Background: Based mainly on the selective antagonism of clozapine at D4 compared with D2 dopamine receptors, hopes have run high that a selective D4 dopamine receptor antagonist might improve the pharmacological treatment of patients with schizophrenia. We report, to our knowledge, the first multicenter study of the antipsychotic potential of a highly specific D4 dopamine receptor antagonist (ie, L-745,870) in patients with acute schizophrenia.
Methods: Thirty-eight acutely psychotic and neuroleptic responsive (by history) newly admitted inpatients with schizophrenia were randomized to 4 weeks of double-blind treatment (2:1) with either L-745,870 (n = 26), 15 mg/d, or placebo (n = 12) after a 3- to 5-day placebo run-in period.
Results: Overall, a greater percentage of patients receiving L-745,870 compared with patients receiving placebo discontinued the study for insufficient therapeutic response (32% vs 16%). At the end of 4 weeks by last observation carried forward analysis, the mean change from baseline to week 4 on the total Brief Psychiatric Rating Scale favored placebo (i.e., -8 points [-15% change from baseline] vs -1 point [-2% change from baseline] for placebo vs L-745,870, P = .09). Similar differences in favor of placebo in changes from baseline mean scores were observed for the not carried forward analysis on the total Brief Psychiatric Rating Scale (P < .03), for not carried forward and last observation carried forward analyses on the sum of selected positive symptom items of the Brief Psychiatric Rating Scale, and for the Clinical Global Impression analysis (P = .03, last observation carried forward). A greater percentage of patients receiving L-745,870 had scores indicative of some level of worsening (compared with baseline) on the total Brief Psychiatric Rating Scale and the Clinical Global Impressions' Severity of Illness Scale as well as positive symptoms compared with those receiving placebo.
Conclusion: The selective D4 dopamine receptor antagonist L-745,870 was ineffective as an antipsychotic for the treatment of neuroleptic responsive inpatients with acute schizophrenia.