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Quetiapine in the Anxiety Dimension of Mood Disorders

A Systematic Review of the Literature to Support Clinical Practice

Crapanzano, Calogero MD; Damiani, Stefano MD, PhD; Guiot, Cecilia MD

Author Information
Journal of Clinical Psychopharmacology: 7/8 2021 - Volume 41 - Issue 4 - p 436-449
doi: 10.1097/JCP.0000000000001420
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Abstract

Mood disorders are a group of heterogeneous conditions characterized by marked variations in mood; according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, they can be classified as bipolar disorder (BD) type I, BD type II, cyclothymic disorder, major depressive disorder (MDD), persistent depressive disorder, premenstrual dysphoric disorder, and BD or MDD not elsewhere defined.

Anxiety has been added as a specifier for mood disorders,1 as their co-occurrence is frequent. In a sample of 138 patients, Boylan et al2 found that 55.8% of patients with BD were diagnosed with at least 1 comorbid anxiety disorder, and 31.8% with 2 or more anxiety disorders: the most common anxiety disorder was generalized anxiety disorder (GAD), followed by panic disorder (PD). In MDD, the estimated rate of comorbidity with anxiety disorders is 59.2%.3 A high comorbidity rate is encountered even when anxiety is considered as the primary disorder: a longitudinal study on 179 subjects showed that 39% of patients with GAD had an additional diagnosis of MDD4; moreover, the authors of the National Comorbidity Study found that 62% of patients with GAD also had a depressive episode (DE) in their lifetime.5

The comorbidity of anxiety disorders in patients with MDD is associated with an earlier age of onset, greater illness severity at onset of treatment, higher chance of chronicization and recurrence, poorer response to treatment, lower quality of life and functioning, greater physical and mental disability, and greater risk of suicide and mortality.6,7 Similarly, anxiety has been correlated with a lower quality of life and treatment outcomes, substance abuse disorders, suicidal behavior, eating disorders, earlier onset of bipolar disease, more severe depressive phases, and a high social burden in patients with BD.8,9

Coplan et al10 recommend to associate quetiapine to antidepressant therapy for the treatment of BD with anxiety symptoms. Canadian guidelines, Canadian Network for Mood and Anxiety Treatments (CANMAT) recommend the use of divalproex, lamotrigine, selective serotonin reuptake inhibitors, or olanzapine-fluoxetine combination only as a second-line intervention to treat anxiety in BD,11 as serotoninergic agents have been linked to affective switches and cycle acceleration in patients with BD.12 Instead, quetiapine and olanzapine are recommended as first-line drugs.

The clinical guidelines for the treatment of BD of the International College of Neuro-Psychopharmacology recommend to add paroxetine, quetiapine, valproate, or lurasidone to ongoing therapy for the treatment of comorbid anxiety in BD.13

Although quetiapine has been used in clinical practice for many years and its efficacy in treating anxiety symptoms is well known,14,15 to the best of our knowledge, no collection of the available findings has yet supported or disconfirmed clinical recommendations.16,17 The aim of our study is hence to evaluate the efficacy of quetiapine in the treatment of the anxiety dimension in mood disorders through a systematic review of the literature. As a secondary outcome, reports concerning adverse effects of quetiapine in the selected studies will be collected and discussed.

MATERIALS AND METHODS

We conducted a systematic review of the literature available between January 1998 and October 2020. PubMed, Web of Science, and Clinicaltrial.gov were searched using the following search builder: (quetiapine AND anxiety AND (depression OR bipolar OR mood)).

Population, Intervention, Comparison, Outcomes and Study (PICOS) design criteria18 for study selection were applied and are reported in Table 1. Articles not in English were excluded. A total of 823 (522 Web of Science, 294 PubMed, and 7 Clinicaltrial.gov) items were retrieved from the search databases and reference cross-check. Duplicates were removed. The remaining studies were independently evaluated by 2 reviewers (C.C. and S.D.) and included or excluded after reaching a final consensus (Table 2). Eight studies reported post hoc analyses on previously collected data. These studies were included as they allowed a more comprehensive review on the topic (Table 3). Figure 1 reports a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flowchart regarding information process through the different phases of this review.19

TABLE 1 - PICOS Criteria for Study Selection
Parameter Inclusion Exclusion
Patients Diagnosis of BD or MDD
Intervention Quetiapine, any dose
Comparator Placebo or other pharmacological treatments
Outcomes Effect on the anxiety-related symptoms (as measured by scores from clinical scales) Absence of measurements concerning the anxiety dimension
Study design RCTs; post hoc analyses of RCTs

