Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: A comparison with haloperidol and placebo

OR OINA Multiple Fixed Doses of "Seroquel" (Quetiapine) in Patients with Acute Exacerbation of Schizophrenia: A Comparison with Haloperidol and Placebo Lisa A. Arvanitis, Barbara G. Miller, and the Seroquel Trial 13 Study Group Five fixed doses of the atypical antipsychotic "Seroquel" (quetiapine) were evaluated to delineate a dose-response relationship, as measured by changes from baseline in Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), and Modified Scale for the Assessment of Negative Symptoms (SANS) summary scores, and to compare efficacy and tolerability opposite placebo and haloperidol. Three hundred sixty-one patients from 26 North American centers entered this double-blind, placebo-controlled trial with acute exacerbation of chronic schizophrenia (DSM-III-R). Patients who completed a single-blind, placebo washout phase were randomized to double-blind treatment with quetiapine (75, 150, 300, 600, or 750 mg daily), haloperidol (12 mg daily), or placebo and evaluated weekly for 6 weeks. At end point, significant differences (p < 0.05, analysis of covariance) in adjusted mean changes from baseline were identified between the four highest doses of quetiapine and placebo for BPRS total, BPRS positive-symptom cluster, and CGI Severity of Illness item scores and between quetiapine 300 mg and placebo for SANS summary score. Differences between quetiapine and haloperidol were not significant. Dose-response modeling showed significant linear and quadratic functions of quetiapine dose for all primary efficacy variables. Notably, no significant safety concerns were identified as dose increased. Quetiapine was no different from placebo across the dose range studied regarding incidence of extrapyramidal symptoms or change in prolactin concentrations. Quetiapine is well tolerated and clinically effective in the treatment of schizophrenia. It is both superior to placebo and comparable to haloperidol in reducing positive symptoms at doses ranging from 150 to 750 mg/day and in reducing negative symptoms at a dose of 300 mg/day. © 1997 Society of Biological Psychiatry

Key Words: Quetiapine, ICI 204,636, Seroquel, schizophrenia, antagonist

antipsychotic,

5-HT2

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See Appendix for individual members of the Seroquel Trial 13 Study Group. From the Zeneca Pharmaceuticals, Wilmington, Delaware. Address reprint requests to Lisa A. Arvanitis, MD, Senior Medical Director, Clinical Research, Zeneca Pharmaceuticals, 1800 Concord Pike, FOC 3rd Ctr, Wilmington, DE 19850. Received August 14, 1996; revised March 18, 1997.

© 1997 Society of Biological Psychiatry

0006-3223/97/$17.00 PII S0006-3223(97)00190-X

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Introduction In the treatment of patients with schizophrenia, selecting the most appropriate, effective, and tolerable antipsychotic agent is key to maximizing the usefulness of pharmacotherapy among individual patients. Whereas clinicians have accepted the shortcomings associated with standard antipsychotic therapy, e.g., partial response, treatment resistance, the need to manage extrapyramidal symptoms (EPS), and events related to prolactinemia, newer agents are changing expectations of drug therapy. "Seroquer' (quetiapine, ICI 204,636) is a new dibenzothiazepine derivative and one of several new "atypical" antipsychotics developed for the treatment of schizophrenia. Clinical development of quetiapine followed preclinical indications of antipsychotic activity with minimal propensity to produce dyskinetic or dystonic effects or sustained elevations in plasma prolactin (Migler et al 1993; Sailer and Salama 1993). Initial findings used to characterize the atypical properties of quetiapine were based on receptor models and standard animal behavioral and EPS liability models. Receptor data showed quetiapine's greater affinity for serotonin (5-HT)2 receptors relative to D 2 receptors (Sailer and Salama 1993), and animal data showed that quetiapine reversed behavior induced by dopamine agonists and had minimal EPS liability in haloperidol-sensitized and drug-naive monkeys (Goldstein 1995). Newer tests, such as c-fos expression and the paw test (Robertson et al 1994; Ellenbrock et al in press), continue to support predictions of antipsychotic activity and good tolerability in humans. Antipsychotic efficacy in patients with acute exacerbation of schizophrenia was confirmed in three early placebo-controlled trials evaluating efficacy and tolerability. In these trials, quetiapine was superior to placebo in reducing the positive and negative symptoms of schizophrenia (Fabre et al 1995; Borison et al 1996; Goldstein and Arvanitis 1995). In the first active-controlled trial (up to 6 weeks of treatment), quetiapine was comparable to chlorpromazine. Throughout phase II development, quetiapine was well tolerated, with somnolence, headache, agitation, and insomnia among the most frequently reported adverse events. Small decreases in thyroxine concentration and increases in weight were also reported across trials and suggested the need to explore these effects in larger trials. Notably, however, in placebo-controlled trials, the incidence of EPS with quetiapine was no different from that seen with placebo on the basis of Simpson-Angus Scale total scores, minimal use of anticholinergic medications, and limited reports of motor system adverse events. Changes in plasma prolactin concentrations were also comparable to those seen with placebo, with resulting concentrations generally within the normal range.

Because an escalating-dose approach was used in phase II trials, fixed-dose trials were needed to establish the dose-response relationship for efficacy and tolerability, as well as guide optimal use of quetiapine. In this trial, we evaluated five fixed doses of quetiapine with two primary objectives: delineate a dose-response relationship as measured by changes from baseline in Brief Psychiatric Rating Scale (BPRS) score (Overall and Gorham 1962) and Clinical Global Impression (CGI) score (Guy 1976); and evaluate quetiapine for efficacy, safety, and tolerability opposite placebo and a standard dose of haloperidol. A third, but exploratory, objective was to investigate a potential relationship between plasma quetiapine concentration and therapeutic response.

M e t h o d s and Materials

Subjects Hospitalized patients with schizophrenia, 18-65 years of age, were recruited from 26 centers in the United States (21) and Canada (5). A diagnosis of acute exacerbation of chronic or subchronic schizophrenia, as defined by the

Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) (American Psychiatric Association 1987), was a key inclusion criterion. Additionally, at trial entry and before randomization, patients were required to have a minimum total score of 27 on the 18-item BPRS ( 0 - 6 scoring), a score of 3 (moderate) on at least two items from the BPRS positivesymptom cluster (conceptual disorganization, suspiciousness, hallucinatory behavior, unusual thought content), and a score of 4 (moderately ill) on the CGI Severity of Illness item. Patients were excluded if they had concurrent Axis I DSM-III-R diagnoses, history of seizure disorder, or any clinically significant medical condition that would interfere with evaluations of efficacy or tolerability. Other reasons for exclusion included participation in another investigational drug trial within 30 days of trial entry, use of depot antipsychotics within one dosing interval, and pregnancy. The trial was approved by center-designated institutional review boards, and written informed consent was obtained after subjects received a complete description of the trial.

