Quetiapine for Bipolar Depression

By: Flavio Guzman, MD.

Quetiapine immediate release (IR) was approved in 2006 for the treatment of depressive episodes in patients diagnosed with bipolar disorder. In 2008, the extended release formulation – quetiapine ER (Seroquel XR) – was also approved for the same indication.

This page curates abstracts of review articles, meta-analyses and randomized controlled trials on the role of quetiapine in the management of bipolar depression. 

Review Articles

Quetiapine: a review of its use in the management of bipolar depression.

CNS drugs
Sanford M, Keating GM,
Adis, Auckland, New Zealand. demail@adis.com
Published: May 2012

Quetiapine (Seroquel®) is an orally administered atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder, including bipolar depression. An extended-release (XR) formulation of quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of quetiapine and quetiapine XR in patients with bipolar depression.

Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and its antipsychotic effects are thought to stem from interactions at these receptors. The antidepressant effects of quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or to reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine.

The efficacy and tolerability of quetiapine was evaluated in five 8-week, randomized, double-blind, placebo-controlled, multicentre or multinational trials in patients with a major depressive episode (MDE) associated with bipolar disorder. Across trials, monotherapy with oral quetiapine 300 or 600 mg/day (or quetiapine XR 300 mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and quetiapine XR were also associated with significantly higher MDE response and remission rates than placebo. Across trials, quetiapine and quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between quetiapine 300 mg/day and 600 mg/day dosage groups.

Patients with bipolar depression who responded to quetiapine during two 8-week acute treatment trials also benefited from continuing quetiapine therapy for up to 52 weeks. Compared with quetiapine responders randomized to placebo, quetiapine responders who continued quetiapine 300 or 600 mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events.

In a randomized, double-blind, placebo-controlled trial, quetiapine maintenance therapy for up to 104 weeks was more efficacious than placebo or lithium in prolonging the time to recurrence of any mood event (primary endpoint). Patients in this trial had bipolar I disorder with mania, depression or a mixed episode as the index episode, and the trial included only patients who were responsive to acute phase quetiapine, which may have introduced a positive bias in favour of quetiapine over lithium during maintenance therapy.

Quetiapine 300 or 600 mg/day and quetiapine XR 300 mg/day was generally well tolerated in patients with bipolar depression, with most treatment-emergent adverse events being of mild to moderate severity. The most frequent adverse events occurring during the acute treatment phase were dry mouth, sedation, somnolence, dizziness (quetiapine and quetiapine XR), constipation (quetiapine) and increased appetite (quetiapine XR). Extrapyramidal symptoms (EPS) occurred across quetiapine and placebo groups, but there were no significant differences between quetiapine and placebo recipients on objective measures of EPS and akathisia. In some trials, quetiapine recipients experienced significantly greater weight gain than placebo recipients. Across trials, some quetiapine recipients had clinically relevant increases in blood glucose or lipid parameters, although these also occurred in patients from other treatment groups. The clinical significance of these changes is uncertain.

In conclusion, quetiapine and quetiapine XR are valuable additions to the first-line treatments for bipolar depression. Further head-to-head trials of quetiapine versus other drug regimens that are effective in bipolar depression would be of considerable interest.

Quetiapine for bipolar depression: a systematic review and meta-analysis.

International clinical psychopharmacology
Chiesa A, Chierzi F, De Ronchi D, Serretti A,
Institute of Psychiatry, University of Bologna, Bologna, Italy.
Published: Mar 2012

Quetiapine has been proposed for depression in bipolar patients but a quantitative analysis is lacking. In the present paper, we review and meta-analyze available data about the short-term and long-term efficacy and tolerability of quetiapine for the depressive phase of bipolar disorder or bipolar depression. A literature research was carried out using three electronic databases. Studies providing measures of efficacy and tolerability of quetiapine, either as monotherapy or as augmentation, for bipolar depression were considered. Seven short-term studies and four maintenance studies were included.

Short-term studies suggested that patients treated with quetiapine monotherapy were significantly more likely than patients treated with placebo and further active comparators to achieve higher response and remission rates as well as more clinical improvements at the endpoint. Such benefits were significant from the first weeks of treatment onward.

Maintenance studies suggested that the combination of quetiapine and mood stabilizers was significantly better than placebo plus mood stabilizers for the prevention of both depressive and manic relapses. Quetiapine was generally well tolerated. Furthermore, several clinical variables moderated outcomes under investigation.

In conclusion, quetiapine could have some advantages over traditional treatments for the treatment of bipolar depression.

Quetiapine monotherapy for bipolar depression.

Expert opinion on pharmacotherapy
Janicak PG, Rado JT,
Psychiatric Clinical Research Center, Rush University, 2150 West Harrison Street, Suite 253, Chicago, IL 60612, USA. pjanicak@rush.edu
Published: Jul 2011

Depression, in the context of bipolar disorder, is more prevalent than hypomania or mania and accounts for most of the disability. Furthermore, the treatment of bipolar depression is more complicated than the treatment of unipolar major depression. Finally, the evidence base for pharmacotherapy of bipolar depression is much smaller than for unipolar depression or hypomania/mania.

AREAS COVERED: The article examines the mechanism of action and pharmacokinetics of quetiapine, its evidence base as a treatment for bipolar depression and related issues of safety and tolerability.

EXPERT OPINION: In the context of bipolar disorder, quetiapine is the only monotherapy approved for the treatment of hypomania/mania, depression and as an adjunctive maintenance therapy. In addition to its antipsychotic properties, this broad mood stabilizing potential may uniquely benefit and simplify the management of some bipolar patients who can tolerate this agent.