TABLE 2 - Original Studies: Characteristics and Main Findings
Source Study Design Country Sample (No. Subjects) Follow-Up, wk Dose, mg/d Main Outcome Anxiety? Positive Findings Negative Findings
Calabrese et al, 2005 QTP vs PLC in BD USA QTP 300 (172)
QTP 600 (170)
PLC (169)
8 300 or 600 No QTP superior to PLC for HAM-A, MADRS, PSQI, Q-LES-Q-SF
Thase et al, 2006 QTP vs PLC in BD USA QTP 300 (155)
QTP 60 (151)
PLC (161)
8 300 or 600 No QTP superior to PLC for HAM-A, MADRS, SDS, Q-LES-Q, CGI-S, CGI-S
McIntyre et al, 2007 QTP vs PLC in antidepressant-resistant MDD Canada QTP (29)
PLC (29)
8 50–600 (mean: 182) Yes QTP superior to PLC for HAM-A, HAM-D, CGI-S, CGI-I, GAS
Garakani et al, 2008 QTP vs PLC as add-on to fluoxetine in MDD USA QTP (57)
PLC (57)
8 25–100 No QTP not superior to PLC for HAM-A, MADRS, CGI-S, CGI-I
Weisler et al, 2009 QTP XR vs PLC in MDD USA QTP 50 (178)
QTP 150 (168)
QTP 300 (176)
PLC (178)
6 50 or 150 or 300 No QTP superior to PLC for HAM-A, HAM-D, CGI-S, MADRS QTP not superior to PLC for Q-LES-Q. QTP 50 not superior to PLC for MADRS
Cutler et al, 2009 QTP XR vs duloxetine vs PLC in MDD USA QTP 150 (147)
QTP 300 (147)
PLC (152)
Duloxetine (141)
6 150 or 300 No QTP and duloxetine superior to PLC for HAM-A, MADRS, CGI-I. QTP superior to PLC for PSQI
Bauer et al, 2009 QTP XR vs PLC in antidepressant-resistant MDD International QTP 150 (166)
QTP 300 (161)
PLC (160)
6 150 or 300 No QTP superior to PLC for HAM-A and psychic anxiety subscale MADRS QTP not superior to PLC for Q-LES-Q
McElroy et al, 2010 QTP XR vs paroxetine vs PLC in BD International QTP 300 (229)
QTP 600 (232)
PLC (118)
Paroxetine (121)
8 300 or 600 No QTP and paroxetine superior to PLC for HAM-A. QTP superior to PLC for MADRS, HAM-D, CGI-BP-S QTP and paroxetine not superior to PLC for SDS
Young et al, 2010 QTP vs Li+ vs PLC in BD International QTP 300 (255)
QTP 600 (263)
Li+ (136)
PLC (129)
8 300 or 600 No QTP superior to PLC for HAM-A, HAM-D, MADRS, CGI-BP, MOS-Cog QTP 300 and Li+ not superior to PLC for SDS
Liebowitz et al, 2010 QTP XR vs PLC to prevent MDD relapses International QTP (387)
PLC (384)
52 50–300 (mean: 177) No QTP superior to PLC for improvement in MADRS, CGI-S, HAM-A total, HAM-A psychic and somatic cluster, PSQI, SDS QTP not superior to PLC for Q-LES-Q
El-Khalili et al, 2010 QTP XR vs PLC in antidepressants-resistant MDD USA QTP 150 (143)
QTP 300 (146)
PLC (143)
6 150 or 300 No QTP superior to PLC for PSQI. QTP 300 mg superior to PLC for HAM-A, MADRS, HAM-D, PSQI, CGI-S, CGI-I QTP 150 not superior to PLC for HAM-A, MADRS, HAM-D, PSQI, CGI-S, CGI-I. QTP not superior to PLC for Q-LES-Q-SF
Sheehan et al, 2012 QTP XR vs VPA vs PLC in BD + PD/GAD lifetime diagnosis USA QTP (49)
PLC (51)
VPA (49)
8 50–300 (mean: 186) Yes QTP superior to divalproex and to PLC for HAM-A, MADRS, SPS, PG-21, CGI-21, YMRS, CGI-BP QTP not superior to placebo and divalproex for SIS and RIS
Chen et al, 2012 QTP XR vs PLC as add-on to antidepressants in BD/MDD or anxiety disorder Taiwan QTP (22)
PLC (13)
8 50–300 (median: 50) Yes QTP superior to PLC for HAM-A and CGI-S at week 4 QTP not superior to PLC for HAM-A and CGI-S at week 8
NCT00857584, 2012 QTP XR vs SRT as add-on in BD Europe QTP (14)
Sertraline (11)
8 300–600 No Statistical significance not measured Statistical significance not measured
Katila et al, 2013 QTP XR vs PLC in elderly MDD International QTP (164)
PLC (171)
9 50–300 (median: 158) No QTP superior to PLC for HAM-A, MADRS, QLES-Q-SF, PSQI, pain VAS
Gao et al, 2014 QTP vs PLC as mono/add-on to mood stabilizer in BD with GAD USA QTP (50)
PLC (50)
8 50–300 (median: 276) No QTP not superior to PLC for HAM-A, HAM-D, CGI-S, Q-LES-Q, QIDS-SR-16
Li et al, 2016 QTP XR vs PLC as mono/add-on therapy to antidepressants in MDD with GAD USA QTP (11)
PLC (12)
8 50–300 (median: 276) No QTP superior to PLC for CGI-S QTP not superior to PLC for HAM-A, HAM-D, QIDS-16 score
Gao et al, 2018 QTP vs Li+ in BD subjects USA QTP (24)
Li+ (18)
16 100–900 (mean: 327) No QTP superior to PLC for CGI-EI QTP not superior to Li+ for HAM-A, MADRS, YMRS, QIDS-SR-16, IFS, CGI-S-BP
Kinrys et al, 2019 QTP + APT vs Li+ + APT in BD with anxiety USA QTP (242)
Li+ (240)
6 100–800 (median: 300) Yes QTP not superior to Li+ for BISS anxiety domain
APT indicates adjunctive personalized therapy; BISS, Bipolar Inventory of Symptoms Scale; CGI-E, Clinical Global Impression–Efficacy Index; CGI-I, Clinical Global Impression–Improvement; CGI-S, Clinical Global Impression–Severity; GAS, Global Assessment Scale; IFS, Iowa Fatigue Scale; Li+, Lithium; MOS-Cog, Medical Outcomes Study Cognitive Scale; PGI-21, Anxiety Patient Global Improvement for Anxiety; PLC, placebo; PSQI, Pittsburgh Sleep Quality Index; QIDS-SR-16, Quick Inventory of Depressive Symptomatology; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire; Q-LES-Q-SF, Quality of Life, Enjoyment, and Satisfaction Questionnaire–Short Form; QTP, quetiapine; RIS, Rapid Ideas Scale; SDS, Sheehan Disability Scale; SIS, Sheehan Irritability Scale; SPS, Sheehan Panic Disorder Scale; VAS, Visual Analog Scale; VPA, divalproex; YMRS, Young Mania Rating Scale.

