REVIEW ARTICLE

CNS Drugs 2008; 22 (1): 49-68 1172-7047/08/0001-0049/$48.00/0 2008 Adis Data Information BV. All rights reserved.

Quetiapine
Dose-Response Relationship in Schizophrenia
Anna Sparshatt, Sarah Jones and David Taylor
Pharmacy Department, Maudsley Hospital, Denmark Hill, London, England

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 1. Fixed-Dose Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 2. Flexible Dosage within Fixed-Dose Range Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 3. Variable-Dose Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 4. Single Fixed-Dose Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 5. Neuroimaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 6. Case Series and Cohort Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 7. Review Articles and Meta-Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 8. Effectiveness Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Abstract

Quetiapine is a widely used second-generation antipsychotic that is effective in the treatment of schizophrenia and bipolar mania. In recent years, various publications have suggested the possibility that, in some patients, higher than licensed dosages are necessary for full therapeutic effect. A high-dose theory of quetiapine activity has developed, leading many prescribers to disregard the formal upper limit of the quetiapine dosage range (750 or 800 mg/day, depending on local labelling). In this review, we examine the clinical and neuroimaging data relating to the use of quetiapine in acute exacerbations of schizophrenia. Fixed-dose efficacy studies of immediate-release (IR) quetiapine suggest dosages of quetiapine of 150450 mg/day are more effective than placebo and no less effective than dosages of 600 or 750 mg/day. A fixed-dose study of extended-release quetiapine indicated that dosages of 600 and 800 mg/day were equally efficacious and numerically superior to 400 mg/day. Dosages of IR quetiapine averaging between 254 and 525 mg/day have been shown to be equivalent in efficacy to standard dosages of conventional and other atypical antipsychotics. Pooled data support these findings. Effectiveness studies using quetiapine in daily doses averaging between 565 and 653 mg revealed quetiapine to be somewhat less effective than some comparator drugs.

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Sparshatt et al.

Support for the use of high-dosage quetiapine (>800 mg/day) is very limited: case reports, albeit numerous, describe quetiapine as showing therapeutic effects only at dosages above the licensed range; some data suggest widespread use of higher dosages in practice; and neuroimaging data suggest inadequate dopamine receptor occupancy at standard dosages (although these findings may reflect the low affinity of quetiapine for dopamine receptors). Overall, robust controlled data strongly suggest that the standard dosage range for quetiapine is appropriate for clinical use. The balance of evidence does not support the belief that higher dosages are required for full therapeutic effect, although higher dosage trials are ultimately required to confirm or refute this hypothesis.

Quetiapine is an effective and widely used second-generation antipsychotic. In recent years, doubts about the appropriateness of its licensed dosage range for acute exacerbations of schizophrenia have been expressed, largely on the basis that the official maximum dosage (750 or 800 mg/day, depending on local labelling) is frequently exceeded in practice.[1] Higher than maximum dosages have also been used in refractory schizophrenia[2] and nonschizophrenic disorders.[3] Such dosages are reportedly well tolerated,[2,4] although unexpected adverse events are occasionally reported.[5] The possibility that the licensed dosage range for quetiapine does not include optimal dosages for some patients has important consequences, both clinical and pharmacoeconomic. This review examines published data relating to the dose-response relationship for quetiapine in acute exacerbations of schizophrenia. In January 2007, we searched EMBASE and MEDLINE using the terms quetiapine, schizophrenia, dose, placebo, trial, efficacy and effectiveness. All relevant references were obtained in full and reference sections of each scrutinized for relevant citations. We selected for review those reports describing the clinical evaluation of quetiapine in acute exacerbations of schizophrenia. In July 2007, the search was repeated and AstraZeneca in the UK was contacted to confirm that our search had re 2008 Adis Data Information BV. All rights reserved.

vealed all relevant reports published in any form. We were not able to obtain any unpublished or data on file reports. 1. Fixed-Dose Trials Trials in which subjects are randomly assigned to single fixed doses of a drug provide the most robust evidence of dose-response relationships, assuming that studies recruit sufficiently large numbers of patients to reveal true differences and include a sufficiently wide range of doses. A single study of multiple, active fixed dosages of immediate-release (IR) quetiapine has been reported.[6] In this trial, subjects with an acute exacerbation of schizophrenia were randomized to one of five dosages of quetiapine, placebo or haloperidol 12 mg/day and evaluated over 6 weeks. Outcome was assessed by changes in Clinical Global Impression-Severity of Illness (CGI-S)[7] score and Brief Psychiatric Rating Scale (BPRS)[8] score (table I). The outcome was almost identical for quetiapine (150, 300, 600 and 750 mg/day) and haloperidol. All treatments other than quetiapine 75 mg/day were significantly more efficacious than placebo. There was no obvious trend for response to improve over the quetiapine dosage range of 150750 mg/day on either clinical outcome scale, with numerically the greatest change in mean BPRS score being seen at
CNS Drugs 2008; 22 (1)

Dose-Response Relationship of Quetiapine in Schizophrenia

51

BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression scale; IR = immediate release; NA = not applicable; PANSS = Positive and Negative Syndrome Scale; XR = extended release; * p < 0.05, ** p < 0.01 vs placebo.

Reference

quetiapine 150 mg/day. Logistic regression failed to demonstrate a predictive relationship between dosage and response. A second fixed-dose study compared three daily doses (400, 600 and 800 mg) of quetiapine extended-release (XR) with one daily dose of quetiapine IR (400 mg) and placebo (table I).[9] All active treatments were significantly more effective than placebo, as assessed by the Positive and Negative Syndrome Scale (PANSS),[10] but change in score was greatest with dosages of 600 and 800 mg/day. There was no direct statistical comparison of one dosage against another, but post hoc analysis of PANSS change for increasing dosages indicated a significant dose-response relationship (p = 0.013; calculated by the Jonckheere-Terpstra test[11]). In addition, quetiapine XR 400 mg/day failed to separate from placebo on one primary outcome measure (CGI-S). Response rates (defined as a 30% reduction in PANSS score) were 30.4% for placebo, 44.1% for quetiapine XR 400 mg/day, 60.4% for XR 600 mg/day, 56.4% for XR 800 mg/day and 52.9% for quetiapine IR 400 mg/day. All active treatments were statistically superior to placebo on this measure. Two further fixed-dose studies have compared three dosage regimens (two effective daily doses and one assumed to be inactive) of IR quetiapine over 6 weeks (see table II).[12,13] In both studies subjects were randomized to 25 mg twice daily, 225 mg twice daily or 150 mg three times daily. In the larger of these trials, efficacy was measured using several rating scales, outcomes for which are shown in table II.[12] In both 450 mg/day groups, scores improved from baseline when compared with the 50 mg/day group, as measured using the BPRS, but with no difference between these two higher dosage groups. However, no statistically significant difference was observed in the proportion of responders (defined as those patients with at least a 30% reduction from baseline in BPRS total score at
CNS Drugs 2008; 22 (1)

