Quetiapine

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Abstract
Quetiapine (Seroquel®), a dibenzothiazepine derivative, is an atypical antipsychotic with demonstrated efficacy in acute schizophrenia. In short-term, randomised, double-blind trials, it was usually more effective than placebo, and was generally effective against both positive and negative symptoms. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (up to 750 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in patients with acute schizophrenia in randomised, double-blind trials; it was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous antipsychotic treatment. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (up to 800 mg/day) were similar to those with risperidone (up to 8 mg/ day) or olanzapine (15 mg/day) [interim analysis]. Efficacy was maintained for at least 52 weeks in open-label follow-up studies in adult and elderly patients. Quetiapine improved cognitive function versus haloperidol, and depressive symptoms and hostility/aggression versus placebo. Quetiapine is well tolerated. It is associated with placebo-level incidence of extrapyramidal symptoms (EPS) across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g. the elderly, adolescents or patients with organic brain disorders) and has a more favourable EPS profile than risperidone. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even normalise. Quetiapine appears to have minimal short-term effects on bodyweight and a favourable long-term bodyweight profile. Preliminary studies indicate that there is a high level of patient acceptability and satisfaction with quetiapine. In conclusion, quetiapine has shown efficacy against both positive and negative symptoms of schizophrenia, and has benefits in improving cognitive deficits, affective symptoms and aggression/hostility. The beneficial effects of quetiapine have been maintained for at least 52 weeks. Quetiapine was effective and well tolerated in hard-to-treat patients, and may be of particular use in these individuals. It is at least as effective as standard antipsychotics and appears to have similar efficacy to risperidone and olanzapine. The relative risk/benefit profile of quetiapine compared with other atypical antipsychotics requires further research in head-to-head trials, although quetiapine’s relatively benign tolerability profile distinguishes it from other commonly used atypical agents, particularly with respect to bodyweight, EPS and plasma prolactin levels. Overall, quetiapine has an excellent risk/benefit profile and is a suitable first-line option for the treatment of schizophrenia. Quetiapine is a dibenzothiazepine derivative, with a relatively higher binding affinity for serotonin 5-HT2 receptors (drug concentration required for 50% inhibition of radioligand binding [IC50] 148 nmol/L) than for dopamine D2 receptors (IC50 329 nmol/L). The drug’s negligible affinity for muscarinic receptors suggests a low risk for anticholinergic adverse effects. In animal models, quetiapine has shown clozapine-like antipsychotic activity predictive of efficacy against both positive and negative symptoms, a low liability to induce extrapyramidal symptoms (EPS) and a reduced propensity to affect prolactin levels. Furthermore, in vitro studies of limbic selectivity suggest that the pharmacological effects of quetiapine are selective for the mesolimbic and mesocortical dopamine systems (responsible for antipsychotic effects), but not the nigrostriatal dopamine system (responsible for EPS). Oral quetiapine (75–250mg every 8 hours) is rapidly absorbed and demonstrates dose-proportional increases in maximum steady-state plasma concentrations and areas under the plasma concentration-time curves from 0 to 8 hours at steady state. Absorption is not significantly affected by food. Quetiapine has a large apparent volume of distribution and is approximately 83% plasma protein bound. Quetiapine is extensively metabolised in the liver; the major metabolic pathway is sulphoxidation by cytochrome P450 (CYP) 3A4. The drug is excreted primarily in the urine (≈73%) as inactive metabolites. The elimination half-life of quetiapine is approximately 6 hours. The pharmacokinetics of quetiapine do not differ in men compared with women, or in adolescents compared with adults and appear unaffected by cigarette smoking or ethnic background. In contrast, apparent oral clearance was up to 50% lower in elderly (aged 63–85 years) than in younger patients (aged 18–43 