Design This study was a 6-week, double-blind, randomized, multicenter, placebo-controlled trial comparing five fixed doses of quetiapine and a standard dose of haloperidol. Initially, patients entered a 7-day, single-blind, placebo washout phase, and all ongoing psychotropic medications were discontinued. Patients with a 20% or greater decrease

Efficacy of Quetiapine

in BPRS total score or a greater than 1-point decrease in CGI Severity of Illness item score at the end of the single-blind phase were considered placebo responders and were withdrawn. Patients eligible to enter the doubleblind phase were then randomized to receive one of seven treatments--75, 150, 300, 600, or 750 mg of quetiapine daily, 12 mg of haloperidol daily, or placebo. Daily treatment was administered in three equally divided doses. The selected quetiapine doses reflected doses from the full range studied in previous quetiapine trials, with the maximum dose selected on the basis of available preclinical toxicology data. The selected haloperidol dose was considered a midrange effective dose on the basis of earlier haloperidol literature and recent studies of other atypical antipsychotics (Van Putten et al 1990; Marder and Meibach 1994; Peuskens 1995; Beasley et al 1996). Initial daily dose was escalated to the randomized fixed dose over 7 days as needed, up to a maximum of 14 days. Patients then received trial treatment at the randomized fixed dose through day 42. For patients randomized to 300, 600, or 750 mg of quetiapine, the protocol-set escalation scheme provided for dose escalation to 300 mg/day over a minimum of 4 days. Patients who did not complete the dose escalation as prescribed were withdrawn. Chloral hydrate was permitted for insomnia (500-1000 mg at bedtime) and acute agitation (500 mg) but was limited to 2000 mg/day. Lorazepam (1-2 mg orally or intramuscularly) was permitted through day 14, up to 8 mg/day on an emergency basis only, for severe agitation or insomnia unresponsive to chloral hydrate. Neither chloral hydrate nor lorazepam was permitted within 6 and 12 hours, respectively, of efficacy assessments. During the double-blind phase, benztropine mesylate was permitted for treatment of EPS, with the dose and duration specified by the treating clinician. Prophylactic use of benztropine mesylate was not permitted.

Efficacy Evaluation For patients who were randomized, the BPRS, CGI, and Modified Scale for the Assessment of Negative Symptoms (SANS) (Andreasen 1984) were used to assess efficacy on a weekly basis, on days 7, 14, 21, 28, 35, and 42. At the trial initiation meeting, investigators were trained and tested on BPRS and SANS scoring using videotapes of patient interviews. To pass, investigators were required to rate 80% of the items within one point of the reference rater for each of the test interviews (two each for BPRS and SANS scoring). Blood samples were obtained weekly from day 21 through day 42, before the 08:00 dose of trial medication to determine trough plasma drug concentrations, and at

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0.5, 3, and 6 hours after the 08:00 dose on day 21 to quantify postdose concentrations. Samples were shipped to the sponsor and analyzed using an high-performance liquid chromatography method with ultraviolet detection, developed, and validated for quantitation of quetiapine.

Safety and Tolerability Adverse events were evaluated daily, with emergent neurological side effects assessed weekly using the SimpsonAngus Scale (Simpson and Angus 1970), modified to include an akathisia item, and the Abnormal Involuntary Movement Scale (AIMS) (Guy 1976). Blood samples were taken at baseline before the double-blind phase and weekly thereafter to evaluate hematologic and hepatic function and on day 28 and day 42 to evaluate prolactin and thyroid function, respectively. Patients underwent physical examinations and electrocardiographic evaluations at trial entry and then at day 42. Blood pressure, heart rate, and temperature were measured at baseline, daily through day 14, and then weekly. Weight was recorded twice: at baseline and at day 42. If treatment was discontinued before day 42, patients underwent all safety and efficacy assessments at the time of withdrawal.

Statistical Analysis With an objective of identifying dose-response relationships, standard sample size calculations were not used. Instead, Monte Carlo simulations were used to show that a sample size of 50 patients per treatment group had a power of greater than .90 to detect various dose-response relationships (e.g., linear, quadratic), using a standard deviation of 15 for change in BPRS total score. Fifty patients per treatment group also provided adequate power (greater than .80) for pairwise comparisons of interest. Statistical significance was defined by p -< .05, with marginal significance defined by .05 < p -<. 10. All tests were two sided.

Efficacy The primary population for the analysis of efficacy included all patients who entered the randomized phase and had efficacy data for baseline and at least one postbaseline trial day. The primary end point for the analysis of efficacy was day 42, the final day of randomized treatment. When patients withdrew before this day, data from their last scheduled trial day were included with day 42 data [last observation carded forward (LOCF) analysis]. Secondary analyses evaluated data at each assessment day before day 42, with last observations carried forward as well. The primary efficacy variables were BPRS total and

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CGI Severity of Illness item scores. The secondary efficacy measures were mean BPRS positive-symptom cluster score, CGI Global Improvement score, SANS summary score (sum of the SANS global ratings), and response rate, with response defined as a reduction of at least 30% from baseline in BPRS total score at any time during the randomized segment of the trial. In an a posteriori analysis, response rates at end point for the quetiapine and haloperidol groups were compared using four different response criteria, i.e., 20%, 40%, 60%, and 80% reduction in BPRS total score. For each efficacy variable (with the exception of the CGI Global Improvement item and end point response rates), pairwise comparisons of changes from baseline between quetiapine treatment groups and the placebo group were made using an analysis of covariance (ANCOVA) (SAS ® PROC GLM, Version 6.09, SAS Institute, Cary, NC). The model included baseline score (the covariate), center, and treatment. The CGI Global Improvement item was analyzed using an analysis of variance (ANOVA) model, which included center and treatment. End point response rates were compared using chi-square methods, with adjustment for multiple comparisons within each level of response (Everitt 1992). Pairwise comparisons between each dose of quetiapine and placebo using adjusted means from ANCOVA were made using Dunnett's multiple comparison procedure. In addition, 95% confidence intervals were constructed for differences in adjusted means for each dose of quetiapine and placebo. For completeness, similar methods were used to obtain pairwise comparisons between each dose of quetiapine and haloperidol. Regression models used to describe the relationship between quetiapine dose and response were fit for each trial day using SAS ® PROC REG. All regression models included patients in the placebo group as having received 0 mg of quetiapine. Initial models included baseline value, center (designated by a set of binary dummy variables), and linear, quadratic, and cubic functions of the natural logarithm of dose as independent variables [The natural logarithm of dose was used because of unequal intervals between doses. The natural logarithm of the placebo group (0 mg of quetiapine) was calculated as follows: log dose l - ([dose I - doseo]/[dose 2 - dosel]) (log dose 2 - log dose1), using the method of Tukey et al (1985).], and change from baseline as the dependent variable. Backward elimination procedures (using p > .10 as the criterion for removal) were then applied to this initial regression model to obtain a more parsimonious model. The relationship between response rate and dose was modeled using logistic regression. Assumptions of ANCOVA and regression analyses were verified.

The relationships between trough plasma concentrations of quetiapine at day 42 and changes from baseline in BPRS total score and CGI Severity of Illness item score were assessed graphically, and by calculating Pearson Product-Moment Correlation Coefficients. Correlation coefficients between plasma concentrations and changes from baseline were also calculated for responders only.