PANSS total score

Outcome (endpoint mean change from baseline)

BPRS total score

1.71 2.24 8.67 8.59 7.68 6.33 7.58 Other Axis I DSM-III-R diagnoses 361 Hospitalized patients, 1865 y of age with a diagnosis of schizophrenia 6-wk, randomized, double-blind, placebocontrolled, multicentre 0.15 0.15 0.16** 0.15** 0.16** 0.15** 0.16 0.25 0.15 0.49 0.69 0.46 0.46 0.69 Placebo (51) Quetiapine IR 75 (53) Quetiapine IR 150 (48) Quetiapine IR 300 (52) Quetiapine IR 600 (51) Quetiapine IR 750 (54) Haloperidol 12 (52)

6-wk, randomized, double-blind, placebocontrolled, multicentre In- or outpatients, 1865 y of age with a diagnosis of schizophrenia 573 Other Axis I DSM-IV diagnosis, substance misuse, hospitalization for >1 mo, treatment resistance, prior depot antipsychotic within one dosing interval Placebo (115) Quetiapine XR 400 (111) Quetiapine XR 600 (111) Quetiapine XR 800 (117) Quetiapine IR 400 (119) 1.0 1.3 1.5** 1.6** 1.3* NA NA NA NA NA

Table I. Multiple fixed-dose studies, vs placebo and haloperidol

2008 Adis Data Information BV. All rights reserved.

Study design

Subjects

No. of subjects

Exclusion criteria

Treatment and dosage [mg/day] (n)

CGI-Severity of Illness

2.06 2.04 2.14** 2.06** 2.08** 2.02* 2.10**

NA NA NA NA NA NA NA

18.8 24.8* 30.9** 31.3** 26.6**

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Sparshatt et al.

Reference

bid = twice daily; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression scale; NS = not stated; ns = not significant; tid = three times daily.

Table II. Single fixed-dose studies, vs low-dose quetiapine

subjects

Significant alcohol or drug abuse

Other Axis I diagnosis, including substance/ alcohol misuse

Exclusion criteria

any time during the trial) in each of the three groups (55% in both 450 mg/day groups, 53% in the 50 mg/ day group). When measuring changes from baseline in CGI-S score, only 225 mg twice daily was shown to cause greater improvement than 25 mg twice daily (p = 0.03). Mean Schedule for the Assessment of Negative Symptoms (SANS)[14] scores decreased in all groups, with improvement significantly greater in the 225 mg twice daily group than in the 25 mg twice daily group (p = 0.02). No other differences were seen between treatment groups. These findings suggest that 450 mg/day is a more efficacious dosage than 50 mg/day. The smaller study observed six subjects over an initial 6-week observation period of the above dosages, followed by a 52-week open treatment phase of dosages up to 800 mg/day.[13] However, the two subjects randomized to 50 mg/day withdrew after 2 weeks following no clinical improvement, and only one subject continued after the 6-week period on variable dosages up to 450 mg/day. The subjects receiving 450 mg/day showed clinical improvement at 6 weeks (mean change in BPRS, SANS and CGI, p-values not reported). There was no difference seen between the two dosage regimens of 450 mg/day in trend over time. These results support those shown by the larger and more informative trial.[12] 2. Flexible Dosage within Fixed-Dose Range Studies An alternative to rigid fixed-dose studies is to randomize subjects to separate ranges of dosages within which flexible dosing is allowed. Such studies give a broad but imprecise impression of doseresponse relationships. Two studies have used flexible dosages of quetiapine within set dosage ranges to evaluate the efficacy and tolerability of the drug in schizophrenia.[15,16] The largest of these studies compared two dosage ranges a high-dosage group (up to 750 mg/day) and a low-dosage group (<250 mg/day)
CNS Drugs 2008; 22 (1)

12

BPRS score [mean change from baseline] 5.41 (p = 0.0503 vs 150 mg tid)

9.98 (p = 0.0055 vs 25 mg bid)

8.59 (p = 0.3943 vs 225 mg bid) 47 (ns compared with 225 mg bid) Quetiapine 150 tid (209)

CGI-Severity of Illness [% showing improvement]

41 (ns compared with 150 mg tid)

Outcome

53 (p = 0.03 compared with 25 mg bid)

Quetiapine 25 bid (209)

Quetiapine 225 bid (200)

No. of

618

Hospitalized patients, 1865 y of age with a diagnosis of schizophrenia

6-wk, randomized, double-blind, parallel group, multicentre

2008 Adis Data Information BV. All rights reserved.

6-wk, randomized, double-blind, trial followed by 52-wk open treatment phase

Study design

Hospitalized patients, 1865 y of age with acute exacerbation of chronic schizophrenia

Subjects

Quetiapine 25 bid (2) Quetiapine 225 bid (2) Quetiapine 150 tid (2)

Treatment and

dosage [mg] (n)

NS NS NS

NS NS NS

13

Dose-Response Relationship of Quetiapine in Schizophrenia

53

with placebo.[15] Actual mean daily doses used were 360 mg and 209 mg, respectively. Design and outcomes are shown in table III. At each evaluation point, the mean decrease in BPRS total score for the high-dosage group was numerically larger than in the low-dosage group, which in turn was larger than in the placebo group. Mean changes from baseline in BPRS total scores were statistically significantly greater at endpoint for the high-dosage group than the low-dosage group (p = 0.04) and greater than placebo from day 14 onwards (p 0.01) and until endpoint (p = 0.001). The low-dosage group showed no difference compared with placebo at any time. CGI-S scores indicated that improvement in the high-dosage group was numerically greater than in the low-dosage group, and a significant difference was seen between the high-dosage and placebo groups at endpoint (p = 0.003). A further analysis of this study removed from data analysis those subjects who received <150 mg/day, as dosages below this were deemed to be subtherapeutic.[17] These modified data then showed superior total score changes in BPRS for the low-dosage group compared with placebo at weeks 4 and 5. The smaller study observed 12 hospitalized male patients diagnosed with schizophrenia in a 21-day trial of increasing dosages of quetiapine or placebo, randomized at a 2 : 1 ratio, respectively.[16] Dosages used were 25 mg/day, titrating up to 250 mg/day for all patients. The titration schedule did not allow for 250 mg/day to be reached until at least day 16 of the trial period. The BPRS and CGI-S were used as measures of efficacy throughout the trial period, with results shown in table III. Change from baseline in all scales was significantly greater at endpoint for patients who received quetiapine, with scores improving steadily from baseline to endpoint. The response rate did not differ between the groups.
2008 Adis Data Information BV. All rights reserved.