TABLE 3 - Post Hoc Studies: Characteristics and Main Findings
Source Study Design (Focus of Post-hoc Analysis) Country Sample (No. Subjects) Follow-Up, wk Dose, mg/d Main Outcome Anxiety? Positive Findings Negative Findings
Hirschfeld et al, 2006 QTP vs PLC in BD USA QTP 300 (172)
QTP 600 (170)
PLC (169)
8 300 or 600 No QTP superior to PLC for HAM-A, HAM-A anxious mood and tension. In BD I, QTP superior to PLC for HAM-A, HAM-A anxious mood and tension, HAM-A psychic and somatic, MADRS inner tension, HAM-D psychic anxiety. In BD II, QTP superior to PLC for HAM-A anxious mood, MADRS inner tension, HAM-D psychic anxiety In BD II, QTP not superior to PLC for HAM-A
Vieta et al, 2007 QTP vs PLC in BD USA QTP 300 (42)
QTP 600 (31)
PLC (35)
8 300 or 600 No QTP superior to PLC for HAM-A, HAM-D, MADRS, PSQI, CGI-S, CGI-I, Q-LES-Q QTP not superior to PLC for YMRS
Weisler et al, 2008 QTP vs PLC in BD USA, Europe QTP 300 (220)
QTP 600 (215)
PLC (222)
8 300 or 600 No QTP superior to PLC for HAM-A, HAM-D, MADRS, CGI-S, CGI-I, Q-LES-Q
Lydiard et al, 2009 QTP vs PLC in BD USA QTP 300 (327)
QTP 600 (321)
PLC (330)
8 300 or 600 Yes QTP superior to PLC for HAM-A total and psychic and somatic anxiety subscale, and MADRS
Thase et al, 2012 QTP XR vs PLC in MDD with/without anxiety (by HAM-A) USA, Europe QTP 150 (315)
QTP 300 (323)
PLC (330)
6 150 or 300 No QTP superior to PLC for HAM-A MADRS, HAM-D, PSQI in patients with and without anxiety. QTP superior to PLC for HAM, MADRS, CGI-S, PSQI in A/S>7 QTP not superior to PLC for HAM-A in A/S<7
Bandelow et al, 2014 QTP XR vs PLC in antidepressant-resistant MDD USA, Europe QTP 150 (309)
QTP 300 (307)
PLC (303)
6 150 or 300 No QTP superior to PLC for MADRS, CGI-S, HAM-A, PSQI in A/S<7 group. QTP 300 superior to PLC for MADRS, CGI-S, HAM-A and PSQI in A/S>7 group. QTP superior to PLC for HAM-A, MADRS, CGI-S, and PSQI in A/S>7 group. QTP 150 superior to PLC for PSQI in A/S<7 group QTP 150 not superior to PLC for MADRS, CGI-S, HAM-A, PSQI in A/S>7 group. QTP not superior to PLC for HAM-A, MADRS, CGI-S in A/S<7 group. QTP 300 not superior to PLC for PSQI in A/S<7 group
Datto et al, 2016 QTP vs PLC vs active comparators in BD USA QTP (1760)
Li+ (121)
Paroxetine (118)
PLC (717)
8 300–600 Yes QTP superior to comparators for HAM-A and CGI-BP-S. Quetiapine superior to Li+ and PLC in improving MADRS score Quetiapine not superior to paroxetine for MADRS score
Gao et al, 2017 QTP vs PLC in BD + GAD with and without recent A/C USA QTP (22)
QTP in A/C (24)
PLC (21)
PLC in A/C (23)
8 150–300 Yes QTP superior to PLC for QIDS-SR-16 QTP not superior to PLC for HAM-A, HAM-D, Q-LES-Q, CGI-BP-S in patients with A/C
A/C indicates alcohol/cannabis use; A/S, HAM-D anxiety/somatization factor; CGI-I, Clinical Global Impression–Improvement; CGI-S, Clinical Global Impression–Severity; Li+, Lithium; PLC, placebo; PSQI, Pittsburgh Sleep Quality Index; QIDS-SR-16, Quick Inventory of Depressive Symptomatology; Q-LES-Q, Quality of Life Enjoyment and Satisfaction Questionnaire; QTP, quetiapine; SNRIs, serotonin-norepinephrine reuptake inhibitors; SRT, sertraline; VPA, divalproex; YMRS, Young Mania Rating Scale.

FIGURE 1
FIGURE 1:
PRISMA flowchart.

The risk of bias was assessed using the Cochrane risk of bias tool20 considering the following items: random sequence generation, allocation concealment, blinding of participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other source of bias as illustrated in Table 4.