Safety and Tolerability All patients who received trial treatment were included in the analyses of safety according to treatment received. Descriptive statistics were used to summarize exposure to trial treatment, concomitant medication use, adverse events including EPS, laboratory data, electrocardiogram (ECG) results, and vital signs assessments. For adverse events that occurred in 1% or more of quetiapine-treated patients and with an incidence greater than that with placebo, logistic regression methods were used to investigate linear dose-response relationships. Descriptive statistics for Simpson-Angus Scale total scores and AIMS scores showed that the majority of patients entered and completed the trial with few, if any, EPS. Because distributions of these data at all trial days were severely skewed, i.e., the majority of patients had minimum total scores, frequency distributions of grouped total scores and grouped change-from-baseline scores (visit score minus baseline score) were calculated, with change scores grouped as improved (change less than 0), no change (change equal to 0), or worsened (change greater than 0). The analyses of the grouped change from baseline for Simpson-Angus Scale total scores and AIMS scores were based on chi-square tests, using Cochran Mantel Haenszel methods to control for center effects. Logistic regression techniques were used to investigate the relationship between quetiapine doses, with groupedchange categories of improved and no change collapsed into one category. Laboratory data were analyzed using a variety of techniques. For change from baseline to the final observation, an ANCOVA model was used and included baseline value (the covariate) and treatment in the model. Pairwise comparisons between adjusted means for active treatment groups and the placebo group were made using Dunnett's tests. Frequencies of protocol-defined clinically significant values for selected laboratory variables [white blood cell and absolute neutrophil counts (ANC), aspartate transaminase (AST) and alanine transaminase (ALT) concentrations, and total triiodothyronine (T3), tetraiodothyronine (T4), and thyroid-stimulating hormone (TSH) concentrations] and selected vital signs [postural changes in blood

Efficacy of Quetiapine

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Table 1. Demographics and Baseline Characteristics Quetiapine

Male/female, No. Mean age (years) (SD) Diagnosis of schizophrenia,a No. (%) Paranoid Undifferentiated Other Mean age at first treatment (years) (SD) Previous hospitalizations, No. (%) 0-5 6-10 11 or more Unknown Response to previous antipsychotics, No. (%) Full response Partial response Poor to no response First exposure Unknown

Placebo (n = 51)

75 mg (n = 53)

150 mg (n = 48)

300 mg (n = 52)

600 mg (n = 51)

750 mg (n = 54)

Haloperidol 12 mg (n = 52)

41/10 36 (8)

39/14 37 (10)

39/9 38 (9)

37/15 38 (9)

38/13 39 (8)

38/16 35(10)

42/10 37(10)

28 (55) 19 (37) 4 (8) 22 (6)

34 (64) 15 (28) 4 (8) 22 (6)

30 (62) 15 (31) 3 (6) 22 (5)

31 (60) 19 (37) 2 (4) 22 (6)

33 (65) 16 (31) 2 (4) 24 (7)

27 (50) 22 (41) 5(10) 22 (7)

28 (54) 19 (37) 5(10) 21 (6)

19 (37) 14 (27) 13 (26) 5 (10)

26 (49) 12 (23) 12 (23) 3 (6)

17 (35) 16 (33) 11 (23) 4 (8)

22 (42) 16 (31) 13 (25) 1 (2)

15 (29) 15 (29) 18 (35) 3 (6)

26 (49) 17 (31) 10 (19) 1 (2)

14 (27) 18 (35) 17 (33) 3 (6)

9 (18) 33 (65) 7 (14) 0 2 (4)

9 (17) 29 (55) 11 (21) 2 (4) 2 (4)

8(17) 25 (52) 12 (25) 2 (4) 1 (2)

6(12) 32 (62) 11 (21) 1 (2) 2 (4)

16(31) 29 (57) 6 (12) 0 0

8(15) 37 (69) 9 (17) 0 0

10(19) 27 (52) 14 (27) 1 (2) 0

Chronic or subchronic, acute exacerbation.

pressure and pulse (individually and combined), supine pulse, temperature, and weight] were tabulated. ANCOVA was used to compare changes from baseline in ECG parameters, with baseline value, center, and treatment included in the model. Pairwise comparisons were made between active treatment groups and placebo using adjusted means and Dunnett's test. Frequencies of ECG findings assessed as clinically significant were tabulated for baseline and final ECGs.

Results Four hundred two prospective subjects were screened for entry; 41 (10%) were not randomized, in most cases (80%) because of withdrawn consent. Therefore, 361 patients with acute exacerbation of chronic or subchronic schizophrenia from 21 U.S. and five Canadian centers were randomized to treatment as follows: placebo, n = 51; quetiapine 75 mg/day (Qtp75), n = 53; 150 mg/day (Qtpl50), n = 48; 300 mg/day (Qtp300), n = 52; 600 mg/day (Qtp600), n = 51; 750 mg/day (Qtp750), n = 54, and haloperidol 12 mg/day, n = 52. No center enrolled more than 8% of randomized patients. Mean patient age was 37 years (range, 1 8 - 6 4 years), with men comprising 76% of the population. The majority (70%) of patients were white with most of the remaining patients black (22% overall). Demographic characteristics and psychiatric history, including age at first onset of psychiatric disease, hospitalization history, and response

to previous antipsychotic medication, were comparable across treatment groups (Table 1). The most common diagnostic subgroup was chronic or subchronic paranoid schizophrenia (in 55% of patients). All seven treatment groups were comparable at baseline with regard to efficacy measure scores; mean BPRS total scores ranged from 44 to 47; CGI Severity of Illness item scores, from 4.9 to 5.1; and SANS summary scores, from 13.9 to 15.5. Of all patients evaluated, 149 (41%) completed 6 weeks of treatment. As expected, lack of efficacy was the primary reason for withdrawal and was seen most often in the placebo group (Table 2). Only 1 patient treated with quetiapine (Qtp750) withdrew because of an adverse event, compared with 4 in the haloperidol group and 2 in the placebo group.

Efficacy Three patients treated with quetiapine (Qtp75, Qtp300, Qtp750) and 2 patients treated with haloperidol were excluded from BPRS analyses because postbaseline data were not available; all but 1 (Qtp750) were excluded from CGI analyses for the same reason.

BPRS Throughout the trial, mean decreases from baseline in BPRS total score were achieved with all treatments, except placebo after day 7. At end point, mean changes from baseline were greatest ( - 8 . 7 and - 8 . 6 ) with Qtpl50 and Qtp300 mg, but comparable with haloperidol and Qtp600

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T a b l e 2. P a t i e n t W i t h d r a w a l s No. patients (%) Quetiapine Placebo (n = 51) Total w i t h d r a w n L a c k o f efficacy Refusal to continue a A d v e r s e experience b Protocol n o n c o m p l i a n c e

35 30 3 2 0

(69) (59) (6) (4)

75 m g (n = 53) 36 27 8 0 1

(68) (51) (15) (2)

150 m g (n = 48) 27 (56) 23 (48) 4 (8) 0 0

300 m g (n = 52) 28 22 5 0 1

600 mg (n = 51)

(54) (42) (10)

24(47) 16(31) 7 (14) 0

(2)

1 (2)

750 mg (n = 54) 28 19 6 1 2

(52) (35) (ll) (2) (4)

Haloperidol 12 m g (n = 52) 34 17 13 4 0

(65) (33) (25) (8)

Percentages for individual reasons for withdrawal are based on the total number of patients per group. a Or failure to return. i, Includes intercurrent illness.

