Low-dose quetiapine: place in therapy?

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Practice points | The evidence for off-label use of antipsychotics | Antipsychotics carry safety concerns | Low-dose quetiapine: useful or overused? | Low-dose quetiapine — is there a place in therapy? | References


Analysis of Australian PBS prescription data has identified a quality use of medicine issue, with atypical antipsychotic use increasing in adults aged 20–59 years without an increase in the prevalence of the key indications for antipsychotic use — bipolar disorder and schizophrenia.1,2

Quetiapine 25 mg tablets are PBS listed as a streamlined authority for use during the titration phase of quetiapine treatment for bipolar disorder and schizophrenia.3

Drug Utilisation Sub-Committee (DUSC) analysis data identified a high level of once-daily use of the 25 mg strength of quetiapine, suggesting there may be use for the treatment of conditions other than schizophrenia or bipolar disorder.2

In response to this concern, from 1 January 2014 the number of PBS-subsidised repeats of 25 mg quetiapine was reduced from five to zero.

Off-label prescribing in psychiatry is common practice and provides the opportunity to treat patients who are refractory to standard treatment or when there is no registered medicine for an indication; however, efficacy, safety and cost-effectiveness of such off-label use may not be established.4

Antipsychotic medicines have significant safety concerns that may be acceptable when treating patients with serious mental illness, but their off-label use carries a less certain benefit-to-risk ratio both in the short and longer term.

Practice points

  • Quetiapine 25 mg tablets are a streamlined authority PBS listing for use during the titration phase of quetiapine treatment for bipolar disorder and schizophrenia.3
    Avoid using low-dose quetiapine for non-approved indications such as treatment of insomnia alone.5
  • Assess risks and benefits before deciding to use an atypical antipsychotic.6
    Atypical antipsychotics can cause serious adverse effects. Regularly monitor both efficacy and safety in people receiving antipsychotics.6
  • What is an atypical antipsychotic (also known as second-generation antipsychotic)?

    Several different terms are used to classify antipsychotic drugs.
       Atypical antipsychotics were once distinguished from typical antipsychotics by their ability to cause fewer extrapyramidal adverse effects and other movement disorders.
       However, this differentiation is less significant now, as atypical antipsychotics have since been shown to have serious adverse effects, and neither group is a single class of medicine.6
       Arguments have been made to abandon this terminology altogether,7 as it now only reflects the length of time the medicines have been available.6

  • Use the lowest effective dose of quetiapine to prevent adverse effects.8
    Note that daily doses < 300 mg for maintenance of bipolar disorder and < 400 mg for schizophrenia are not considered effective8 and even low doses (~100 mg daily) are associated with adverse effects such as weight gain.9,10
  • Explain the need for regular medical monitoring to manage the risks of antipsychotic therapy and to deal with problems quickly.
    Encourage patients to report troublesome adverse effects so that these can be responded to appropriately (e.g. by dose reduction or a change in medicine or lifestyle changes).
  • Treatment of generalised anxiety disorder and depression with low-dose controlled-release quetiapine has been shown to reduce symptoms in specialist settings.6,11
    However, controlled-release quetiapine is not a first-line treatment, and data from clinical trials show patients treated with doses ranging from 50–300 mg for generalised anxiety are more likely to discontinue treatment because of adverse effects compared with patients taking placebo or active treatment.11
  • Use of low-dose quetiapine for sedation in non-psychotic indications such as insomnia may delay treatment of underlying conditions.
    Most people develop insomnia secondary to an identifiable stressor, medical or psychiatric condition, poor sleep practice, medicine or substance use — identify secondary causes, treat and manage these first.12
  • Be aware of the potential for quetiapine misuse
    In a sample of people who inject drugs in urban areas of Australia, more than 30% reported non-prescribed use of quetiapine tablets, and a few participants reported non-oral use.13

The evidence for off-label use of antipsychotics

There is a growing concern that antipsychotics are being used in people with non-psychotic illnesses. A DUSC report has highlighted the concern that among people aged 20–59 these medicines were being used for the treatment of conditions other than schizophrenia or bipolar disorder.2

Of special concern is an increase in the use of quetiapine 25 mg tablets once daily, which is well below the minimum dose recommended for bipolar disease or schizophrenia.2

A previous NPS MedicineWise Health News and Evidence article from September 2013 identified a similar quality use of medicine problem with off-label use of antipsychotics as a means of behaviour control in people with dementia, especially in residential aged-care and other specialised-care facilities.14

