Quetiapine

Abstract

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. 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. 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. 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. 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,...