Hyperprolactinemia: Monitoring children on long-term risperidone How to address evidence of potential for developmental eff ects with sustained use ® Dowden Health Media erum prolactin increases in children and adolescents when risperidone therapy begins, then decreases CopyrightFor personalS useover time only in many patients. When prolactin levels remain elevated, evidence suggests that children may experience adverse effects such as delayed sexual matu- ration or reduced bone growth because of hypothalamic- pituitary-gonadal axis (HPG) dysfunction. To help you make informed prescribing decisions, we discuss what the evidence says about the effects of elevated prolactin in children and adolescents. We then MASTERFILE / suggest clinical steps to help you manage hyperprolac- tinemia when prescribing risperidone. EDELSTON OWEN © Pediatric indications Jeff rey Ali, MD, MSc Based on short-term clinical trials of effi cacy and tol- Associate professor erability, risperidone is FDA-approved for 3 pediatric Manpreet Khemka, MBBS indications: First-year resident • short-term treatment of acute mania or mixed epi- sodes associated with bipolar I disorder in patients Department of psychiatry and human behavior age 10 to 17 University of Mississippi Medical Center • schizophrenia treatment in patients age 13 to 17 Jackson, MS • treatment of irritability (including aggression, self- injury, temper tantrums, and mood swings) associ- ated with autistic disorder in patients age 5 to 16. Recommended risperidone dosages are lower for children and adolescents than for adults (Table 1). Off- label pediatric uses described in case reports include psychotic, mood, disruptive, movement, and pervasive Current Psychiatry 64 November 2008 developmental disorders. For mass reproduction, content licensing and permissions contact Dowden Health Media. 64_CPSY1108 64 10/15/08 10:15:04 AM Table 1 Recommended risperidone dosing for pediatric indications* Indication Starting dose Maximum dose Acute mania or 0.5 mg once daily in morning 2.5 mg/d mixed episodes or evening Irritability in autism 0.25 mg/d for patients 0.5 mg/d for patients weighing <20 kg weighing <20 kg 0.5 mg/d for patients weighing ≥20 kg 1 mg/d for patients weighing ≥20 kg Schizophrenia 0.5 mg once daily in morning 3 mg/d or evening * FDA-approved dosages; individualize based on response and tolerability Source: Drug facts and comparisons. St. Louis, MO: Wolters Kluwer Health; 2008:949-50 Table 2 Factors that regulate prolactin secretion Clinical Point Effect Factors Mechanism Age- and sex-specifi c Inhibitory Dopamine, gonadotropin-associated D2 receptor stimulation normal prolactin protein, acetylcholine of lactotroph cells ranges vary from Stimulatory Serotonin, thyrotropin-releasing Through 5-HT1A hormone, cholecystokinin and 5-HT2 lab to lab, and levels show marked circadian variation Prolactin physiology also infl uenced by thyrotropin-releasing Prolactin’s primary physiologic function hormone.6 A rare association between pi- is to cause breast enlargement during tuitary tumors and atypical antipsychotics pregnancy and milk secretion during lac- has been proposed as a probable cause of tation.1 A polypeptide hormone, prolactin sustained prolactin elevation.7 is secreted by lactotroph cells in the ante- Pituitary prolactin secretion is regulated rior pituitary, under the complex control of by neuroendocrine neurons in the hypo- stimulatory and inhibitory factors (Table 2). thalamus, specifi cally in the tuberoinfun- Its pulsatile secretion peaks 13 to 14 times dibular tract that extends from the arcuate daily, with approximately 95 minutes be- nucleus of the mediobasal hypothalamus tween pulses. (tuberal region) and projects to the median Serum prolactin levels show marked cir- eminence (infundibular region). Neurose- cadian variation.2 The reference value for cretory dopamine neurons of the arcuate serum prolactin is 1 to 25 ng/mL for wom- nucleus inhibit prolactin secretion. Hence, en and 1 to 20 ng/mL for men. The higher prolactin secretion increases when anti- prolactin levels seen in women begin after psychotic therapy results in dopamine re- puberty and presumably are caused by ceptor blockade. estrogen’s stimulatory effect.3 Age- and sex- Antipsychotics vary in affi nity for the specifi c normal prolactin ranges vary wide- D2 dopamine receptor, rate of dissocia- ly and from lab to lab (Table 3, page 66). tion from the receptor, and ability to act on the receptor as both a dopamine agonist Risperidone is a strong dopamine D2 and (which lowers serum prolactin) and a do- serotonin 5HT-2A antagonist with low af- pamine antagonist (which increases serum fi nity for alpha-1 and alpha-2 adrenergic prolactin). Based on adult and pediatric receptors and histamine H1 receptors.4 data, the relative potency of antipsychotic Antagonism of these receptors is thought drugs in inducing hyperprolactinemia to explain the drug’s therapeutic effects is roughly risperidone > haloperidol > and many of its side