( - 7 . 6 and - 7 . 7 , respectively). Differences in change from baseline (Table 3, Figure 1) were significant at end point between each of the four highest doses of quetiapine and placebo (from low to high dose: p = .002, p = .002, p = .006, and p = .022). Significance was reached as early as day 14 with Qtp150 and Qtp300 (day 14 mean change: - 6 . 6 and -7.1, respectively; placebo, +0.02) and as early as day 21 with Qtp600 and Qtp750 (day 21 mean change: - 6 . 7 and -7.2, respectively; placebo +l.1). Differences beT a b l e 3. A s s e s s m e n t s

Assessment

tween haloperidol and placebo were significant at end point (p = .002) and from day 14 onward, whereas differences between quetiapine (all doses) and haloperidol were not. Negative mean changes in BPRS positive-symptom cluster scores, reflecting reduction in positive symptoms, were seen at each assessment day for all treatments except placebo at end point (+0.05), with magnitude of change always greater with active treatment (quetiapine and haloperidol) than with placebo. At end point, mean change

of Efficacy: End Point Changes from Baseline ~ (Last Observation Carried Forward) Placebo (n = 51)

Qtp75 (n = 52)

Qtpl50 (n = 48)

Qtp300 (n = 51)

Qtp600 (n = 51)

Qtp750 (n = 53)

Haloperidol (n = 50)

45.3 + 9.2 46.7 + 14.4 1.71 -+ 2.06

45.7 -+ 10.9 43.8 +_ 18.5 - 2 . 2 4 -+ 2.04

47.2 _+ 10.1 38.2 _+ 17.0 - 8 . 6 7 - 2.14 r

45.3 _+ 10.9 36.6 -+ 18.3 - 8 . 5 9 _+ 2.06 t

43.5 _+ 11.3 35.9 -+ 18.9 - 7 . 6 8 _+ 2.08 r

45.7 -+ 11.0 39.2 _+ 17.2 - 6 . 3 3 -+ 2.02 g

44.0 _+ 9.0 36.3 -+ 15.5 - 7 . 5 8 -+ 2.10 r

3.7 -+ 0.9 3.8 _+ 1.2 0.05 _+ 0.17

3.8 -+ 0.8 3.5 _+ 1.6 - 0 . 3 8 -+ 0.17

4.0 -+ 0.9 3.2 _+ 1.5 - 0 . 7 4 _+ 0.18 r

3.8 _+ 0.9 2.9 -+ 1.6 - 0 . 8 7 _+ 0.17f

3.5 -+ 0.9 2.8 - 1.6 - 0 . 7 3 -+ 0.17 t

3.6 -+ 1.0 3.0 _+ 1.4 - 0 . 5 8 + 0.17 g

3.6 -+ 0.8 2.9 _+ 1.4 - 0 . 7 4 -+ 0 . 1 8 r

4.9 _+ 0.8 5.2 -+ 1.2 0.25 + 0.15

4.9 _+ 0.9 4.8 _+ 1.3 - 0 . 1 5 +- 0.15

5.0 -+ 0.9 4.5 _+ 1.3 - 0 . 4 9 - 0.16r

5.1 4- 0.9 4.4 _+ 1.5 - 0 . 6 9 _+ 0.15 r

4.9 _ 0.8 4.4 +_ 1.5 - 0 . 4 6 -+ 0.16 t

5.0 + 0.8 4.5 4- 1.2 - 0 . 4 6 _+ 0 . 1 5 r

5.0 -+ 0.8 4.3 +_ 1.3 - 0 . 6 9 -+ 0.16 t

N/A 4.78 -+ 0.23 N/A

N/A 4.22 + 0.22 N/A

N/A 3.74 - 0.23 r N/A

N/A 3.56 -+ 0.23 r N/A

N/A 3.58 - 0.23 t N/A

N/A 3.93 - 0.22 g N/A

N/A 3.54 - 0.23 r N/A

13.9 -+ 3.7 15.0 _+ 4.0 0.76 +- 0.51

14.6 - 3.5 14.0 +_ 3.9 - 0 . 6 2 -+ 0.53

B P R S scores b Total Baseline E n d point Change Positive-symptomsc Baseline E n d point Change C G I scores d Severity o f Illness Baseline E n d point Change Global I m p r o v e m e n t Baseline End point Change S A N S s u m m a r y score e Baseline End point Change

14.7 - 3.1 14.0 _+ 3.9 - 0 . 7 8 -+ 0.54

14.2 -+ 3.3 12.8 --_ 4.5 - 1 . 5 6 4- 0.51 f

14.3 +- 3.8 13.5 - 4.9 - 0 . 9 8 -+ 0.52

15.5 -+ 4.1 14.7 -+ 4.2 - 0 . 5 0 +_ 0.52

14.7 _+ 3.7 12.9 -+ 3.9 - 1 . 8 3 + 0.51 f

Adjusted mean change - SE from ANCOVA, except CGI Global Improvement, then mean score from ANOVA. b Item scoring 0 to 6. Conceptual disorganization, suspiciousness, hallucinatory behavior, unusual thought content. a n = 54, Qtp750. e Total of global ratings for affective blunting, alogia, avolition-apathy, anhedonia-sociality, and attention; n = 50, placebo; n = 46, Qtp75; n = 45, Qtpl50; n = 49, Qtp300; n = 49, Qtp600; n = 48, Qtp750; n = 50, haloperidol. f p < .01 vs. placebo. S p < .05 vs. placebo.

Efficacy of Quetiapine

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Quetiapine (mg/day) Figure 1. Dose response for BPRS total score (day 42, last observation carried forward). was greatest with Qtp300 (-0.87) (Table 3). Changes with Qtpl50 (-0.74), Qtp600 (-0.73), and haloperidol (-0.74) were comparable, whereas changes with Qtp75 (-0.38), Qtp750 (-0.58), and placebo (+0.05) were smaller. Differences in mean change from baseline between each of the four highest doses of quetiapine and placebo were significant at end point (from low to high dose: p = .006, p = .001, p = .006, p = .038). Significance was reached as early as day 21 with Qtp300, Qtp600, and Qtp750 (day 21 mean change: -0.84, -0.77, and -0.72, respectively; placebo, -0.07). Differences between haloperidol and placebo were significant at end point (p = .001), whereas differences between quetiapine (all doses) and haloperidol were not.

At end point, differences between haloperidol and placebo were significant as well (p = .000), whereas differences between quetiapine (all doses) and haloperidol were not. Adjusted mean CGI Global Improvement scores were similar at end point for patients treated with the four highest doses of quetiapine (3.56-3.93) and haloperidol (3.54) and were significantly lower (p < .01) than the score achieved with placebo (4.8). Among quetiapine groups, the lowest score was achieved with Qtp300, which produced significantly more improvement, compared with placebo, from day 14 onward (day 14 mean score: 3.56; placebo, 4.48). Significant differences between Qtpl50, Qtp600, and Qtp750 and placebo were achieved from day 21 onward. Differences between quetiapine and haloperidol at end point were not significant.

