient age 15 receiving risperidone, 6 mg/d.20
Holzer et al21 described 5 adolescents who showed symptoms of elevated prolactin after 3 to 15 months while taking risperidone, 2 to 6 mg/d, as treatment for psychosis.
Long-term health risks?
Some evidence suggests an association between elevated serum prolactin and carcinogenesis and infertility in adults. No studies have examined these long-term risks in children and adolescents who develop hyperprolactinemia from risperidone treatment. A link may be possible, however, if prolactin elevation affects postpubertal and HPG axis development.
Breast cancer. Halbriech et al22 reviewed mammograms and charts of 275 female psychiatric hospital patients age >40 and 928 women of similar age at a hospital radiology clinic. The incidence of breast cancer among psychiatric patients was:
- >3.5 times higher than among radiology clinic patients
- 9.5 times higher than in the general population.
The authors speculated that the observed increased breast cancer incidence in psychiatric patients could be associated with medications, although high rates of cigarette smoking and alcohol consumption also might have played a role.
A case-control study by Hankinson et al23 of blood samples collected from women in the Nurses’ Health Study found a statistically significant association between hyperprolactinemia and breast cancer. This analysis included 306 postmenopausal women diagnosed with breast cancer and 448 controls matched for age, postmenopausal hormone use, and time of day and month when blood samples were drawn.
Several putative mechanisms have been proposed to explain a possible role of prolactin in breast carcinoma. Breast tissue—whether normal or cancerous—expresses the prolactin receptor, but the density of prolactin receptors is higher in tumor tissue. In several mouse models, prolactin induces tumor formation and increases tumor growth rates.23,24
Infertility. As noted, hyperprolactinemia can cause HPG axis dysfunction.9 A retrospective review by Sigman and Jarow25 linked endocrine disorders with infertility in 10% of 1,035 consecutive men attending 2 infertility centers. Hyperprolactinemia accounted for infertility in 0.4% of that population. No studies have associated hyperprolactinemia with female infertility.
Targeting hyperprolactinemia
When prescribing risperidone, consider obtaining a baseline serum prolactin level, especially in sexually mature patients. Repeat after 2 months, and ask the patient about menstruation, nipple discharge, sexual functioning, and pubertal development. Sexual side effects may be difficult to ascertain in patients receiving antipsychotics because of psychiatric comorbidities in this population.
Elevation without symptoms. If serum prolactin is elevated after 2 months but the patient has no clinical symptoms, repeat evaluation after another 2 months without altering the risperidone dosage. As discussed, serum prolactin tends to decline and may normalize with continued antipsychotic therapy in adults and children. A reasonable approach may be to wait 6 to 12 months for symptoms to resolve and hyperprolactinemia to diminish in patients who benefit from risperidone and have no or mild prolactin-related symptoms.8