TABLE 4 - Cochrane's Classification for Risk of Bias
Source Random Sequence Generation Allocation Concealment Blinding of Participants Blinding of Outcome Assessment Incomplete Outcome Data Selective Outcome Reporting Other Source of Bias
Calabrese et al, 2005 Low Low Low Low Low Low Low
Thase et al, 2006 Low Low Low Low Low Low Low
Hirschfeld et al, 2006 Low Low Low Low Low Low Low
Vieta et al, 2007 Low Low Low Low Low Low Low
McIntyre et al, 2007 Low Low Low Low Low Low High
Garakani et al, 2008 Low Low Low Low High High Unclear
Weisler et al, 2008 Low Low Low Low Low Low Low
Weisler et al, 2009 Low Low Low Low Low Low Low
Cutler et al, 2009 Low Low Low Low Low Low Low
Bauer et al, 2009 Low Low Low Low Low Low Low
Lydiard et al, 2009 Low Low Low Low Low Low Low
McElroy et al, 2010 Low Low Low Low Low Low Low
Young et al, 2010 Low Low Low Low Low Low Low
Liebowitz et al, 2010 Low Low Low Low Low Low Low
El-Khalili et al, 2010 Low Low Low Low Low Low Low
Thase et al, 2012 Low Low Low Low Low Low Low
Sheehan et al, 2012 Low Low Low Low Low Low Unclear
Chen et al, 2012 Low Low Low Low Low Low High
NCT00857584, 2012 Low Low Low Low Unclear Unclear High
Katila et al, 2013 Low Low Low Low Low Low Low
Gao et al, 2014 Low Low Low Low Unclear Unclear Unclear
Bandelow et al, 2014 Low Low Low Low Low Low Low
Li et al, 2016 Low Low Low Low High High High
Datto et al, 2016 Low Low Low Low Low Low Low
Gao et al, 2017 Low Low Low Low Low Low High
Gao et al, 2018 Low Low Low Low Low Low High
Kinrys et al, 2019 Low Low Low Low Low Low Low

RESULTS

We selected a total of 19 randomized controlled trials (RCTs) regarding the use of quetiapine in mood disorders. Table 2 reports the design of the study, the sample size and the duration, the daily average dose, and the change in assessment score.

Quetiapine and BD

In BD, some studies compared quetiapine versus placebo, whereas others used an active comparator, taking into consideration the effectiveness on depressive symptoms as the primary outcome. Two studies demonstrated that quetiapine monotherapy was more effective than placebo in the treatment of anxiety symptoms of DEs in BD.21,22 Young et al23 demonstrated the effectiveness of quetiapine monotherapy over both placebo and lithium in the treatment of depressive and anxiety symptoms. In another study with a smaller sample size, quetiapine and lithium were both effective in improving anxiety symptoms: quetiapine was found not to be significantly superior to lithium in improving Hamilton Anxiety Scale (HAM-A) total score; however, a larger decrease in anxiety symptom severity was found in the quetiapine group.24 Kinrys et al25 found similar results with larger sample sizes. McElroy et al26 showed that a quetiapine dose of 300 or 600 mg/d was more effective than placebo when treating acute depressive symptoms in BD I and II; the same study did not find significant improvements when comparing paroxetine versus placebo. Both quetiapine and paroxetine were effective on anxiety symptoms.26 Sheehan et al27 conducted a randomized, placebo-controlled trial with quetiapine extended release (XR) and divalproex XR monotherapies in patients with BD and a co-occurring PD or GAD. Quetiapine was superior to placebo and divalproex XR in reducing depressive and anxiety symptoms as measured by the Clinical Global Improvement Scale for Anxiety (CGI-21 anxiety), Sheehan Panic Disorder Scale, the HAM-A, and the Patient Global Improvement for Anxiety (PGI-21 anxiety) scale.27 Finally, a multicentric prospective, open-label, controlled (active comparator), randomized study for the evaluation of the efficacy of quetiapine XR versus sertraline in addition to previous mood stabilizer treatment (lithium or valproate) in the treatment of the adult bipolar depression found that the mean changes in total Montgomery-Åsberg Depression Rating Scale (MADRS) score and HAM-A from baseline to weeks 2, 4, and 8 were higher in the quetiapine XR group when compared with the sertraline group. However, a measure of significance was not available for this study.28

One study did not demonstrate statistically significant differences between quetiapine and placebo on depressive and anxiety symptoms in depressed bipolar patients with comorbid GAD. The authors underlined how the results of their study disagree with the data available in the literature on the efficacy of quetiapine both in pure bipolar depression and in pure GAD, suggesting that data from relatively “pure” bipolar patients may not be generalizable to a highly comorbid population.29

Quetiapine and BD: Data From Secondary Analyses

The RCT from Calabrese et al21 was examined by several post hoc analyses concerning the anxiety dimension: a first study on 542 patients with bipolar depression showed that quetiapine improved HAM-A total and HAM-A anxious mood item and tension item scores when compared with placebo. When bipolar types I and II were considered separately, quetiapine showed significant improvement in the scores considered [HAM-A total score, HAM-A anxious mood and tension items, HAM-A psychic and somatic subscales, MADRS inner tension item, and Hamilton Rating Scale for Depression (HAM-D) psychic anxiety item]. The same result was observed for BD type II, with the exception of HAM-A.30 Two post hoc analyses included the results from Thase et al22 with a different final sample size. Again, quetiapine was superior to placebo in improving depressive and anxiety symptoms as measured by the HAM-A total score.31,32 A second post hoc analysis on these 2 RCTs confirmed and extended these findings on 978 patients, showing that quetiapine was superior to placebo in relieving both depressive and anxiety symptoms for patients with rapid-cycle BD.33

A post hoc analysis of 4 RCTs on bipolar depression21–23,26,34 analyzed a total of 2873 patients to describe changes in the severity of depression, anxiety, and overall burden of illness during 8 weeks of treatment with quetiapine versus lithium, paroxetine, and placebo. Quetiapine showed earlier and greater improvements than comparators as measured by the MADRS, HAM-A, Clinical Global Impression-Bipolar Severity (CGI-BP-S) total scores.35

Nevertheless, not all findings are concordant. A post hoc analysis of the RCT from Gao et al29 on their study from 2014 showed that the effect of quetiapine XR did not differ from placebo in reducing depression, anxiety symptoms, alcohol, and cannabis in bipolar patients with recent alcohol/cannabis use. However, in patients without recent alcohol/cannabis use, placebo was even better than quetiapine XR in reducing depressive and anxiety symptoms.36

