When we began this process, we were doctoral students and a faculty member in a research methods course. As students, we were facing a review of the literature for our dissertations. We encountered several different ways of conducting a review but were unable to locate any resources that synthesized all of the various synthesis methodologies. Our purpose is to present a comprehensive overview and assessment of the main approaches to research synthesis. We use ‘research synthesis’ as a broad overarching term to describe various approaches to combining, integrating, and synthesizing research findings.
We conducted an integrative review of the literature to explore the historical, contextual, and evolving nature of research synthesis. We searched five databases, reviewed websites of key organizations, hand-searched several journals, and examined relevant texts from the reference lists of the documents we had already obtained.
We identified four broad categories of research synthesis methodology including conventional, quantitative, qualitative, and emerging syntheses. Each of the broad categories was compared to the others on the following: key characteristics, purpose, method, product, context, underlying assumptions, unit of analysis, strengths and limitations, and when to use each approach.
The current state of research synthesis reflects significant advancements in emerging synthesis studies that integrate diverse data types and sources. New approaches to research synthesis provide a much broader range of review alternatives available to health and social science students and researchers.
Since the turn of the century, public health emergencies have been identified worldwide, particularly related to infectious diseases. For example, the Severe Acute Respiratory Syndrome (SARS) epidemic in Canada in 2002-2003, the recent Ebola epidemic in Africa, and the ongoing HIV/AIDs pandemic are global health concerns. There have also been dramatic increases in the prevalence of chronic diseases around the world [1] – [3] . These epidemiological challenges have raised concerns about the ability of health systems worldwide to address these crises. As a result, public health systems reform has been initiated in a number of countries. In Canada, as in other countries, the role of evidence to support public health reform and improve population health has been given high priority. Yet, there continues to be a significant gap between the production of evidence through research and its application in practice [4] – [5] . One strategy to address this gap has been the development of new research synthesis methodologies to deal with the time-sensitive and wide ranging evidence needs of policy makers and practitioners in all areas of health care, including public health.
As doctoral nursing students facing a review of the literature for our dissertations, and as a faculty member teaching a research methods course, we encountered several ways of conducting a research synthesis but found no comprehensive resources that discussed, compared, and contrasted various synthesis methodologies on their purposes, processes, strengths and limitations. To complicate matters, writers use terms interchangeably or use different terms to mean the same thing, and the literature is often contradictory about various approaches. Some texts [6] , [7] – [9] did provide a preliminary understanding about how research synthesis had been taken up in nursing, but these did not meet our requirements. Thus, in this article we address the need for a comprehensive overview of research synthesis methodologies to guide public health, health care, and social science researchers and practitioners.
Research synthesis is relatively new in public health but has a long history in other fields dating back to the late 1800s. Research synthesis, a research process in its own right [10] , has become more prominent in the wake of the evidence-based movement of the 1990s. Research syntheses have found their advocates and detractors in all disciplines, with challenges to the processes of systematic review and meta-analysis, in particular, being raised by critics of evidence-based healthcare [11] – [13] .
Our purpose was to conduct an integrative review of the literature to explore the historical, contextual, and evolving nature of research synthesis [14] – [15] . We synthesize and critique the main approaches to research synthesis that are relevant for public health, health care, and social scientists. Research synthesis is the overarching term we use to describe approaches to combining, aggregating, integrating, and synthesizing primary research findings. Each synthesis methodology draws on different types of findings depending on the purpose and product of the chosen synthesis (see Additional File 1 ).
Based on our current knowledge of the literature, we identified these approaches to include in our review: systematic review, meta-analysis, qualitative meta-synthesis, meta-narrative synthesis, scoping review, rapid review, realist synthesis, concept analysis, literature review, and integrative review. Our first step was to divide the synthesis types among the research team. Each member did a preliminary search to identify key texts. The team then met to develop search terms and a framework to guide the review.
Over the period of 2008 to 2012 we extensively searched the literature, updating our search at several time points, not restricting our search by date. The dates of texts reviewed range from 1967 to 2015. We used the terms above combined with the term “method* (e.g., “realist synthesis” and “method*) in the database Health Source: Academic Edition (includes Medline and CINAHL). This search yielded very few texts on some methodologies and many on others. We realized that many documents on research synthesis had not been picked up in the search. Therefore, we also searched Google Scholar, PubMed, ERIC, and Social Science Index, as well as the websites of key organizations such as the Joanna Briggs Institute, the University of York Centre for Evidence-Based Nursing, and the Cochrane Collaboration database. We hand searched several nursing, social science, public health and health policy journals. Finally, we traced relevant documents from the references in obtained texts.
