Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in May 2013. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

There is some evidence that quetiapine monotherapy improves the symptoms of generalised anxiety disorder (GAD) compared with placebo, and limited evidence suggests that it is not more effective than antidepressants. Other limited evidence suggests that adding quetiapine to an antidepressant does not improve symptoms in GAD that has not responded to the antidepressant alone. People taking quetiapine are more likely to discontinue treatment because of adverse effects compared with placebo or active treatment.

Licencing status: off-label.

Effectiveness

  • Moderate evidence suggests that quetiapine monotherapy at most doses statistically significantly improved rates of GAD response or remission compared with placebo (4 RCTs lasting 8–9 weeks) but not compared with escitalopram or paroxetine (2 RCTs lasting 8 weeks).

  • Adding quetiapine to an antidepressant did not statistically significantly improve symptoms in GAD that had not responded to the antidepressant alone (3 RCTs lasting 8 weeks).

Safety

  • The most commonly reported adverse effects are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia.

  • SPC warns about the potential for several other important adverse effects, e.g. suicidal ideation, tardive dyskinesia, neuroleptic malignant syndrome, severe neutropenia (see the SPC for full details).

  • Acute withdrawal symptoms have been described after abrupt cessation of quetiapine.

Patient factors

  • Once-daily dosage regimen.

  • Discontinuation due to adverse effects statistically significantly more likely with quetiapine compared with placebo or active treatment.

Cost

  • Up to around £80 per 28 days, depending on dose and formulation.

  • Prolonged-release formulation is considerably more costly than the immediate-release formulation.

Key points

Quetiapine is an atypical antipsychotic. It does not have UK marketing authorisation for treating GAD and so this is an off-label use of quetiapine.

NICE has published a clinical guideline on generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults. Evidence relating to quetiapine in GAD was not assessed as part of the guideline development because it was expected that this would be a subject of a NICE technology appraisal. The technology appraisal was suspended indefinitely after withdrawal of the licensing application by the manufacturer.

Evidence for quetiapine monotherapy in GAD comes from 4 randomised controlled trials (RCTs: Bandelow et al. 2010, n=873; Khan et al. 2011a, n=951; Meredith et al. 2012, n=854; Mezhebovsky et al. 2012, n=450). All were short term: 3 lasted 8 weeks and 1 lasted 9 weeks. They found that at most doses, prolonged-release quetiapine monotherapy was statistically significantly more effective in GAD compared with placebo, but was statistically significantly more likely to cause people to discontinue treatment because of adverse events. The studies found no statistically significant difference in efficacy between prolonged-release quetiapine and paroxetine or escitalopram, although they may not have had sufficient statistical power to detect such a difference. Again, at most doses quetiapine was statistically significantly more likely to cause people to discontinue treatment because of adverse events.

Three RCTs have investigated the efficacy of quetiapine as augmentation of antidepressant therapy for GAD that has not responded to other treatments (refractory GAD). The largest of these included 409 people with refractory GAD (Khan et al. 2011b) and lasted 8 weeks. This double-blind study was adequately powered for its primary outcome (improvement of Hamilton Anxiety Rating Scale [HAM-A] score from baseline) but did not detect a statistically significant difference between prolonged-release quetiapine and placebo for this outcome, or rates of response or remission. Quetiapine appeared to have been less well tolerated than placebo, although statistical analysis of rates of adverse events and withdrawals because of adverse events was not reported.

Two other RCTs (Simon et al. 2008 and Altamura et al. 2011) did not find a statistically significant benefit from quetiapine in addition to antidepressants in people with refractory GAD. These also lasted 8 weeks and were small (22 and 20 participants, respectively). These trials are likely to have been statistically underpowered.

The summary of product characteristics states that the most commonly reported adverse effects of quetiapine are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia. It also warns about the potential for several other important adverse effects, including suicidal ideation, tardive dyskinesia, neuroleptic malignant syndrome and neutropenia. Acute withdrawal symptoms have also been described after abrupt cessation of quetiapine (see the summary of product characteristics for full details).

The NICE clinical guideline on GAD assessed the evidence for augmentation of antidepressant therapy with antipsychotics other than quetiapine. The Guideline Development Group concluded that antipsychotic augmentation should not be routinely used and should be provided only in specialist settings. The guideline recommends that antipsychotics should not be offered for GAD in primary care.

About this evidence summary

'Evidence summaries: unlicensed or off-label medicines' summarise the published evidence for selected unlicensed or off-label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision-making and support the construction and updating of local formularies.

The summaries support decision-making on the use of an unlicensed or off-label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual.

The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance.