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Amisulpride Prolactin Mechanism — MRCPsych Paper B MCQ

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HardSchizophrenia & PsychosisAmisulpride Prolactin MechanismMRCPsych Paper B

A 26-year-old man with first-episode psychosis has a normal prolactin concentration before starting amisulpride 400 mg daily. Three weeks later, his prolactin is 2200 mU/L. Which pharmacokinetic–pharmacodynamic property best explains the marked propensity of amisulpride to elevate prolactin?

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Correct answer: A — Limited central penetration produces greater D2/D3 blockade at the pituitary, which lies outside the blood–brain barrier

Explanation lettering: B = shown as A · C = shown as B · E = shown as C · A = shown as E

Amisulpride is a selective D2/D3 antagonist with relatively limited blood–brain barrier penetration. The anterior pituitary lies outside the blood–brain barrier, so pituitary lactotroph D2 receptors can experience disproportionately high amisulpride exposure and occupancy relative to central D2/D3 sites. Blocking these receptors removes dopamine's tonic inhibition of prolactin secretion, producing marked hyperprolactinaemia. Amisulpride is not a partial D2 agonist (A) and has no clinically relevant 5-HT2A (C) or muscarinic M1 (D) affinity. It is also weakly metabolised and predominantly eliminated unchanged by the kidneys, so formation of an active CYP2D6 metabolite (E) does not explain the effect.

Reference: Bressan RA et al. Prolactinemia is uncoupled from central D2/D3 dopamine receptor occupancy in amisulpride treated patients. Psychopharmacology. 2004;175(3):367–373. https://pubmed.ncbi.nlm.nih.gov/14997280/