We included works that met the following inclusion criteria: (1) published in English; (2) discussed the history of research synthesis; (3) explicitly described the approach and specific methods; or (4) identified issues, challenges, strengths and limitations of the particular methodology. We excluded research reports that resulted from the use of particular synthesis methodologies unless they also included criteria 2, 3, or 4 above.
Based on our search, we identified additional types of research synthesis (e.g., meta-interpretation, best evidence synthesis, critical interpretive synthesis, meta-summary, grounded formal theory). Still, we missed some important developments in meta-analysis, for example, identified by the journal's reviewers that have now been discussed briefly in the paper. The final set of 197 texts included in our review comprised theoretical, empirical, and conceptual papers, books, editorials and commentaries, and policy documents.
In our preliminary review of key texts, the team inductively developed a framework of the important elements of each method for comparison. In the next phase, each text was read carefully, and data for these elements were extracted into a table for comparison on the points of: key characteristics, purpose, methods, and product; see Additional File 1 ). Once the data were grouped and extracted, we synthesized across categories based on the following additional points of comparison: complexity of the process, degree of systematization, consideration of context, underlying assumptions, unit of analysis, and when to use each approach. In our results, we discuss our comparison of the various synthesis approaches on the elements above. Drawing only on documents for the review, ethics approval was not required.
We identified four broad categories of research synthesis methodology: Conventional, quantitative, qualitative, and emerging syntheses. From our dataset of 197 texts, we had 14 texts on conventional synthesis, 64 on quantitative synthesis, 78 on qualitative synthesis, and 41 on emerging syntheses. Table 1 provides an overview of the four types of research synthesis, definitions, types of data used, products, and examples of the methodology.
Types of Research Synthesis | Definition | Data Types Used | Products | Examples |
1. Conventional Synthesis | Older forms of review with less-systematic examination, critique, and synthesis of the literature on a mature topic for re-conceptulization or on a new topic for preliminary conceptualization | , – | ||
2. Quantitative Synthesis | Combining, aggregating, or integrating quantitative empirical research with data expressed in numeric form | , – – – | ||
3. Qualitative Synthesis | Combining, aggregating, or integrating qualitative empirical research and/or theoretical work expressed in narrative form | – – , – , , – , – – , – – , – | ||
4. Emerging Synthesis | Newer syntheses that provide a systematic approach to synthesizing varied literature in a topic area that includes diverse data types | – – – – , , – |
Although we group these types of synthesis into four broad categories on the basis of similarities, each type within a category has unique characteristics, which may differ from the overall group similarities. Each could be explored in greater depth to tease out their unique characteristics, but detailed comparison is beyond the scope of this article.
Additional File 1 presents one or more selected types of synthesis that represent the broad category but is not an exhaustive presentation of all types within each category. It provides more depth for specific examples from each category of synthesis on the characteristics, purpose, methods, and products than is found in Table 1 .
4.1.1. what is it.
Here we draw on two types of categorization. First, we utilize Dixon Woods et al.'s [49] classification of research syntheses as being either integrative or interpretive . (Please note that integrative syntheses are not the same as an integrative review as defined in Additional File 1 .) Second, we use Popay's [80] enhancement and epistemological models .
The defining characteristics of integrative syntheses are that they involve summarizing the data achieved by pooling data [49] . Integrative syntheses include systematic reviews, meta-analyses, as well as scoping and rapid reviews because each of these focus on summarizing data. They also define concepts from the outset (although this may not always be true in scoping or rapid reviews) and deal with a well-specified phenomenon of interest.
Interpretive syntheses are primarily concerned with the development of concepts and theories that integrate concepts [49] . The analysis in interpretive synthesis is conceptual both in process and outcome, and “the product is not aggregations of data, but theory” [49] , [p.12]. Interpretive syntheses involve induction and interpretation, and are primarily conceptual in process and outcome. Examples include integrative reviews, some systematic reviews, all of the qualitative syntheses, meta-narrative, realist and critical interpretive syntheses. Of note, both quantitative and qualitative studies can be either integrative or interpretive
The second categorization, enhancement versus epistemological , applies to those approaches that use multiple data types and sources [80] . Popay's [80] classification reflects the ways that qualitative data are valued in relation to quantitative data.
