Quetiapine for Depression

By Flavio Guzmán, MD

Quetiapine ER (Seroquel XR) was approved by the FDA as adjunct to antidepressants for the treatment of major depressive disorder in 2009.

This page curates review articles, meta-analyses and randomized controlled trials on the role of quetiapine XR as augmenting agents and as monotherapy in the treatment of major depression.

Review articles

Quetiapine extended release: adjunctive treatment in major depressive disorder

Quetiapine extended release (XR) is a once-daily oral formulation of the atypical antipsychotic quetiapine that is available for use as adjunctive therapy in major depressive disorder (MDD).

Systemic quetiapine exposure after orally administered quetiapine XR is similar to that of quetiapine immediate release at the same dosage, although quetiapine XR is absorbed more slowly and plasma concentrations are more stable over time. In two 6-week, randomized, double-blind, placebo-controlled, multinational trials in patients with MDD with an inadequate response to antidepressants, quetiapine XR 300 mg/day adjunctive to antidepressant reduced depressive symptoms significantly more than antidepressant plus placebo, according to changes in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores.

In one trial, adjunctive quetiapine XR 150 mg/day also led to significantly greater reductions in MADRS total scores than antidepressant plus placebo. MDD response rates were significantly higher with adjunctive quetiapine XR 300 mg/day (but not 150 mg/day) than with antidepressant plus placebo. The numbers needed to treat to achieve an additional response over antidepressant plus placebo were 11-18 and 8-9 in the quetiapine XR 150 and 300 mg/day dosage groups, respectively.

Treatment-emergent adverse events were mostly of mild to moderate severity; 1% of adjunctive quetiapine XR and 1.3% of antidepressant plus placebo recipients reported serious adverse events.

Quetiapine xr: current status for the treatment of major depressive disorder.

Quetiapine fumarate extended release (XR) has been approved for treatment of schizophrenia and bipolar disorder. Quetiapine may have antidepressant effects through effects on 5-HT(2A) receptor, 5-HT1A receptor, dopamine receptor, glutamate receptor and norepinephrine transporter.

Recently, 7 large-scale randomized, double-blind, placebo (2-studies with active comparator)-controlled clinical trials have demonstrated that quetiapine XR has clinically meaningful efficacy as monotherapy and adjunct therapy to antidepressants for the treatment of adult patients with major depressive disorder (MDD). In such clinical trials, quetiapine XR was generally well tolerated, although weight gain and changes in metabolic parameters, consistent with the known profile of quetiapine, were observed in some patients.

As of December 2009, the United States Food and Drug Administration has approved quetiapine XR for the adjunct treatment of MDD. From the data of currently available clinical trials, this review provides an overview of the data and clinical implications for quetiapine XR in the treatment of MDD to enhance clinicians understanding of the use of quetiapine XR in the treatment of MDD.

Meta-analyses and pooled analyses

Quetiapine monotherapy in acute phase for major depressive disorder: a meta-analysis of randomized, placebo-controlled trials.

BACKGROUND: Schizophrenia and bipolar depression trials suggest that quetiapine may have an antidepressant effect.

OBJECTIVES: This meta-analysis aimed to determine the efficacy, acceptability and tolerability of quetiapine treatment for major depressive disorder (MDD). Only the randomized controlled trials (RCTs) comparison between quetiapine and placebo were included. The authors searched such clinical trials carried out between 1991 and February 2012.MEDLINE, EMBASE, CINHL, PsycINFO and Cochrane Controlled Trials Register were searched in February 2012.

DATA SOURCES: Study populations comprised adults with MDD or major depression.

STUDY ELIGIBLE CRITERIA, PARTICIPANTS AND INTERVENTIONS: Eligible studies were randomized, placebo-controlled trials of quetiapine monotherapy carried out in adults with MDD and presenting endpoint outcomes relevant to: i) depression severity, ii) response rate, iii) overall discontinuation rate, or iv) discontinuation rate due to adverse events. No language restriction was applied.

STUDY APPRAISAL AND SYNTHESIS METHODS: All abstracts identified by the electronic searches were examined. The full reports of relevant studies were assessed, and the data of interest were extracted. Based on the Cochrane methods of bias assessment, risks of bias were determined. The studies with two risks or less were included. The efficacy outcomes were the mean change scores of depression rating scales, the overall response rate, and the overall remission rates. The overall discontinuation rate was considered as a measure of acceptability. The discontinuation rate due to adverse events was a measure of tolerability. Relative risks (RRs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were computed by using a random effect model.