3. Variable-Dose Studies Variable-dose studies usually allow flexible dosing within a single range of dosages. Average dosages used may give some indication of optimal dosages in practice, assuming the range of dosages allowed includes the optimal dosage. In the earliest of eight studies examining variable doses, quetiapine and placebo were compared in subjects with an acute exacerbation of schizophrenia.[18] Subjects were randomized to either placebo or quetiapine, starting at 25 mg three times daily and titrated upwards to a maximum of 750 mg/ day, although dosages >500 mg/day were limited to 14 days of use. Study design and details are shown in table IV. Analysis of the change in BPRS total and positive factor clusters and CGI-S scales showed that at endpoint the numerical superiority of quetiapine over placebo did not reach significance (table IV). The mean daily dose of quetiapine was 307 mg (range 58526 mg). The efficacy of quetiapine has also been compared with haloperidol,[19] risperidone[20,21] and chlorpromazine[22] in separate variable-dose studies. These trials ranged in duration from 6 weeks to 4 months, with dosages of all drugs titrated against patient response and tolerability. Exclusion criteria and mean daily doses differed between the trials, as displayed in table IV. Very few differences in outcome were reported. In the comparison with chlorpromazine,[22] no differences were detected in primary outcome measures. Treatment response was defined as a decrease of 50% in BPRS total score: 65% of the quetiapine subjects (mean daily dose 407 mg) and 52% of the chlorpromazine group met this criterion, which was a statistically significant difference. In the earlier risperidone comparison (an open study sponsored by the manufacturer of quetiapine),[20] no differences in primary outcome were found, but, using the Hamilton Rating Scale for Depression (HAM-D),[23] a significant improvement
CNS Drugs 2008; 22 (1)

54

Table III. Flexible-dose within fixed range studies No. of subjects and mean [mean; mg/ day] (n) response (%)a CGI-Severity of Illness [mean change from baseline] BPRS [mean change from baseline] 53b 15 (p = 0.003 vs placebo) placebo) (p = 0.001 vs 0.6 0.13 8.7 1.64 Exclusion criteria Dosage range (mg/day) Outcome Reference

Study design

Subjects

6-wk, randomized, diagnoses, suicidal behaviour 750 max. [360] (96)

Hospitalized patients,

286

Other Axis I DSM-III-R

High-dosage group:

double-blind,

1865 y of age with

placebo-controlled,

a diagnosis of

2008 Adis Data Information BV. All rights reserved.

multicentre Low-dosage group: 250 max. [209] (94) (p = 0.08 vs high dosage) Placebo (96) 37 0.1 0.13 (p = 0.23 vs low dosage) 12 dependence, suicidal ideation every 4 days to reach a dosage of 250 mg/day (8) Placebo (4) 50 1.0 1.6 rising by 25 or 50 mg Alcohol/drug Quetiapine 25 mg/day, 100 (p = 0.09 vs placebo) 2.9 0.6 (p = 0.02 vs placebo) 50 0.3 0.13

schizophrenia 4.2 1.62 (p = 0.04 vs high dosage) 1.0 1.61 (p = 0.15 vs low dosage) 20.9 8.5 (p = 0.04 vs placebo) 16

3-wk, double-blind,

Hospitalized patients,

parallel group,

1865 y of age with a

placebo-controlled,

diagnosis of

rising-dose

schizophrenia

4.7 13.2

A decrease of at least 30% from baseline BPRS total score at any time during treatment phase.

Difference in the distribution of responders in treatment groups is p = 0.05.

CNS Drugs 2008; 22 (1)

Sparshatt et al.

BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression scale; max. = maximum.

Dose-Response Relationship of Quetiapine in Schizophrenia

55

in depressive symptoms was seen in the quetiapine group (mean daily dose 253.9 mg) compared with risperidone. In the later comparison with risperidone,[21] outcomes were similar but risperidone showed some advantage in treating positive symptoms, and significantly more quetiapine subjects left the study early because of lack of efficacy (24.3% vs 13.7%). Mean dosage of quetiapine was 525 mg/ day. In the comparison with haloperidol, quetiapine showed no advantages and was marginally effective (mean daily dose 455 mg).[19] Three further studies compared flexible-dose quetiapine with comparators in studies of varied design.[24-26] The long-term efficacy of quetiapine was examined in 23 male patients.[24] Although originally a 3-year study, only five subjects completed weeks 7796 before the trial terminated. Design and exclusion criteria are shown in table V. Subjects were initiated on quetiapine in hospital before discharge and dosages were then adjusted according to response. At 1 year, 30% of subjects remained on quetiapine. Mean final daily dose of quetiapine for those withdrawing at week 12 or before was 362 184.8 mg, while those withdrawing at 25 weeks or less was 592 178.2 mg and those finishing at or after 25 weeks was 614 197.6 mg. Mean dosages of those who remained in the study also increased from a mean of 261 mg/day at week 1 to 560 mg/day by weeks 7796. Patients who relapsed were subsequently stabilized on alternative antipsychotics (n = 19). Measures of efficacy were not reported other than numbers of patients still taking quetiapine at each timepoint. The effect of quetiapine on cognitive and functional improvement was compared with conventional antipsychotics in 40 outpatients with schizophrenia.[25] Patients were randomized to either continue on their current typical antipsychotic or to switch to quetiapine for 6 months. Design and inclusion/exclusion criteria are shown in table V.
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Neurocognitive and functional assessment was carried out at 3 and 6 months. Symptoms were assessed using the BPRS. The mean dosage of quetiapine used by endpoint was 319.25 142.53 mg/day (compared with the conventional antipsychotic chlorpromazine equivalent of 348.00 348.28 mg/ day). Mean change in BPRS scores was not reported other than to state that there were no significant differences between the groups with respect to symptomatology; however, there was a significant difference in cognitive function summary scores, with the quetiapine group performing better than those taking conventional antipsychotics (p = 0.023). A further 4-week variable-dose trial of quetiapine in 12 hospitalized patients examined the treatment of schizophrenia refractory to treatment with typical antipsychotics.[26] Design and exclusion criteria are shown in table V. Subjects were initiated at a quetiapine dosage of 50 mg/day and titrated up to 500 mg/day by day 6. This dosage was then maintained or increased up to a maximum of 750 mg/day. The mean maintenance dosage used was 654.2 mg/day. The primary efficacy measure was change in total PANSS score. Mean total PANSS score was significantly reduced between baseline and endpoint (113.0 14.98 and 93.8 23.7, respectively; p = 0.006) Response was defined as a 20% decrease in PANSS total score by endpoint. Fifty percent of the subjects had shown response by endpoint. 4. Single Fixed-Dose Study One study used a single fixed-dose of quetiapine compared with a fixed dose of haloperidol.[27] This trial examined outpatients who were all shown to have symptoms that had only partially responded or shown no response to fluphenazine 20 mg/day after 4 weeks. Patients were then randomized to quetiapine 600 mg/day or haloperidol 20 mg/day for 8 weeks. Study design and exclusion criteria are
CNS Drugs 2008; 22 (1)

56

Table IV. Variable-dose comparisons vs baseline No. of subjects dosage [mg/day] (n) Exclusion criteria Comparator drug and Outcome Reference

