A 48-year-old woman with a 12-year history of schizophrenia on risperidone presents with galactorrhea and amenorrhea for the past 6 months. Her pregnancy test is negative. Serum prolactin is 95 ng/mL (normal < 20 ng/mL). Brain MRI shows no pituitary adenoma. What is the mechanism behind this adverse effect?

• A Stimulation of 5-HT2A receptors in the hypothalamus
• B Inhibition of alpha-1 adrenergic receptors in the anterior pituitary
• C Anticholinergic blockade reducing dopaminergic tone
• D Blockade of D2 receptors in the tuberoinfundibular pathway ✓

Explanation

Dopamine normally exerts tonic inhibition on prolactin secretion via D2 receptors in the tuberoinfundibular pathway (hypothalamic neurons projecting to the median eminence). Risperidone and other typical antipsychotics are potent D2 antagonists that block this inhibitory tone, leading to hyperprolactinemia. Among second-generation antipsychotics, risperidone and amisulpride are most notorious for prolactin elevation because they do not readily penetrate the blood-brain barrier at the pituitary level. Quetiapine and clozapine cause minimal prolactin elevation.

Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.

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