Quetiapine: An Effective Antipsychotic in First-Episode Schizophrenia Despite Only Transiently High Dopamine-2 Receptor Blockade

Background: It has been suggested that transiently high dopamine-2 (D2) receptor occupancy by antipsychotic medication may be sufficient for inducing an antipsychotic response. We treated patients experiencing their first episode of schizophrenia with a single daily dose of quetiapine to achieve a transient daily peak of D2 receptor blockade, to determine if this would lead to an antipsychotic response.

Method: Fourteen patients with a DSM-IV diagnosis of schizophrenia or schizophreniform or schizoaffective disorder were treated with quetiapine titrated to a single daily dose (mean ± SD dose at the time of the positron emission tomography [PET] scan = 427 ± 69 mg) for 12 weeks. Peak D2 occupancy approximately 2 hours postdose and trough D2 occupancy approximately 20 hours postdose were determined using PET and [11C]raclopride. Clinical symptoms and side effects were measured at baseline and every 2 weeks during the treatment phase.

Results: Quetiapine administration led to a mean peak D2 occupancy of 62% ± 10% 2 hours postdose, which declined to 14% ± 8% approximately 20 hours postdose. Ten (71%) of 14 patients responded to treatment with quetiapine, scoring "much improved" or greater on the Clinical Global Impressions-Improvement scale. Plasma drug levels and peak D2 occupancy were highly correlated (r = 0.84; p = .003), as were prolactin and plasma drug levels when measured 2.5 hours after drug administration (r = 0.60; p < .05). Mean weight gain for the 10 subjects who completed the 12-week study was 4.2 ± 4.6 kg (9.3 ± 10.2 lb). No clinically relevant motor side effects occurred during the trial.

Conclusion: Patients with a first episode of schizophrenia responded to treatment with a single daily dose of quetiapine despite only transiently high D2 receptor occupancy. Our findings raise the question of whether continuously high D2 blockade is necessary for obtaining an antipsychotic response. Future studies aimed at evaluating the relative merits of "transiently high" versus "continuously high" D2 occupancy are warranted.

J Clin Psychiatry 2002;63(11):992-997