Study design

Subjects

6-wk, randomized, double-blind, placebo controlled, multicentre 448 Quetiapine: 50800, mean dosage 455 (221) 728 Quetiapine: 50800, mean dosage 253.9 (553) 13.0 0.94 (p = 0.68) NA Risperidone: mean dosage 4.4 (175) 11.8 1.3 Not used 18.7 1.63 (p = 0.1275) 0.92 0.09 (p = 0.0359) Not used 20 NA Haloperidol: mean dosage 8 (227) 22.1 1.63 Not used 1.17 0.08 19

Hospitalized patients, 1860 y of age with a diagnosis of schizophrenia

109

Other Axis I DSM-III-R diagnoses, suicidal behaviour

Placebo (55) Quetiapine: mean dosage 307, range 58526 (54)

PANSS [mean CGI-Severity BPRS [mean change from of Illness change from baseline] [mean change baseline] from baseline] 2.1 2.39 Not used 0.2 0.18 0.2 0.18 8.1 2.39 (p = 0.07) (p = 0.07) 18

6-wk, randomized, double-blind,

Hospitalized males and females, over 18 y of

2008 Adis Data Information BV. All rights reserved.

parallel group

age with acute exacerbation of schizophrenia

4-mo, randomized, open-label, multicentre

Outpatients over 18 y of age with a diagnosis

of schizophrenia, schizoaffective disorder, major depressive disorder with psychotic features, Alzheimers disease with psychotic symptoms, vascular dementia or dementia due to substance misuse 673 Other disorders, prior lack of response, pregnancy, lactation Risperidone: mean dosage 5.2 (335) 18.1 1.4

8-wk, randomized, double-blind, multicentre

1865 y of age with a diagnosis of schizophrenia with moderate to severe symptoms

41.8% much or very much improved

Not used

21

Quetiapine: mean dosage 525 (338) 201 NA

15.1 1.4 (ns) Chlorpromazine: mean Not used dosage 384 (100) Quetiapine: 50750, mean dosage 407 (101)

39.0% much or very much improved 1.09 1.23 (p-value NS)

Not used

6-wk, randomized, double-blind,

Hospitalized males and females, 1864 y

18.0 18.4 (p-value NS)

22

parallel group

of age with acute exacerbation of schizophrenia, or schizophreniform disorder

CNS Drugs 2008; 22 (1)

Sparshatt et al.

BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression scale; NA = not applicable; NS = not stated; ns = not significant; PANSS = Positive and Negative Syndrome Scale.

Dose-Response Relationship of Quetiapine in Schizophrenia

57

Table V. Other variable-dose studies Study design 3-y, open-label Subjects Male, aged 1860 y, weight 64100 kg, DSM-IV diagnosis of schizophrenia Aged 1855 y, taking antipsychotics at a stable dose for at least 3 mo Aged 2060 y, DSM-IV diagnosis of schizophrenia, with known resistance to first-generation antipsychotics No. of subjects 23 Exclusion criteria Other Axis I disorder, positive drug urine test, current or history of nonresponse to clozapine Psychiatric hospitalization for a minimum of 1 y before the study Other Axis I or II diagnosis, alcohol or drug abuse in previous 6 mo Reference 24

6-mo, open-label, rater-blinded 4-wk, short-term, single-blind pilot trial

40 12

25 26

shown in table VI. At endpoint, PANSS and BPRS total scores, as well as CGI-S score, had shown a numerically greater change from baseline in the quetiapine group compared with the haloperidol group, although this was not statistically significant on any scale. The results suggested that 600 mg/day of quetiapine is at least as effective as haloperidol 20 mg/day in patients with symptoms that have not fully responded to other antipsychotic treatment, although has not been shown to be significant. Three case reports have described the use of quetiapine in treatment-resistant schizophrenia.[28] Three patients with a diagnosis of treatment-resistant schizophrenia are reported to have responded to quetiapine at dosages of 500 mg/day, 700 mg/day, and 375 mg twice daily, having not responded to several previous antipsychotics each and experiencing years of illness. These case reports support the findings of the single fixed-dose study already discussed, indicating a possible role for quetiapine in treatment-resistant schizophrenia. 5. Neuroimaging Studies Neuroimaging techniques such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT) have been applied to the use of quetiapine in humans. These trials were designed to estimate the dopamine receptor occupancy of quetiapine. Although a secondary consideration, some studies showed improvement in clinical efficacy measures for quetiapine across dif 2008 Adis Data Information BV. All rights reserved.

ferent dosage ranges, although subject numbers are very small and efficacy data incomplete for many studies. As might be expected, the study findings demonstrate that plasma concentrations of quetiapine increase with larger dosages of quetiapine (table VII). The mean half-life of dopamine D2 receptor binding was shown to be greater with higher dosages (maximum mean peak binding was 44% at quetiapine 450 mg/day)[29] and to decrease rapidly over 24 hours after a dose to 0%.[30] This is believed to be because of the low affinity of quetiapine for D2 receptors.[31] All studies showed D2 receptor binding to be substantially less than that seen with other effective antipsychotics, with the exception of clozapine most antipsychotics demonstrate occupancies >65% when showing antipsychotic activity.[32] Dosages of quetiapine ranged from 150 to 750 mg/day. The most recent study showed that D2 receptor binding of quetiapine varied according to the brain area examined (lowest in the putamen, highest in the temporal cortex [33.5% vs 46.9%]).[33] 6. Case Series and Cohort Studies A 15-month open-label, variable-dose study examined 35 patients with a diagnosis of schizophrenia or other psychotic disorder.[36] Patients received quetiapine at starting dosages of 100 or 400 mg/day, titrating upwards by 50100 mg/day every 12 days to a maximum daily dose of 1600 mg. The modal dosage used was 800 mg/day, with 12 patients prescribed >1000 mg/day for an average of
CNS Drugs 2008; 22 (1)

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Sparshatt et al.

Reference

Outcome [endpoint mean change from baseline]

BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression scale; PANSS = Positive and Negative Syndrome Scale.

PANSS total score

(p = 0.234)

11.50

8.87

4 weeks, before decreasing to a maintenance dosage of 200600 mg/day. Statistical analysis was not reported; however, the study showed that at 4 weeks, 94.3% of subjects had shown an improvement in global symptoms, and an improvement was seen in all subjects who received >800 mg/day. A rapid response was reported in terms of a decrease in hostility, restlessness and insomnia at days 13, irrespective of the initial dosage. Hallucinations were reported to improve after 1 week and delusions improved after 3 weeks, although dosages >800 mg/ day were reported to be necessary to eliminate these symptoms. There are a number of single case reports in the literature. The first of these described rapid dose escalation of quetiapine to 600 mg by day 7 of treatment in a 34-year-old male with a diagnosis of treatment-resistant schizophrenia that had been treated with zuclopenthixol decanoate 200 mg weekly immediately before quetiapine.[37] Baseline PANSS total score fell from 90 to 60 by day 77 during the study period. Symptoms of tardive dyskinesia also improved during this time, as determined by an improvement in adverse effects on the Abnormal Involuntary Movement Scale (AIMS),[38] with a fall from a score of 21 at baseline to 2 at day 77. A further case study reported the use of high-dose quetiapine, up to 1000 mg/day, in a 12-year-old male with conduct disorder and attention-deficit hyperactivity disorder.[39] Minimal improvement in symptoms had previously been seen in response to stimulants, lithium and olanzapine 15 mg/day. No improvement in symptoms was seen at a dosage of quetiapine of 300 mg/day, but once increased to 1000 mg/day (400 mg in the morning and 600 mg at night) a dramatic improvement in his psychiatric symptoms was reported. At day 90, the patient continued to be maintained at 1000 mg/day with no adverse effects reported.
CNS Drugs 2008; 22 (1)

