Summary

• As with other drugs that antagonize dopamine D2 receptors, risperidone elevates prolactin (PRL) levels and the elevation persists during chronic administration.¹
• Risperidone is associated with higher levels of PRL elevation than other antipsychotic agents.¹
• Based on The Endocrine Society Clinical Practice Guideline for the Diagnosis and Treatment of Hyperprolactinemia (2011) and The American Psychiatric Association (APA) Practice Guidelines for the Treatment of Patients with Schizophrenia (2020), treatment of hyperprolactinemia differs depending on whether the patient is symptomatic or asymptomatic.^2,3
• Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving PRL-elevating compounds.¹ While most patients with schizophrenia on risperidone have elevated PRL levels, the majority of patients do not exhibit short-term PRL-related adverse events (AEs).⁴
• There is conflicting data on whether PRL increases with risperidone in adults are dosedependent.^4-10
• A network-based meta-analysis of randomized trials comparing the efficacy and safety of adjunctive aripiprazole, metformin, and paeoniae-glycyrrhiza decoction (PGD) noted that compared with placebo and other treatment groups, PGD was effective in treating risperidone-induced hyperprolactinemia.¹¹
  • The best-ranked treatments across all studies of antipsychotic-induced hyperprolactinemia were aripiprazole <5 mg/day, aripiprazole >10 mg/day, and aripiprazole 5 mg/day, in that order.
  • The best-ranked treatments for risperidone-induced hyperprolactinemia were PGD 1:1, aripiprazole 20 mg/day, and PGD 2:1, in that order.
• A review of randomized trials and case reports assessed the efficacy of adjunctive aripiprazole in treating psychotropic-induced hyperprolactinemia.¹²
  • Risperidone was administered as monotherapy in 3 studies; in 2 such studies, after 8 weeks of treatment, the resolution rate was reported to be 46.7% with adjunctive aripiprazole 10 mg and 20.0%, 51.7%, and 66.7% with aripiprazole 5, 10, and 20 mg, respectively.^13-15
  • It was noted that 83.3% of women receiving aripiprazole 10 mg/day continued to experience abnormal menstruation. Galactorrhea reduced from 67.7% to 14.2% after the 8-week treatment with aripiprazole. This improvement was not significantly different from placebo.¹⁵
  • Among 25 patients treated with risperidone, 24 (96%) had normalized PRL levels.^12,16-21
    • After aripiprazole initiation, the mean PRL level at the last follow-up was 15.0 ng/mL and the mean percent reduction was 65.8%.
• A prospective, open-label, 8-week study evaluated the mean change in serum PRL levels from baseline effected by aripiprazole 5-20 mg/day in 24 outpatients (17 female; 7 male) with risperidone-, amisulpride-, or sulpiride-induced hyperprolactinemia.²²
  • In patients with risperidone-induced hyperprolactinemia, mean PRL levels at week 8 reduced to 77 ng/mL from 18.3 ng/mL at baseline (P<0.001).
  • PRL normalization was not significantly associated with sex.
• A randomized, crossover study assessed the efficacy of PGD 45 g/day vs bromocriptine (BMT) 5 mg/day in treating 20 female patients with schizophrenia experiencing risperidoneinduced hyperprolactinemia. Patients were divided into 2 dose groups consisting of 10 patients, each. Patients in the first group received PGD 45 g/day x 4 weeks followed by BMT 5 mg/day x 4 weeks. This order was reversed in the second group. A 4-week washout period separated each 4-week treatment session. Both groups received maintenance treatment with risperidone (average maintenance risperidone dose: 4.1 mg/day).²³
  • Multiple comparisons revealed significant decreases in PRL levels with both PGD and BMT in the first (P≤0.004) and second (P≤0.005) treatment sessions; the amplitude of PRL decrease was also similar with both PGD and BMT (first treatment session, 24.2% and 21%, respectively; P=0.767; second treatment session, 23.6% and 27.6%, respectively; P=0.744).
  • Pooled data from both sessions revealed that PGD-treated patients experienced significantly greater improvement in hyperprolactinemia-related AEs (including menstrual resumption, alleviation of menstrual pain and galactorrhea, and facial acne disappearance) vs BMT-treated patients (55.6% vs 16.7%; P=0.037).
• An open-label, 8-week study assessed the efficacy and safety of cabergoline 0.125-0.25 mg/week in treating symptomatic hyperprolactinemia (males, PRL >18 ng/mL; females, >29 ng/mL) in 6 male and 13 nonmenopausal female outpatients with schizophrenia (average maintenance risperidone dose: 3.1 mg/day).²⁴
  • At a dose of 0.125 mg/week, 58% of patients (men, n=4; women, n=7) experienced normalization of PRL levels (baseline vs final, 64.4±31.7 vs 8.6±5.9 ng/mL; P=0.003). The remaining 8 patients had significant but nonnormalized decreases in PRL levels (baseline vs final, 116.9±60.5 vs 84.7±44.7 ng/mL; P=0.036), irrespective of sex, age, or risperidone dose.
    • Most responders (n=8/11) had below-average baseline PRL levels (86.5±51.9 ng/mL).
  • Hyperprolactinemic symptoms resolved during the treatment period or ≤1 month after cabergoline withdrawal in all but 2 patients with normalized PRL levels. Symptoms did not resolve in patients with nonnormalized PRL levels.

MANAGEMENT OF HYPERPROLACTINEMIA

The Endocrine Society Clinical Practice Guideline for the Diagnosis and Treatment of Hyperprolactinemia (2011)² includes several recommendations for the treatment of hyperprolactinemia, which differ depending on whether the patient is symptomatic or asymptomatic.

• In symptomatic patients with suspected medication-induced hyperprolactinemia, the guideline recommends discontinuing the medication for 3 days or using an alternative medication and then reassessing PRL levels.
  • The first step should be discontinuation of the drug. If that is not possible, the drug should be substituted with another drug of similar action that does not cause hyperprolactinemia.
  • Alternative antipsychotics may include those with lower dopamine antagonist activity or aripiprazole (antipsychotic with both dopamine agonist and dopamine antagonist activity).
  • Use of dopamine agonists to treat hyperprolactinemia should only be considered if substitution with an alternative medication is not possible owing to the potential to exacerbate psychosis.
• In asymptomatic patients, the guideline recommends no treatment. However, if the patient also has hypogonadal symptoms or low bone mass, therapy with estrogen or testosterone should be considered.

The American Psychiatric Association (APA) Practice Guidelines for the Treatment of Patients with Schizophrenia (2020)³ provide several recommendations for the management of clinical symptoms due to antipsychotic-induced hyperprolactinemia.

• If a patient is experiencing symptoms of PRL elevation, the dose of antipsychotic drug should be reduced, or the patient should be switched to an antipsychotic with less effect on PRL, such as a drug with partial agonist activity at dopamine receptor.
• Administration of a dopamine agonist such as BMT should also be considered.

SELECTED ADDITIONAL REFERENCES

Additional single blind/OL studies^25-32 and case reports^19,33-41 discussing treatments of risperidone-induced hyperprolactinemia have been referenced for your review. Recent reviews of antipsychotic-induced hyperprolactinemia have also been included.^42-45

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 17 August 2023.