Relationship between dopamine D-2 occupancy, clinical response, and side effects: A double-blind PET study of first-episode schizophrenia

Objective: Since all antipsychotics block dopamine D-2 receptors, the autho rs investigated how well D-2 receptor occupancy in vivo predicts clinical r esponse, extrapyramidal side effects, and hyperprolactinemia. Method: In a double-blind study, 22 patients with first-episode schizophrenia were rando mly assigned to 1.0 or 2.5 mg/day of haloperidol. After 2 weeks of treatmen t, D-2 receptor occupancy was determined with [C-11]raclopride and positron emission tomography and clinical response, extrapyramidal side effects, an d prolactin levels were measured. Patients who showed adequate responses co ntinued taking their initial doses, those who did not respond had their dos es increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for al l patients. Results: The patients showed a wide range of D-2 occupancy (38% -87%). The degree of receptor occupancy predicted clinical improvement, hyp erprolactinemia, and extrapyramidal side effects. The likelihood of clinica l response, hyperprolactinemia, and extrapyramidal side effects increased s ignificantly as D-2 occupancy exceeded 65%, 72%, and 78%, respectively. Con clusions: The study confirms that D-2 occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consist ent with a "target and trigger" hypothesis of antipsychotic action, i.e., t hat the D-2 receptor specificity of antipsychotics permits them to target d iscrete neurons and that their antagonist properties trigger within those n eurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D-2 occupancy and si de effects in this study helps explain many of the observed clinical differ ences between typical and atypical antipsychotics.