CGI-Severity of Illness

27

Quetiapine 600 (140)

Haloperidol 20 (141)

Drug and dosage [mg/day] (n)

(p = 0.105) nonresponders, acute

BPRS total score

6.95

4.78

(p = 0.221)

0.53

0.38

Treatment-resistant

Exclusion criteria

schizophrenia,

clozapine

schizophrenia in last

exacerbation of

No. of subjects

Male/female outpatients

281

>18 y of age with a

Table VI. Single fixed-dose study

2008 Adis Data Information BV. All rights reserved.

blind, multicentre trial

randomized, double-

8-wk, international,

Study design

diagnosis of

Subjects

schizophrenia

3 mo

Dose-Response Relationship of Quetiapine in Schizophrenia

59

A commentary article discussed clinical experience with rapid dose escalation of quetiapine up to dosages of 400 mg/day by day 4 of treatment in patients with schizophrenia.[40] This dose escalation was reported to be achievable without an increased incidence of adverse effects. The case of a patient who had not responded to quetiapine 800 mg/day was discussed. With an increase to 1600 mg/day, the patients schizophrenia went into full remission with no reported adverse effects. There is also a report detailing experience with seven hospitalized patients (aged 2745 years) who had diagnoses of treatment-resistant schizophrenia or schizoaffective disorder.[2] Quetiapine was introduced up to the licensed maximum dosage of 800 mg/day and then increased if there was no response, with dosages ranging from 1200 to 2400 mg/day. At these dosages, mild to marked clinical improvements were reported in positive symptoms, violent behaviour, behavioural disturbances and sociability. The patients were followed until symptom exacerbation and, therefore, change in treatment or until the end of the study period, whichever occurred first. Four of the seven patients had deteriorated by endpoint, despite initial improvement on high-dose quetiapine. Adverse effects noted were sedation, orthostasis, dysphagia and a nocturnal startle reaction, which all responded to dose reduction. 7. Review Articles and Meta-Analysis There have been numerous review articles concerning quetiapine and its use in schizophrenia. Many of these are general overviews of the various clinical trials using quetiapine, while others are pooled data and meta-analyses of the data presented in this article. A combined analysis[41] incorporated three randomized, placebo-controlled trials that have been previously discussed.[6,15,18] The data from the three trials were pooled in order to determine the efficacy of quetiapine, and data from subjects receiving
2008 Adis Data Information BV. All rights reserved.

<150 mg/day was removed as this was deemed a subtherapeutic dosage. The remaining subjects were then divided into two groups those receiving <400 mg/day (n = 257) and those receiving more than this (n = 164). Both groups showed significantly greater improvement in BPRS positive symptom score than placebo from week 2 onwards (p < 0.01 at week 2 and p < 0.001 at weeks 36). The difference was numerically greater in the >400 mg/day group, but not significantly greater than the lower dosage group. Total BPRS score was not commented on. A further report by the same author[42] described the open-label extension stage of the trial by Arvanitis and Miller[6] pooled with two other randomized, double-blind trials.[12,19] All patients who responded to the 6-week phase of these trials and continued into the open-label extension phase were included. Mean quetiapine dosage and changes in BPRS and CGI-S scores in the pooled analysis are shown in table VIII. Statistical significance was not reported. A similar analysis pooled data and recruited patients from the open-label phase of four trials[43] (two trials described in the paragraph above[12,19] and two PET scan studies of subjects administered quetiapine at dosages of 450750 mg/day[30,31]). During the open-label extension phase, subjects could be prescribed up to 850 mg/day. In total, 674 subjects were included, with a mean daily dose of 472.4 175.5 mg and a mean duration of exposure of 42.2 67.3 weeks. During the study, 617 (91.5%) subjects withdrew from the open-label phase, with the main reason for withdrawal being lack of efficacy (n = 315 [46.7%]). Other reasons for withdrawing from the study were adverse effects, non-adherence and lost to follow up. Results are shown in table IX. Changes from baseline in all efficacy scales were statistically significant at each timepoint (p 0.001). A further review by the same author discusses the importance of early intervention in treating schizoCNS Drugs 2008; 22 (1)

60

Table VII. Neuroimaging studies No. of Exclusion criteria subjects mean D2 receptor occupancy [%] (range) 8 No other antipsychotics and no depot antipsychotic for 2 mo before trial period No systematic ratings/ clinical measures used. At day 14, eight subjects remained in the trial with good symptom control and all clinically improved on fixed dose of 150 mg TDS PANSS Baseline mean: 62.8 17.1 Wk 1012: 52.9 24.4 (p = 0.007) CGI Baseline mean: 4.2 0.7 Wk 1012: 29 1.7 (p = 0.001) 12 h post dose: 150 mg/day = 22 300 mg/day = 57 450 mg/day = 14 11 600 mg/day = 19 1 12 h post dose: 150 mg/day = 29 4 ng/mL 300 mg/day = 50 28 ng/mL 450 mg/day = 172 111 ng/mL 600 mg/day = 201 113 ng/mL (p = 0.008, dose/plasma concentration correlation) 30 44 (2168) at 2 h 27 (654) at 12 h 402.8 at 2 h and 7.2 at 26 ha 29 plasma concentration Clinical efficacy measures PET/SPECT results and plasma concentrations Reference

Study design and method

Subjects

1-wk escalation to 150 mg tid, then fixed dosage of 450 mg/day for 29 days. Four PET scans over 26-h period after withdrawal

Male, DSM-III-R diagnosis of schizophrenia

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Dosages of 150 mg/day (n = 3), 300 mg/day (n = 3), 450 mg/day (n = 3), 600 mg/day (n = 3), not completed (n = 3). Doses held then PET scan at days 21 and 28, then flexible dosing (range 150600 mg/ day) for 8 wk

Aged 1845 y, DSM-IV diagnosis of schizophrenia

15

No other major illness or substance misuse. No depot antipsychotics within last 12 mo

Patient 1 1 NA PANSS total Day 1: 98 Day 21: 100 CGI NA Day 1: 94 Day 21+: 76 NA 34

3 wk haloperidol 20 mg IM every 3 wk, then oral haloperidol 15 mg/ day for 20 wk, then quetiapine 750 mg/day for 2 wk. SPECT on day 1 of switch and then on day 21

Male, 33 y of age, DSM-IV diagnosis of schizophrenia

Patient 2 1 PANSS total Day 14: 67 Day 90: 60 CGI NA Day 14: 51 Day 90: 28 NA

Zuclopenthixol 200 mg once weekly for 6 mo. 5-wk break then quetiapine 600 mg/day for 90 days. SPECT scan days 14 and 90

Male, 34 y of age, DSM-IV diagnosis of schizophrenia

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Sparshatt et al.

