PROTOCOL: Treatment for depressive disorder among adults: An evidence and gap map of systematic reviews

Abstract This is the protocol for a Campbell evidence and gap map. The objective of the map is to map available systematic reviews on the effectiveness of treatments for depressive disorders among adults. Specifically, this EGM includes studies on the effectiveness of treatments across a range of outcome domains.

symptoms will be included. Although bipolar depressive disorder was separated from depressive disorders in DSM-V, it will also be included in the present review due to its high frequency among adults (American Psychiatric Association, 2013).

| The intervention
Depressive disorders have attracted worldwide attention (Belkin, 2016;Saxena, 2019), and many programs have been developed to prevent this mental health crisis, such as Manochaitanya (Manjunatha, 2016), President's Program (Mirza, 2019), and the mental health Gap Action Program developed by the World Health Organization. The recommendations for the general adult population provided by the APA Guideline Development Panel identified three types of treatment for initial or relapse depression: psychotherapy, pharmacotherapy, and complementary and alternative treatments (American Psychological Association, 2019). In more detail: • Psychotherapy is any psychological service provided by a trained professional that primarily uses forms of communication and interaction to assess, diagnose, and treat dysfunctional emotional reactions, ways of thinking, and behavior patterns.
Psychotherapy may be provided to individuals, couples, families, or members of a group (American Psychological Association, 2015). There are many types of psychotherapy.
The main approaches generally include behavioral therapy, cognitive therapy (including cognitive, cognitive-behavioral, and mindfulness-based therapy), interpersonal psychotherapy, psychodynamic therapy, and supportive therapy (American Psychological Association, 2019).
• Pharmacotherapy refers to the use of pharmacological agents in the treatment of mental disorders (American Psychological Association, 2015), and second-generation antidepressants such as venlafaxine, trazodone, bupropion, and mirtazapine are recommended in the guideline (American Psychological Association, 2019).
• Complementary and alternative treatments, also called complementary and alternative medicine (CAM), are a group of therapies and healthcare systems that fall outside the realm of conventional western medical practice. These include but are not limited to acupuncture, chiropractic, meditation, aromatherapy, homeopathy, naturopathy, osteopathy, touch therapy, reflexology, reiki, and the use of certain dietary supplements (American Psychological Association, 2015).
There are many treatments for depression, but more than 75% of adults from low-and middle-income countries receive no treatment (Evans-Lacko, 2018). Furthermore, evidence regarding the effectiveness of interventions is not uniform, covering different intervention types, settings, and target populations and making it difficult to navigate (Gabriel, 2022;Lee, 2022;Wickersham, 2022). Therefore, this study aims to produce an evidence and gap map (EGM) of systematic reviews, based on the Campbell Guidelines of EGMs (White, 2020). Specifically, this study seeks to produce an EGM of systematic reviews concerned with interventions for the treatment of depressive disorders. This EGM is designed to collect and display all systematic reviews that reported the effectiveness of interventions to treat depressive disorder to inform research commissioning and provide a scientific basis for the development of healthcare policies and practices.

| Why it is important to develop the EGM
Although the American Psychiatric Association (APA) had released guidelines for the treatments of depression (American Psychological Association, 2019), not all interventions were considered, particularly in the era of rapid development of science and technology. For instance, several new therapies have emerged that may be a better choice for some patients, such as animal-assisted therapy (Majić, 2013), virtual reality exposure therapy (Baghaei, 2021), and e-mental health apps (Porras-Segovia, 2020). However, updating guidelines is time-consuming and costly. Moreover, the "best treatment" is not only determined by effectiveness but also by resource availability, patient preferences, and doctors' experience. Hence, whilst waiting for updated guidelines an EGM is a useful starting point for decision-makers and members of the public seeking evidence-based advice.
The EGM is a table that offers a visual presentation of the available evidence for a particular sector. The map provides an overview of what studies are available but does not summarize the findings. It is a decision-making and research priority-setting tool that highlights gaps in research and provides information for strategic health and social policies, programs, and research priorities (Saran, 2020;White, 2020). It is estimated that 85% of research investment is wasted, and some of these problems can be avoided by prioritizing research, including using systematic reviews (SRs) to rigorously evaluate available evidence before funding or conducting new research (Chalmers, 2014). EGMs can be used to avoid unnecessary duplication and determine whether there is sufficient evidence on which to base decisions or sufficient research for knowledge synthesis (Snilstveit, 2016).

