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JOURNAL ARTICLE

Quetiapine : A Review of its Use in Schizophrenia

N S Gunasekara, C M Spencer
CNS Drugs 1998, 9 (4): 325-40
27521016

SYNOPSIS: Quetiapine, a dibenzothiazepine derivative, is one of several new 'atypical' antipsychotic agents. In preclinical studies, the drug was predicted to have antipsychotic efficacy and a low propensity to induce extrapyramidal effects. Quetiapine has been shown to be effective in the short term (up to 6 weeks) treatment of patients with schizophrenia in several large well designed trials. In general, clinical efficacy is dose related, with maximum effects occurring at a dosage ≥ 250 mg/day. Quetiapine is at least as effective as chlorpromazine and haloperidol, with similar between- treatment improvements in the various rating scales used to assess overall and negative symptoms. Quetiapine is associated with significantly fewer extrapyramidal effects than haloperidol and may have some advantages over chlorpromazine in this regard. There have been no reports of agranulocytosis attributed to quetiapine and the drug did not produce an elevation in serum prolactin levels in patients with schizophrenia. Headache, somnolence and dizziness are common adverse events that are reported more often with quetiapine than with placebo. Quetiapine is associated with small dose-related decreases in total and free thyroxine; however, cessation of treatment usually results in reversal of these effects. The drug is also associated with asymptomatic, generally transient elevations in hepatic transaminases. Although the antipsychotic activity of quetiapine has been well demonstrated in 6-week studies, its long term effectiveness, position relative to other atypical antipsychotic agents and efficacy in refractory schizophrenia remain to be fully determined. Nevertheless, on the basis of available data, quetiapine should provide a valuable alternative to classical antipsychotic agents in the short term treatment of patients with schizophrenia.

PHARMACODYNAMIC PROPERTIES: Quetiapine is a dibenzothiazepine derivative with greater in vitro binding affinity for serotonin 5-HT2 receptors than for dopamine D2 receptors. 12 hours after the final dose of a 4-week course of quetiapine 150mg 3 times daily, in vivo dopamine D2 and 5-HT2 receptor occupancies were 27 and 58%, respectively. Electrophysiological studies in rats have not consistently demonstrated selectivity of quetiapine for mesolimbic dopaminergic pathways. However, immediate-early gene expression studies indicate that the drug has preferential action on limbic structures. Quetiapine is active in many animal behavioural models that are predictive of antipsychotic activity. Notably, studies in animal models considered predictive of the potential to induce extrapyramidal effects indicate that quetiapine is less likely to induce these effects than the classical antipsychotic haloperidol. Quetiapine also significantly improved performance on measures of neurocognitive function that are generally ascribed to the prefrontal cortex in patients with schizophrenia. Quetiapine is not associated with elevations in plasma prolactin levels in patients with schizophrenia.

PHARMACOKINETIC PROPERTIES: Quetiapine is rapidly absorbed after oral administration. Maximum steady-state plasma concentrations (C(SS) max) and areas under the plasma concentration-time curves from 0 to 8 hours at steady state (AUC(SS) 0-l8h) were dose proportional and similar in men and women. The drug has a large volume of distribution (approximately 700L). Quetiapine is extensively metabolised in the liver. The major metabolic pathway involves sulphoxidation by cytochrome P450 3A4. Pharmacokinetic drug interactions may occur when quetiapine is coadministered with inducers or inhibitors of this enzyme. The half-life of quetiapine is approximately 6 hours. In elderly patients, C(SS) max and AUC(SS) 0-8h values were approximately 20 to 30% higher and apparent oral clearance values were up to 50% lower than in younger patients. Mean oral clearance was reduced by approximately 25% in patients with hepatic cirrhosis or severe renal impairment, compared with healthy controls.

THERAPEUTIC EFFICACY: In short term trials (6 weeks), quetiapine was generally significantly more effective than placebo in improving the positive and negative symptoms of schizophrenia. These improvements appeared to be dose dependent: in a recent study, while there was no significant difference in major efficacy criteria between low-dose quetiapine (maximum daily dose 250 mg/day) and placebo, high-dose quetiapine (maximum daily dose 750 mg/day) was significantly more effective than placebo. Results of a recent trial support twice daily administration of quetiapine. There was no significant difference in efficacy parameters between 2 and 3 times daily administration of a total dose of 450 mg/day. Data from a large comparative trial indicate that quetiapine and chlorpromazine are equally effective in treating patients with schizophrenia; mean Brief Psychiatric Rating Scale (BPRS) total scores decreased by about 18 points in each treatment group from a baseline of >40. In addition, reductions from baseline in the negative scale score of the Positive and Negative Symptom Scale were not significantly different between treatments. Quetiapine 300 mg/day was found to have therapeutic equivalence with haloperidol 12 mg/day as measured by the BPRS, Clinical Global Impression Scale severity of Illness item and the Modified Scale for the Assessment of Negative Symptoms. Preliminary data from patients enrolled in open-label extensions to short term trials suggest that initial reductions in BPRS scores with quetiapine are maintained over 1 year of treatment.

TOLERABILITY: Pooled tolerability data from placebo-controlled trials show that the most common adverse events which were reported more often with quetiapine than with placebo were headache (19.4 vs 17.5%), somnolence (17.5 vs 10.7%) and dizziness (9.6 vs 4.4%). Postural hypotension, tachycardia, constipation, dry mouth, dyspepsia and transient liver enzyme elevations also occurred in ≥5% of quetiapine recipients. Agitation and insomnia, which were seen with quetiapine therapy (but were observed at a similar incidence with placebo) are thought to be an expression of the underlying psychotic illness. Quetiapine treatment is associated with weight gain of approximately 2.1kg in short term clinical trials. There were no statistically significant differences in the proportions of quetiapine-versus placebo-treated patients experiencing potentially important changes in ECG parameters including QT, QTc and PR intervals. Quetiapine demonstrated little potential for the induction of extrapyramidal effects across the range of doses used in clinical trials. The drug was not significantly different from placebo with respect to the incidence of extrapyramidal signs/symptoms but showed significant advantages over haloperidol. In addition, quetiapine may have some advantages over chlorpromazine with respect to these symptoms. Quetiapine has not been associated with agranulocytosis or elevations in plasma prolactin levels in patients with schizophrenia. However, asymptomatic elevations in hepatic transaminases (particularly alanine aminotransferase) have been measured. These were transient with continued treatment in most instances. Treatment with quetiapine is associated with small dose-related decreases in levels of total and free thyroxine. These changes usually reverse with treatment cessation. Preliminary data indicate that quetiapine is well tolerated for up to 2 years in patients with schizophrenia. Although causality has not been established, the possibility of lenticular changes with long term quetiapine treatment cannot be excluded and 6-monthly slit lamp eye examinations are recommended in some countries.

DOSAGE AND ADMINISTRATION: The recommended target dosage of quetiapine in otherwise healthy adults with schizophrenia is 300 to 450 mg/day administered as 2 doses. Treatment should be initiated at a dosage of 50 mg/day. Daily incremental adjustments should then be made until target dose is reached by day 4. Thereafter, dosage may be titrated according to clinical response and tolerability within the range 150 to 750 mg/day. Quetiapine should be used with caution in the elderly and in patients with renal or hepatic impairment. A starting dose of 25 mg/day is recommended in these patients, with daily dosage increases of 25 to 50mg to an effective dose, which is likely to be lower than that in other patients.

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