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Licensed Indication:
Quetiapine ‘is indicated for the treatment of schizophrenia.’¹

Background information
Schizophrenia is the most common form of severe mental illness, with a lifetime risk of developing the disease of 0.5-1%.² There is no ‘cure’ for schizophrenia. Traditional or ‘typical’ antipsychotic drugs such as chlorpromazine and haloperidol, appear to act centrally by blocking dopamine (D₂) receptors in the brain. As a group, they relieve symptoms in at least 75% of patients during an acute attack.³ However, in many patients the improvement seen is only partial and in general the typical antipsychotics produce much less improvement in negative than positive symptoms. All can produce extrapyramidal symptoms (EPS) to varying degrees. Antimuscarinic side effects, drowsiness and hypotension may also be a problem with some phenothiazines eg thioridazine.

Newer ‘atypical’ antipsychotic drugs appear to have an additional blocking action on serotonin receptors. They are more likely to relieve the negative symptoms of schizophrenia, and are relatively free from the EPS seen with the typical antipsychotics. Clozapine, the prototype atypical antipsychotic, is now well established in the treatment of schizophrenia. Other atypical antipsychotics currently available in the UK include risperidone, olanzapine, amisulpride, & quetiapine.

Dosage and Administration
The daily dose of quetiapine should be titrated from 50mg to 300mg over days 1-4 of therapy. Thereafter, the daily dose should be titrated to the usual effective range of 300- 450mg (to a maximum of 750mg) depending on the patient's clinical response and tolerability. The starting dose and dosage increments should be lower in elderly patients and patients with renal and hepatic impairment (refer to Summary of Product Characteristics [SPC]). Quetiapine should be administered twice daily, with or without food.

Clinical Efficacy
Quetiapine has been compared with placebo and to typical antipsychotic drugs (chiefly haloperidol) in a number of randomised, double-blind, controlled trials. A Cochrane systematic review which pooled these data has been published and was last updated in May 2000.⁴ Eleven randomised, double-blind, controlled studies were included in the review; 7 fully published studies, and 4 unpublished poster presentations (1 of which has subsequently been published in full).

Three studies compared quetiapine solely with placebo, and seven to typical antipsychotics (1 to chlorpromazine, 5 to haloperidol, and 1 to mosapramine [an antipsychotic available in Japan]). The remaining study was a non-comparative dose-frequency trial.

All studies were of short duration. Apart from one study of 21 days (n = 12), and one of 6 months (n = 25), the other nine were of 6 or 8 weeks duration. The daily dose range of quetiapine evaluated across the studies was 50- 750mg. The mean daily dose of haloperidol evaluated ranged from 6.7- 20mg.

Across the studies, 2725 patients were enrolled, with patient numbers in the individual studies ranging from 12–618. Most patients were men in their thirties, and all met DSM-III-R, DSM-IV or ICD-10 diagnostic criteria for schizophrenia. All patients were ‘at least moderately ill’ (a Clinical Global Impression [CGI] score ³ 4).

The efficacy of quetiapine was assessed using symptom scales, predominantly the CGI scale to evaluate global state, and the Brief Psychiatric Rating Scale (BPRS) to assess changes in psychotic symptoms. The Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) were used inconsistently.

Results indicate that compared with placebo, quetiapine treatment improved patients' global state and psychotic symptoms (both positive and negative). Compared to the typical antipsychotics (chiefly haloperidol) quetiapine produced similar improvements in these parameters.

The Cochrane systematic reviewers identified 3 limitations of their review:

1. the substantial drop-out rates across the studies (36-64%) made assessment of the clinical significance of the results difficult.
2. it was difficult to generalise the findings to patients outside the set inclusion criteria of the studies.
3. because of the short duration of the studies, no conclusions could be drawn regarding the medium and long-term effects of quetiapine.

There are no fully published comparisons of quetiapine with other atypical antipsychotics in patients with schizophrenia. A 4-month, open-label study comparing quetiapine with risperidone in 751 adult outpatients with psychotic disorders (~35% with schizophrenia) has been published as a poster.⁵

Overall results, which were presented graphically, appeared to demonstrate similar efficacy with quetiapine and risperidone (mean daily doses 317mg and 4.5mg respectively).