| Existing EGMs
We searched the Campbell Library, Cochrane Library, PubMed, EPPI, and 3ie (International Initiative for Impact Evaluation) and identified two EGMs related to the treatment of depression (Britton, 2021;Campisi, 2020). Campisi et al. (2020) created an EGM regarding micronutrients for depression among children and adolescents with 30 primary research publications. They found that the most frequently studied micronutrients were vitamin D, zinc, iron, folate, and vitamin B-12. Britton et al. (2021) collected evidence on mindfulness-based interventions for depression and interpreted its mechanisms with the self-related processes, including self-concept, rumination, self-compassion, self-efficacy, and self-esteem. Whether using participant or intervention studies, these two EGMs did not meet the need among adults with depressive symptoms. Therefore, it will be useful to develop an EGM on the treatments for depression among adults.

| OBJECTIVES
The objective of the map is to map available systematic reviews on the effectiveness of treatments for depressive disorders among adults. Specifically, this EGM includes studies on the effectiveness of treatments across a range of outcome domains.

| EGM: Definition and purpose
This EGM is an effectiveness map of interventions for depression, in which the primary dimensions are intervention categories (rows) and indicator domains (columns). Secondary dimensions, such as country and target group, are included as filters (White, 2020). We will adapt EGM methods from various key studies (Bragge, 2011;Snilstveit, 2016;White, 2020) and utilize a five-stage process: • Define a framework, which determines the scope and inclusion and exclusion criteria; • Identify available evidence (search).
• Appraise the quality of evidence.
• Extract, code, and summarize the data that relate to the objectives.
• Visualize and present the findings in a user-friendly format.
We will use the EPPI-Mapper mapping tool developed by the EPPI-Centre to display identified studies using the framework described below.

| Framework development and scope
After discussions and recommendations with stakeholders and advisory panels on August 8, 2022, a framework for the main classification items of different intervention populations and groups was finalized. We further defined the scope and framework for consultation with our research group, which included researchers from evaluation and evidence synthesis (HW and YKH), education (GLP), public health (LJY), psychiatrist (WW), and psychotherapist (QK and XZ). Finally, the EGM will include two dimensions of the framework: interventions and indicators/ outcomes. We will follow the standard EGM framework as a matrix where the rows are intervention domains and the columns are indicator/ outcome categories.

| Stakeholder engagement
The group members for this EGM include researchers from evaluation and evidence synthesis (Howard White), education (Liping Guo), public health (Jieyun Li), health and wellbeing (Kehu Yang), health statistics and services (Yaogeng Chen), doctors of psychiatric (Wen Wang), and psychotherapist (Kun Qiao and Zheng Xu). Feedback from the group members was received and assimilated into the framework plan at the title registration stage. The stakeholders will be engaged at all stages of the EGM to review and comment on interventions, studies, outputs, map findings and provide advice on dissemination channels.
There has been extensive stakeholder engagement in the preparation of the framework. This has included: • Stakeholders' online consultation meetings at least bimonthly in discussing the direction and scope of EGM.
• One-on-one calls with stakeholders not able to attend the larger stakeholder consultations.
• Three rounds of piloting and revising the coding framework using selected eligible or ineligible studies. The details were shown in Tables 1-3.
• Further stakeholder consultation is planned for January 2023.
Each of these intended users has participated in defining the intervention and outcome framework. The participation of the advisory group members will contribute to greater alignment of global and national efforts in forming the basis for improving the evidence base on depressive disorder.