Quetiapine and MDD

In addition to BDs, quetiapine is also effective on anxiety symptoms in MDD. Liebowitz et al37 suggested that quetiapine may be useful as maintenance therapy because it is superior to placebo in stabilizing improvements in HAM-A total score. The efficacy of quetiapine compared with placebo on depressive (MADRS total score) and anxiety symptoms (HAM-A total score) in MDD was also confirmed in other 4 studies with a comparable study design, the same primary outcome, and large sample size (700, 487, 335, and 446).38–41 In a study from 2007, adding quetiapine to selective serotonin reuptake inhibitors or venlafaxine was more effective than placebo in patients with MDD, comorbid anxiety symptoms, and residual depressive symptoms.42 Another study found that quetiapine versus placebo was effective in reducing depressive and anxiety symptoms similarly to duloxetine versus placebo; quetiapine was effective and safe, with a significant improvement in symptoms demonstrated from week 1.43 Some negative findings have also been reported: a randomized, double-blind, placebo-controlled trial on quetiapine augmentation of fluoxetine in MDD indicated that add-on therapy of quetiapine to fluoxetine improved sleep over the first few weeks of treatment, but failed in accelerating the improvement in depression or anxiety as measured by MADRS, HAM-A, and CGI scores when compared with the fluoxetine plus placebo group.44 In another study, limited by the small sample size, augmentation of antidepressant treatment with quetiapine XR improved HAM-A and CGI-S scores at week 4 but not at week 8 in patients with either a primary anxiety disorder or a mood disorder with comorbid anxiety symptoms.45 Finally, in a study with probably insufficient power due to the low numerosity of the sample, quetiapine did not improve HAM-A total score when compared with placebo.46

Quetiapine and MDD: Data From Secondary Analyses

In a post hoc analysis of 2 RCTs,41,43 quetiapine XR resulted superior to placebo in improving depressive symptoms in both anxious and nonanxious groups of patients as measured by HAM-A scale and HAM-D anxiety/somatization factor score.47 A post hoc analysis starting from 2 different RCTs38,39 evaluated adjunctive quetiapine XR (150 or 300 mg/d) in patients with MDD and inadequate response to antidepressants. A first analysis divided 2 groups of patients using HAM-A scores (anxious and nonanxious). For the nonanxious group, both quetiapine dosages were better than placebo in reducing HAM-A and MADRS total score, whereas in the anxious group, this effect was observed only for quetiapine 300 mg. A second analysis divided the groups based on the scores in HAM-D anxiety/somatization factor. Quetiapine 150 and 300 were better than placebo in the anxious group.48

Reported Adverse Effects

Adverse drug effects for quetiapine, placebo, and other drugs are reported in Table 5. Four studies did not collect the presence of side effects.25,30,47,48 Among the other 23 studies, the most investigated symptoms were dry mouth (100% of the studies), dizziness (96%), sedation (87%), somnolence (87%), constipation (78%), nausea (74%), extrapyramidal-like symptoms (70%), headache (61%), fatigue (57%), weight gain (52%), and diarrhea (52%).