Limited longer-term data on quetiapine treatment of up to 4 years in patients with schizophrenia have been reported in poster presentations and as data on file. These data come from open-label extension studies of short-term clinical trials. In 89 patients who took quetiapine for at least 52 weeks, improvements in global state and psychotic symptoms seen during the 6-week clinical trial periods were maintained.⁶

Data on file reporting quetiapine use of up to 4 years report similar effects.⁷ Of 674 patients who entered open-label extension studies, 511 completed at least one assessment at 13 weeks, 305 at 6 months, 190 at 1 year, and 39 completed 4 years of treatment. Significant improvements from baseline were seen on each of the BPRS, SANS, and CGI severity of illness scales by weeks 4 or 13 (p £ 0.004), which were maintained over the 4-year study period (data presented graphically).

Adverse Effects
The pooled data from the placebo-controlled studies indicate that the need for medication for EPS, the incidence of parkinsonism, akathisia, dystonia, constipation, and low postural blood pressure, was similar across both groups. The incidence of dizziness, dry mouth, and sleepiness was significantly higher with quetiapine than placebo (relative risk [RR] 2.23, 3.67, 2.00 respectively).⁴

In the active-comparator studies, the incidence of parkinsonism, akathisia, dystonia, and the need for medication for EPS was lower with quetiapine than with the other antipsychotics (RR 0.22, 0.24, 0.14, 0.40 respectively). The incidence of dry mouth was higher with quetiapine than with the typical antipsychotics (RR 2.85).⁴

A published review of the safety of quetiapine⁸ also notes that in clinical trials, the most frequently reported adverse events with quetiapine were somnolence, headache, and dizziness.

Data from open-label extension studies indicate that 91.8% of patients taking quetiapine for up to 4 years did not report EPS-related adverse events.⁹

Some weight gain was seen with quetiapine in clinical trials. Analysis of clinical trial data from 2216 patients showed weight gain of +2.08kg in 778 patients during the first 5-6 weeks of quetiapine therapy, which was maintained at 9-12 months in 360 patients for whom data are available.⁸

The SPC for quetiapine states that in clinical trials, quetiapine was not associated with a persistent increase in QTc interval, but as with other antipsychotics, caution should be exercised when quetiapine is prescribed with drugs known to prolong the QTc interval, especially in the elderly.¹ In clinical trials, 13 of 826 patients treated with quetiapine (compared with 2 of 155 with placebo) had clinically significant prolongation of the QTc interval (>0.5 seconds). Clinical consequences occurred in 1 of these 13 patients; vital signs showed intermittent evidence of tachycardia upon standing.¹⁰

Costs
At current prices one year’s treatment costs:

• £1376–£2064 with quetiapine 300-450mg/day
• £940–£1424 with risperidone 4-6mg/day
• £1272–£2544 with olanzapine 10-20mg/day
• £87–£154 with haloperidol 10-20mg/day.

Summary
Quetiapine is an atypical antipsychotic licensed for the treatment of schizophrenia.

In short-term 6 or 8 week studies, quetiapine demonstrated greater improvement in patients global state and psychotic symptoms than placebo, and similar efficacy to typical antipsychotics, chiefly haloperidol. Data on file on up to 4 years treatment with quetiapine suggest that these improvements were maintained over the longer-term.

The most common adverse events seen with quetiapine in clinical trials were somnolence, postural hypotension, dizziness, headache, and dry mouth. The incidence of EPS with quetiapine was similar to placebo.

There are no fully published trials comparing its effects to other atypical antipsychotics in patients with schizophrenia. Fully published clinical trial data on long-term efficacy and safety are still limited.

1. AstraZeneca. Seroquel. Summary of Product Characteristics 2000.
2. Anon. Drug treatments for schizophrenia. Effective Health Care 1999;5:1-12.
3. Anon. The drug treatment of patients with schizophrenia. DTB 1995;33:81-6.
4. Srisurapanont M, Disayavanish C, Taimkaew K. Quetiapine for schizophrenia (Cochrane Review). The Cochrane Library 2001;1.
5. Reinstein M, Bari M, Ginsberg L, Sandler N, Mullen J. Quetiapine and risperidone in outpatients with psychotic disorders: results of the QUEST trial. Poster presented at the American Psychiatric Association's Annual Meeting, May 15-20, Washington D.C. 1999.
6. Rak I, Raniwalla J. Maintenance of long-term efficacy with 'Seroquel'. Poster presented at the Winter Workshop 5-11 February, Davos, Switzerland. 2000.
7. Data on file S0091. AstraZeneca 2001.
8. Dev V, Raniwalla J. Quetiapine. A review of its safety in the management of schizophrenia. Drug Safety 2000;23:295-307.
9. Data on file S0092. AstraZeneca 2001.
10. Data on file.S008. AstraZeneca 2000.

© MTRAC, Department of Medicines Management