| Conceptual framework
Depression can result from a complex interaction of psychological, physical, behavioral, and other factors (Pandey, 2021;Ratanasiripong, 2012;World Health Organization, 2017), and there are various treatment mechanisms (Britton, 2021;Xie, 2021). For example, pharmacotherapy mainly reduces the activity of brain nerves by reducing neurotransmitters in the body, thus stabilizing the mood of patients with depression; psychological therapy as well as educational program and training aim to correct cognitive bias, improve behavioral coping ability, and promote positive behaviors to empower the suffers of depression.
Besides, relieving physical pain, relaxing the body, and balancing nutrition are complementary treatments for depression. The conceptual framework for depression is shown in Figure 1. The present EGM aims to provide a classification of treatments for depression.

| EGM framework interventions
This EGM focuses on systematic reviews of effectiveness studies of interventions, with a primary aim of treatment or reducing depressive

| EGM framework population dimension
The primary population of interest for this map is adults (over 18 years old). We will sub-categorize the adult population according to age group, gender and sexual orientation, career, and health state (as shown in Table 6). The population dimension will be listed as a filter. For studies assessing effects with people who are providing services, we will subcategorize according to whether they are professionals or volunteers.
3.6 | Inclusion and exclusion criteria 3.6.1 | Types of study design We will include only systematic reviews that conduct meta-analyses of randomized controlled trials (RCTs). According to the definition of F I G U R E 1 Conceptual framework for depression.   systematic review from Campbell Collaboration and our objective, a systematic review met the following four criteria will be included: (1) clear inclusion and exclusion criteria;

Type of depression
(2) an explicit search strategy; (3) systematic coding and analysis of included studies; (4) metaanalysis. If a systematic review included the primary studies using RCT and quasi-experimental designs (QED), we will only include the data from RCTs. -RCTs (SMD = −2.202).

Type of depression
Major depressive disorder Protocols for ongoing research will be included. Qualitative reviews, integrative reviews, rapid reviews, reviews of reviews, and evidence synthesis/summaries are beyond the inclusion criteria.
Primary studies are excluded.

| Types of intervention/problem
We will include systematic reviews assessing any interventions with an explicit aim of reducing depressive symptoms, including educational programs and training, psychotherapy, physical therapy, pharmacological treatment, physical activity, and any interventions that aim to treat depression in adults.

| Types of the population
The target population is adults (aged 18 and over) with depressive symptoms including those with any other mental and/or physical problems, and professionals or volunteers providing services to the target population. If a review covered both adults and children, we will extract the independent information on adults if available.

| Types of outcome measures
We will include systematic reviews that assess the effect of interventions on depressive symptoms and related symptoms, such as anxiety, stress, suicide intention, life and social skills, and adverse events by the pharmacy or other treatments.

| Other eligibility criteria
Studies will not be limited by geographic location. Due to the limitation of team members, only studies published in English and Chinese will be included. There is no restriction on publication time.

Types of location/situation (as applicable)
Not applicable.

Types of settings
Any settings, such as hospitals, communities, and institutions, will be included.

| Search methods and sources
The search for EGM will be conducted in three stages: • Stage 1: Pilot for screening and coding of included studies (deadline: January 2023).
• Stage 2: Search for relevant systematic reviews from academic databases and international organizations (deadline: February 2023). 3.7.1 | Database search for stage 2 The following international electric databases will be searched: • Social Sciences Citation Index (via Web of Science) • ScienceDirect (https://www.sciencedirect.com/) • Taylor & Francis Online Database (https://www.tandfonline.com/) • JSTOR (https://www.jstor.org/) • PsychArticles (via ProQuest) Selective serotonin reuptake inhibitors (SSRI) are any of a class of antidepressants that are thought to act by blocking the retake of serotonin into serotonin-containing pre-synaptic neurons in the central nervous system (American Psychological Association, 2015). (Omori, 2009) "We conducted a systematic review to synthesize the best available evidence on the efficacy of fluvoxamine for adult patients suffering from major depression in comparison with other active anti-depressive agents." Serotoninnorepinephrine reuptake inhibitors (SNRIs) Serotonin-nor epinephrine reuptake inhibitors (SNRIs) are a class of antidepressants that exert their therapeutic effects by interfering with the presynaptic of both serotonin and norepinephrine by the neurons that released them (American Psychological Association, 2015). Tetracyclic antidepressants (TeCAs) are a class of antidepressants closely related to TCAs, and the mechanisms of action of these drugs are similar to TCAs with monoamine modulation as their hallmark feature. (Macedo, 2011) "To evaluate the efficacy and frequency of adverse events with pirlindole in comparison with active comparators."