TABLE 5 - Rates of Adverse Effects Reported by Each Study
Side Effects Reported, %
Source Drug Dry Mouth Sedation Somnolence Dizziness Constipation Headache Nausea Fatigue EPS/Tremor Respiratory Symptoms Weight Gain Increased Appetite
Calabrese et al, 2005 PLC 7.8 6.1 8.3 8.3 4.4 20.0 12.8 4.4 2.2 10.0 1.7
QTP 300 40.6* 29.6* 27.4* 16.8* 11.7* 12.3 7.8 8.9 6.7 5.0 8.5
QTP 600 44.1* 32.2* 24.4* 22.8* 11.1* 10.0 8.9 11.7 2.2 7.2 9.0
Thase et al, 2006 PLC 18.0 10.2 4.8 5.4 3.0 16.8 13.2 7.8 6.6 2.8
QTP 300 42.7 32.2 29.8 14.0 8.2 8.8 7.6 9.4 13.3 3.9
QTP 600 47.0 27.4 29.8 16.1 10.1 8.3 10.7 11.3 10.1 8.6
McIntyre et al, 2007 PLC 13.7 48.2 48.2 24.1 0.0 27.5 10.3 10.3 20.6
QTP 65.5 86.2 86.2 20.6 13.7 13.7 3.4 34.0 17.2
Garakani et al, 2008 PLC + fluoxetine 8.8 7.0 12.3 22.8 12.3 7.0
QTP + fluoxetine 12.3 26.3* 17.5 14.0 5.3 8.7
Weisler et al, 2009 PLC 8.8 11.0 11.0 5.5 2.8 14.9 6.1 4.4 3.9 3.9
QTP 50 22.1 27.1 18.2 8.8 7.2 12.2 7.7 6.1 3.3 4.4
QTP 150 37.5 35.8 19.9 10.8 8.5 13.6 8.5 8.0 5.7 5.1
QTP 300 41.3 30.7 29.1 10.6 8.9 14.5 8.9 6.1 5.0 4.5
Cutler et al, 2009 PLC 8.9 5.1 7.0 10.8 6.4 9.6 0.0 3.2 7.0 1.9
QTP 150 33.6 38.8 24.3 14.5 5.9 10.5 2.6 4.6 2.0 5.9
QTP 300 38.2 36.8 27.0 19.1 8.6 36.2 5.3 5.3 2.6 3.9
Duloxetine 18.8 16.1 12.8 16.8 11.4 9.6 6.7 8.1 4.0 2.0
Bauer et al, 2009 PLC + ADP 6.8 4.3 3.1 7.5 3.7 6.2 3.1 5.0 6.2
QTP 150 + ADP 20.4 9.6 16.8 11.4 4.2 5.4 13.2 4.2 3.0
QTP 300 + ADP 35.6 12.9 23.3 9.2 10.4 5.5 14.7 4.9 3.1
McElroy et al, 2010 PLC 5.6 4.8 8.1 5.6 1.6 12.9 5.6 3.2 2.4 2.4
QTP 300 21.8 12.8 18.9 11.5 5.8 9.9 5.8 6.6 8.2 3.3
QTP 600 25.8 16.0 17.6 13.9 9.0 9.8 9.0 7.8 9.8 5.3
Paroxetine 9.9 8.3 5.8 6.6 5.0 15.7 12.4 3.3 4.1 2.5
Young et al, 2010 PLC 1.5 1.5 3.8 5.3 2.3 13.7 7.6 4.6
QTP 300 14.2* 6.2 18.1* 9.6 4.6 7.3 3.8 5.8
QTP 600 15.0* 5.2 17.6* 11.2 7.9 8.6 5.6 10.9
Lithium 7.4* 0.7 8.8 4.4 2.9 9.6 16.9 14.0
Liebowitz et al, 2010 PLC 1.6 0.3 0.0 4.4 0.3 11.4 9.9 2.6 1.8 6.5 1.6 0.0
QTP 3.6 2.6 3.8 6.6 2.0 6.9 3.6 4.3 2.8 7.2 9.7 0.0
El-Khalili et al, 2010 PLC + ADP 8.8 4.1 4.1 5.4 3.4 13.5 8.1 4.7 3.4 0.7 5.4
QTP 150 + ADP 35.1 16.9 29.1 11.5 7.4 14.2 8.8 15.0 3.4 2.0 5.4
QTP 300 + ADP 44.3 22.1 28.9 14.1 10.7 7.4 10.1 6.7 8.1 6.0 6.7
Sheehan et al, 2012 PLC 14.0 6.0 33.0 2.0 24.0 27.0 8.0
QTP 31.0* 12.0 49.0 2.0 8.0 18.0 14.0
Divalproex 6.0 6.0 37.0 6.0 24.0 24.0 12.0
Chen et al, 2012 PLC 6.0 3.0 3.0 3.0 6.0 3.0 0.0 3.0 8.0
QTP 19.0 8.0 11.0 11.0 8.0 3.0 3.0 3.0 8.0
NCT00857584, 2012 QTP 21.4 35.6 14.2 7.1
Sertraline 0.0 7.6 7.6 0.0
Katila et al, 2013 PLC 10.5 8.1 15.1 2.3 16.3 4.7 4.1 2.3 4.1
QTP 20.5 33.1 19.3 6.0 21.1 5.4 7.8 7.2 5.4
Gao et al, 2014 PLC 20.0 31.1 13.3 6.7 6.7 2.2
QTP 58.7 45.7 10.9 15.2 4.3 8.7
Li et al, 2016 PLC 8.3 0.0 0.0 16.6 0.0 16.6 8.3
QTP 54.5* 35.4* 35.3* 9.0 27.2 45.4 0.0
Gao et al, 2018 QTP 50.0* 55.0 30.0 10.0 5.0* 15.0 0.0 5.0 10.0
Lithium 0.0 54.5 6.6 0.0 26.0 13.3 13.3 6.6 6.6
Vieta et al, 2007 PLC 0.0 7.9 7.9 13.2 2.6 5.3 0.0 2.6 3.3
QTP 300 48.9 29.8 25.5 21.3 12.8 28.5 4.3 4.3 11.2
QTP 600 42.4 30.3 21.2 24.2 21.2 21.2 9.1 12.1 12.2
Weisler et al, 2008 PLC 12.2 8.3 7.0 7.4 3.0 3.9 3.0
QTP 300 40.9 25.9 32.8 15.5 9.1 11.2 5.4
QTP 600 44.0 26.7 31.0 19.8 12.1 11.6 9.2
Lydiard et al, 2009 PLC 12.7 8.1 6.6 6.9 3.7 2.6 1.2
QTP 300 43.3 30.9 28.6 15.4 10.0 4.3 2.9
QTP 600 43.7 29.9 27.0 19.5 10.6 6.3 5.7
Datto et al, 2016 PLC BD-I 8.0 6.4 5.6 7.8 3.2 13.8 10.0 4.4 0.8 5.8 2.2
PLC BD-II 9.5 5.8 7.4 5.8 4.5 17.8 9.1 5.8 0.8 5.0 2.1
QTP BD-I 28.8 17.7 13.6 13.4 8.5 8.8 7.0 6.2 2.1 3.4 7.0
QTP BD-II 31.3 20.3 20.6 14.9 7.8 10.2 7.4 9.2 2.5 2.4 7.0
Lithium BD-I 4.6 1.1 5.7 4.6 2.3 15.8 11.5 1.1 3.4 2.3 2.3
Lithium BD-II 12.2 0.0 14.3 4.1 4.1 15.6 26.5 2.0 10.2 0.0 2.0
Paroxetine BD-I 9.2 7.9 1.3 7.9 7.9 15.8 9.2 1.3 2.6 2.6 2.6
Paroxetine BD-II 11.1 8.9 13.3 4.4 0.0 15.6 17.8 6.7 2.2 0.0 2.2
Gao et al, 2017 PLC without A/C 13.6 2.3 4.5
PLC with A/C 9.1 6.1 9.1
QTP without A/C 16.4 13.7 2.7
QTP with A/C 23.4 14.1 6.3
Source Drug Insomnia Pain Anxiety Irritability Diarrhea Dyspepsia Blurred Vision Urinary Disturbances Increased Dreaming Decreased Appetite Sexual Dysfunction Other Side Effects
9.0 akathisia
Calabrese et al, 2005 PLC 12.0
QTP 300 9.0
QTP 600
Thase et al, 2006 PLC
QTP 300
QTP 600 31.0 13.7 10.3 17.2 3.4 0.0 10.3 flu-like
McIntyre et al, 2007 PLC 0.0 10.3 0.0 13.7 10.3 13.7 6.8
QTP 7.0 12.3 22.8
Garakani et al, 2008 PLC + fluoxetine 3.5 7.0 14.0
QTP + fluoxetine 7.7 2.2 3.9 8.8 2.8 0.6
Weisler et al, 2009 PLC 5.0 1.7 6.1 6.6 2.2 1.7
QTP 50 6.8 5.7 5.7 6.3 5.7 1.1
QTP 150 6.7 5.0 3.4 3.4 2.8 2.2
QTP 300 7.0 4.5 6.4 4.5 1.9 1.3 0.6 0.6 0.6 hyperhidrosis
Cutler et al, 2009 PLC 1.3 1.3 4.7 3.9 5.3 3.3 6.6 3.3 0.0
QTP 150 1.3 5.9 2.6 5.3 5.3 2.0 2.0 0.0 0.0
QTP 300 14.8 0.0 10.7 0.0 2.7 5.4 2.7 5.4 7.4
Duloxetine
Bauer et al, 2009 PLC + ADP
QTP 150 + ADP
QTP 300 + ADP 10.5 5.6 4.0 2.4 0.0
McElroy et al, 2010 PLC 2.1 0.4 1.6 3.3 0.8
QTP 300 2.0 2.5 2.9 5.7 0.8
QTP 600 13.2 5.0 6.6 1.7 5.0
Paroxetine 5.3 3.8
Young et al, 2010 PLC 3.3 2.3
QTP 300 1.1 2.6
QTP 600 8.8 6.6
Lithium 14.8 3.1 6.8 0.5
Liebowitz et al, 2010 PLC 5.6 0.8 5.4 1.5
QTP 6.8 6.1 6.8 0.7
El-Khalili et al, 2010 PLC + ADP 10.8 6.1 6.8 0.7
QTP 150 + ADP 8.1 3.4 6.7 2.0
QTP 300 + ADP 8.0 2.0 tingling
Sheehan et al, 2012 PLC 2.0 16.0
QTP 4.0 2.0
Divalproex 3.0 3.0
Chen et al, 2012 PLC 0.0 3.0
QTP 0.0 0.0 0.0
NCT00857584, 2012 QTP 15.3 15.3 15.3
Sertraline 5.8 7.0
Katila et al, 2013 PLC 7.8 5.4
QTP 6.7 2.2
Gao et al, 2014 PLC 10.9 6.5
QTP 25.0 0.0 0.0 0.0
Li et al, 2016 PLC 0.0 9.0 9.0 9.0*
QTP 0.0* 15.0 15.0
Gao et al, 2018 QTP 26.6 0.0 0.0
Lithium 2.6
Vieta et al, 2007 PLC 4.3
QTP 300 12.0
QTP 600
Weisler et al, 2008 PLC
QTP 300
QTP 600 2.0
Lydiard et al, 2009 PLC 3.4
QTP 300 5.3
QTP 600 6.6 2.6 4.8 2.8 1.8 flu-like
Datto et al, 2016 PLC BD-I 6.2 4.1 7.8 2.5 2.5
PLC BD-II 2.8 1.1 3.2 4.2 1.2
QTP BD-I 1.6 2.7 3.3 5.2 2.7
QTP BD-II 9.2 4.6 2.3 3.4 2.3
Lithium BD-I 8.2 2.0 14.3 2.0 2.0
Lithium BD-II 10.5 3.9 7.9 2.6 0.0
Paroxetine BD-I 17.8 6.7 4.4 0.0 6.7
Paroxetine BD-II
Gao et al, 2017 PLC without A/C
PLC with A/C
QTP without A/C
QTP with A/C
The first half of the table presents side effects Dry Mouth, Sedation, Somnolence, Dizziness, Constipation, Headache, Nausea, Feature, EPS/Tremor, Respiratory Symptoms, Weight Gain, and Increased Appetite.
The second half of the table presents side effects Insomnia, Pain, Anxiety, Irritability, Diarrhea, Dyspepsia, Blurred Vision, Urinary Disturbances, Increased Dreaming, Decreased Appetite, Sexual Dysfunction, and Other Side Effects.
*Statistical difference with placebo tested and significant.
Statistical difference with placebo tested and not significant.
A/C indicates alcohol/cannabis use; ADP, antidepressant; PLC, placebo; QTP, quetiapine.

