Health Technology Review

Quetiapine for Major Depressive Disorder

Main Take-Aways

• Quetiapine could be used as second-line augmentation treatment for major depressive disorder in patients who had partial or no response to an adequate dose and duration of 2 or more antidepressants.

• Second-line antipsychotics, such as quetiapine, in combination with an antidepressant, may be used as a first-line treatment for major depressive disorder that is very severe or has associated psychotic features.

• Quetiapine may reduce symptoms of depression and improve social functioning compared with lithium.

Key Messages

What Is the Issue?

• Quetiapine is a second-generation antipsychotic (SGA) or atypical antipsychotic drug primarily used for treating schizophrenia and bipolar disorder. Quetiapine extended-release is also indicated by Health Canada for the symptomatic relief of major depressive disorder (MDD) when currently available approved antidepressant drugs have failed.

• Decision-makers are interested in understanding the evidence regarding quetiapine’s clinical effectiveness, safety, and place in therapy relative to other medications for the treatment of MDD.

What Did We Do?

We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2020.

What Did We Find?

• The evidence suggests that quetiapine and other SGAs (particularly aripiprazole, brexpiprazole, cariprazine, olanzapine, risperidone, and ziprasidone) have similar efficacy but have unique safety profiles when used for the treatment of adults with treatment-resistant MDD.

• The evidence also suggests that treatment with quetiapine reduced symptoms of treatment-resistant depression compared to treatment with lithium.

• Evidence-based guidelines recommend using quetiapine as a second-line augmentation treatment option for MDD in patients whose disease had partial or no response to an adequate dose of initial pharmacotherapy.

• The Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline recommends atypical antipsychotics such as quetiapine in combination with an antidepressant as the first-line treatment for MDD with psychotic features. The Royal Australian and New Zealand College of Psychiatrists (RANZCP) guideline suggests using quetiapine as monotherapy or adjunct therapy for patients with major depression.

What Does It Mean?

• Quetiapine could be used as second-line augmentation treatment for MDD in patients whose disease had partial or no response to an adequate dose and duration of 2 or more antidepressants (i.e., those with treatment-resistant depression or difficult to treat depression). SGAs such as quetiapine, in combination with an antidepressant, may be used as a first-line treatment for MDD that is very severe or has associated psychotic features.

• Quetiapine may reduce symptoms of depression and improve social functioning compared with lithium. However, patients reported more side effects with quetiapine than lithium and viewed the side effects of lithium as more manageable.

• Factors such as patient characteristics, patient tolerability, patient values, side effect profiles of different treatment options, and clinician expertise may also be important to guide choice of treatment for MDD.

Context and Policy Issues

What Is Major Depressive Disorder?

Major depressive disorder (MDD) is a mental illness defined by a depressed mood or loss of interest or pleasure in doing activities that were previously enjoyed (i.e., anhedonia) that lasts most of the day for at least 2 consecutive weeks, without a history of mania or hypomania.¹ In 2022, 7.6% of people aged 15 and older in Canada had had at least 1 major depressive episode in the previous 12 months.² Treatment-resistant depression is a subset of MDD in which a patient’s disease does not respond to 2 or more adequate trials of antidepressant medications.³ “Difficult to treat” deрrеsѕiοn has also been used to describe patients whose disease does not respond sufficiently to antidepressants.³

MDD involves more than having decreased interest or depressed mood.⁴ Individuals diagnosed with MDD typically experience 4 or more of the following symptoms along with either depressed mood or anhedonia: insomnia or hypersomnia, unintended change in appetite or weight, increased restlessness or slowing down, fatigue or low energy, poor concentration or memory, feelings of worthlessness or guilt, or recurrent suicidal thoughts and behaviours.⁴

The symptoms of MDD can impair an individual’s ability to function at home, at work, or in social settings.^4,5 People with MDD are at a higher risk of developing and experiencing poorer health outcomes from a range of comorbid medical conditions such as diabetes, metabolic syndrome, obesity, and cardiovascular disease.⁶ Thus, treatments that improve symptoms of depression and functional outcomes are a priority for MDD treatment.⁷

What Are Current Treatment Options for MDD?

The treatment goals for MDD are to achieve symptom remission, restore baseline functioning, and prevent relapse.⁴ Remission refers to resolution of symptoms. Evidence suggests that a delay in treatment is associated with poorer clinical outcomes,⁷ so early diagnosis and treatment is critical to achieving remission of symptoms and functional recovery.⁷

Standard treatment approaches for MDD include the use of antidepressant medications, psychotherapy, or a combination of both.⁴ Exercise and other supplemental interventions can be used as an alternative to standard treatment in some individuals with mild MDD and as an adjunct to standard treatment for all individuals with MDD.⁴ The choice of treatment strategies is primarily based on depression severity, though other factors such as patient preference, treatment availability, cost, and ease of use should be considered. The severity of depression depends on the degree of functional impairment and the number, frequency, intensity, and duration of an individual’s symptoms.⁴

What Is Quetiapine?