years). Patients with hepatic cirrhosis or severe renal impairment (creatinine clearance 8–33 mL/min/1.73m2) had reduced (by ≈25%) mean oral clearance compared with healthv controls. Quetiapine may potentially interact with drugs that are potent inducers (e.g. phenytoin, carbamazepine, barbiturates, rifampicin or glucocorticoids) or inhibitors (e.g. ketoconazole, itraconazole, fluconazole and erythromycin) of CYP3A4. In short-term, randomised, double-blind trials in patients with acute schizophrenia, quetiapine (up to 750 mg/day) was generally significantly more effective than placebo at improving psychopathology (Brief Psychiatric Rating Scale [BPRS] total score, p ≤ 0.05; Clinical Global Impression [CGI] scales, p ≤ 0.01). The drug has shown efficacy against both positive (improvement in BPRS positive symptoms cluster score, p = 0.003 for quetiapine ≤750 mg/day) and negative (measured using Scale for the Assessment of Negative Symptoms, p ≤ 0.05) symptoms of schizophrenia versus placebo. Responses observed with quetiapine were clinically meaningful (defined as an improvement of ≥30% from baseline in BPRS total score) in approximately 50% of recipients. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (mean 384 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in the management of patients with acute schizophrenia in randomised, double-blind trials of 6–12 weeks’ duration (measured using BPRS and Positive and Negative Symptom Scale [PANSS] total scores, and response rates). The similar efficacy of quetiapine to haloperidol in this patient group was confirmed in a meta-analysis of four double-blind trials. Furthermore, quetiapine 600 mg/day was at least as effective as haloperidol 20 mg/day in the treatment of patients with schizophrenia nonresponsive or partially responsive to previous antipsychotic treatment (fluphenazine titrated to 20 mg/day for 4 weeks); indeed, clinical response (improvement of ≥20% in PANSS score) was higher in quetiapine than in haloperidol recipients (52.2% vs 38.0%, p = 0.043). In addition, quetiapine (up to 750 mg/day) was effective in the management of schizophrenia in patients who were switched from standard (e.g. haloperidol) or atypical antipsychotic agents (including olanzapine and risperidone) following an inadequate response or intolerance in a noncomparative trial; most patients switched to quetiapine had a decrease of ≥1 point on the Index of Clinical Benefit, and significant improvements from baseline were observed at week 12 in PANSS and CGI Severity of Illness scores (both p < 0.001). Interim results suggest similar efficacy for quetiapine (600 mg/day), olanzapine (15 mg/day) and risperidone (5 mg/day) in a small, randomised, rater-blinded trial. Furthermore, improvements in overall psychopathology and the positive and negative symptoms of schizophrenia were similar with quetiapine (up to 800 mg/ day) to those with risperidone (up to 8 mg/day) in a double-blind trial in patients with acute schizophrenia, as were response rates (26.5% and 26.9%) in this trial, or in a nonblind trial in patients with psychoses. In this latter trial, there were no significant differences between treatments in a subgroup of patients with schizophrenia. In a preliminary analysis, quetiapine improved symptoms and overall psychopathology in a small number of patients with first-episode schizophrenia. Improvements with quetiapine were maintained for up to 130 weeks in adult patients with schizophrenia and for at least 52 weeks in elderly patients with the disease in open-label, follow-up studies. In randomised, double-blind trials in patients with schizophrenia, quetiapine also had benefits in improving cognitive function (especially verbal reasoning and fluency) compared with haloperidol (p < 0.05) and depressive symptoms compared with placebo or risperidone. Posthoc analyses suggest that quetiapine (150–750 mg/day) is effective compared with placebo in the treatment of patients displaying hostility and aggression (p < 0.001 for reduction in Behavioural Agitation Scores). Quetiapine is well tolerated in patients with schizophrenia. Dizziness, orthostatic hypotension, dry mouth and dyspepsia were the only adverse events with an incidence of ≥5% that occurred in at least twice as many quetiapine as placebo recipients in a pooled analysis of 3- to 6-week placebo-controlled trials. Most adverse events were mild to moderate in intensity. There was no significant difference between quetiapine and placebo groups in