RESULTS: A total of 1,497 participants in three RCTs were included. All trials examined the quetiapine extended-release (XR). The pooled mean change scores of the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAM-D) of the quetiapine-treated group were higher than those of the placebo-treated group with the WMDs (95%CI) of -3.37 (-3.95, -2.79) and -2.46 (-3.47, -1.45), respectively. All studies defined the response and remission as ≥ 50% reduction of the MADRS total score and the MADRS total score of ≤8 at endpoint, respectively.

The overall response and remission rates were significantly greater in the quetiapine-treated group with RRs (95%CIs) of 1.44 (1.26, 1.64) and 1.37 (1.12, 1.68), respectively. The pooled discontinuation rate was not significantly different between groups with an RR (95%CI) of 1.16 (0.97, 1.39). The pooled discontinuation rate due to adverse event was greater in the quetiapine group with an RR (95%CI) of 2.90 (1.87, 4.48). With respect to sleep time, the pooled mean change Pittsburgh Sleep Quality Index (PSQI) scores of the quetiapine-treated group was also significantly higher than that of the placebo-treated group [WMD (95%CI) of -1.21 (-1.81, -0.61)].

LIMITATIONS: Variety of quetiapine XR doses and the small number of RCTs were key limitations of this meta-analysis.

CONCLUSIONS:Based on the limited evidence obtained from three RCTs, quetiapine XR is effective for adult patients with MDD. The high dropout rate due to adverse events suggests that some MDD patients may not be able to tolerate quetiapine XR. Due to the balance of its efficacy benefit and risk of side effects, as the overall discontinuation rate shown, the acceptability of this agent is not more than placebo. These results should be viewed as the very preliminary one. Further studies in this area are warranted.

IMPLICATION OF KEY FINDINGS: Quetiapine may be an alternative antidepressant. However, both risk and benefit of this agent should be taken into account for an individual patient with MDD.

Quetiapine xr efficacy and tolerability as monotherapy and as adjunctive treatment to conventional antidepressants in the acute and maintenance treatment of major depressive disorder: a review of registration trials.

Results from pivotal registration trials in major depressive disorder cohere with outcomes from effectiveness studies indicating that the majority of individuals receiving single-agent pharmacotherapy fail to achieve and sustain symptomatic remission. Several factors provided the impetus for this review: suboptimal efficacy with existing pharmacotherapy for major depressive disorder, quetiapine XR efficacy in the acute and maintenance treatment of bipolar depression, emerging pharmacodynamic evidence that quetiapine XR (and/or its metabolites) uniquely engages monoaminergic systems salient to symptom relief in depressive syndromes, the increasing use of second-generation antipsychotics in the treatment of major depressive disorder and the recent FDA review of quetiapine XR in major depressive disorder.

Studies reviewed herein are pivotal registration trials that evaluated the acute and maintenance efficacy and tolerability of quetiapine XR (as monotherapy and as adjunctive treatment) in major depressive disorder. In addition, we also review recent investigations characterizing the pharmacodynamic effect of quetiapine’s principal active metabolite, norquetiapine.

All studies were obtained from AstraZeneca (Wilmington, DE, USA) and have been presented at national/international scientific meetings. Taken together, extant studies demonstrated that quetiapine XR (50 – 300 mg) provides rapid and sustained symptomatic improvement in the acute and maintenance treatment of major depressive disorder.

Quetiapine XR may also offer advantages relative to duloxetine in time to onset of antidepressant action. The major limitations of quetiapine XR use in major depressive disorder relate to weight gain and disrupted glucose/lipid homeostasis as well as sedation/somnolence. Quetiapine XR has tolerability advantages compared with duloxetine on measures of sexual dysfunction. The data from the studies reviewed herein also indicate that quetiapine XR poses a low risk for extrapyramidal side effects in middle-aged and elderly individuals with major depressive disorder.

Extended release quetiapine fumarate in major depressive disorder: analysis in patients with anxious depression.

BACKGROUND: A pooled analysis was performed on data from two studies evaluating the efficacy of once-daily extended-release quetiapine fumarate (quetiapine XR) monotherapy for patients with major depressive disorder.

Through these analyses (based on Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) measures), we aim to further evaluate the efficacy of quetiapine XR in depressed patients with high levels of anxiety symptoms.

METHODS: Secondary analyses were conducted of pooled individual patient data from two 8-week (6-week randomized phase, 2-week drug discontinuation phase), double-blind, placebo-controlled studies of quetiapine XR (50-300 mg/day).

Outcomes included change from randomization at Week 6 in Montgomery Åsberg Depression Rating Scale (MADRS) total score for patients with anxious and nonanxious depression.