Although the adverse effects of quetiapine seem to be dose dependent in some instances, data do not converge on a clear trend in this sense.

Only 7 studies reported statistical differences between quetiapine and placebo or other drugs as for their adverse effects profile. According to their results, quetiapine use was associated with significantly higher incidence of symptoms of dry mouth,21,23,27,46 sedation,21,23,44,46 somnolence,21,23,46 dizziness,21 constipation,21,23 and blurred vision46 relative to placebo; however, other studies reported no significant differences in these symptoms.23,27,44,46 When compared with duloxetine,43 paroxetine,26,35 sertraline,28 divalproex,27 and lithium,23,24,35 quetiapine showed a better safety profile concerning symptoms of headache, nausea, insomnia, and diarrhea; in relation to lithium, it may also cause less extrapyramidal-like manifestations23,35 and pain.24

Several studies reported anxiety, insomnia, and irritability among adverse effects. When compared with placebo, quetiapine was associated with lower rates of anxiety,26,35,42,44 insomnia,23,26,35,37,41–43,46 and irritability,37,42 whereas other studies reported opposite effects.39–41,43,46 When tested versus active comparators, quetiapine was also associated with less anxiety, insomnia, and irritability relative to duloxetine,43 paroxetine,26,35 sertraline,28 and lithium.23,35 One study showed an opposite trend, favoring lithium; however, the difference was not statistically significant.24

