QUETIAPINE IN PATIENTS WITH SCHIZOPHRENIA - A HIGH-DOSE AND LOW-DOSE DOUBLE-BLIND COMPARISON WITH PLACEBO

Background: Quetiapine fumarate (Seroquel [ICI 204,636]) is an atypica l dibenzothiazepine antipsychotic with a greater affinity for 5-hydrox ytryptamine(2) (5-HT2) receptors than for D-2 dopamine receptors; its efficacy in patients with schizophrenia was shown in early phase 2 tri als (maximum dose, 750 mg/d). Methods: In this multicenter, double-bli nd, placebo-controlled trial, 286 patients hospitalized with chronic o r subchronic schizophrenia (DSM-III-R) were randomized to 6 weeks of t reatment with high-dose quetiapine fumarate (less than or equal to 750 mg/d), n = 96; low-dose quetiapine fumarate (less than or equal to 25 0 mg/d), n = 94; or placebo, n = 96. The Brief Psychiatric Rating Scal e (BPRS) and Clinical Global Impression Severity of Illness item score s were the primary efficacy variables. Secondary efficacy variables in cluded the BPRS positive-symptom cluster score, the Modified Scale for the Assessment of Negative Symptoms summary score (United States only ), and the total score from the negative scale of the Positive and Neg ative Syndrome Scale (Europe only). Scores were analyzed using an anal ysis of covariance for change from baseline at end point with last obs ervations carried forward. The model included baseline score (covariat e), center, and treatment. Extrapyramidal symptoms were assessed using the Simpson-Angus Scale and the Barnes Akathisia Scale; abnormal invo luntary movements were assessed using the Abnormal Involuntary Movemen t Scale. Frequency distributions of grouped change-from-baseline score s were analyzed using chi(2) tests. Results: Of 280 patients in whom t he efficacy of quetiapine was evaluated, 159 (42% of those receiving h igh-dose treatment; 57%, low-dose treatment; and 59%, placebo) withdre w before trial completion, primarily because of treatment failure. Sig nificant (P < .001, BPRS; P = .003, Clinical Global Impression Severit y of Illness item; and P = .003, BPRS positive-symptom cluster) differ ences were identified between patients receiving high-dose quetiapine and placebo for both primary efficacy variables, with end point differ ences in the BPRS positive-symptom cluster score showing quetiapine's consistency in reducing positive symptoms. The reduction of negative s ymptoms was less consistent; high-dose quetiapine was superior on the Modified Scale for the Assessment of Negative Symptoms but not on the negative scale of the Positive and Negative Syndrome Scale. Quetiapine was well tolerated and did not induce extrapyramidal symptoms, sustai ned elevations of prolactin, or clinically significant changes in hema tologic parameters. Conclusions: Quetiapine is an effective antipsycho tic with a favorable safety profile. The optimum dose is probably grea ter than 250 mg/d.