Quetiapine: Dose-response relationship in schizophrenia

Pharmacy Department, Maudsley Hospital, Denmark Hill, London, England.
CNS Drugs (Impact Factor: 5.11). 02/2008; 22(1):49-68; discussion 69-72. DOI: 10.2165/00023210-200822010-00004
Source: PubMed


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 150-450 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. 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.

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    • "It is generally well-known that, within the recommended dose range, quetiapine is well-tolerated and clinically effective for the treatment of schizophrenia. According to the review of literature by Sparshatt et al.,23 150-450 mg/d dosages of immediate-release (IR) quetiapine are more effective than placebo treatment. Furthermore, this review showed IR quetiapine dosages averaging between 254 and 525 mg/d are equivalent in efficacy to standard dosages of both conventional and other atypical antipsychotics. "
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    ABSTRACT: This study aimed to examine the effectiveness of quetiapine and the effects of dosage relates to its effectiveness on schizophrenia and schizoaffective disorder in a naturalistic setting in Korean people. This study was a 24-week, open-label, non-comparative, naturalistic study of quetiapine in patients diagnosed with schizophrenia and schizoaffective disorder according to DSM-IV. We stratified the patients into mild [(clinical global impression severity (CGI-S) <4 at baseline)] and severe groups (CGI-S >/=4 at baseline). We investigated the response rate, defined as clinical global impression improvement (CGI-I) </=2, in the severe group and the aggravation rate in the mild group using the last-observation-carried-forward (LOCF) and the Kaplan-Meier method (K-M). During the 24 weeks, 151 (18.4%) of the participants dropped out of the study. There was a significant decrease in the mean CGI-S score, from 4.5+/-1.1 at baseline to 2.8+/-1.1 at 24 weeks. The response rate of severe group was 54.5% (estimated by LOCF) and 73.3% (K-M estimated) at 24 weeks. All patients who completed the study had taken a mean quetiapine dosage of 507.9+/-245.9 mg daily. The decrease of CGI-S score in high-dose group (the maximum dose was 750 mg/d or above) was statistically significant than that in recommended-dose group (the maximum dose was less than 750 mg/d). This study demonstrated the long-term effectiveness of quetiapine in the treatment of schizophrenia and schizoaffective disorder in a naturalistic setting in Korean people. This study suggests that higher than recommended quetiapine dosages could be more effective in some patients.
    Full-text · Article · Jun 2010 · Psychiatry investigation
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    • "" Examples of these differences include disease severity, chronicity, and the presence of comorbid psychiatric and medical conditions. Moreover, in the absence of knowledge about the dose–response relationship, study design for registration protocols may err on the side of caution when selecting doses or timing of titration to maximum dose, with the unintentional consequence of sacrificing efficacy, such as possibly evidenced by quetiapine (Citrome, 2008). Although " prescribing-based evidence " is not a substitute for " evidence-based prescribing, " fixed-dose studies of secondgeneration antipsychotics to clearly elucidate dose–response relationships are generally lacking (Citrome and Volavka, 2002; Davis and Chen, 2004). "
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    ABSTRACT: Antipsychotic dosing used in clinical practice can differ from dosing originally recommended in product labeling. This has been reported for olanzapine and quetiapine, where higher doses are commonly used. This may be the case for ziprasidone as well. To characterize changes over time in dosing for the initial and subsequent prescriptions of first-line second-generation antipsychotics used during treatment episodes for outpatients with schizophrenia and bipolar disorder, the 2001-2005 Thomson MarketScan Medicaid Database (Medicaid) and the 2001-2006 MarketScan Commercial Claims and Encounters Database (Commercial) were analyzed. Dose trends were evaluated using autoregressive time-series models. Data were available for 49180 treatment episodes of schizophrenia (4683 Commercial and 44497 Medicaid) and 83289 treatment episodes of bipolar disorder (57961 Commercial and 25328 Medicaid). The initial prescription mean daily and overall mean daily doses of ziprasidone in schizophrenia episodes significantly increased across the Medicaid and Commercial populations, with similar trends observed for bipolar episodes. The first (May 2001) and last (December 2005) observed 3-month mean daily doses for ziprasidone were 112 mg/d and 138 mg/d for patients with schizophrenia and 93 mg/d and 113 mg/d for those with bipolar disorder in the Medicaid cohort, with similar findings for the Commercial cohort. Consistently significant trends in dose changes were not observed for the other medications, although quetiapine and olanzapine doses generally increased while aripiprazole and risperidone doses generally decreased. There remains a need for controlled randomized clinical trials that test fixed doses of antipsychotics to ascertain the dose-response relationship within the dose range used in contemporary clinical practice.
    Full-text · Article · Mar 2009 · Schizophrenia Research
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