Norepinephrine and dopamine reuptake inhibitors (NDRIs)
Norepinephrine and dopamine reuptake inhibitors (NDRIs) are drugs that function by inhibiting the reuptake of the neurotransmitters norepinephrine and dopamine. This leads to increased neural concentrations of these activating neurotransmitters, resulting in increased stimulation of the central nervous system. (Smith, 2021) "The objective of this systematic review is to assess the efficacy and safety of methylphenidate (MPH) in the treatment of geriatric depression."

Complementary and alternative treatments
Physical therapy (PT) physical therapy (PT) is the treatment of pain, injury, or disease using physical or mechanical methods, such as exercise, heat, water, massage, or electric current (American Psychological Association, 2015). (Tu, 2021) "This systematic review and metaanalysis aimed to investigate the efficacy of acupuncture on CSAP-associated anxiety and depression." Physical activity (PA) Physical activity is defined as any bodily movement produced by contraction of skeletal muscle that increases energy expenditure above the basal level (American Psychological Association, 2015). (Schuch, 2016) "To evaluate the antidepressant effects of exercise in older adults, using randomized controlled trial (RCT) data." Art therapy (AT) Art therapy is the use of artistic activities, such as painting and clay modeling, in psychotherapy and rehabilitation (American Psychological Association, 2015). (Chan, 2011) "The objective of this review was to determine the effectiveness of music listening in reducing depressive symptoms in adults."

Traditional Chinese Medicine (TCM)
Traditional Chinese medicine (TCM) is a system of medicine at least 23 centuries old that aims to prevent or heal disease by maintaining or restoring yinyang balance. (Armour, 2019) "This systematic review and meta-analysis examined the effectiveness of acupuncture in major depressive disorder." Dietary supplement Dietary supplements are chemical substances like minerals, vitamins, and antioxidants, which are part of normal nutrition but also can added to normal nutrition in the shape of more or less pure substances (Hoffmann, 2019). (Appleton, 2016) "The objective of this review is to assess the effects of n-3PUFAs compared with comparator (eg, placebo, antidepressant treatment, standard care) for MDD in adults."

Other intervention Educational program and training
Education program and training is the process of teaching or acquiring knowledge and skills related to depression disorder (American Psychological Association, 2015). (Barry, 2019) "The present meta-analysis and systematic review provides the first synthesis of all existing studies in which Memory Specificity Training has been tested within the context of emotional disorders." e-Mental health apps e-Mental health apps are smartphone apps aim to improve quality and increase access to mental health care (Bakker, 2016). (Linardon, 2019) "We conducted a metaanalysis of 66 randomized controlled trials of app-supported smartphone interventions for mental health problems." Other treatments / / T A B L E 5 Indicator/outcome domain.

Adherence to treatment
Adherence to treatment is the extent to which a person's behavior-taking medication, following a diet and/or executing lifestyle changes, corresponds with agreed recommendations from a healthcare provider (Ahmed, 2014) / Remission of depressive symptom

Major depressive disorder
Major depressive disorder (MDD), also known simply as depression, is a mental disorder, characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities (American Psychological Association, 2015). (Appleton, 2016) "To assess the effects of w-3 polyunsaturated fatty acids compared with a comparator for major depressive disorder (MDD) in adults."

Persistent depressive disorder
Dysthymia, also known as persistent depressive disorder (PDD), is a mental and behavioral disorder, specifically a disorder primarily of mood, consisting of the same cognitive and physical problems as depression, but with longer-lasting symptoms (American Psychological Association, 2015).

/ Premenstrual dysphoric disorder
Premenstrual dysphoric disorder (PMDD) is a severe and disabling form of premenstrual syndrome. Bipolar depression, anxiety disorders, and other Axis I disorders are more common in those with PMDD (American Psychological Association, 2015).