Quetiapine is available in 2 oral formulations — immediate-release tablets in 25 mg, 100 mg, 200 mg, and 300 mg doses of quetiapine fumarate⁸ and extended-release tablets in 50 mg, 150 mg, 200 mg, 300 mg, and 400 mg doses of quetiapine fumarate.⁹ Quetiapine is an atypical or second-generation antipsychotic (SGA) drug primarily used for treating schizophrenia and bipolar disorder.⁸ Additionally, the extended-release formulation is also indicated as an adjunct or augmentation treatment for adults with MDD when currently available antidepressant drugs have failed either due to lack of efficacy and/or lack of tolerability.⁹ Off-label use of quetiapine has been documented for several conditions such as agitation, delirium, delusional infestation, posttraumatic stress disorder, and insomnia.¹⁰ The side effects of quetiapine include somnolence, dizziness, dry mouth, withdrawal (discontinuation) symptoms, elevations in serum triglyceride levels, elevations in total cholesterol (predominantly low-density lipoprotein cholesterol), decreases in high-density lipoprotein cholesterol, weight gain, decreased hemoglobin, and extrapyramidal symptoms (involuntary movements induced by medications).^8,9

Why Is It Important to Do This Review?

Higher doses of quetiapine and concomitant use with central nervous system drugs are associated with an increased risk of adverse effects.^11,12 There are many available treatment options for depression but limited direct comparative trials of quetiapine versus relevant comparators. Findings from a previous Canada’s Drug Agency (CDA-AMC) report published in 2020 indicated that while quetiapine monotherapy may be more efficacious than some antidepressants in older adults, and some guidelines have recommended quetiapine as add-on therapy in treatment-resistant depression, its comparative efficacy remains uncertain, and it is associated with higher rates of adverse events (AEs) relative to its alternatives. These findings, which were limited by lack of direct comparative trials, underscore the need for an updated review of the current evidence on the efficacy and safety of quetiapine for treatment of people with MDD.

Research Questions

1. What is the clinical effectiveness and safety of quetiapine versus other drug interventions for adults with MDD?

2. What are the evidence-based guidelines regarding the use and administration of quetiapine for adults with MDD?

Methods

Literature Search Methods

An information specialist conducted a literature search on key resources including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, and the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were quetiapine and depression. Search filters were applied to limit retrieval to health technology assessments, systematic reviews (SRs), meta-analyses, indirect treatment comparisons, randomized controlled trials (RCTs), controlled clinical trials, and guidelines. The search was completed on April 11, 2025, and limited to English-language documents published since January 1, 2020.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. As an update to a previous CDA-AMC report on quetiapine for MDD, articles were included if they were made available since the previous search date and were not included in the 2020 CDA-AMC report. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

HTA = health technology assessment; MA = meta-analysis; NMA = network meta-analysis; RCT = randomized controlled trial.

^aA guideline is defined as a systematically developed statement or set of statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. A guideline is considered evidence-based if a systematic search of the literature was undertaken to inform the recommendations.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1 or they were duplicate publications. SRs in which all relevant studies were captured in other more recent or more comprehensive SRs were excluded. Primary studies retrieved by the search were excluded if they were captured in 1 or more included SRs. Guidelines with an unclear methodology were also excluded.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess Systematic Reviews 2 (AMSTAR 2)¹³ for SRs, the ISPOR (the Professional Society for Health Economics and Outcomes Research) questionnaire to assess the relevance and credibility of a network meta-analysis¹⁴ for network meta-analyses (NMAs), the Standards for Reporting Qualitative Research (SRQR)¹⁵ for qualitative research, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument for guidelines.¹⁶ Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 285 citations were identified in the literature search. Following screening of titles and abstracts, 259 citations were excluded and 26 potentially relevant reports from the electronic search were retrieved for full-text review. Six potentially relevant publications were retrieved from the grey literature search for full-text review. Of these 32 potentially relevant articles, 22 publications were excluded for various reasons, and 10 publications met the inclusion criteria and were included in this report. The included publications were 3 SRs,^17-19 1 RCT,²⁰ 1 qualitative study,²¹ and 5 evidence-based guidelines.^22-26 Appendix 1 presents the PRISMA²⁷ flow chart of the study selection.

Summary of Study Characteristics

Appendix 2 provides details regarding the characteristics of the included publications.

Included Studies for Research Question 1: What Is the Clinical Effectiveness and Safety of Quetiapine Versus Other Drug Interventions for Adults With MDD?

Study Design

Three SRs,^17-19 1 RCT,²⁰ and 1 qualitative study²¹ were included to answer research question 1. The SRs were authored by Bai et al. (2025),¹⁷ Guo et al. (2024),¹⁸ and Yan et al. (2022).¹⁹ The 2 primary studies included an RCT by Cleare et al. (2025)²⁰ and a qualitative study by McKeown et al. (2022).²¹

The SR by Bai et al. (2025)¹⁷ included 23 RCTs in total and used Bayesian network meta-regression to compare the efficacy of SGA augmentation (including quetiapine) to antidepressants in the treatment of treatment-resistant depression. The literature search covered available literature from electronic database inception to May 15, 2024. The follow-up duration of the included trials ranged from 6 weeks to 16 weeks. The effect size was obtained using a fixed-effects model or random-effects model based on the I² value, which describes the percentage of total variation across trials that is due to heterogeneity rather than chance or sampling error.