Continued next page

Table VII. Contd No. of Exclusion criteria subjects mean D2 receptor occupancy [%] (range) 10b No depot antipsychotics for last 12 mo before study entry. No substance misuse PANSS used but not reported, other than that four patients had improved PANSS scores 750 mg/day = 41 (2850) [n = 4] 450 mg/day = 30 (2141) [n = 3] 300 mg/day = 1 (2 to 4) [n = 2] 150 mg/day = 13 [n = 1] Mean striatal D2 receptor occupancy Peak: 62.0 9.8 Trough: 14.3 7.9 (p = 0.001) Comparison of responders and nonresponders at wk 4 Nonresponse: mean peak 60.3 10.78 Response: 65.9 7.9 (p = 0.0446) Mean occupancy ranged from 15.8% to 64.3% depending on dose and brain area 1 h post-dose: 31 589 530 ng/mL (range 17145 ng/mL) 2.5 h post-dose: 493 163 ng/mL (range 184827 ng/mL) Mean trough 20 h post-dose: 29 15 ng/mL (range 956 ng/ mL) Plasma concentration increased with dose but not evaluated because of small patient numbers 35 plasma concentration Clinical efficacy measures PET/SPECT results and plasma concentrations Reference

Study design and method

Subjects

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1-wk dose-escalation phase until 450 or 750 mg/day. Maintained at that dosage for 21 days then dosage decreased if stable to dosages of 750, 450, 300 or 150 mg/day until day 49 if deemed clinically appropriate. PET scans 2 h post-dose on days 28, 35, 42, 49 Schizoaffective, schizophreniform disorder. No prior antipsychotic for more than 16 cumulative wk in their lifetime. No history of poor response to medication or unstable medical illness or substance misuse PANSS Mean baseline: 82.6 7.9 Wk 4: 70.5 13.2 Wk 12: 61.9 16.4 (p < 0.001) CGI-S Mean baseline: 4.6 0.7 Wk 12: 3.1 0.9 (p = 0.001)

Male, DSM-III-R diagnosis of schizophrenia

Dose-Response Relationship of Quetiapine in Schizophrenia

Titration from 50 mg bid to target dosage of 400 mg/day, maintained until end of wk 4, then adjusted to 750 mg/day. PET scans after 4 wk of treatment

DSM-IV episode 14 of schizophrenia, 1645 y of age,

Regular administration of quetiapine. PET scans 2 h after last oral dose

DSM-IV diagnosis of schizophrenia, 1850 y of age. Prescribed quetiapine 200700 mg as single doses

23

History of medical illness or trauma

Mean baseline BPRS score: 16.6 7.9 Subjects treated with 400700 mg had lower scores (13.7 vs 18.8 [ns])

NS

33

Units not specified.

Four subjects had PET scans.

CNS Drugs 2008; 22 (1)

bid = twice daily; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression scale; CGI-S = CGI-Severity subscale; IM = intramuscularly; NA = not applicable; NS = not stated; ns = not significant; PANSS = Positive and Negative Syndrome Scale; PET = positron emission tomography; SPECT = single positron emission computerized tomography; tid = three times daily.

61

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Sparshatt et al.

Table VIII. Pooled data from long-term extension studies[42] Timepoint BPRS total score (mean dosage 439.5 mg/day) [n] 40.67 (95% CI 39.44, 41.90) [258] 13.94 (95% CI 12.93, 14.95) [258] CGI-S score (mean dosage 438.5 mg/day) [n] 4.81 (95% CI 4.73, 4.90) [259] 3.00 (95% CI 2.88, 3.11) [259]

Baseline 6 wk 156 wk

9.04 (95% CI 4.62, 13.46) 2.43 (95% CI 1.92, 2.95) [24] [23] BPRS = Brief Psychiatric Rating Scale; CGI-S = Clinical Global Impression Scale-Severity subscale.

phrenia.[44] The results of previously included trials are discussed to support the use of quetiapine in the early stages of schizophrenia.[6,15,18] Case reports are also included in order to report the successful treatment with quetiapine of two patients in the early stages of their illness. Dosages used were 300 and 600 mg/day, with symptoms resolving in both cases. A review article, based on a PubMed search to obtain all articles related to high-dose quetiapine use, discussed the high dosages of quetiapine used in clinical practice.[1] This was reported alongside a discussion of trends in dosing in a large state hospital in the US. The mean dosage used in this hospital was 620 mg/day, but patients who were non-White, with admission of >1 year and prior admission history were more likely to receive >750 mg/day (p < 0.05). Dosages in excess of 1200 mg/day were also being used. The efficacy of these high dosages is not described and the trials reported on in the review have been discussed previously.[6,15,22] 8. Effectiveness Studies Effectiveness studies examine the use of drugs in comparatively naturalistic settings and compare drugs using pragmatic outcomes rather than surro-

gate markers. A series of trials reported during 20052006, known as the CATIE (Clinical Antipsychotic Trials in Intervention Effectiveness) trials,[45-47] compared the efficacy of several antipsychotics. In the first phase of the study,[45] olanzapine, quetiapine, risperidone and ziprasidone, as well as the typical antipsychotic perphenazine, were compared in patients with chronic schizophrenia (n = 493). Dosages of quetiapine used were in the range of 200800 mg/day, with a mean modal dosage of 543.4 mg/day. At 18 months, 18% of subjects who had been prescribed quetiapine remained on this treatment, while 21%, 25%, 26% and 36% remained on ziprasidone, perphenazine, risperidone and olanzapine, respectively. The difference in time to discontinuation between quetiapine and olanzapine was statistically significant (p = 0.001), but it should be noted that the mean dosage of olanzapine administered was above the licensed maximum for this drug (20 mg/day). Further to this phase, subjects who discontinued in the first stage were then re-randomized to a different drug from the above antipsychotics, excluding perphenazine (n = 444).[47] Quetiapine was used in dosages of 200800 mg/day (n = 63). Again, efficacy was measured by time to discontinuation. The time to discontinuation was longer for subjects taking risperidone (median 7.0 months) and olanzapine (6.3 months) than those taking quetiapine (4.0 months) and ziprasidone (2.8 months). In those who discontinued their previous treatment in stage 1 because of inefficacy (n = 184), olanzapine was shown to be more effective than quetiapine and ziprasidone, and risperidone was shown to be more effective than quetiapine, as measured by median time to discontinuation for any reason. Changes in PANSS

Table IX. Pooled data from open-label studies (reproduced from Kasper et al.,[43] with permission) Rating scale BPRS total: difference from baseline Week 26 (n = 305) 15.8 15.7 Week 104 (n = 86) 25.6 12.6 Week 208 (n = 39) 27.5 19.0 p-Value (vs baseline) 0.001 0.001

1.2 1.5 2.1 1.4 2.4 1.6 CGI-S: difference from baseline BPRS = Brief Psychiatric Rating Scale; CGI-S = Clinical Global Impression Scale-Severity subscale.