CGI The patterns of change in CGI Severity of Illness item scores were similar to those seen for BPRS total score (negative mean changes from baseline with all treatments, except placebo after day 7). At end point, mean changes from baseline were greatest with Qtp300 and haloperidol (-0.69, both groups); changes with Qtpl50, Qtp600, and Qtp750 were comparable ( - 0 . 4 6 to -0.49) (Table 3). Differences in change from baseline (Figure 2) were significant at end point between each of the four highest doses of quetiapine and placebo (+0.25) (from low to high dose: p = .004, p = .000, p = .005, p = .004). Significance was reached as early as day 14 with Qtp300 (day 14 mean change: -0.48; placebo, +0.10) and day 21 with Qtpl50, Qtp600, and Qtp750 (day 21 mean change: -0.31, -0.45, and -0.49, respectively; placebo, +0.23).

SANS Throughout the trial, all treatment groups except the placebo group showed improvement in negative symptoms as indicated by decreases from baseline in mean SANS summary scores. At end point, differences in change from baseline were significant between Qtp300 and placebo and between haloperidol and placebo (p < .01 for both) (Table 3). Significant differences in change from baseline between quetiapine and placebo were also noted as early as day 14 with Qtp300 (day 14 mean change: -1.53 vs. +0.68 with placebo). Although differences between Qtp600 and placebo were marginally significant at end point (mean change, - 0 . 9 8 vs. +0.76, p = .062), they were significant on the 3 assessment days before end point (day 21 mean change: - 1 . 0 6 vs. +0.88; day 28

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- 1.4 -1.2

E

-1.0

-0.8 = 00 tO

-0.6

,--

-0.4

E -o •

-0.2

#

o# lw

0.0

'--i

~" <

0.2

e"

#p
0.4 |'

Placebo

75

I

/

150

300

I

600

/

750

J//

I

Haloperidol

Quetiapine (rng/day) Figure 2. Dose response for CGI Severity of Illness item score (day 42, last observation carried forward).

mean change: - 1.23 vs. +0.80; and day 35 mean change: - 0 . 8 8 vs. + 1.12, respectively). Differences between haloperidol and placebo were significant throughout the trial, whereas differences between quetiapine (all doses) and haloperidol were not.

Response Rate In the planned analysis, the greatest response rates were seen with Qtp300 and haloperidol, in 51% and 50% of patients treated, respectively. Response rates with placebo and Qtp75 were identical at 35%, whereas rates varied slightly among the other quetiapine groups (46%, Qtpl50; 45%, Qtp600; and 49%, Qtp750). In the a posteriori analysis, response rates at end point were significantly higher with Qtp300 and Qtp600 at the 20%, 40%, and 60% level, with Qtpl50 at the 20% and 40% level, and with Qtp750 at the 20% level, compared with placebo (Table 4). Response rates for the haloperidol group were always lower than the best response seen among quetiapine groups at the 20%, 40%, and 60% levels; at the 80% level,

the response rate for the haloperidol group was the same as that for Qtp300 and Qtp600.

Dose Response Dose-response modeling using BPRS scores, CGI scores, and SANS summary scores showed significant linear (all p < .002) and quadratic (all p < .01) functions of log-dose. Negative coefficients for the linear function of log-dose indicated that larger negative change scores (i.e., greater improvement) were predicted by increasing dose. The significance of the quadratic term in the models most likely reflected the slightly attenuated response to treatment seen with Qtp600 and Qtp750. Logistic regression showed no significant functions of log-dose as predictors of response rate (as defined per protocol).

Plasma Concentrations Mean plasma levels at day 42 from lowest to highest dose of quetiapine were 13.9, 27.8, 43.9, 91.1, and 93.7 ng/mL.

Table 4. Response Rates at End Point Relative to % Change from Baseline in BPRS Total Score No. patients (%) % decrease in BPRS total score at end point -->20 ~40 ->60 ->80 a p < .0083.

Placebo (n = 51)

Qtp75 (n = 52)

Qtpl50 (n = 48)

Qtp300 (n = 51)

Qtp600 (n = 51)

Qtp750 (n = 53)

Haloperidol (n = 50)

8 (16) 3 (6) 1 (2) 0

14 (27) 10 (19) 6 (12) 2 (4)

22 (46)~ 14 (29)a 6 (13) 0

22 (43)" 13 (25)" 9 (18)" 3 (6)

23 (45)a 14 (27)a 9 (18)" 3 (6)

27 (51)" 13 (25) 4 (8) 0

19 (38) 10 (20) 8 (16) 3 (6)

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Table 5. Adverse Events with an Incidence of 10% or Greater in Any Treatment Group, Plus EPS Adverse Events No. patients (%) Quetiapine Adverse event Agitation~ Constipation Dizziness Dyspepsia Headache Insomnia Postural hypotension Somnolence EPS (overall) b Akathisia ParkinsonismC Dystonia

Placebo (n = 51)

75 mg (n = 53)

150 mg (n = 48)

300 mg (n = 52)

600 mg (n = 51)

750 mg (n = 54)

11 (22) 3 (6) 4 (8) 1 (2) 7 (14) 5(10) 4 (8) 4 (8) 9(18) 4 (8) 5(10) 1 (2)

9 (17) 3 (6) 3 (6) 3 (6) 7 (13) 2 (4) 2 (4) 4 (8) 4 (8) 1 (2) 3 (6) 1 (2)

3 (6) 5(10) 2 (4) 1 (2) 13 (27) 3 (6) 3 (6) 4 (8) 3 (6) 1 (2) 2 (4) 0

7 (13) 1 (2) 5 (10) 2 (4) 16 (31) 3 (6) 6 (12) 3 (6) 2 (4) 0 2 (4) 0

6 (12) 6(12) 5 (10) 4 (8) 11 (22) 3 (6) 7 (14) 5(10) 4 (8) 0 4 (8) 1 (2)

5 (9) 6(11) 6 (11) 10(19) 10 (19) 3 (6) 7 (13) 6(11) 3 (6) 1 (2) 2 (4) 0

Haloperidol 12 mg

(n = 52) 5 (10) 3 (6) 3 (6) 4 (8) 10 (19) 6(12) 1 (2) 3 (6) 19(37) 8(15) 15(29) 1 (2)

a Event most often rated as severe, in 4 patients treated with quetiapine 600 mg and in 1 patient each treated with quetiapine 75, 300, and 750mg and placebo. b Patients may have had more than one EPS adverse event. c Includes akinesia, cogwheel rigidity, extrapyramidal syndrome, hypertonia, hypokinesia, neck rigidity, and tremor.

On day 21, when postdose plasma levels were determined, mean concentrations were generally highest 3 hours after administration of the reference dose. Median plasma concentrations did not appear to have any relationship with efficacy measures at any point.