effects, including olanzapine > ziprasidone > quetiapine > Current Psychiatry hyperprolactinemia.5 Prolactin release is clozapine > aripiprazole.8 Even though Vol. 7, No. 11 65 65_r1_CPSY1108 65 10/16/08 1:23:22 PM Table 3 Sample age- and sex-specifi c reference ranges for serum prolactin (ng/mL)* Age Males Females 0 to 1 month 3.7 to 81.2 0.3 to 95.0 Prolactin 1 to 12 months 0.3 to 28.9 0.2 to 29.9 1 to 3 years 2.3 to 13.2 1.0 to 17.0 4 to 6 years 0.8 to 16.9 1.6 to 13.1 7 to 9 years 1.9 to 11.6 0.3 to 12.9 10 to 12 years 0.9 to 12.9 1.9 to 9.6 13 to 15 years 1.6 to 16.6 3.0 to 14.4 Adult 2.1 to 17.7 2.8 to 29.2 Clinical Point Female: nonpregnant 2.8 to 29.2 The prolactin level Female: pregnant 9.7 to 208.5 that triggers gonadal Postmenopausal 1.8 to 20.3 * Reference values may vary from lab to lab hypofunction Source: LabCorp, Birmingham, AL appears to vary substantially among individual patients risperidone ranks highest in the hierarchy tinemia—which can be seen more read- to cause hyperprolactinemia, it is accepted ily in sexually mature adolescents than in as the fi rst-line antipsychotic in children children—include: and adolescents. This is probably because • amenorrhea or oligorrhea risperidone: • breast enlargement or engorgement in • has been in clinical use longer than females and males other atypical antipsychotics except • galactorrhea (females > males) clozapine • decreased libido • has received FDA approval for 3 pedi- • erectile dysfunction. atric indications. Although evidence is inconclusive, other problems may be associated with increased prolactin in children and adolescents. These Prolactin and the HPG axis include failure to enter or progress through Elevated serum prolactin inhibits the hy- puberty,8 increased risk of benign breast tu- pothalamus’ pulsatile release of gonado- mors,22 and reduced bone density.10 trophin-releasing hormone (GnRH), which Bone changes. Decreased estrogen related in turn decreases the pituitary’s secretion to hyperprolactinemia may inhibit bone of follicle-stimulating hormone (FSH) and mineralization, causing osteopenia, osteo- luteinizing hormone (LH). In women, pro- porosis, and increased fracture risk.10 The lactin also blocks the feedback effect of mechanism of bone density loss may be es- estradiol on LH secretion (Figure, page 71). trogen’s osteoclast activating and osteoblast The prolactin level that triggers gonadal inhibiting action. The level and duration of hypofunction appears to vary substantial- prolactin elevation that can hamper bone ly among individuals.9 growth has not been defi ned, although evi- dence suggests a pervasive effect: Symptoms of elevated prolactin can occur • 65% of a group of 38 premenstrual pa- as a direct result of prolactin’s physiologic tients developed osteoporosis or osteopenia effect on breast tissue or indirectly through when taking risperidone or typical antipsy- hypogonadism related to decreased chotics for schizophrenia for a mean of 8 Current Psychiatry 66 November 2008 FSH and LH. Symptoms of hyperprolac- years.11 continued on page 69 66_CPSY1108 66 10/15/08 10:15:16 AM continued from page 66 • Bone loss has persisted 2 years after al16 reached a similar conclusion in a pro- prolactin normalized in adolescents with spective study of 40 children treated with prolactinomas.12 atypical antipsychotics for 4 to 15 weeks. Ups and downs. Prolactin levels increase sharply in the fi rst weeks of risperidone Hyperprolactinemia treatment, peak at around 6 to 8 weeks, in children and adolescents and then trend downward toward nor- We suggest that children and adolescents mal.17 In a post hoc analysis of pooled data receiving prolonged risperidone treatment from 5 clinical trials totaling 700 patients can present with symptoms similar to age 5 to 15, Findling et al17 reported that those associated with hyperprolactinemia mean serum prolactin: secondary to other causes, including: • peaked in the fi rst 1 to 2 months of pa- • prolactinomas (the most common tients’ starting risperidone, 0.02 to 0.06 cause)13 mg/kg/d • thyrotropin-releasing hormone stimu- • returned to within or close to normal lation in primary hypothyroidism range by 3 to 5 months. • hypoglycemia No correlation was seen between pro- Clinical Point • inherited endocrine syndromes lactin elevation and side effects that could Prolactin levels peak • physiologic stress be attributed to prolactin. at around 6 to 8 • medications. In a 2-part study, Anderson et al18 ex- The most common presenting symp- amined the short- and long-term effects weeks of risperidone toms of prolactinomas are headache, amen- of risperidone treatment on prolactin in treatment, then orrhea, and galactorrhea. A few patients children age 5 to 17 with autism. In the ini- trend downward 13 have delayed puberty. In a review of hy- tial double-blind, placebo-controlled trial, toward normal perprolactinemia in children, Massart and 101 children were randomly assigned to Saggese14 proposed a correlation between risperidone 1.8 mg/d, or placebo.