THE EFFECTS OF A SELECTIVE D-4 DOPAMINE-RECEPTOR ANTAGONIST (L-745,870) IN ACUTELY PSYCHOTIC INPATIENTS WITH SCHIZOPHRENIA

Background: Based mainly on the selective antagonism of clozapine at D -4 compared with D-2 dopamine receptors, hopes have run high that a se lective D-4 dopamine receptor antagonist might improve the pharmacolog ical treatment of patients with schizophrenia. We report, to our knowl edge, the first multicenter study of the antipsychotic potential of a highly specific D, dopamine receptor antagonist tie, L-745,870) in pat ients with acute schizophrenia. Methods: Thirty-eight acutely psychoti c and neuroleptic responsive (by history) newly admitted inpatients wi th 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) aft er a 3- to 5-day placebo run-in period. Results: Overall, a greater pe rcentage of patients receiving L-745,870 compared with patients receiv ing placebo discontinued the study for insufficient therapeutic respon se (32% vs 16%). At the end of 4 weeks by last observation carried for ward analysis, the mean change from baseline to week 4 on the total Br ief Psychiatric Rating Scale favored placebo (ie, -8 points [-15% chan ge from baseline] vs -1 point [-2% change from baseline] for placebo v s L-745,870, P = .09). Similar differences in favor of placebo in chan ges from baseline mean scores were observed for the not carried forwar d analysis on the total Brief Psychiatric Rating Scale (P < .03), for not carried forward and last observation carried forward analyses on t he sum of selected positive symptom items of the Brief Psychiatric Rat ing Scale, and for the Clinical Global Impression analysis (P = .03, l ast observation carried forward). A greater percentage of patients rec eiving L-745,870 had scores indicative of some level of worsening (com pared with baseline) on the total Brief Psychiatric Rating Scale and t he Clinical Global Impressions' Severity of Illness Scale as well as p ositive symptoms compared with those receiving placebo. Conclusion: Th e selective D-4 dopamine receptor antagonist L-745,870 was ineffective as an antipsychotic for the treatment of neuroleptic responsive inpat ients with acute schizophrenia.