/ Depressive disorder with another medical condition
Depressive disorder with another medical condition, such as cancer, diabetes, pregnancy (American Psychological Association, 2015). (Wang, 2016) "This study aims at concluding the current evidence on the therapeutic effects of acupoints stimulation for cancer patients with anxiety and depression." Bipolar depression Bipolar disorder, previously known as manic depression, is a mood disorder characterized by periods of depression and periods of abnormally-elevated mood that last from days to weeks each (American Psychological Association, 2015). (Kishimoto, 2016) "Parallel-group or crossover randomized controlled trials comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses." Other specific depressive symptoms / / Unspecified Unspecified depressive symptom. (Ekers, 2008) "Studies included participants who were adults, treated in community or in-patient settings with a primary diagnosis of depression."

Symptoms of depresson
Anxiety Anxiety is an emotion characterized by an unpleasant state of inner turmoil and includes subjectively unpleasant feelings of dread over anticipated events (American Psychological Association, 2015). (Hu, 2019) "dyadic intervention was associated with statistically and clinically significant improvements in patient total QOL." Physical fitness Physical fitness is a state of health and well-being and, more specifically, the ability to perform aspects of sports, occupations, and daily activities (American Psychological Association, 2015). T A B L E 6 Population dimension.

Population categories Definitions
Age Adult age refers to people aged 18 and over. The following sub-groups will be coded: 18-60 years and ≥60 years

Gender Male and female based on biological indicators
LGBT community Studies where the principal population group being studied identify as LGBT Below, the search strategy for CNKI is provided: Population keywords: Depressive symptom keywords: -篇关摘= 抑郁 + 心理

Study design keywords:
-篇关摘= 系统评价 + 元分析 + 荟萃分析 + meta分析 3.7.2 | Searching other resources We will consult the following sources of grey literature and search websites of organizations for mental health research to identify relevant unpublished studies and reports. The following grey literature resources will be searched using the keyword "depression": • World Health Organization (https://www.who.int/) • American Psychological Association (https://www.apa.org/) • Centers for Disease Control and Prevention (https://www.cdc.

gov/)
• National Institute of Mental Health (https://www.nimh.nih.gov/) • Open Grey (http://www.opengrey.eu/) In addition, we will also survey Google Scholar using the keyword "depression intervention" and scan the first 50 pages for relevant studies. Moreover, relevant reviews cited in previous systematic reviews on depression will be scanned, and reference lists of included studies will also be searched.

| Unit of analyses
Each entry in the map will be a systematic review of effectiveness. If a review contains multiple interventions, the reviewers will extract all data as dependent reports that are eligible for this EGM. The final EGM will identify the number of studies covered by the map in each sector or subsector.

| Report structure
The EGM report will include the following sections: executive summary, background, intervention, results, and conclusion. The executive summary will summarize the report, providing key findings and implications for future policy planning and research. The background of this study will comprehensively describe the current situation of depressive disorder in adults and its impact on society.
Examples of existing interventions are described and the goals of EGM are clarified. In addition, we will describe the scope by defining an intervention and outcome framework.
The description of the methods will include a definition of the data sources and methods of searching, the inclusion and exclusion criteria, study selection, study confidence appraisal, data extraction methods, and the approach to presentation/visualization. This section will provide a table in the text showing one full search from a database and a PRISMA flow chart. An appendix will provide full search strategies used for each database, including any restrictions and filters used.
The outcome will show the number, type, and quality of the studies retrieved for the outcome categories, the population targeted for the specific study, and the change in outcomes after the intervention.
The conclusion is expected to provide insights for researchers and decision-makers, build on the evidence base in this field, and identify key areas for future research. Moreover, we will include studies considering the impact of conducting EGM.
The following tables and figures will be included: • Figure: PRISMA flow chart table.
• Table: Number of studies by intervention and subcategories.
• Table: Number of studies by population.
• Table: Number of studies by intervention category and study confidence.