Randomized controlled trials

A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I).

The Journal of clinical psychiatry
Young AH, McElroy SL, Bauer M, Philips N, Chang W, Olausson B, Paulsson B, Brecher M,  ,
Institute of Mental Health, Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia BC V6T 1Z3, Canada. allan.young@ubc.ca
Published: Feb 2010


The aim of this study was to compare the efficacy and tolerability of quetiapine and lithium monotherapy with that of placebo for a major depressive episode in bipolar disorder.


802 patients with DSM-IV-defined bipolar disorder (499 bipolar I, 303 bipolar II) were randomly allocated to quetiapine 300 mg/d (n = 265), quetiapine 600 mg/d (n = 268), lithium 600 to 1800 mg/d (n = 136), or placebo (n = 133) for 8 weeks. Primary endpoint was the change in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The study was conducted from August 2005 to May 2007.


Mean MADRS total score change from baseline at week 8 was -15.4 for quetiapine 300 mg/d, -16.1 for quetiapine 600 mg/d, -13.6 for lithium, and -11.8 for placebo (P < .001 for both quetiapine doses, P = .123 for lithium, vs placebo). Quetiapine 600 mg/d was significantly more effective than lithium in improving MADRS total score at week 8 (P = .013). Quetiapine-treated (both doses), but not lithium-treated, patients showed significant improvements (P < .05) in MADRS response and remission rates, Hamilton Depression Rating Scale (HDRS), Clinical Global Impressions-Bipolar-Severity of Illness and -Change, and Hamilton Anxiety Rating Scale (HARS) scores at week 8 versus placebo. Both quetiapine doses were more effective than lithium at week 8 on the HDRS and HARS. The most common adverse events were somnolence, dry mouth, and dizziness with quetiapine (both doses) and nausea with lithium.


Quetiapine (300 or 600 mg/d) was more effective than placebo for the treatment of episodes of acute depression in bipolar disorder. Lithium did not significantly differ from placebo on the main measures of efficacy. Both treatments were generally well tolerated.

Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study.

Bipolar disorders
Vieta E, Calabrese JR, Goikolea JM, Raines S, Macfadden W,  ,
Bipolar Disorders Programme, Clinical Institute of Neuroscience, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain. evieta@clinic.ub.es
Published: Jun 2007


To investigate the efficacy and tolerability of quetiapine monotherapy in patients with bipolar I or II disorder with a rapid-cycling disease course.


Adult patients with a DSM-IV diagnosis of bipolar disorder, most recent episode depressed, with a rapid-cycling disease course from a previously completed multicenter trial randomized to 8 weeks of treatment with quetiapine 600 mg/day (n = 31), quetiapine 300 mg/day (n = 42), or placebo (n = 35) were included in this sub-analysis. The primary efficacy variable was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score.


Quetiapine (600 and 300 mg/day) provided significantly greater mean reductions from baseline to week 8 in the MADRS total score than placebo (-21.1, -20.7 versus -11.6, both p < 0.001) in this patient population. Effect sizes in patients with a rapid-cycling disease course were 1.2 (600 mg/day) and 1.1 (300 mg/day) and were similar for bipolar I (0.98 and 1.22) and bipolar II (1.45 and 0.97) sub-groups. Significant improvements were also noted on the Clinical Global Impression, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Pittsburgh Sleep Quality Index, and Quality of Life Enjoyment and Satisfaction Questionnaire scales. Quetiapine was generally well tolerated with moderate increases in weight and extrapyramidal side effects compared to placebo. The incidence of treatment-emergent mania was similar to placebo.


Quetiapine monotherapy (600 or 300 mg/day) is clinically effective and well tolerated in the short-term treatment of depressive episodes in patients with bipolar I or II disorder who have a rapid-cycling disease course.

Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study).

Journal of clinical psychopharmacology
Thase ME, Macfadden W, Weisler RH, Chang W, Paulsson B, Khan A, Calabrese JR,  ,
Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA 15213-2593, USA. thaseme@upmc.edu
Published: Dec 2006

This study evaluated the efficacy and tolerability of quetiapine monotherapy for depressive episodes in patients with bipolar I or II disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) who were randomized to 8 weeks of double-blind treatment with quetiapine (300 or 600 mg/d; once daily, evening dosing) or placebo.

Patients were assessed weekly using the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D). The primary end point was change in MADRS total score from baseline to Week 8 (analysis of covariance/last-observation-carried-forward analysis).

Of 509 patients randomized, 59% completed the study. Improvements from baseline in mean MADRS total scores were significantly greater with quetiapine 300 and 600 mg/d than with placebo from first evaluation (Week 1) through Week 8 (both P <or= 0.001 vs. placebo). Therapeutic effect sizes at Week 8 were 0.61 and 0.54 for quetiapine 300 and 600 mg/d, respectively. Improvements in mean HAM-D scores were also significantly greater with both quetiapine doses than with placebo (P < 0.001) as early as Week 1 and throughout the study.

The MADRS response and remission rates were also significantly greater in both quetiapine dose groups compared with placebo. Improvements in primary and secondary outcomes were observed with both 300 and 600 mg/d quetiapine without major differences between the doses.

Common adverse events included dry mouth, sedation, somnolence, dizziness, and constipation. The incidence of treatment-emergent mania or hypomania was lower with quetiapine treatment than placebo.

This study demonstrates that quetiapine monotherapy is an effective and well-tolerated treatment for depressive episodes in bipolar disorder, confirming the results observed from a previous study (BipOLar DEpRession [BOLDER] I).


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