Tolerability Approximately 70% of all patients received treatment for at least 2 weeks. Across quetiapine groups, mean duration of treatment was lowest, 23 days, with Qtp75, highest, 30 days, with Qtp300, and 29 days in each of the three other groups. Median duration of treatment appeared to increase with dose up to 600 mg/day, from 15 to 42 days (decreasing slightly to 37 days with Qtp750). In the haloperidol and placebo groups, mean duration of treatment was 25 days; median duration of treatment was 22 and 23 days, respectively, less than that for groups treated with Qtpl50 to Qtp750. Among patients treated with quetiapine, 61% (Qtp600) to 68% (Qtp75) received at least one dose of chloral hydrate, compared with 79% treated with haloperidol and 78% treated with placebo; 43% (Qtp600) to 62% (Qtp75) received at least one dose of lorazepam compared with 62% treated with haloperidol and 49% treated with placebo. Treatment for EPS was infrequent in all but the haloperidol group. Among patients treated with quetiapine, 12% or fewer (--<6) per treatment group received benztropine mesylate, compared with 14% in the placebo group and 48% in the haloperidol group. Across the quetiapine dose range, the use of benztropine mesylate did not increase with increasing dose.

Overall, the types of adverse events recorded were not unexpected (Table 5), and most were rated mild. Only three adverse events--headache, constipation, and dyspepsia-occurred at an incidence rate twice that of placebo, and none of these events led to withdrawal. Agitation and insomnia, events possibly reflective of the underlying illness, were reported in all treatment groups. As expected, the incidence of agitation was greatest with placebo (22%) and Qtp75 (17%), whereas the incidence of insomnia was greatest with placebo (10%) and haloperidol (12%). Among quetiapine groups, the incidence of insomnia was consistently low, between 4% and 6%. Postural hypotension and dizziness occurred in all treatment groups but in more patients treated with Qtp300, Qtp600, and Qtp750 (12-14% for postural hypotension, 10-11% for dizziness). Postural hypotension caused 1 patient (Qtp750) to withdraw from treatment and was the only adverse event among quetiapine groups to lead to withdrawal. In all but 1 patient (Qtp300), dizziness was associated with clinically significant postural changes in pulse rate or blood pressure. Tests for linear dose-response relationships among adverse events evaluated were significant for abdominal pain, dyspepsia, and weight gain. Adverse events reflective of EPS were reported for more patients treated with haloperidol (37%) than for patients treated with either quetiapine (4-8%) or placebo (16%) (Table 5). No patients treated with quetiapine were withdrawn because of EPS, compared with 4 treated with haloperidol and 1 treated with placebo. At end point, unadjusted mean changes from baseline in Simpson-Angus Scale total scores were negative, indicat-

242

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Improved }--'-'-] No change I

Worsened

100 90 80 t'Q~

70 60

~5

50

~

40

~ ID

aO 20 10 0 Placebo

75

150

300

600

750

Haloperidol

Quetiapine (rng/day) Figure 3. Simpson-Angus Scale total score, grouped responses at end point. The difference between quetiapine 300 mg and placebo was marginally significant (p = .08) favoring quetiapine (more patients improved, fewer worsened); differences between the remaining quetiapine doses and placebo were not significant (from lowest to highest dose of quetiapine, p = .85, .92, .73, and .63). The difference between haloperidol and placebo was marginally significant (p = .09) favoring placebo. ing improvement in EPS, for all groups except the haloperidol group (+1.1). Among the groups showing improvement, change from baseline increased with quetiapine dose, from - 0 . 6 (placebo) through - 1 . 8 (Qtp600, Qtp750). Grouped change responses showed that the greatest percentage of patients in each quetiapine group and in the placebo group improved (46-55% quetiapine; 44% placebo), while smaller percentages worsened (6-24% quetiapine; 22% placebo) (Figure 3). Conversely, in the haloperidol group, the greatest percentage of patients worsened (43%), while the smallest percentage remained the same (20%). The best groupedchange response at end point was achieved with Qtp300 (55% improved, 39% did not change, and 6% worsened); the difference versus grouped-change response with placebo was marginally significant (p = .075), favoring Qtp300. The difference between placebo and haloperidol at end point was marginally significant (p = .094), favoring placebo. Among treatment groups, most patients (38-50% quetiapine, 46% haloperidol, 45% placebo) had no change in AIMS scores at end point. The proportions of patients who either improved or worsened were similar within and across treatment groups, except more patients treated with Qtp750 improved (35% vs. 16% worsened).

Dose-response analysis using grouped-change scores on the Simpson-Angus Scale showed that increases in quetiapine dose up to 300 rag/day decreased the proportion of patients in the worsened category, a relationship similar to that found for the efficacy variables. No relationship was found using AIMS grouped-change scores.

Laboratory Findings Differences in mean changes from baseline between placebo and all quetiapine groups were not significant for any hematologic variable. No cases of severe neutropenia or agranulocytosis were identified. Seventeen (7%) patients treated with quetiapine had increases in ALT concentrations to levels predefined as clinically significant [3 X upper limit of normal (ULN)], with concurrent clinically significant AST elevations in only 4 patients; changes in total bilirubin and alkaline phosphatase concentrations were not significant. Patients were clinically asymptomatic, and most values either returned to baseline values or were decreasing at the time of trial completion or withdrawal. Maximum ALT (679 U/L, 14x ULN) and AST (286 U/L, 7 × ULN) concentrations occurred in 1 patient but did not lead to withdrawal. Treatment with quetiapine was associated with a dose-

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Table 6. Change from Baseline in Prolactin at End Point Quetiapine Plasma prolactin (ng/mL) (mean) Baseline Adjusted change (from ANCOVA) p value vs. placebo

Haloperidol

Placebo (n = 19)

75 mg (n = 19)

150 mg (n = 25)

300 mg (n = 31)

600 mg (n = 28)

750 mg (n = 28)

12 mg (n = 24)

11.84 1.99

10.00 -0.51

17.12 -2.10

12.03 -0.21

9.93 -0.76

17.25 - 1.93

9.50 18.30

.969

dependent decrease in total T4 and free T4 concentrations, which generally occurred within a few days of treatment initiation without further decline. Smaller decreases in total T3 and reverse T3 were seen only at the higher doses, and changes in thyroid-binding globulin and TSH were not seen. Decreases in total T4 and free T4 were generally within 20% of the lower limit of normal, and clinical hypothyroidism did not occur. At the final evaluation, prolactin concentrations from lowest to highest dose of quetiapine were 10.4, 13.6, 12.0, 9.8, and 13.9 ng/mL, compared with 14.7 ng/mL for placebo and 28.8 ng/mL for haloperidol. Differences in changes from baseline between quetiapine (regardless of dose) and placebo were not significant; in contrast, however, the difference between placebo and haloperidol was significant (p = .0075) (Table 6). Among quetiapine groups, patterns of change for both men and women reflected those seen for the group as a whole.