RESULTS: Of 968 patients included in the analysis, 788 (81.4%) were classified as anxious depressed (defined as HAM-D anxiety/somatization factor score ≥ 7) and 180 (18.6%) were nonanxious. For patients with anxious depression and nonanxious depression, statistically significant differences versus placebo in MADRS total score were recorded for quetiapine XR 150 mg/day (-3.24, P < .001 and -4.82, P < .01, respectively) and 300 mg/day (-3.57, P < .001 and -3.39, P < .05, respectively) at Week 6.

In the second analysis using an alternate definition of anxious depression (baseline HAM-A total score ≥ 20), quetiapine XR 150 and 300 mg/day resulted in significant differences versus placebo in MADRS total score reduction in patients with high and lower levels of anxiety.

The adverse event (AE) profile was similar irrespective of baseline anxiety levels, although patients with anxious depression reported a somewhat greater incidence of AEs.

CONCLUSION: Quetiapine XR monotherapy improved symptoms of depression in patients with higher and lower levels of anxiety.

Efficacy of extended release quetiapine fumarate monotherapy in patients with major depressive disorder: a pooled analysis of two 6-week, double-blind, placebo-controlled studies.

Prospectively planned pooled analysis evaluating the efficacy of quetiapine extended release (XR) monotherapy in major depressive disorder (MDD). Data were pooled from two 6-week, randomized, double-blind, placebo-controlled studies of quetiapine XR in outpatients with MDD.

The primary endpoint was Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from randomization at week 6. Other evaluations were MADRS response/remission, Hamilton Rating Scale for Anxiety, and subgroup analyses. A total of 968 patients were randomized to quetiapine XR, 150 mg/day (n=315), 300 mg/day (n=323), or placebo (n=330).

The mean MADRS total score reductions from randomization were significant at week 6 with quetiapine XR, 150 mg/day (-14.7; P<0.001) and 300 mg/day (-14.7; P<0.001) versus placebo (-11.1), with significant reductions versus placebo from week 1 onward. Response rates (week 6): 52.7% (P<0.001) quetiapine XR 150 mg/day and 49.5% (P<0.001) quetiapine XR 300 mg/day versus placebo (33.0%). MADRS remission (score≤8; week 6): 23.5% (P=0.208) quetiapine XR 150 mg/day and 28.8% (P<0.01) quetiapine XR 300 mg/day versus placebo (19.4%).

Quetiapine XR (both doses) significantly improved eight of 10 MADRS items versus placebo at week 6. The therapeutic effect of quetiapine XR was neither limited to nor driven by factors such as sex, age, or severity of depression. In patients with MDD, quetiapine XR (150 and 300 mg/day) monotherapy reduced depressive symptoms, with significant improvements compared with placebo from week 1 onward.

Randomized controlled trials

Randomized, double-blind study of the efficacy and tolerability of extended release quetiapine fumarate (quetiapine xr) monotherapy in elderly patients with major depressive disorder.

OBJECTIVES: This study assessed the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder (MDD). DESIGN: An 11-week (9-week randomized; 2-week posttreatment phase), double-blind, placebo-controlled, Phase III study (D1448C00014).

SETTING: A total of 53 centers in Argentina, Estonia, Finland, Russia, Ukraine, and the United States.

PARTICIPANTS: A total of 338 patients (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD, age ≥66 years, Hamilton Rating Scale for Depression [HAM-D] total score ≥22, HAM-D Item 1 [depressed mood] score ≥2) were randomized (mean age: 71.3 years).

INTERVENTION: Patients were randomized to quetiapine XR (n = 166; flexible-dosing 50-300 mg/day) or placebo (n = 172).

MEASUREMENTS: Primary outcome was Montgomery Åsberg Depression Rating Scale (MADRS) total score change from randomization at Week 9.

RESULTS: At Week 9, quetiapine XR (least squares [LS] means: -16.33, standard error [SE]: 0.95; mean change: -16.0, standard deviation [SD]: 9.3) significantly reduced MADRS total score from randomization versus placebo (LS means [SE]: -8.79 [0.94]; mean [SD]: -9.0 [9.9]); significant improvements were also seen at Week 1 (LS means [SE]: -4.65 [0.53] versus -2.56 [0.53], respectively; mean [SD]: -4.3 [5.1] versus -2.4 [3.7], respectively). At Week 9, secondary outcome variables significantly improved with quetiapine XR versus placebo, including MADRS response (≥50% reduction in total score); MADRS remission (total score ≤8); HAM-D total, HAM-A total, HAM-A psychic and somatic cluster, and Clinical Global Impressions-Severity of Illness (CGI-S) total scores; proportion of patients with CGI-Improvement score of 2 or less; Q-LES-Q-SF% maximum total, Pittsburgh Sleep Quality Index global, and pain Visual Analog Scale scores. Common adverse events (>10% patients with quetiapine XR) were somnolence, headache, dry mouth, and dizziness.