Antipsychotics carry safety concerns

These examples of inappropriate use are of concern because atypical antipsychotics can lead to weight gain, sedation and fatigue, and long-term use has been shown to contribute to the development of chronic conditions such as diabetes.15,16

During clinical trials of quetiapine treatment for bipolar disorder or schizophrenia, common side effects, including weight gain, sleepiness, increased lipid levels, dry mouth and dizziness, occurred at low and high daily doses (100–750 mg).15

Antipsychotics, including quetiapine, are also associated with some significant and severe adverse effects such as rare but potentially fatal neuroleptic malignant syndrome.6,15

Emerging research has linked antipsychotic use to mortality. Recent data from a large retrospective cohort study showed that taking antipsychotics such as quetiapine almost doubles the risk of sudden cardiac death compared with non-users of antipsychotics (adjusted incidence-rate ratio for quetiapine of 1.88; 95% CI (1.30 to 2.71) and the risk increases with higher doses.17

In addition to this risk, postmarketing reports have warned of QT prolongation associated with overdose,15 which could lead to life-threatening arrhythmias.6 Quetiapine is also known to have abuse potential — be aware of the potential for misuse.13

Even low doses carry risk

There are limited data concerning the adverse effects of low-dose quetiapine but the data available show taking low-dose quetiapine is also associated with adverse effects.

In a study of 43 psychiatric patients aged 19–65 prescribed low-dose quetiapine (mean daily dose of 120 mg at the end of the study) for the off-label management of insomnia, significant changes in weight (mean increase 2.22 kg, p = 0.037) and BMI (mean increase of 0.8 points from BMI 31 kg/m2, p = 0.048) were reported over the 11-month study period.9

It should be noted that, in addition to quetiapine, all participants were receiving at least one additional psychotropic medication, increasing the risk of metabolic adverse effects and potentially confounding results.

Similar results were seen in another study of patients treated with low-dose quetiapine (≤ 100 mg daily). Weight gain increased from baseline over a 12-month period; at 12 months weight gain was 4.8 kg (p < 0.001).10

Quetiapine may mask underlying conditions and delay proper treatment

Use of low-dose quetiapine for sedation in non-psychotic indications such as insomnia may delay treatment of underlying conditions.

Most people develop insomnia secondary to an identifiable stressor, medical or psychiatric condition, poor sleep practice, medicine or substance use.12 Identify secondary causes and manage these first.12

Low-dose quetiapine: useful or overused?

The PBS analysis estimated that of all patients on a regimen that contained a PBS-listed antipsychotic, 38% included quetiapine at various doses.2

The analysis extrapolated data from a sample of patients to investigate if quetiapine 25 mg was concomitantly supplied with higher doses of antipsychotics.

Of the 23% of patients taking 25 mg quetiapine, most were taking it in combination with an antidepressant, but a large proportion (~40%) were taking it as a single agent.2

Following the DUSC analysis, psychiatrists commented that low doses of quetiapine do not necessarily equate to off-label use but rather show there are different severities of bipolar disorder and schizophrenia, and people taking other agents require a lower dosage for combination use.

They also noted that it may be preferable to other agents used for sedation, which may be habit-forming.18

The combination use of various antipsychotic agents, including concomitant use of antipsychotics with antidepressant, anxiolytic and mood-stabilising agents, is common in the management of schizophrenia and related psychoses.19,20

However, there are no clear standards or guidelines for this off-label use, and the risks of adverse effects increase when combining these medicines with other centrally acting medicines.15,21

Low-dose quetiapine — is there a place in therapy?

Low doses of the controlled-release formulation of quetiapine tablets are PBS listed for treatment of bipolar disorder and schizophrenia.21

They are not PBS listed but are TGA approved for treatment-resistant patients, as monotherapy in generalised anxiety and as adjunctive therapy for depression under psychiatrist supervision, when the usual effective dose is 150 mg once daily.21

For generalised anxiety disorder the dose should not exceed 150 mg once daily.8 Controlled-release quetiapine may also be part of treatment in patients with depression with psychotic symptoms.6

Whereas treatment with controlled-release quetiapine does seem to be efficacious in specialist settings for reducing symptoms of generalised anxiety disorder and depression, efficacy must be weighed against its possible adverse effects.