2008 Adis Data Information BV. All rights reserved.

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Dose-Response Relationship of Quetiapine in Schizophrenia

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scores showed improvement to be significantly greater in the olanzapine group than the quetiapine group (estimated mean difference 6.8; SE = 2.4; p = 0.005) and the ziprasidone group (difference 5.9; SE = 2.1; p = 0.005), but not in the risperidone group. Another arm of the study compared subjects with treatment-resistant symptoms who had discontinued in the initial trial and were then randomized to clozapine, olanzapine, risperidone or quetiapine.[46] The mean modal dosage of quetiapine used was 642.9 mg/day. Again, differences were seen in time to discontinuation, with clozapine being significantly superior to quetiapine (p = 0.01) and risperidone (p < 0.02) but not olanzapine. When reporting numbers of subjects withdrawing from the study because of lack of efficacy, clozapine was superior to olanzapine (p < 0.02), quetiapine (p = 0.004) and risperidone (p = 0.003). In the most recent effectiveness study, quetiapine was compared with five other antipsychotics in a randomized naturalistic evaluation of patients hospitalized with relapsed schizophrenia (n = 327).[48] Quetiapine was found to be significantly less effective than haloperidol (89% no longer required hospital care), olanzapine (92%) and risperidone (88%). In the quetiapine group, 64% of subjects still required hospital treatment at endpoint (p < 0.0001); mean dosage was 652.5 mg/day (up to 1200 mg/day was allowed). 9. Conclusion Before discussing the data presented in this review, it is worth first considering the nature of the dose-response relationship seen with antipsychotic drugs. For all drugs there will be low dosages that provoke no therapeutic effect and higher dosages beyond which no further effect is seen. In between these extremes, successively larger dosages give rise to successively larger effects. This is the so-called linear portion of the (s-shaped) dose-response curve;
2008 Adis Data Information BV. All rights reserved.

25 Change in BPRS score (%) 20 15 10 5 0 0 5 0 100 200 (Placebo) 300 400 500 600 700 800 75 150

300

600 750

Quetiapine fixed dosage (mg/day) Fig. 1. Quetiapine fixed-dose vs response. BPRS = Brief Psychiatric Rating Scale.

its slope dictates dosing strategies in clinical practice. For some drugs the slope is nearly vertical, such that once a threshold dosage is reached almost all of the clinical effect is seen (examples include paracetamol [acetaminophen] and thiazide diuretics). Where the slope tends more towards the horizontal there is greater opportunity to increase dosage for a gradually greater effect; good examples here are morphine and furosemide (frusemide) therapeutic effects increase over a wide dosage range. Evidence relating to antipsychotics strongly suggests a threshold-type relationship; all studied drugs show a near-vertical linear portion of the dose-response curve[49] and threshold dosages are reasonably well established for drugs such as risperidone (4 mg/ day)[50] and haloperidol decanoate (100 mg/ month).[51] These threshold dosages are also the dosages at which maximal effect is seen; dosage increases provide no additional effect. Given the uniformity of the shape of antipsychotic dose-response relationships, one might expect quetiapine to show similar properties. Doseresponse curves are usually drawn from data derived from fixed-dose clinical trials. When a curve is drawn using the major fixed-dose study of IR quetiapine[6] (figure 1), the curve demonstrates a nearvertical linear portion, with the threshold dosage at 150 mg/day. There is no additional benefit from using 600 or 750 mg/day. In fact, a change in
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Sparshatt et al.

symptom scores is numerically less at these higher dosages. Of course statistical power considerations are important here; the study may not have had sufficient statistical power to reveal small or even moderate differences in outcome and, given the small number of subjects and high rate of dropout, confidence intervals for each dosage are likely to be very wide. Notably, however, if 150 and 300 mg/day subject groups are combined and compared with the two higher-dosage groups combined (thereby increasing study power), the lower-dosage group is numerically superior, hence ruling out any possibility of there being statistically significant advantage for the higher-dosage group. This suggests only a very remote possibility of dosages higher than 300 mg/day offering increased efficacy, and even then differences are likely to be small. Also of note here is the observation that analyses of pooled data have failed to demonstrate advantages to higher dosages. Nonetheless, these analyses of pooled data did not include results from the fixed-dose study of quetiapine XR.[9] This comparatively large study gives a somewhat different view of the dose-response relationship of quetiapine. Dosages of quetiapine XR 600 and 800 mg/day were numerically superior to 400 mg/day (XR and IR) and there appeared to be a statistically significant relationship between increasing dosage and therapeutic effect. This study included approximately twice the number of subjects per study dosage than the previously mentioned trial and had substantially fewer dropouts, thereby affording increased statistical power. This greater power suggests an important difference in effect between 400 mg/day and 600 or 800 mg/ day dosages (the lowest dosage is less efficacious) but not between 600 and 800 mg/day (outcomes were nearly identical). Therefore, it becomes possible that the optimal dosage of quetiapine is >400 mg/day (as suggested by occasional poor results seen with dosages around this value[18]); however,
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this trial strongly suggests, given its power to show differences, that no further benefit is likely to be seen at dosages >600 mg/day, at least in antipsychotic-responsive patients such as those recruited into the study. Taken together, these two major fixed-dose studies do not suggest that dosages above the licensed dosage range are likely to offer increased efficacy; however, no certainty can be expressed on this issue since there are no evaluations of fixed dosages >800 mg/day. It is possible (although unlikely given the results of the two studies conducted) that dosages of, say, 1000 or 2000 mg/day provide better efficacy than lower licensed dosages. Without robust evaluations of dosages of this magnitude it is impossible to rule out this possibility. Studies using fixed ranges of quetiapine dosages are relatively less informative about dose-response relationships but are helpful in some respects. In the largest of these studies, a mean dosage of quetiapine 209 mg/day was not superior to placebo and was clearly inferior to a mean dosage of 360 mg/day.[15] This suggests a different threshold for effect to that already described one >209 mg/day (although excluding those on <150 mg/day showed a slightly higher mean dosage to separate from placebo[17]). Perhaps of equal importance, however, is the fact that prescribers in the higher dosage range group did not use the full range of dosages available: mean dosage prescribed (360 mg/day) was closer to the lowest allowable dosage than to the highest (750 mg/day). This suggests that prescribers in the higher dosage group titrated dosages to give acceptable efficacy and tolerability and were able to do so without, in general, increasing the dosage towards the upper end of the allowable range (other possibilities include the likelihood that adverse effects or tolerability inhibited further dosage increases or that researchers abandoned treatment before trying higher dosages, as evidenced by the high dropout rates in some studies). This pattern of prescribing
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tentatively suggests that dosages around 300400 mg/day were observed to be acceptably therapeutic; there was no clear escalation of dosages in search of effect. Contrast this to the lower dosage group in which the average dosage used approaches the maximum allowable dosage, reflecting dosage escalation towards the maximum allowable dosage in search of efficacy. Variable-dose studies are informative on a similar basis; the difference between the mean dosage used and the maximum allowable dosage offers reassurance (or otherwise) that the true optimal dosage is within the dosage range allowed, notwithstanding the possibility that tolerability or other problems constrain dosage increases. In one study. a mean dosage of 307 mg/day did not separate from placebo, but dosages of 750 mg/day were allowed.[18] Other studies were more successful: a mean dosage of 455 mg/day was equivalent to haloperidol 8 mg/day;[19] a mean dosage of 254 mg/day was equivalent to risperidone 4.4 mg/day;[20] a mean dosage of 525 mg/day was broadly equivalent to risperidone 5.2 mg/day;[21] and a mean dosage of 407 mg/day was equivalent to chlorpromazine 384 mg/day.[22] In each study the maximum allowable dosage was 750 or 800 mg/day. None of these studies suggest that the licensed range of dosages is insufficient or inadequate in any way there was no pressure on the maximum dosage in search of efficacy. Moreover, if quetiapine is equivalent to comparator antipsychotics at mean dosages ranging from 254 to 525 mg/day then, if the high-dose theory is to be accepted, higher dosages are likely to be superior to standard antipsychotics, an unlikely proposition, but one which cannot be discounted in the absence of robust high-dose studies. A further consideration is the type of patient recruited into trials, particularly strictly controlled efficacy studies. Many trials, for example, excluded subjects with a history of misuse of alcohol or elicit substances. It is possible that dose-response rela 2008 Adis Data Information BV. All rights reserved.