| Filters for presentation
We will present results as a matrix of interventions (rows) and outcomes (columns) and assess the availability of evidence across the additional filters. In addition to the interventions and outcomes, the following filters will be coded (details are in Tables 7 and 8): • Period of depression: lifetime, 12 months, 6 months, 1 month, and not stated.
• Number of episodes: depression episode, depression recurrence, and not stated; • The implementer of treatment: self-help, healthcare provided, and provided by mental health professionals or volunteers.
• Effectiveness of interventions: We will record whether the systematic review reported a mean positive statistically significant effect, a mean statistically significant negative effect, or no statistically significant difference between treatment and comparison conditions.
• Conflict of interest: yes, no, and unclear.
• Quality of studies: high, moderate, low, and critically low.

| Dependency
Each entry in the map will be a systematic review of effectiveness.
The final EGM will identify the number of studies covered by the map in each sector or subsector.
3.9 | Data collection and analysis 3.9.1 | Screening and study selection Two reviewers (Ren JJ and Huang XY) will independently screen the titles and abstracts of all retrieved articles. Furthermore, titles and abstracts will be screened by Rayyan based on population, T A B L E 9 Items of AMSTAR-2.

No. Item Evaluation
1 Did the research questions and inclusion criteria for the review include the components of PICO? Yes/no 2 Did the report of the review contain an explicit statement that the review methods were established before the conduct of the review and did the report justify any significant deviations from the protocol?
Yes/partial/no If meta-analysis was performed, did the review authors assess the potential impact of ROB in individual studies on the results of the meta-analysis or other evidence synthesis?
Yes/no/no meta-analysis conducted 13 Did the review authors account for ROB in individual studies when interpreting/discussing the results of the review?
Yes/no 14 Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?
Yes/no 15 If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?
Yes/no/no meta-analysis conducted 16 Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?
Yes/no GUO ET AL.
Full texts of potentially eligible studies will then be retrieved and screened in Excel. The reviewers will compare the results, and conflicts will be resolved through discussion or by a third reviewer (Xu Z). Authors of studies or reviews are not contacted for missing information.

| Data extraction and management
Coding is the process of capturing the required data from included studies, such as study population, intervention, and study design.
Coding will be done independently by two coders (Li JY and Xu Z) using EPPI Mapper, with a third-party arbitrator (Guo LP) in the event of disagreement. The studies will be coded based on intervention category and sub-category, indicator/outcome domain, and subdomain; treatment population, country, and population characteristics. In addition, coding includes critical appraisal, which is described in Section 3.5. Guo LP will be responsible for data management.
3.9.3 | Tools for assessing the risk of bias/study quality of included reviews The reliability of the study findings in the included systematic reviews will be assessed using a measurement tool to assess systematic reviews (AMSTAR-2). This progress will be conducted independently by two reviewers (Li JY and Xu Z), with any disagreements will be resolved by a third reviewer (Yang KH). The items of AMSTAR-2 are shown in Table 9 (Shea, 2017).

| Methods for mapping
We will use the EPPI Mapper mapping tool developed by the EPPI-Centre to display identified studies using the framework described above.

Content expertise
• Zheng Xu is a teacher at the Psychological Counselling Centre of Lanzhou University.
• Kun Qiao is the deputy director of the Institute of Medical Physiology and Psychology at the School of Basic Medical Sciences of Lanzhou University.
• Wen Wang is an associate doctor of the psychiatry department of the First Hospital of Lanzhou University.
• Yaogeng Chen is a professor focused on the mental crisis at the School of Science at Ningxia Medical University.

Systematic review expertise
All authors are experienced systematic reviewers, which means they are proficient in carrying out the various processes in a Systematic Review, such as eligibility screening, quality assessment, and coding. Kehu Yang is the director of the Evidence-based Social Sciences Laboratory at Lanzhou University and the author of several Chinese evidence-based textbooks.

EGM methods expertise
Howard White is the lead adviser on evidence mapping and the second coauthor. He has authored a paper on mapping methods used by different agencies that assisted the development of Campbell guidelines and standards for Evidence and Gap Maps and is the author of published and ongoing maps, such as homelessness, disability, violence against children, and youth employment, including the first mega-map on child welfare and the map of maps in international development.

Information retrieval expertise
All authors have previous experience in developing search strategies.
Screening, coding, analysis, and writing will be led by Liping Guo.
Overall supervision is provided by Kehu Yang and Howard White.

SOURCES OF SUPPORT
Internal sources