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.