DISCUSSION

Possible Basis for Quetiapine Efficacy in Reducing Depression and Anxiety in Mood Disorders

Quetiapine received Food and Drug Administration approval in 1997 for the treatment of schizophrenia in adult patients, but it has been proven effective in a wide range of conditions such as mood disorders, anxiety disorders, autism spectrum disorders, dementia, and delirium.49 It is a second-generation antipsychotic characterized by antagonism for D2 receptors as well as for H1, 5-HT2A, 5-HT2C, and alpha-1 receptors.50 Quetiapine has a relevant hepatic first-pass metabolism; among its metabolites, norquetiapine (produced by the action of isoenzyme CYP3A4 in the cytochrome P450 system) has the most significant psychoactive effect. It acts as a norepinephrine reuptake transporter inhibitor, showing antagonist activity for the H1, 5-HT1A, 5-HT1E, 5-HT2A, 5-HT2B, and 5-HT7 receptors; the alpha-1 adrenergic receptor; and the M1, M3, and M5 muscarinic receptors.51,52 Because quetiapine resulted effective in the treatment of psychotic disorders as well as mood and anxiety disorders, it can be considered as a multifunctional psychoactive drug. A possible explanation of its wide array of effects can thus be given by the action exerted on all the monoaminergic systems by both the parent and the metabolite compounds.53 A second source of information comes from animal studies, where norquetiapine showed antidepressant activity on rodents forced under stressing conditions. Furthermore, both quetiapine and its metabolite exhibited effects on anxiety-related behaviors. These effects were mediated either by a full agonism54 or by a partial agonism for 5-HT1A receptors.55 Other studies reported that quetiapine treatment prevents anxiety-related behaviors in mice by several mechanisms: i) improving the density of GABAergic neurons56; ii) exerting a neuroprotective effect against the neurotoxic activity of dl-amphetamine57; iii) exerting an antidepressant and anxiolytic-like effect after the occurrence of a global cerebral ischemia58; iv) reducing glial activation and neuroinflammation59; and v) showing H1 antagonist activity, which has been demonstrated to decrease anxiety in rodents.60,61 Preliminary data have been provided by neurofunctional imaging: functional magnetic resonance imaging study on the human brain found that the anxiolytic effect of quetiapine in a sample of 15 patients (mean dose of 167 ± 41 mg at week 8) may be related to an increased resting state cortico-amygdalar connectivity.62

On the clinical side, the improvement in anxiety symptoms given by quetiapine could be mediated either by a direct anxiolytic effect or indirectly by its stabilizing effect on mood. This is not surprising if one considers the shared genetic vulnerability for anxiety and mood disorders: a review of 23 twin studies and 12 family studies suggests that there is substantial overlap among the genetic factors of MDD and anxiety disorders, GAD in particular (correlation between genetic factors varying from 0.86 to 1.00).63 The deep intertwinement between mood and anxiety disorders is further supported by the therapeutic effect that mood stabilizers such as lamotrigine, valproate, olanzapine, and quetiapine exert on anxiety-related symptoms.64–66 These considerations are coherent with previous hypotheses according to which anxiety can be considered (at least, in part) an epiphenomenon surging from an underlying mood disorder, rather than a true comorbid disorder.67,68 This view partially relates to the concept of mixed states, where depressed and elevated symptoms coexist along a continuum of clinical configurations combining the dimensions of mood, thought, and activity.69,70 For instance, the sedative and antipsychotic effects exerted by quetiapine may help stabilize the level of activity and thought components, respectively. In fact, anxiety can be understood as a form of excitation or hyperarousal together with irritability and agitation.71,72 The presence of excitatory symptoms during mixed depression should not be underestimated, as the use of antidepressants in these patients might be associated with adverse effects such as insomnia and agitation.73 For what concerns the thought component, the role of second-generation neuroleptics—including quetiapine—in the treatment of mixed states has been receiving increasing support.71

Concerning the trials included in our review, the tools used to measure anxiety do not make it possible to discriminate between anxiety as a true comorbid disorder and anxiety as a manifestation of hyperarousal in mixed states, which would be expected to respond to antiexcitatory agents such as quetiapine. Therefore, we could only rely on indirect factors to establish a differentiation between the 2 conditions. First, we assessed whether studies reported an improvement of anxiety independently from other features of the underlying mood disorder. Most trials report that anxiety improves alongside depression symptoms, thus failing to suggest a specific antianxiety effect of quetiapine. In addition, 1 study checked for an association between changes in anxiety and sedative adverse effects, observing that the decrease in anxiety levels was similar in patients who reported sedation or somnolence and those who did not, thus suggesting that the apparent effect of quetiapine on anxiety was independent from these adverse effects.30

Limitations

This study is not without limitations. First, in 5 studies, the sample size was relatively small (fewer than 50 subjects), with a high probability of not reaching a sufficient statistical power. Second, data on anxiety were a secondary outcome in most studies. Thus, conducting new trials that primarily focus on the anxiety dimension in mood disorders may add novel and more fine-grained findings to the literature. In addition, measures of anxiety that were used by included trials could not differentiate between anxiety as a comorbid condition or as a state of hyperarousal in mixed depression; for this reason, our discussion on this distinction was limited to speculative considerations.

CONCLUSIONS

The evidence provided by the selected RCTs showed with good levels of concordance that quetiapine is effective to control anxiety-related symptoms in patients with mood disorders. Anxiety-related symptoms showed a better response to quetiapine than to placebo or an active comparator in both unipolar and bipolar depression.

AUTHOR DISCLOSURE INFORMATION

The authors declare no conflicts of interest.

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Keywords:

quetiapine; mood disorders; bipolar disorders; major depressive disorder; anxiety

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