tionships established in these patients do not reflect those in substance or alcohol misusers (typical patients in many areas) in whom higher dosages might be required. Conversely, most trials recruited relapsed and acutely ill, hospitalized patients who might be said to be more likely to require higher dosages than, say, outpatients or first-episode patients. These two competing influences may balance out overall the established optimal dosage for risperidone in non-alcohol/substance misusing hospitalized patients[50] is similar to the average dosage used in practice.[52] Also of note is the recruitment in most trials of subjects known to be responsive to treatment. Effective dosage ranges may well be different in refractory illness. Effectiveness data from the CATIE trials do little to support the high-dose theory for quetiapine. In largely responsive (i.e. not clearly treatment resistant) patients[45,47] quetiapine dosages averaging between 500 and 600 mg/day were used (titration to 800 mg/day was allowed). Although such dosages proved relatively less effective than some other antipsychotics (in the case of olanzapine, administered at higher than licensed dosages) there was no clear pressure on dosing in the search for efficacy. In patients with treatment-resistant symptoms,[46] the mean modal dosage of 642.9 mg/day does suggest dosage increases in the search for effect. Despite this high average dosage, quetiapine was found to be inferior to several comparators. In the effectiveness study of McCue and colleagues,[48] a mean daily dose of 652.5 mg was inferior to comparator drugs, and dosages of up to 1200 mg/day were allowed. These effectiveness data appear to suggest that quetiapine itself is rather less effective than some other antipsychotics. It might be argued, however, that restricting the dosage to 800 mg/day (or even 1200 mg/day) unfairly constrained clinicians in seeking to gain the optimal effect from the drug. Nonetheless, as already seen, the fact that mean dosages used were substantially below the maximum allowable
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dosage militates against this proposition, although it remains possible, if unproven, that higher dosages might be needed in patients with refractory symptoms. Note, however, that in patients with partially resistant symptoms[27] a dosage of 600 mg/day seemed adequate. The case studies and series cited in this review do, of course, suggest that higher dosages of quetiapine (often >1000 mg/day) can be effective where lower dosages from the licensed dosage range have failed. It would be wrong to doubt the veracity of these reports but one should bear in mind the uncontrolled, open nature of these mini trials, and also consider the probable reluctance of journals to publish and authors to submit reports of the failure of high-dosage quetiapine treatment (about whose existence we can say nothing). One important observation, however, is that high dosages seem to be well tolerated, indicating that tolerability is unlikely to be a constraining influence on dosages in clinical trials. Dopamine receptor occupancy studies of quetiapine have produced perplexing results. Measured mean striatal D2 occupancies range from 2% at 150 mg/day[30] to 62% at 750 mg/day.[31] In the latter study, responders had significantly higher mean peak occupancies (65.9%) than nonresponders (60.3%). Thus, neuroimaging data suggest unusually low receptor occupancies for quetiapine, i.e. occupancies generally below the suggested threshold of that required for response (65%).[53] The observation that mean occupancy of 65.9% produced a response where lower occupancies did not show any effect could be taken as evidence that higher dosages are required for effect (these occupancies were achieved at a dosage of 750 mg/day). However, lower occupancies were shown to be effective in other studies[29,30,35] and, perhaps more importantly, measured D2 receptor occupancies are thought to at least partly reflect competition for receptor sites between quetiapine and the radioactive ligand (i.e. they do not reflect occupancy in the absence of the
2008 Adis Data Information BV. All rights reserved.

ligand).[54] (This fast-dissociation theory has been put forward by Kapur and Seeman[32]). Considering together all the data presented in this review, it can be seen that there is substantial, if inconclusive, evidence that the optimal dosage of quetiapine is within the range 150800 mg/day, with most data pointing towards an optimal dosage of around 300400 mg/day and some very cogent data suggesting that slightly higher dosages (at least of the XR preparation) are optimal. In contrast, there are no scientifically robust data suggesting that dosages higher than the licensed range provide improved response or other clinical benefits. In fact, studies using higher mean dosages tend to show quetiapine to be inferior to comparator drugs. Evidence suggesting improved response at higher dosages is limited to uncontrolled case reports of patients with treatment-resistant schizophrenia and is, on a theoretical basis, supported only by an unconventional interpretation the results of receptor occupancy studies. The balance of probabilities indicate that the current licensed dosage range for quetiapine is appropriate, but fixed-dose studies of dosages above the licensed range are required before the full dose-response relationship for quetiapine can be firmly established. Acknowledgements
No sources of funding were used to assist in the preparation of this review. Professor Taylor has received consultancies fees, lecturing honoraria and/or research funding from AstraZeneca, Janssen-Cilag, Servier, Sanofi-Aventis, Lundbeck, Bristol-Myers Squibb, Novartis, Eli Lilly and Wyeth. He has also received royalties from Gaskell and Informa Healthcare. Ms Sparshatt and Ms Jones have no conflicts of interest that are directly relevant to the content of this review.

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31.

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Correspondence: Prof. David Taylor, Pharmacy Department, Maudsley Hospital, Denmark Hill, London, SE5 8AZ, England. E-mail: David.Taylor@slam.nhs.uk

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