The primary rating instrument used for assessing manic symptoms in these trials was YMRS, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score).

The results of the trials follow:

Monotherapy

In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking SEROQUEL were dosed in a range between 400 and 800 mg per day.

Adjunct Therapy

In this 3-week placebo-controlled trial, 170 patients with acute bipolar mania (YMRS ≥ 20) were randomized to receive SEROQUEL or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. SEROQUEL was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score.

The majority of patients in this trial taking SEROQUEL were dosed in a range between 400 and 800 mg per day. In a similarly designed trial (n=200), SEROQUEL was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect.

Schizophrenia

The efficacy of SEROQUEL in the treatment of schizophrenia was established in 3 short-term (6-week) controlled trials of inpatients with schizophrenia who met DSM III-R criteria for schizophrenia. Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of SEROQUEL and haloperidol.

Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS), a more recently developed but less well evaluated scale, was employed for assessing negative symptoms.

The results of the trials follow:

1. In a 6-week, placebo-controlled trial (n=361) involving 5 fixed doses of SEROQUEL (75, 150, 300, 600 and 750 mg/day on a tid schedule), the 4 highest doses of SEROQUEL were generally superior to placebo on the BPRS total score, the BPRS psychosis cluster and the CGI severity score, with the maximal effect seen at 300 mg/day, and the effects of doses of 150 to 750 mg/day were generally indistinguishable. SEROQUEL, at a dose of 300 mg/day, was superior to placebo on the SANS.
2. In a 6-week, placebo-controlled trial (n=286) involving titration of SEROQUEL in high (up to 750 mg/day on a tid schedule) and low (up to 250 mg/day on a tid schedule) doses, only the high dose SEROQUEL group (mean dose, 500 mg/day) was generally superior to placebo on the BPRS total score, the BPRS psychosis cluster, the CGI severity score, and the SANS.
3. In a 6-week dose and dose regimen comparison trial (n=618) involving two fixed doses of SEROQUEL (450 mg/day on both bid and tid schedules and 50 mg/day on a bid schedule), only the 450 mg/day (225 mg bid schedule) dose group was generally superior to the 50 mg/day (25 mg bid) SEROQUEL dose group on the BPRS total score, the BPRS psychosis cluster, the CGI severity score, and on the SANS.

Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 compared to those older than 40. The clinical significance of this finding is unknown.

Animal Toxicology

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