Evidence-Based Reviews

Hyperprolactinemia: Monitoring children on long-term risperidone

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How to address evidence of potential for developmental effects with sustained use.


 

References

Serum prolactin increases in children and adolescents when risperidone therapy begins, then decreases over time in many patients. When prolactin levels remain elevated, evidence suggests that children may experience adverse effects such as delayed sexual maturation 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 suggest clinical steps to help you manage hyperprolactinemia when prescribing risperidone.

Pediatric indications

Based on short-term clinical trials of efficacy and tolerability, risperidone is FDA-approved for 3 pediatric indications:

  • short-term treatment of acute mania or mixed episodes associated with bipolar I disorder in patients age 10 to 17
  • schizophrenia treatment in patients age 13 to 17
  • treatment of irritability (including aggression, self-injury, temper tantrums, and mood swings) associated 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 developmental disorders.

Table 1

Recommended risperidone dosing for pediatric indications*

IndicationStarting doseMaximum dose
Acute mania or mixed episodes0.5 mg once daily in morning or evening2.5 mg/d
Irritability in autism0.25 mg/d for patients
weighing <20 kg
0.5 mg/d for patients weighing ≥20 kg
0.5 mg/d for patients weighing
<20 kg
1 mg/d for patients weighing ≥20 kg
Schizophrenia0.5 mg once daily in morning or evening3 mg/d
* FDA-approved dosages; individualize based on response and tolerability
Source: Drug facts and comparisons. St. Louis, MO: Wolters Kluwer Health; 2008:949-50

Prolactin physiology

Prolactin’s primary physiologic function is to cause breast enlargement during pregnancy and milk secretion during lactation.1 A polypeptide hormone, prolactin is secreted by lactotroph cells in the anterior pituitary, under the complex control of stimulatory and inhibitory factors (Table 2). Its pulsatile secretion peaks 13 to 14 times daily, with approximately 95 minutes between pulses.

Serum prolactin levels show marked circadian variation.2 The reference value for serum prolactin is 1 to 25 ng/mL for women and 1 to 20 ng/mL for men. The higher prolactin levels seen in women begin after puberty and presumably are caused by estrogen’s stimulatory effect.3 Age- and sex-specific normal prolactin ranges vary widely and from lab to lab (Table 3).

Risperidone is a strong dopamine D2 and serotonin 5HT-2A antagonist with low affinity for alpha-1 and alpha-2 adrenergic receptors and histamine H1 receptors.4 Antagonism of these receptors is thought to explain the drug’s therapeutic effects and many of its side effects, including hyperprolactinemia.5 Prolactin release is also influenced by thyrotropin-releasing hormone.6 A rare association between pituitary tumors and atypical antipsychotics has been proposed as a probable cause of sustained prolactin elevation.7

Pituitary prolactin secretion is regulated by neuroendocrine neurons in the hypothalamus, specifically in the tuberoinfundibular tract that extends from the arcuate nucleus of the mediobasal hypothalamus (tuberal region) and projects to the median eminence (infundibular region). Neurosecretory dopamine neurons of the arcuate nucleus inhibit prolactin secretion. Hence, prolactin secretion increases when antipsychotic therapy results in dopamine receptor blockade.

Antipsychotics vary in affinity for the D2 dopamine receptor, rate of dissociation from the receptor, and ability to act on the receptor as both a dopamine agonist (which lowers serum prolactin) and a dopamine antagonist (which increases serum prolactin). Based on adult and pediatric data, the relative potency of antipsychotic drugs in inducing hyperprolactinemia is roughly risperidone > haloperidol > olanzapine > ziprasidone > quetiapine > clozapine > aripiprazole.8 Even though risperidone ranks highest in the hierarchy to cause hyperprolactinemia, it is accepted as the first-line antipsychotic in children and adolescents. This is probably because risperidone:

  • has been in clinical use longer than other atypical antipsychotics except clozapine
  • has received FDA approval for 3 pediatric indications.

Table 2

Factors that regulate prolactin secretion

EffectFactorsMechanism
InhibitoryDopamine, gonadotropin-associated protein, acetylcholineD2 receptor stimulation of lactotroph cells
StimulatorySerotonin, thyrotropin-releasing hormone, cholecystokininThrough 5-HT1A and 5-HT2

Table 3

Sample age- and sex-specific reference ranges for serum prolactin (ng/mL)*

AgeMalesFemales
0 to 1 month3.7 to 81.20.3 to 95.0
1 to 12 months0.3 to 28.90.2 to 29.9
1 to 3 years2.3 to 13.21.0 to 17.0
4 to 6 years0.8 to 16.91.6 to 13.1
7 to 9 years1.9 to 11.60.3 to 12.9
10 to 12 years0.9 to 12.91.9 to 9.6
13 to 15 years1.6 to 16.63.0 to 14.4
Adult2.1 to 17.72.8 to 29.2
Female: nonpregnant 2.8 to 29.2
Female: pregnant 9.7 to 208.5
Postmenopausal 1.8 to 20.3
* Reference values may vary from lab to lab
Source: LabCorp, Birmingham, AL

Prolactin and the HPG axis

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