ECG Findings and Vital Signs No statistically significant differences were seen between quetiapine and placebo groups for mean change from baseline in atrial or ventricular rates; among quetiapine groups, small increases in atrial rates [from 2 to 10 beats per minute (bpm)] appeared dose-related. No statistically significant differences were seen between quetiapine and placebo groups for changes in P-R, QRS, or Q-T intervals. Among quetiapine groups, changes in QT c intervals ranged from - 0 . 0 0 2 sec (Qtp75 and Qtp750) to +0.008 sec (Qtp600); changes with placebo and haloperidol were similar: -0.005 and +0.004 sec, respectively. The greatest difference in change from baseline (seen between placebo and Qtp600) was not considered clinically significant. No patients had QT c intervals greater than 0.5 sec. Slight mean increases from baseline were seen in pulse rates in all treatment groups (2-5 bpm, standing pulse) but did not appear dose-related in patients treated with quetiapine. Mean increases in weight with quetiapine, from low to high dose, were +0.9, +2.9, +2.0, +2.6, and +2.3 kg, respectively, and were greater than those seen with haloperidol (+0.3 kg) or placebo ( - 0 . 8 kg). Increases from baseline of 7% or greater were considered clinically significant and

.734

.971

.930

.749

.008

were seen in greater proportions of quetiapine-treated patients: from low to high dose in 11%, 17%, 10%, 16%, and 13% versus 4% with haloperidol and 6% with placebo. Changes did not necessitate treatment withdrawal or appear dose-related on the basis of descriptive statistics.

Discussion Five fixed doses of quetiapine were evaluated in a randomized, 6-week, placebo-controlled, multicenter trial in patients with acute exacerbation of chronic schizophrenia. Completion rate was comparable to those seen in other trials of atypical antipsychotics (32-47%) (Marder and Meibach 1994; Peuskens 1995). At fixed doses of 150-750 mg/day, quetiapine was consistently superior to placebo in treating the positive symptoms of schizophrenia, and at the maximally effective dose of 300 mg/day, superior in treating negative symptoms as well. Dose-response modeling showed significant linear and quadratic functions of quetiapine dose. In all measures of efficacy, quetiapine was comparable to haloperidol. Across the dose range studied, quetiapine was well tolerated and maintained an atypical profile in that it was no different from placebo with regard to incidence of EPS and changes in prolactin concentrations. Importantly, results from this fixed-dose trial confirm conclusions from previously reported Phase II trials in which flexible dosing was used, namely that quetiapine was superior to placebo in reducing positive and negative symptoms with good tolerability, and that maximum benefit was probably seen with a dose greater than 250 mg/day (Fabre et al 1995; Borison et al 1996). In those trials, mean effective doses ranged from 306 to 360 mg, falling in line with the dose that gave the maximal benefit in this trial. Although populations varied somewhat across these studies, patients met the same diagnostic and inclusion criteria, lending validity to the comparison. Recent discussions as to whether the items rated on the SANS attention subscale correlate with a negative symptom construct prompted an a posteriori analysis of SANS data in which attention scores were excluded. Results were similar to those seen in the planned analysis, with differences in change from baseline (LOCF) between quetiapine

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8IOLPSYCHIATRY 1997;42:233-246

300 mg/day and placebo remaining significant at end point (p = .0099) and on days 21 (p = .0008), 28 (p = .0053), and 35 (p = .0021). Quetiapine continues to be well tolerated; no doserelated increases in EPS and no other significant safety issues were identified with increasing dose over the 6-week period. This suggests that patients who respond best to higher doses of quetiapine may not be limited to smaller doses because of tolerability factors, unlike treatments with other antipsychotics (Marder and Meibach 1994; Beasley et al 1996). In this trial, only three adverse events--headache, constipation, and dyspepsia--occurred at an incidence rate twice that of placebo, and none of these events led to withdrawal. The higher incidence of constipation was unexpected given quetiapine's low in vitro binding at muscarinic-cholinergic receptors (IC5o > 10000 nmol/L). As expected, agitation occurred more frequently with placebo and the lowest quetiapine dose. Other events typical of antipsychotics were reported as well, including somnolence, dizziness, and postural hypotension. No cases of severe neutropenia or agranulocytosis were identified. These results reflect similar findings from all quetiapine trials completed to date and are noteworthy because more than 2700 patients have received quetiapine without untoward effects on hematologic function. Consistent changes in thyroid hormone levels noted in Phase II quetiapine trials were also noted in this trial, in which decreases, primarily in total T4 and free T4, appeared dose-related. Changes did not lead to treatment withdrawal for any patient, and because decreases were generally within 20% of the normal range, they were not considered clinically significant. Given the lack of change in TSH, it is unlikely that quetiapine exerts its effects directly on the pituitary gland. This pattern of hormonal response appears to be similar to that seen in patients treated with phenytoin and, to a lesser extent, carbamazepine (Smith and Surks 1984; Roy-Byme et al 1984; Surks and Sievert 1995). The effects of these drugs on thyroid hormones are complex, and the mechanism is not well understood; however, most patients affected remain clinically euthyroid. Data from longer-term trials with quetiapine (data on file) show that decreases in thyroid hormones are not progressive. Although quetiapine was associated with a greater mean weight gain compared with haloperidol and placebo, no patients were withdrawn as a result. When reported as an

L.A. Arvanitis et al

adverse event, weight gain appeared to be related to dose, but no clear dose-response relationship was evident relative to clinically significant weight gain. Generally mean increases were greater at day 42 for patients who completed the trial (1.5-4.5 kg) than for patients who withdrew. In any case, weight gain over a 6-week period may or may not be clinically significant given that it may be a function of well-being resulting from improvement in psychosis. In conclusion, this trial, as well as earlier trials, has shown that quetiapine is clinically effective in the treatment of acute exacerbation of chronic or subchronic schizophrenia. Superiority to placebo and comparability to haloperidol in reducing positive symptoms were shown across a dose range of 150-750 mg/day and in reducing negative symptoms at a dose of 300 mg/day. Determining quetiapine's effects on other domains of psychopathology (e.g., primary negative symptoms, cognitive function, quality of life) and in other patient populations, as well as comparing quetiapine's efficacy and tolerability with that of newer antipsychotics, are subjects for future study. Quetiapine is well tolerated; evidence to date suggests that quetiapine offers a better general safety profile than standard or first-generation atypical antipsychotics. Patients treated with quetiapine generally maintain good hematological profiles and good ECG profiles; treatment has not been associated with any cases of agranulocytosis or problems with changes in QT c intervals. Across the dose range studied, increasing dose to obtain maximal efficacy, within a 6-week period, does not appear to place patients at increased risk for adverse events. Notably, the incidence of EPS with quetiapine is no different from that seen with placebo on the basis of Simpson-Angus Scale total scores; reports of EPS adverse events (none of which have led to withdrawal); and minimal use of benztropine mesylate and other anticholinergics. The trial duration, however, limits any discussion about the propensity of quetiapine to produce tardive dyskinesia. Quetiapine does not cause sustained elevations in plasma prolactin, and adverse events typically resulting from prolactinemia are not expected. This trial was supportedby a grant from Zeneca Pharmaceuticals. The authors thank Suzanne Bristow-Marcalus, BSP, ELS, for writing support, Jean Fennimore, BS RN, for trial organization and management support, Jacqueline Fiore and GaryFritz for trial monitoringsupport, and members of the Seroquel data managementteam.

References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press.