The SR by Guo et al. (2024)¹⁸ included 72 RCTs and used NMAs to assess the efficacy and safety of 2 SGAs (brexpiprazole and quetiapine), physical therapies (electroconvulsive therapy and transcranial magnetic stimulation) and novel medications (i.e., esketamine, ketamine, psilocybin) for treatment-resistant depression. The literature search dates covered available literature from electronic database inception to January 28, 2024. The median duration of treatment was 8 weeks (range, 2 to 12 weeks). The SR by Guo et al. (2024)¹⁸ was broader in scope as it included additional network comparisons beyond those of interest for the current review (i.e., different types of physical therapies and placebo). Only the relevant comparisons of quetiapine versus other drug interventions will be described further in this report.

The SR by Yan et al. (2022)¹⁹ included 33 RCTs and used NMAs to evaluate the comparative efficacy and acceptability of SGAs (including quetiapine) as adjunctive therapy in combination with antidepressants in patients with suboptimal antidepressant responses. The literature search covered available literature from electronic database inception to May 25, 2021. A frequentist random-effects NMA using multivariate meta-analysis was performed. Dichotomous outcomes were reported as odds ratios with 95% credible intervals.

The 2 primary studies were the RCT by Cleare et al. (2025)²⁰ and the qualitative study by McKeown et al. (2022).²¹ The RCT by Cleare et al. (2025), referred to as the “Lithium Versus Quetiapine in Depression” (LQD). study was a phase IV, head-to-head. Pragmatic. open-label superiority trial that compared the clinical effectiveness and cost-effectiveness of quetiapine and lithium augmentation for adults with treatment-resistant depression. The study was conducted between December 5, 2016, and July 26, 2021. Patients were randomized using a 1:1 ratio to lithium or quetiapine and followed up for 12 months or 52 weeks. Only the clinical effectiveness component is relevant to this rapid review.

The qualitative study by McKeown et al. (2022)²¹ was conducted to explore patient perspectives and experiences of augmentation treatment with quetiapine versus lithium in treatment-resistant depression. It was an optional add-on to the LQD trial, conducted with a subset of participants. Between November 2018 and February 2020, LQD study participants were invited to participate in semistructured interviews at their week 52 study assessments after randomization to treatment arms.

Country of Origin

All 3 SRs were conducted in China.^17-19 The RCT²⁰ and the qualitative study²¹ were conducted in the UK.

Patient Population

The patient population in the 5 studies (SRs,^17-19 the RCT,²⁰ and the qualitative study²¹) were adults with treatment-resistant depression.

The SR by Bai et al. (2025)¹⁷ included 10,679 patients across 23 RCTs. The average age of the participants varied between 38.1 to 46.6 years. The proportion of females ranged from 35.5% to 78.0%.¹⁷

The SR by Guo et al. (2024)¹⁸ included 12,105 patients across 72 RCTs. The mean age of the participants was 46.6 years (standard deviation [SD] = 11.9 years) and 69.3% of the participants on average were female across the included studies.

The SR by Yan et al. (2022)¹⁹ consisted of 4,543 and 6,059 patients across 33 RCTs randomized to the placebo and antipsychotics groups, respectively. The mean age of the participants was 44.5 years (SD = 11.5 years). The majority of the participants (65%) in the included studies were female.

A total of 212 patients were enrolled in the RCT by Cleare et al. (2025). ²⁰ The mean age of the participants was 42.4 years (SD = 14 years), and there were more female (54%) than male (46%) participants.

The qualitative study by McKeown et al. (2022)²¹ consisted of 32 patients with a mean age of 43.1 years (15 years). The proportion of female participants (59.4%) was higher than male participants (40.6%).

Interventions and Comparators

In the SR by Bai et al. (2025),¹⁷ quetiapine as augmentative therapy was compared with antidepressant therapy and other SGAs of varying dosing regimens. Eight SGAs with up to 24 dosing regimens were compared: aripiprazole, brexpiprazole, cariprazine, olanzapine, combination olanzapine and fluoxetine, quetiapine, risperidone, and ziprasidone. Similarly, the SR by Yan et al. (2022)¹⁹ compared the same SGAs as the Bai et al. (2025) SR, except the olanzapine-fluoxetine combination. Unlike the Bai et al. (2025) SR, multiple dosing regimens of the SGAs were not accounted for in the Yan et al. (2022) NMA. In the SR by Guo et al. (2024),¹⁸ 5 drug interventions were compared which included 2 SGAs (i.e., brexpiprazole, quetiapine), esketamine, ketamine and psilocybin. The SR by Guo et al. (2024)¹⁸ also compared physical interventions to these drugs, which were out of scope and excluded in this review.

The intervention examined in the Cleare et al. (2025) RCT²⁰ was quetiapine and the comparator was lithium. The McKeown et al. (2022) qualitative study²¹ investigated patient experiences with quetiapine and lithium.

Outcomes

One or more of the following outcomes were assessed across the 3 SRs^17-19 and 1 RCT:²⁰ response rate, remission rate, illness severity, symptom severity, medication adherence, and AEs. Patient-reported outcome measures were captured in the RCT²⁰ by Cleare et al. (2025), and included Quick Inventory of Depressive Symptomatology via Self-Report (QIDS-SR), Medication Adherence Report Scale (MARS), Patient-Rated Inventory of Side Effects (PRISE), and Work and Social Adjustment Scale (WSAS) scores.

Brief descriptions of the outcomes measured in the included SRs and RCT are as follows:

• Response rate: Defined as the proportion of patients achieving a 50% or greater reduction in total score on standardized depression observer rating scales from baseline. The scales used were the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale.

• Remission rate: Defined as the total number of patients whose standardized depression scale score was less than a predefined threshold or specific cut-off. The SR by Guo et al. (2024)¹⁸ defined remission as a MADRS score 10 or lower or a Hamilton Depression Rating Scale score of 8 or lower for at least 2 subsequent treatments or at least 5 days.

• Clinical Global Impression-Severity (CGI-S): A Clinician-rated scale for assessing overall illness severity in terms of subjective well-being, problems or symptoms, life functioning, and risk and/or harm.

• QIDS-SR: A self-report scale that measures the burden of depressive symptom severity over the past 7 days.

• MARS score: A self-report questionnaire that assesses participant adherence to the trial medication.

• PRISE: Used to assess the presence and severity of side effects.

• WSAS: A self-report tool to assess functional impairment due to mental health in 5 key domains: work, home, social leisure activities, private leisure activities, and personal or family relationships. A higher score is associated with greater illness severity.

• Discontinuation due to an AE: Defined as the proportion of patients withdrawing from the trial due to any AE.

• All-cause dropout rate: Defined as the percentage of participants withdrawing from the trial for whatever reason.

In the SR by Bai et al. (2025),¹⁷ the primary outcome was change in MADRS score, the secondary outcome was MADRS response rate, and the tertiary outcomes were CGI-S score and remission rates. The SR by Guo et al. (2024)¹⁸ examined response rate, remission rate, tolerability, and safety as primary outcomes. The SR by Yan et al. (2022)¹⁹ examined response rate and all-cause dropout rate or discontinuation as primary outcomes, while remission rates and discontinuation due to an AE were secondary outcomes. The primary outcomes in the RCT²⁰ were QIDS-SR score and time to all-cause treatment discontinuation. Multiple secondary outcomes were measured in the RCT, including disease severity (MADRS score), EQ-5D (used for economic analysis in the trial and out of scope for this review), social functioning (WSAS score), adherence (MARS score), weight, diastolic BP and systolic BP, CGI-S score, and PRISE score.

Included Studies for Research Question 2: What Are the Evidence-Based Guidelines Regarding the Use and Administration of Quetiapine for Adults With MDD?

Study Design

Five evidence-based guidelines^22-26 were included to answer the research question 2. The guidelines are the 2023 American College of Physicians (ACP) guideline,²² the 2023 Canadian Network for Mood and Anxiety Treatments (CANMAT) guideline,²³ the 2022 National Institute for Health and Care Excellence (NICE) guideline,²⁴ the 2022 US Department of Veterans Affairs and Department of Defense (VA/DoD) guideline,²⁵ and the 2020 Royal Australian and New Zealand College of Psychiatrists (RANZCP) guideline.²⁶

All guidelines were broad in scope and included recommendations for nonpharmacological treatments beyond those relevant to this review, such as psychotherapy, complementary and alternative medicine, and lifestyle (e.g., exercise) models of care delivery. Only the recommendations relevant to quetiapine (or SGAs as a therapeutic class) will be discussed in this report.

All the guidelines reported that systematic literature reviews were conducted to inform the recommendations. The systematic review for the 2023 ACP guideline²² focused on RCTs and nonrandomized studies to synthesize the comparative effectiveness and safety of treatments. Additionally, 2 rapid reviews informed the ACP guideline: 1 rapid review informed on patient values and preferences, and 1 rapid review informed on cost-effectiveness. The review for the 2023 CANMAT guideline²³ prioritized SRs and meta-analyses and used RCTs where SRs were unavailable.

To develop the 2022 NICE guideline,²⁴ the committee focused on evidence gathered through a systematic literature review. The quality of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. However, this guideline did not report the strength of the recommendation and quality of the evidence that informed the recommendation in the main guideline publication; rather, it was reported in separate evidence review documents.

The systematic literature review for the 2022 VA/DoD guideline²⁵ included SRs and RCTs. The literature review for the 2020 RANZCP guideline²⁶ focused on SRs and meta-analyses. Evidence-based recommendations were developed using the Australian National Health and Medical Research Council levels of evidence for treatment studies. Where evidence was insufficient, absent, or its clinical impact and relevance uncertain, the Mood Disorders Committee developed expert consensus-based recommendations after extensive deliberations.

Country of Origin

The ACP²² and VA/DoD²⁵ guideline applies to the US. The CANMAT guideline applies to Canada.²³ The NICE guideline applies to the UK²⁴ and the RANZCP guideline²⁶ applies to Australia and New Zealand.²⁶

Patient Population

The target patient population in the ACP²² guideline includes adults in the acute phase of MDD. The CANMAT²³ and VA/DoD²⁵ guidelines are intended for adults with MDD. The intended population of the NICE guidleine²⁴ is adults with depression, while the target population for the RANZCP guideline²⁶ are people of any age with mood disorders, mainly depression and bipolar disorder.

The intended users of the ACP²² guideline include ambulatory care clinicians caring for adults in the acute phase of MDD. The CANMAT²³ is intended for community-based psychiatrists and mental health providers, similar to the VA/DoD²⁵ guideline, which is intended for primary care providers and mental health providers caring for patients with MDD. The NICE guideline²⁴ has a broader and more inclusive scope and is meant for health care professionals, commissioners, providers of health and public services for people with depression, individuals with depression, and their families and carers. The RANZCP guideline²⁶ is intended for clinicians (psychiatrists and psychologists), primary care physicians, clinicians, and carers involved in managing patients with mood disorders.

Interventions and Practice Considered

All 5 guidelines^22-26 covered multiple types of interventions and practices for the management of depression — pharmacological treatments and at least 1 type of nonpharmacological treatment. Nonpharmacological treatments included psychotherapy,^22-26 complementary and alternative treatments, lifestyle interventions^22-26 (e.g., physical activity or exercise, sleep, diet), and models of care^24,25 (e.g., team-based interdisciplinary or collaborative care model, telehealth visits, in-person treatments).

Outcomes

Guidelines considered a range of outcomes relevant to this review, including symptom remission, treatment response, functional improvement, functional restoration, quality of life, recurrence rate, recurrence prevention, AEs, and suicidal behaviour.

Summary of Critical Appraisal

Critical Appraisal of SRs and Primary Studies

The study rationale and objectives for the 3 SRs,^17-19 Bai et al. (2025),¹⁷ Guo et al. (2024),¹⁸ and Yan et al. (2022),¹⁹ were clearly stated. The literature search methods, search strategy, and criteria for the SRs were clearly presented. The comprehensiveness of the literature search of multiple databases and 2 or more reviewers involved in study screening, selection, data extraction, and risk of bias evaluation contributed to the validity of the 3 SRs.^17-19 NMA are based on the integration of direct and indirect comparisons, which allows for the comparison of interventions not directly compared in head-to-head trials. Some methods were applied to make the results more reliable, such as the evaluations of heterogeneity and inconsistency in each of the 3 SRs,^17-19 and sensitivity analysis in 2 SRs.^18,19 Risk of bias assessment was conducted for individual articles using validated tools such as the Cochrane Risk of Bias tool.^17-19 Additionally, the certainty of evidence in the Guo et al. (2024)¹⁸ SR was assessed using the Confidence in Network Meta-Analysis (CINeMA) framework. Funding sources and competing interests of authors were reported for all 3 SRs. Overall, the SRs were conducted with a relatively good methodology and presented a transparent, robust synthesis of the evidence.

In the RCT by Cleare et al. (2025),²⁰ the authors described the objective, patient characteristics, intervention, outcome, and findings. The clinical effectiveness analyses were conducted using the intention-to-treat population and per-protocol populations. Sample size and statistical methods appeared appropriate. The long follow-up duration of 52 weeks provides a more relevant duration to compare treatment effectiveness in clinical practice as patients with treatment-resistant depression have chronic symptoms that fluctuate in severity. Blinded assessment of some outcome measures (MADRS and CGI-S) resulted in reduced measurement bias and added to the validity of the study. However, there were limitations. Not all outcomes were assessed by blinded raters and patient responses on the QIDS-SR questionnaire were self-rated and may be affected by patient’s subjectivity, recall bias, or social desirability. In addition, the higher rate of treatment discontinuation and withdrawal from the study before 12 months in the lithium group compared to the quetiapine group may have differential effects on outcomes.

In the qualitative study by McKeown et al. (2022),²¹ the authors described the significance of the study, purpose, and objectives. The type of qualitative approach, research paradigm, researchers’ characteristics, and reflexivity were not reported. The context and setting of the research, particularly as a part of an ongoing RCT, were described. The methods for data collection and analysis appear appropriate; however, the process of data management and security, verification of data integrity, and anonymization and/pr deidentification of excerpts were not described. The report did not include the techniques used to ensure the trustworthiness of the findings, such as an audit trail and concurrent data collection and analysis. Evidence (e.g., quotes from participants) was reported to substantiate analytic findings.

Critical Appraisal of Guidelines

All the guidelines clearly stated their scope and purpose, in terms of the objectives, guideline questions, intended users, and target population. While 4 of the 5 guidelines (ACP,²² CANMAT,²³ NICE,²⁴ and VA/DoD²⁵) sought to gather the views and perspectives of people with depression, the RANZCP guideline²⁶ did not state that they sought the views and preferences of the target population and therefore the recommendations may not be reflective of the views of people with mood disorders.

Four of the guidelines, ACP,²² CANMAT,²³ NICE,²⁴ and VA/DoD,²⁵ used comprehensive methods to search for evidence and reported on their search strategy. The RANZCP guideline²⁶ did not report on the search strategy or key search terms used, search dates, or inclusion or exclusion criteria. Including details on these elements of the search strategy increases its reproducibility and helps the reader determine if the search was comprehensive or if important evidence may have been missed. Four of the guidelines, ACP,²² CANMAT,²³ NICE,²⁴ and VA/DoD,²⁵ included an explicit link between the recommendations and supporting evidence or rationale. The RANZCP guideline²⁶ reported on the evidence supporting some of the recommendations for depression management; however, limited details of specific evidence supporting the quetiapine recommendation for the treatment of MDD were provided. The RANZCP guideline appears to have given significant weight to the consensus-driven process for developing the recommendations. It also focused more on recommendations for bipolar disorder than depression. All 5 guidelines were validated through an external review by relevant experts, public panels, or interest groups before publication. Funding sources and competing interests of authors were reported in all guidelines.

Additional details regarding the strengths and limitations of the included publications are provided in Appendix 3.

Summary of Findings

Clinical Effectiveness of Quetiapine Versus Other Drug Interventions for Adults With MDD

• In the SR by Bai et al. (2025),¹⁷ brexpiprazole 2 mg to 3 mg (standardized mean difference = 0.155; 95% confidence interval [CI], 0.042 to 0.268) and combination olanzapine plus fluoxetine (standardized mean difference = 0.141; 95% CI, 0.019 to 0.264) were more effective as adjuvant treatment of treatment-resistant depression than quetiapine. No treatment was favoured between quetiapine and other antipsychotics or between quetiapine and antidepressant treatment.

• In the Cleare et al. (2025)²⁰ RCT, statistically significant differences in MADRS score were found between quetiapine and lithium, with results favouring quetiapine (adjusted mean difference = −2.98; 95% CI −5.87 to −0.09).

• In the SR by Guo et al. (2024),¹⁸ no treatment was favoured for response rates between quetiapine and the other medications — brexpiprazole, esketamine, ketamine, and psilocybin.

• Evidence from the Bai et al. (2025) SR¹⁷ found that quetiapine was associated with higher remission rates than risperidone 0.5 mg to 2 mg (hazard ratio = 0.17; 95% CI, 0.047 to 0.632) and ziprasidone 160 mg (hazard ratio = 0.091; 95% CI, 0.01 to 0.816). Evidence did not show statistically significant differences between quetiapine and the other drug interventions (i.e., other SGAs and antidepressants).

• Psilocybin was associated with higher odds of remission from depression compared with quetiapine in the Guo et al. (2024) SR¹⁸ (odds ratio = 3.07; 95% CI, 1.21 to 7.82). No statistically significant differences were observed between quetiapine and other medications, including brexpiprazole, esketamine, and ketamine.

• In the SR by Yan et al. (2022),¹⁹ no significant differences in response and remission rates were found in comparisons of quetiapine and other SGAs.

• QIDS-SR scores measured in the Cleare et al. (2025)²⁰ RCT showed a greater improvement in symptoms of depression in the quetiapine group compared with the lithium group (adjusted mean difference = −68.36; 95% CI −129.95 to −6.76).

Safety Outcomes

• No significant differences in tolerability were found in the comparison of quetiapine with other SGAs in the SR by Yan et al. (2022).¹⁹

• No significant differences in tolerability and safety were observed for quetiapine compared with other medications such as brexpiprazole, esketamine, ketamine, and psilocybin in the Guo et al. (2024)¹⁸ SR.

• Time to all-cause discontinuation did not significantly differ between the quetiapine and lithium groups in the RCT by Cleare et al. (2025).²⁰

• In the RCT by Cleare et al. (2025), ²⁰ 15 serious AEs were reported in 7 of 107 patients (7%) in the quetiapine group and 17 serious AEs were reported in 11 of 105 patients (11%) in the lithium group. One patient in the lithium group had acute renal failure.

• The results from the RCT by Cleare et al. (2025)²⁰ demonstrated that side effects, as measured by the PRISE, and physical parameters (weight and blood pressure) were similar between the quetiapine and lithium groups.

• No safety data regarding misuse or diversion of quetiapine were found in the included studies.

Social Functioning

Social functioning was reported in the RCT by Cleare et al. (2025).²⁰ Quetiapine resulted in a significant improvement in social functioning compared with lithium (adjusted mean difference = −3.64; 95% CI −6.28 to −0.99). Social functioning was not reported in the SRs or qualitative study.

Patient Experience and Perspectives

• The qualitative study by McKeown et al. (2022)²¹ reported on patient experiences and perspectives of quetiapine and lithium augmentation medications, such as initial concerns, experience of side effects, perception of treatment efficacy, and positive perception of treatment monitoring. Patients expressed greater apprehension toward lithium over quetiapine before treatment initiation. By contrast, patients reported side effects to a greater extent for quetiapine compared to lithium during treatment (e.g., sedation, weight gain, and appetite changes). They viewed the side effects of lithium to be more manageable.

• While most patients perceived treatment with either medication (quetiapine or lithium) as beneficial, some patients perceived treatment to be ineffective. Clinical monitoring was perceived positively in terms of regular appointments, reassurance regarding the ease and speed of communication with study team and clinicians, and acceptance of blood monitoring for patients treated with lithium.

Guidelines Regarding the Use of Quetiapine

• The 2023 ACP guideline²² recommends switching to a different second-generation antidepressant or augmenting with a second pharmacologic treatment such as quetiapine for patients in the acute phase of moderate to severe MDD whose disease does not respond to initial treatment with an adequate dose of a second-generation antidepressant.

• The 2023 CANMAT guideline²³ recommends quetiapine in combination with a first-line antidepressant for MDD with psychotic features. The guideline recommends quetiapine as a second-line treatment option for adults with MDD. The guideline also recommends quetiapine as a second-line adjunctive treatment option for adults with difficult to treat depression. Atypical psychotics such as quetiapine in combination with an antidepressant may be used as a first-line treatment for MDD with psychotic features.

• The NICE guideline²⁴ recommends combination treatment for people with depression with psychotic symptoms that includes an antidepressant medication and an antipsychotic medication (for example, olanzapine or quetiapine).

• The VA/DoD guideline²⁵ provides recommendations for patients with MDD who have demonstrated partial or no response to an adequate trial of initial pharmacotherapy. One of the recommendations is augmenting with an SGA such as aripiprazole, brexpiprazole, cariprazine, olanzapine, quetiapine, or risperidone.

• The RANZCP guideline²⁶ recommends that SGAs such as lurasidone, quetiapine, and olanzapine be used either as monotherapy or adjunctively in the treatment of major depression. New drugs such as aripiprazole and brexpiprazole are indicated for adjunctive treatment of major depression.

The study findings from all included publications are provided in Appendix 4.

Limitations

The evidence base for the SRs^17-19 was drawn from clinical trials and thus may not be reflective of real-world practice with respect to the use of quetiapine. Important factors such as concurrent treatments and comorbidities were not explored. Many patients with depression have coexisting mental health and chronic medical conditions; however, patients with these conditions were excluded from participation in the trials, which may limit the generalizability of the evidence. There was heterogeneity among the primary studies included in the SRs in terms of patient and study characteristics, and inconsistency in the reported outcomes. The influence of these factors on the SR findings is unknown. The SR by Yan et al. (2022)¹⁹ did not consider drug doses in the analysis due to the unavailability of this information in the original articles.

In the RCT by Cleare et al. (2025),²⁰ not all outcomes were assessed by blinded raters; patient responses on the QIDS-SR questionnaire were self-rated and may have been affected by patients’ subjectivity, recall bias, or social desirability. The higher rate of treatment discontinuation and withdrawal from the trial before 12 months in the lithium group compared to the quetiapine group may have had differential effects on outcomes. In the qualitative study by McKeown et al. (2022),²¹ recall bias is a limitation as interviews were conducted 52 weeks after the patients were first enrolled in the trial.

No safety data regarding misuse or diversion of quetiapine were found in the included studies. The lack of data may be due to the type of study designs specified in the eligibility criteria for the current review rather than absence of misuse in the existing literature.

This report is limited by the quantity and the quality of available evidence. Five evidence-based guidelines were identified that included recommendations on the use of quetiapine specifically or the therapeutic class of SGAs more broadly for MDD. Additionally, the quality of evidence supporting the recommendations was rated as low for 2 guidelines (ACP²² and VA/DoD²⁵) and was not reported for 2 guidelines, NICE²⁴ and RANZCP.²⁶ Only the recommendations included in the 2023 CANMAT guideline²³ were based on evidence that was rated as high quality by the authors.

Conclusions and Implications for Decision- or Policy-Making

We identified 3 SRs,^17-19 1 RCT,²⁰ 1 qualitative study,²¹ and 5 evidence-based guidelines^22-26 relevant to the research questions.

Evidence from the SRs included in this review suggests that quetiapine and other SGAs (particularly aripiprazole, brexpiprazole, cariprazine, olanzapine, risperidone, and ziprasidone) have similar efficacy and safety for the treatment of adults with treatment-resistant MDD. Evidence from the included RCT suggests that quetiapine reduced depression symptoms and improved social functioning compared with lithium. While not an approved indication by the FDA or Health Canada, lithium has long been used as an augmentation treatment for MDD. In the qualitative study by McKeown et al. (2022),²¹ patients perceived both quetiapine and lithium to improve depression. However, they reported more side effects with quetiapine than lithium and viewed the side effects of lithium to be more manageable.

The included guidelines suggest using quetiapine as a second-line augmentation treatment option for MDD in patients whose disease had partial or no response to an adequate dose of 2 or more antidepressant medications (i.e., those with difficult to treat depression). In addition, the CANMAT guideline recommends a combination of an antidepressant and antipsychotic as a first-line treatment for MDD with psychotic features. The RANZCP guideline suggests using quetiapine as monotherapy or adjunct therapy for patients with major depression.

Implications for Clinical Practice

The findings of this review suggest that antipsychotics such as quetiapine could be used as a second-line augmentation treatment option for MDD in patients whose disease had partial or no response to an adequate dose of 2 or more antidepressants (i.e., those with treatment-resistant depression or difficult to treat depression). The findings of this review also suggest that SGAs such as quetiapine, in combination with an antidepressant, may be used as a first-line treatment for MDD that is very severe or has associated psychotic features. According to the included RCT, quetiapine is more beneficial than lithium in reducing depressive symptoms and improving functioning in treatment-resistant depression. Factors such as patient characteristics, patient tolerability, patient values, side effect profiles of different treatment options, and clinician expertise may also be important to guide treatment choice for people with MDD. The findings of this review should be interpreted in conjunction with the previous 2020 CDA-AMC report, which provides additional context and evidence on the use of quetiapine for MDD.

Acknowledgement

Clinical Expert

This individual has kindly provided comments on the report:

Diane McIntosh, BSc Pharmacy, MD, FRCP

Psychiatrist

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Appendix 1: Selection of Included Studies

Figure 1: PRISMA²⁷ Flow Chart of Study Selection

Appendix 2: Characteristics of Included Publications

Table 2: Characteristics of Included Systematic Reviews

CGI-S = Clinical Global Impression-severity; ECT = electroconvulsive therapy; HAM-D17 = Hamilton Rating Scale for Depression, 17 item version; MADRS = Montgomery-Asberg Depression Scale; MDD = major depressive disorder; NMR = Network meta-regression; RCT = randomized controlled trials; TMS = transcranial magnetic stimulation; TRD = treatment-resistant depression.

Note: This table has not been copy-edited.

Table 3: Characteristics of Included Randomized Controlled Trial

CGI-S = Clinical Global Impression-Severity; MADRS = Montgomery-Asberg Depression Rating Scale; MARS-5 = five‐item Medication Adherence Report Scale; MDD = major depressive disorder; PRISE = Patient-Rated Inventory of Side Effects; QIDS-SR = self-rated Quick Inventory of Depressive Symptomatology; RCT = randomized controlled trials; TRD = treatment-resistant depression; WSAS = Work and Social Adjustment Scale.

Note: This table has not been copy-edited.

Table 4: Characteristics of Included Qualitative Study

HTA = health technology assessment; LQD = Lithium vs quetiapine in depression study; TRD = treatment-resistant depression.

Note: This table has not been copy-edited.

Table 5: Characteristics of Included Guidelines

ACP = American College of Physicians; CAM = complementary and alternative medicine; CANMAT = Canadian Network for Mood and Anxiety Treatments; CPG = clinical practice guideline; DBS = deep brain stimulation; DoD = US Department of Defense; ECT = electroconvulsive therapy; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; MDD = major depressive disorder; QoL = quality of life; RANZCP = Royal Australian and New Zealand College of Psychiatrists; RCT = randomized controlled trial; SR = systematic review; TRD = treatment-resistant depression; USPSTF = US Preventive Services Task Force; VA = US Department of Veterans Affairs.

Note: This table has not been copy-edited.

Appendix 3: Critical Appraisal of Included Publications

Please note that this appendix has not been copy-edited.

Table 6: Strengths and Limitations of Clinical Studies

Table 7: Strengths and Limitations of Qualitative Study Using SRQR Checklist¹⁵

SRQR = Standards for Reporting Qualitative Research.

Table 8: Strengths and Limitations of Guidelines Using AGREE II¹⁶

AGREE II = Appraisal of Guidelines for Research and Evaluation II; CANMAT = Canadian Network for Mood and Anxiety Treatments; DoD = US Department of Defense; ECT = electroconvulsive therapy; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; MDD = major depressive disorder; RANZCP = Royal Australian and New Zealand College of Psychiatrists; USPSTF = US Preventive Services Task Force; VA = US Department of Veterans Affairs.

Appendix 4: Main Study Findings

Please note that this appendix has not been copy-edited.

Table 9: Summary of Findings by Outcome — MADRS Score

Table 10: Summary of Findings by Outcome — MADRS Response Rate

Table 11: Summary of Findings by Outcome — CGI-S Score

Table 12: Summary of Findings by Outcome — MADRS Remission Rate

Table 13: Summary of Findings by Outcome — Additional Efficacy Outcomes

MARS-5 = five‐item Medication Adherence Report Scale; QIDS-SR = self-rated Quick Inventory of Depressive Symptomatology; RCT = randomized controlled trials; WSAS = Work and Social Adjustment Scale

Table 14: Summary of Findings by Outcome — Safety Outcomes

Table 15: Summary of Findings by Outcome — Patient Experience

Table 16: Summary of Recommendations in Included Guidelines

MDD = major depressive disorder; MDE = major depressive episode; NR = not reported in guideline publication; SGA = second-generation antipsychotic.