overall incidence of treatment discontinuation due to adverse events. The tolerability of quetiapine in long-term trials was similar to that in short-term trials. Quetiapine has a low propensity to induce EPS in patients with schizophrenia in both short- and long-term treatment. Importantly, placebo-level EPS occurred across all quetiapine dosages tested (75–750 mg/day) in a fixed-dose study. EPS occurred with a significantly lower incidence in quetiapine than in haloperidol or chlorpromazine recipients with schizophrenia, and quetiapine had a more favourable EPS profile than risperidone in patients with DSM-IV psychoses; quetiapine recipients were less likely to experience substantial EPS or receive concurrent medication for EPS than risperidone recipients (both p < 0.001). Current data suggest that quetiapine has a low risk for EPS in vulnerable patient groups, including the elderly, adolescents and patients with organic brain disorders; however, additional research is needed to confirm these predominantly preliminary results. Unlike risperidone and amisulpride, quetiapine (across its therapeutic dose range) does not appear to be associated with sustained increases in plasma prolactin levels; indeed, reductions in prolactin levels were noted in many patients in the quetiapine clinical trials programme. Furthermore, quetiapine may normalise prolactin levels in patients previously treated with antipsychotics. The placebo-level effect of quetiapine on plasma prolactin levels is reflected in the low incidence of hormonal and sexual adverse events in the quetiapine clinical trials programme. Quetiapine appears to have a minimal short-term effect on bodyweight and a favourable effect on bodyweight in the long term. There was little change in corrected QT intervals and no clinically significant changes in clinical chemistry parameters with quetiapine therapy in clinical trials. In addition, agranulocytosis or lens changes have not been causally linked to quetiapine treatment. Long-term treatment with quetiapine was associated with good patient acceptability and satisfaction in an open-label multicentre study using a nonvalidated questionnaire. Limited pharmacoeconomic analyses suggest that, despite its relatively high acquisition cost, quetiapine may not add to the overall costs of treating schizophrenia and has the potential to be cost saving, although additional research is required. Results from a Markov model (constructed, in part, from a randomised, double-blind trial in patients nonresponsive or partially responsive to previous antipsychotic therapy) indicate that, over 5 years, the higher acquisition cost of quetiapine relative to haloperidol was offset by lower costs for other medications, inpatient hospitalisations and outpatient care; thus, the two treatments had similar overall per-patient costs (£38 106 vs £38 350; year of costing not reported). Indirect costs were not considered in this analysis, which was from the perspective of the UK National Health Service. Quetiapine was the dominant treatment relative to risperidone, achieving greater effectiveness for less cost in a cost-utility analysis of clinical data from a 4-month, randomised, open-label study in outpatients with schizophrenia or other psychotic disorders. Average daily costs for quetiapine and risperidone were SUS6.38 and $US7.85; incremental gains in utilities (0.23 vs 0.12; last-observation-carried-forward analyses) equated to an average incremental gain in quality-adjusted life years for quetiapine recipients of 3.85 years per patient (p < 0.05). In adult patients with schizophrenia, quetiapine is licensed to dosages of 750 or 800 mg/day. The target dosage of quetiapine recommended in the manufacturer’s prescribing information is 300–400 or 450 mg/day, although the manufacturer more recently suggests that the initial target dosage should be 600 mg/day to achieve optimum response. A faster rate of titration (increments of 200 mg/day) than that recommended in the current prescribing information (25–50mg twice daily) may be appropriate in acutely ill patients. Patients responding to quetiapine should receive the lowest effective dosage for maintenance therapy. A slower rate of titration and lower target dose should be considered in elderly patients and those with a predisposition to hypotensive reactions. An initial dosage of 25 mg/day is recommended in patients with hepatic impairment, with subsequent increments of 25–50 mg/day until an effective dosage is reached.