CONCLUSION: In elderly patients with MDD, quetiapine XR monotherapy (50-300 mg/day, flexibly dosed) is effective at improving depressive symptoms, with symptom improvement observed as early as Week 1. Overall tolerability and safety were consistent with the known profile of quetiapine.Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: a placebo-controlled, randomized study.

BACKGROUND: Evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) once-daily monotherapy for patients with major depressive disorder (MDD).

METHODS: In this 10-week, (8-week active treatment phase and 2-week drug-discontinuation/tapering phase), multicenter, parallel-group, placebo-controlled, double-blind, randomized, Phase III study (D1448C00003: Opal), patients initially received quetiapine XR 150 mg/day or placebo. At Week 2, inadequate responders (<20% reduction in MADRS total score) were up-titrated to 300 mg/day quetiapine XR or matching placebo for the final 6 weeks. Primary endpoint: change from randomization to Week 8 in MADRS total score. Secondary endpoints included: MADRS response (≥50% reduction in total score from randomization) and changes from randomization to Week 8 in HAM-D and CGI-S.

RESULTS: 310 patients were randomized.At Week 8, quetiapine XR significantly reduced mean MADRS total score versus placebo (-16.49 vs -13.10, respectively; p<0.01). Mean MADRS score was significantly reduced by quetiapine XR versus placebo at Week 1 (p<0.05). MADRS response rates were significantly greater at Week 8 for quetiapine XR versus placebo (61.9% vs 48.0%, respectively; p<0.05). Significant changes in HAM-D total score and CGI-S were seen at Week 8 for quetiapine XR versus placebo. Withdrawal rates due to AEs were 9.9% and 2.6% for quetiapine XR and placebo, respectively. Common AEs (>10% any group during the randomized phase) for quetiapine XR and placebo, respectively were dry mouth (32.9% and 6.5%), sedation (21.7% and 1.9%), somnolence (20.4% and 5.2%), and headache (10.5% and 10.3%).

LIMITATIONS: The study was not designed to compare quetiapine XR 150 mg/day and 300 mg/day; it was intended to reflect dose titration that might occur in clinical practice.

CONCLUSIONS: Quetiapine XR monotherapy is effective in patients with MDD, with symptom improvement seen as early as Week 1, and tolerability results consistent with the known profile of quetiapine.

Other: commentary and opinion

Early onset of action and sleep-improving effect are crucial in decreasing suicide risk: the role of quetiapine xr in the treatment of unipolar and bipolar depression.

Although the possibilities of antidepressive pharmacotherapy are continuously improving, the rate of nonresponders or partial responders is still relatively high. Suicidal behavior, the most tragic consequence of untreated or unsuccessfully treated depression, commonly observed in the first few weeks of antidepressive treatment before the onset of therapeutic action, is strongly related to certain symptoms of depression like insomnia.

The present paper reviews the newly discovered and well-documented antidepressive effect of quetiapine in bipolar and unipolar depression with special focus on its early onset of action and its sleep-improving effects. Both beneficial effects play an important role in the reduction of suicidal risk frequently observed in depressed patients.

Quetiapine: novel uses in the treatment of depressive and anxiety disorders.

IMPORTANCE OF THE FIELD: Quetiapine, an atypical antipsychotic, has been approved for the treatment of schizophrenia, acute mania, bipolar depression and unipolar major depression. However, it is often used (off-label) to treat other depressive disorders and anxiety disorders in children and adults.

AREAS COVERED IN THIS REVIEW: This article reviews the evidence for the safety and efficacy of quetiapine in these populations, as both monotherapy and augmentation to other psychotropics.

WHAT THE READER WILL GAIN: This article provides an in-depth review of the published literature on the topic and also provides recommendations for use.There is strong evidence to support the use of quetiapine in major depressive and generalized anxiety disorders, and preliminary support for treatment-resistant and psychotic depression.

TAKE HOME MESSAGE: There is reasonable evidence of its benefits as an augmenting agent in obsessive-compulsive disorder, while data in other anxiety disorders are limited but promising. While long-term tolerability data are limited, quetiapine appears well tolerated in the short-term. Further randomized controlled trials are needed to confirm the efficacy and tolerability of quetiapine, both short- and long-term, in many of these conditions.

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