A Double-Blind, Randomized, Placebo-Controlled Study of the Dopamine D3 Receptor Antagonist ABT-925 in Patients With Acute Schizophrenia

There is substantial preclinical and clinical evidence to suggest a potential role for the dopamine D-3 receptor in the treatment of schizophrenia. ABT-925 is a selective dopamine D-3 receptor antagonist with an approximately 100-fold higher in vitro affinity for dopamine D-3 versus D-2 receptors. This double-blind, randomized, placebo-controlled, escalating-dose, parallel-group study assessed the efficacy and safety of ABT-925 in the treatment of patients with acute exacerbation of schizophrenia. One hundred fifty-five patients were assessed over a 6-week double-blind treatment period (placebo: n = 48; ABT-925 50 mg once daily [QD]: n = 53; ABT-925 150 mg QD: n = 54). The primary efficacy measure was mean change from baseline to final evaluation on the Positive and Negative Syndrome Scale total score. Secondary measures of efficacy and pharmacokinetic parameters were also assessed. Safety assessments included adverse event monitoring, laboratory tests, vital signs, movement rating scales, and electrocardiogram measures. No statistically significant treatment effect was observed with ABT-925 50 mg QD or 150 mg QD compared with placebo on primary or secondary efficacy end points. Pharmacokinetic parameter estimates increased with dose in a linear fashion. ABT-925 50 mg QD and 150 mg QD were generally well tolerated, with adverse event profiles similar to that of placebo. Findings from a concurrent positron emission tomography study among healthy volunteers suggest that the ABT-925 doses used in this study may not have been sufficient to adequately occupy D-3 receptors, thereby underscoring the importance of pharmacodynamic markers, such as PET, in determining appropriate compound doses before embarking on studies in a target population.