Andreasen N (1984): Modified Scale for the Assessment of Negative Symptoms. NIMH Treatment Strategies in Schizophrenia Study. Washington, DC: Department of Health and

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Human Services, Public Health Administration. Publication ADM 9-102. Beasley CM Jr, ToUefson G, Tran P, Satterlee W, Sanger T, Hamilton S, and the Olanzapine HGAD Study Group (1996): Olanzapine versus placebo and haloperidol: Acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 14:111-123. Borison RL, Arvanitis LA, Miller BG, and the US SEROQUEL Study Group (1996): ICI 204,636, an atypical antipsychotic: Efficacy and safety in a muiticenter, placebo-controlled trial in patients with schizophrenia. J Clin Psychopharmacol 16:158-169. Ellenbrock BA, Lubbers LJ, Cools AR (1996): The activity of 'Seroquel' (ICI 204,636) in animal models for atypical properties of antipsychotics: A comparison with clozapine. Neuropsychopharmacology 15:406-416. Everitt BS (1992): The Analysis of Contingency Tables, 2nd ed. London: Chapman & Hall. Fabre LF, Arvanitis LA, Pultz J, Jones VM, Malick JB, Slotnick VB (1995): ICI 204,636, a novel atypical antipsychotic: Early indication of safety and efficacy in patients with chronic and subchronic schizophrenia. Clin Ther 17:366-378. Goldstein JM (1995): Pre-clinical pharmacology of new atypical antipsychotics in late stage development. Expert Opin Invest Drugs 4:291-298. Goldstein JM, Arvanitis LA (1995): ICI 204,636 (SEROQUELXM): A dibenzothiazepine atypical antipsychotic. Review of preclinical pharmacology and highlights of Phase II clinical trials. CNS Drug Rev 1:50-73. Guy W (ed) (1976): ECDEU Assessment Manual for Psychopharmacology, rev ed. Rockville, MD: US Department of Health, Education, and Welfare. Publication ADM 76-338. Marder SR, Meibach RC (1994): Risperidone in the treatment of schizophrenia. Am J Psychiatry 151:825- 835.

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Migler BM, Litwin LC, Sutton EB, Malick JB (1993): Seroquel: Behavioral effects in conventional and novel tests for atypical antipsychotic drug. Psychopharmacology 112:293-307. Overall JE, Gorham DR (1962): The Brief Psychiatric Rating Scale. Psychol Rep 10:799-812. Peuskens J for the Risperidone Study Group (1995): Risperidone in the treatment of patients with chronic schizophrenia: A multi-national, multi-centre, double-blind, parallelgroup study versus haloperidol. Br J Psychiatry 166:712726. Robertson GS, Matsumura H, Fibiger HC (1994): Induction patterns of Fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity. Pharmacol Biochem Behav 271:1058-1066. Roy-Byrne PP, Joffe RT, Uhde TW, Post RM (1984): Carbemazepine and thyroid function in affectively ill patients: Clinical and theoretical implications. Arch Gen Psychiatry 41:11501153. Sailer CF, Salama AL (1993): Seroquel: Biochemical profile of a potential atypical antipsychotic. Psychopharmacology 112: 285-292. Simpson GM, Angus JW (1970): A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 212:11-19. Smith PJ, Surks MI (1984): Multiple effects of 5,5'-diphenylhydantoin on the thyroid hormone system. Endocr Rev 5:514524. Surks MI, Sievert R (1995): Drugs and thyroid function. N Engl J Med 333:514-524. Tukey JW, Ciminera JL, Heysee JF (1985): Testing the statistical certainty of a response to increasing doses of a drug. Biometrics 41:295-301. Van Putten T, Marder SM, Mintz J (1990): A controlled dose comparison of haloperidol in newly admitted schizophrenic patients. Arch Gen Psychiatry 47:754-758.

Appendix: Seroquel Trial 13 Study Group Center

Investigator

Affiliation

0001 0002 0003 0004 0005 0006

Richard L. Borison, MD Wesley M. Pitts, MD Zafar A. Sharif, MD Mark B. Hamner, MD Marvin I. Herz, MD Janet E. True, MD Dawn Velligan,MD Mary Ann Knesevich,MD GregoryOxenkrug, MD, PhD Joyce Small, MD Richard Steinbook,MD Marc Hertzman, MD Paul E. Keck, MD John W. Newcomer, MD Jeffrey Grace, MD

Medical College of Georgia, Augusta, GA VA Medical Center, Jackson, MS Creedmoor Psychiatric Center, Queens Village, NY VA Medical Center, 116A, Charleston, SC Universityof Rochester Strong Ties Annex, Departmentof Psychiatry, Rochester, NY San Antonio State Hospital, San Antonio,TX

0007 0008 0009 0010 0011 0012 0013 0014

Terrell State Hospital, Terell, TX St Elizabeth's Medical Center, SEMC/Departmentof Psychiatry, Boston, MA Department of Psychiatry, Larue D. Carter Memorial Hopsital, Indianapolis,IN Jackson Memorial Medical Center, Mental Health Institute, Miami, FL North Arundel Hospital, Glen Bumie, MD Universityof CincinnatiCollege of Medicine, BiologicalPsychiatry Center, Cincinnati,OH WashingtonUniversitySchool of Medicine, Departmentof Psychiatry, St Louis, MO Buffalo Psychiatric Center, Buffalo, NY

(continued)

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L.A. Arvanitis et al

Center

Investigator

Affiliation

0015 0016 0017 0018 0019 0015 0016 0017 0018 0019 0020 0021 0022 0023 0024 0025

John Rotrosen, MD Rajiv Tandon, MD Sharon G. Dott, MD James M. Ferguson, MD Donald E. N. Addington, MD John Rotrosen, MD Rajiv Tandon, MD Sharon G. Dott, MD James M. Ferguson, MD Donald E. N. Addington, MD Gordon W. MacEwan, MD Vasavan N. P. Nair, MD Christian L. Shriqui, MD Richard Williams, MD David G. Daniel, MD G. Michael Shehi, MD William M. Patterson, MD Charles H. Merideth, MD

Department of Psychiatry, New York VA Medical Center, New York, NY University of Michigan Medical Center, Dept of Psychiatry, Ann Arbor, MI University of Texas Medical Branch, Dept of Psychiatry and Behavioral Sciences, Galveston, TX Pharmacology Research Corporation, Salt Lake City, UT Foothills Hospital, Calgary, Alberta Department of Psychiatry, New York VA Medical Center, New York, NY University of Michigan Medical Center, Dept of Psychiatry, Ann Arbor, MI University of Texas Medical Branch, Dept of Psychiatry and Behavioral Sciences, Galveston, TX Pharmacology Research Corporation, Salt Lake City, UT Foothills Hospital, Calgary, Alberta St. Vincent's Hospital, Vancouver, BC Douglas Hospital Research Centre, Verdun, Quebec Hospital Robert-Giffard, Beauport, Quebec Calgary General Hospital, Department of Psychiatry, Calgary, Alberta Neuropsychiatric Services of Greater Washington, Inc, Falls Church, VA Birmingham Research Group, Birmingham, AL

0026

Affiliated Research Institute, San Diego, CA 92108