Existing data and current guidelines do not support use of atypical antipsychotics for the treatment of generalised anxiety disorder in primary care settings.6,11 Patients who require antipsychotics and are refractory to standard treatment should always be referred to a psychiatrist.6

Current data do not support use of low- or high-dose quetiapine for insomnia. Although quetiapine has been shown to improve sleep latency in patients with non-psychotic illness,22 the improvement was not sustained for longer than 1 week.

Furthermore, the benefit does not outweigh the risks of quetiapine treatment in non-psychotic illness. Studies have not been designed to assess the impact of adverse effects from quetiapine use on sleep, but it is possible that adverse effects such as leg movements and restlessness may limit its effectiveness.5

  1. Access Economics for SANE Australia. Schizophrenia: Costs. An analysis of the burden of schizophrenia and related suicide in Australia. 2002. [Fulltext] (accessed 14 March 2014).
  2. Australian Government Department of Health. DUSC Review on the Utilisation of Antipsychotics. August 2013. [Online] (accessed 14 March 2014).
  3. Australian Government Department of Health. Quetiapine 25 mg. 2014. [Online] (accessed 24 March 2014).
  4. McKean A, Monasterio E. Off-label use of atypical antipsychotics: cause for concern? CNS Drugs 2012;26:383–90. [PubMed]
  5. Wine JN, Sanda C, Caballero J. Effects of quetiapine on sleep in nonpsychiatric and psychiatric conditions. Ann Pharmacother 2009;43:707–13. [PubMed]
  6. Therapeutic Guidelines. Psychotropic. Version 7, 2013. Melbourne: Therapeutic Guidelines Ltd. [Online] (accessed 14 March 2014).
  7. Tyrer P, Kendall T. The spurious advance of antipsychotic drug therapy. Lancet 2009;373:4–5. [PubMed]
  8. Australian Medicines Handbook Drug Choice Companion: Aged Care: 3rd edn. Adelaide: Australian Medicines Handbook Ltd, 2010.
  9. Cates ME, Jackson CW, Feldman JM, et al. Metabolic consequences of using low-dose quetiapine for insomnia in psychiatric patients. Community Ment Health J 2009;45:251–4. [PubMed]
  10. Williams SG, Alinejad NA, Williams JA, et al. Statistically significant increase in weight caused by low-dose quetiapine. Pharmacotherapy 2010;30:1011–5. [PubMed]
  11. National Institute for Health and Care Excellence. Evidence summary: unlicensed or off-label medicine. ESUOM12: Generalised anxiety disorder: quetiapine. May 2013. [Online] (accessed 19 March 2014).
  12. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4:487–504. [PubMed]
  13. Reddel SE, Bruno R, Burns L, et al. Prevalence and associations of quetiapine fumarate misuse among an Australian national city sample of people who regularly inject drugs. Addiction 2014;109:295–302 (first published online: 25 Nov 2013: DOI: 10.1111/add.12395). [Online]
  14. Gustafsson M, Karlsson S, Lovheim H. Inappropriate long-term use of antipsychotic drugs is common among people with dementia living in specialized care units. BMC Pharmacol Toxicol 2013;14:10. [PubMed]
  15. AstraZeneca Pty Ltd. Seroquel quetiapine fumarate Product Information. August 2013. [Online] (accessed 14 March 2014).
  16. Pan A, Sun Q, Okereke OI, et al. Use of antidepressant medication and risk of type 2 diabetes: results from three cohorts of US adults. Diabetologia 2012;55:63–72. [PubMed]
  17. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009;360:225–35. [PubMed]
  18. Hanrahan C. Antipsychotic script doubt. Medical Observer, 11 September 2013. [Online] (accessed 14 March 2014).
  19. Chakos MH, Glick ID, Miller AL, et al. Baseline use of concomitant psychotropic medications to treat schizophrenia in the CATIE trial. Psychiatr Serv 2006;57:1094–101. [PubMed]
  20. Pickar D, Vinik J, Bartko JJ. Pharmacotherapy of schizophrenic patients: preponderance of off-label drug use. PLoS One 2008;3:e3150. [PubMed]
  21. AstraZeneca Pty Ltd. Seroquel XR quetiapine fumarate Product Information. August 2013. [Onlne] (accessed 14 March 2014).
  22. Todder D, Caliskan S, Baune BT. Night locomotor activity and quality of sleep in quetiapine-treated patients with depression. J Clin Psychopharmacol 2006;26:638–42. [PubMed]