January 2008

Treating Behavioral Problems in Dementia
No drug is clearly efficacious for behavioral problems in dementia, and all are associated with significant risks.

Prolactin Elevation and Antipsychotics
Risperidone (Risperdal) seems to increase prolactin more than conventional and other second-generation antipsychotics; adjunctive aripiprazole (Abilify) may lower antipsychotic-induced hyperprolactinemia.

In Brief
Atomoxetine Effective for ADHD in Preschool Children; Excessive Body Weight Increases Risk of Dementia

Treating Adolescent Mania
Olanzapine (Zyprexa) effectively treats adolescent bipolar disorder but appears to cause harmful medical consequences in young patients.

Isotretinoin and Depression
Depression is a possible side effect of treatment with isotretinoin (Accutane and others).

Prolactin Elevation and Antipsychotics

January 2008

Because of their strong blockade of dopamine D2 receptors, conventional antipsychotics increase prolactin release from the pituitary and can cause hyperprolactinemia. Elevated prolactin may lead to gynecomastia, galactorrhea, decreased fertility, menstrual irregularities, sexual dysfunction, and decreased bone mineral density. By inhibiting the hypothalamo-pituitary-gonadal axis, hyperprolactinemia may cause bone loss in patients with schizophrenia.1 Hyperprolactinemia has also been associated with increased risk of breast and possibly other cancers. Most second-generation antipsychotics do not elevate prolactin, with the exception of risperidone (Risperdal).

Bushe and Shaw looked at hyperprolactinemia (defined as prolactin levels greater than 700 mIU/L in women and greater than 500 mIU/L in men) during treatment with antipsychotics in a naturalistic cohort of 194 outpatients with schizophrenia or bipolar disorder.2 Among patients taking a single antipsychotic, hyperprolactinemia was found most often in those taking risperidone: 69% (24/35) versus 6% of patients treated with olanzapine (1/16), 5% of those taking clozapine (1/21), and 33% of those taking typical antipsychotics (27/83). Of 18 patients prescribed oral risperidone, all of 10 women (100%) and 5 of 8 men (63%) developed hyperprolactinemia. In the group taking long-acting risperidone (LAR, Risperdal Consta), all 6 women (100%) had hyperprolactinemia but only 3 of 11 men (27%).

Lai et al report on a series of patients who experienced marked elevation of serum prolactin when they were switched from conventional depot antipsychotics to LAR.3 These authors enrolled 12 men and 12 women with schizophrenia who had been taking conventional antipsychotics for at least 3 months. The average age of the patients was about 42 years, and the mean duration of previous treatment was 16.5 years. Their mean dosage of conventional depot antipsychotics was 237 mg of chlorpromazine equivalents daily.

When the patients were switched to LAR, the initial dose was 25 mg every 2 weeks. After 4 weeks, the LAR dose could be adjusted based on clinical indicators. The average last dose of LAR was 30.7 ± 6.4 mg. After the switch to LAR, plasma prolactin levels increased from 27.67 ± 28.5 ng/mL to 55.85 ± 43.0 ng/mL (P = .004). Hyperprolactinemia (defined as a prolactin level above 15.20 ng/mL for men or 23.03 ng/mL for women) increased from 33.3% to 75% for the men and 58.3% to 91.7% for the women. Three of the 12 women reported new-onset dysmenorrhea following the switch to LAR.

In an independent report, Lorenz and Weinstein write of a 29-year-old man with a history of bipolar I disorder who developed hyperprolactinemia while taking haloperidol (Haldol and others).4 Because of poor adherence to oral medication regimens, the patient was treated intramuscularly (IM) with the decanoate form of haloperidol. At a dose of 150 mg IM every 4 weeks, he developed gynecomastia. This resolved when the haloperidol decanoate dose was decreased to 100 mg IM every 4 weeks.

Six months later, the patient was admitted to an acute care psychiatric unit for manic psychosis. He had received an IM injection of haloperidol decanoate, 125 mg, earlier that day from his outpatient psychiatrist. In the hospital, an additional 50 mg of haloperidol decanoate IM was administered, while supplemental oral haloperidol was tapered and discontinued. Six days after admission, the patient's prolactin level was 35.2 ng/mL, considered substantially elevated. Doctors added aripiprazole (Abilify), 30 mg po daily, to the patient's medication regimen. Three days later, aripiprazole was decreased to 15 mg daily. Prolactin levels 1 and 2 weeks after aripiprazole was initiated had plunged to 2.1 and 2.6 ng/mL, respectively. The patient's psychosis improved without apparent adverse effects. He was discharged on the combination of IM haloperidol decanoate and po aripiprazole.

Prolonged elevation of prolactin levels can produce unpleasant side effects and possibly adverse long-term effects on health. Fortunately, antipsychotic-induced hyperprolactinemia often decreases over time (BTP 2007;30:25). The reports above highlight two interesting observations. The Bushe and Shaw case series and the one from Lai et al suggest that risperidone, including LAR, may increase prolactin to a greater extent than conventional oral and depot antipsychotics and certainly more than other second-generation agents. Lorenz and Weinstein's case suggests that adjunctive aripiprazole, possibly through its partial dopamine agonism, lowers antipsychotic-induced hyperprolactinemia. Both suggestions are worth follow-up and corroboration. Meanwhile, clinicians observing symptoms and signs that might reflect hyperprolactinemia should order a plasma prolactin level.

1Kishimoto T, Watanabe K, Shimada N, Makita K, Yagi G, Kashima H: Antipsychotic-induced hyperprolactinemia inhibits the hypothalamo-pituitary-gonadal axis and reduces bone mineral density in male patients with schizophrenia. J Clin Psychiatry, in press.

2Bushe C, Shaw M: Prevalence of hyperprolactinemia in a naturalistic cohort of schizophrenia and bipolar outpatients during treatment with typical and atypical antipsychotics. J Psychopharmacol 2007;21:768.

3Lai YC, Chiou CC, Chen CH, Huang MC: Significant elevations of prolactin levels in patients who shifted from conventional depot antipsychotics to long-acting risperidone. J Clin Psychopharmacol 2007;27:523-524.

4Lorenz RA, Weinstein B: Resolution of haloperidol-induced hyperprolactinemia with aripiprazole. J Clin Psychopharmacol 2007;27:524-525.