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Quetiapine

A Review of its Use in the Treatment of Bipolar Depression

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Summary

Abstract

Quetiapine (Seroquel®) is the only atypical antipsychotic approved in the US for use as monotherapy in both bipolar mania and depression, offering potential compliance advantages. Monotherapy with oral quetiapine 300 mg/day is effective in the treatment of patients with bipolar I or II depression. Rapid and sustained improvements in depressive and anxiety symptoms are seen with quetiapine, as well as improvements in health-related quality of life (HR-QOL). Quetiapine is generally well tolerated in bipolar depression and is not associated with an increased risk of treatment-emergent mania. Thus, despite the current lack of data from active comparator trials, quetiapine monotherapy should be considered a first-line option for the acute treatment of bipolar depression.

Pharmacological Properties

The precise mechanism of action of quetiapine in bipolar depression is unknown, although it has been suggested that its antidepressant activity may be linked to its higher affinity for serotonergic than dopaminergic receptors. Quetiapine is not associated with elevation of prolactin levels and has a low propensity to induce extrapyramidal symptoms, most likely reflecting its relatively low affinity for, and its rapid dissociation from, dopamine D2 receptors.

Oral quetiapine is rapidly absorbed and undergoes extensive hepatic metabolism, meaning that dosage adjustment may be needed in patients with hepatic impairment. Caution is recommended when quetiapine is co-administered with cytochrome P450 (CYP) 3A4 inhibitors such as ketoconazole, erythromycin, itraconazole and fluconazole. In addition, higher maintenance dosages of quetiapine may be needed in patients receiving concomitant CYP3A4 inducers (e.g. phenytoin, carbamazepine).

Clinical Efficacy

The efficacy of monotherapy with oral quetiapine 300 or 600 mg/day in adults with bipolar I or II disorder and a major depressive episode was demonstrated in two well designed 8-week trials (the BOLDER I and II trials) [n = 511 and 467]. In both BOLDER I and II, Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at week 8 were reduced from baseline to a significantly greater extent with quetiapine than with placebo (the change from baseline in MADRS total scores was the primary endpoint). In addition, the proportion of patients who had responded or were in remission at week 8 was significantly higher with quetiapine than with placebo. No additional benefit was seen in patients receiving quetiapine 600 mg/day compared with those receiving quetiapine 300 mg/day.

Improvements in Hamilton Depression Rating Scale (HAM-D) total and HAM-D item 1 (depressed mood) scores were significantly greater with quetiapine than with placebo, as were improvements on the Clinical Global Impression-Severity of Illness scale. In terms of anxiety symptoms, improvements from baseline in Hamilton Anxiety Rating Scale total scores were significantly greater with quetiapine than with placebo.

In both the BOLDER I and II trials, HR-QOL was improved to a significantly greater extent with quetiapine 300 mg/day than with placebo, as shown by the change from baseline in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form scores. A significantly greater improvement in the quality of sleep occurred with quetiapine 300 or 600 mg/day than with placebo, as shown by the change from baseline in Pittsburgh Sleep Quality Index scores (assessed only in BOLDER I). Sheehan Disability Scale (SDS) scores (assessing functional improvement) were improved to a significantly greater extent with quetiapine 600 mg/day than with placebo, although no significant difference was seen between quetiapine 300 mg/day and placebo recipients (SDS scores were assessed only in BOLDER II).

Apost hoc pooled analysis of the BOLDER I and II trials revealed significantly greater reductions in mean MADRS item 10 (suicidal thoughts) and HAM-D item 3 (suicide) scores in patients receiving quetiapine than in those receiving placebo. Among quetiapine recipients, the incidence of treatment-emergent suicidal ideation or suicide attempt was low and similar to that seen in placebo recipients.

Exploratory subgroup analyses revealed that quetiapine was effective in reducing MADRS total scores in patients with bipolar I depression and patients with rapid-cycling bipolar disorder. In patients with bipolar II depression, quetiapine was significantly more effective than placebo in a combined analysis of the BOLDER I and II trials, and in BOLDER II alone, but not in BOLDER I alone (the separate BOLDER trials were not powered to detect between-treatment differences in subgroups of patients).

Tolerability

Quetiapine was generally well tolerated in patients with bipolar depression, according to the results of the BOLDER I and II trials. In BOLDER I, the incidence of dry mouth, sedation, somnolence, dizziness and constipation was significantly higher in patients receiving quetiapine 300 or 600 mg/day than in patients receiving placebo. Changes in scores on the Simpson-Angus Rating Scale and the Barnes Akathisia Rating Scale did not differ between quetiapine and placebo recipients. Compared with placebo, quetiapine was not associated with an increased risk of treatment-emergent mania in either trial. Only modest weight gain was seen in quetiapine recipients in these short-term studies and there were no significant differences between quetiapine and placebo recipients in terms of fasting serum glucose levels.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Wolters Kluwer Health / Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Gillian M. Keating & Dean M. Robinson

  2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

    Gillian M. Keating & Dean M. Robinson

Authors
  1. Gillian M. Keating
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  2. Dean M. Robinson
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Corresponding author

Correspondence to Gillian M. Keating.

Additional information

Various sections of the manuscript reviewed by: J. Cookson, The Royal London Hospital, London, England; H. Grunze, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany; S.H. Kennedy, University Health Network, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada; D.J. Muzina, Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, Ohio, USA; H.A. Swartz, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; M.E. Thase, Department of Psychiatry, Western Psychiatric Institute Clinic, Pittsburgh, Pennsylvania, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘quetiapine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘quetiapine’ and ‘bipolar depression’. Searches were last updated 23 April 2007.

Selection: Studies in patients with bipolar depression who received quetiapine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Quetiapine, bipolar depression, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Keating, G.M., Robinson, D.M. Quetiapine. Drugs 67, 1077–1094 (2007). https://doi.org/10.2165/00003495-200767070-00008

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