In the enhancement model , qualitative data adds something to quantitative analysis. The enhancement model is reflected in systematic reviews and meta-analyses that use some qualitative data to enhance interpretation and explanation. It may also be reflected in some rapid reviews that draw on quantitative data but use some qualitative data.
The epistemological model assumes that quantitative and qualitative data are equal and each has something unique to contribute. All of the other review approaches, except pure quantitative or qualitative syntheses, reflect the epistemological model because they value all data types equally but see them as contributing different understandings.
By and large, the quantitative approaches (quantitative systematic review and meta-analysis) have typically used purely quantitative data (i.e., expressed in numeric form). More recently, both Cochrane [81] and Campbell [82] collaborations are grappling with the need to, and the process of, integrating qualitative research into a systematic review. The qualitative approaches use qualitative data (i.e., expressed in words). All of the emerging synthesis types, as well as the conventional integrative review, incorporate qualitative and quantitative study designs and data.
Four types of research questions direct inquiry across the different types of syntheses. The first is a well-developed research question that gives direction to the synthesis (e.g., meta-analysis, systematic review, meta-study, concept analysis, rapid review, realist synthesis). The second begins as a broad general question that evolves and becomes more refined over the course of the synthesis (e.g., meta-ethnography, scoping review, meta-narrative, critical interpretive synthesis). In the third type, the synthesis begins with a phenomenon of interest and the question emerges in the analytic process (e.g., grounded formal theory). Lastly, there is no clear question, but rather a general review purpose (e.g., integrative review). Thus, the requirement for a well-defined question cuts across at least three of the synthesis types (e.g., quantitative, qualitative, and emerging).
This is a contested issue within and between the four synthesis categories. There are strong proponents of quality appraisal in the quantitative traditions of systematic review and meta-analysis based on the need for strong studies that will not jeopardize validity of the overall findings. Nonetheless, there is no consensus on pre-defined criteria; many scales exist that vary dramatically in composition. This has methodological implications for the credibility of findings [83] .
Specific methodologies from the conventional, qualitative, and emerging categories support quality appraisal but do so with caveats. In conventional integrative reviews appraisal is recommended, but depends on the sampling frame used in the study [18] . In meta-study, appraisal criteria are explicit but quality criteria are used in different ways depending on the specific requirements of the inquiry [54] . Among the emerging syntheses, meta-narrative review developers support appraisal of a study based on criteria from the research tradition of the primary study [67] , [84] – [85] . Realist synthesis similarly supports the use of high quality evidence, but appraisal checklists are viewed with scepticism and evidence is judged based on relevance to the research question and whether a credible inference may be drawn [69] . Like realist, critical interpretive syntheses do not judge quality using standardized appraisal instruments. They will exclude fatally flawed studies, but there is no consensus on what ‘fatally flawed’ means [49] , [71] . Appraisal is based on relevance to the inquiry, not rigor of the study.
There is no agreement on quality appraisal among qualitative meta-ethnographers with some supporting and others refuting the need for appraisal. [60] , [62] . Opponents of quality appraisal are found among authors of qualitative (grounded formal theory and concept analysis) and emerging syntheses (scoping and rapid reviews) because quality is not deemed relevant to the intention of the synthesis; the studies being reviewed are not effectiveness studies where quality is extremely important. These qualitative synthesis are often reviews of theoretical developments where the concept itself is what is important, or reviews that provide quotations from the raw data so readers can make their own judgements about the relevance and utility of the data. For example, in formal grounded theory, the purpose of theory generation and authenticity of data used to generate the theory is not as important as the conceptual category. Inaccuracies may be corrected in other ways, such as using the constant comparative method, which facilitates development of theoretical concepts that are repeatedly found in the data [86] – [87] . For pragmatic reasons, evidence is not assessed in rapid and scoping reviews, in part to produce a timely product. The issue of quality appraisal is unresolved across the terrain of research synthesis and we consider this further in our discussion.
All research syntheses share a common purpose -- to summarize, synthesize, or integrate research findings from diverse studies. This helps readers stay abreast of the burgeoning literature in a field. Our discussion here is at the level of the four categories of synthesis. Beginning with conventional literature syntheses, the overall purpose is to attend to mature topics for the purpose of re-conceptualization or to new topics requiring preliminary conceptualization [14] . Such syntheses may be helpful to consider contradictory evidence, map shifting trends in the study of a phenomenon, and describe the emergence of research in diverse fields [14] . The purpose here is to set the stage for a study by identifying what has been done, gaps in the literature, important research questions, or to develop a conceptual framework to guide data collection and analysis.
The purpose of quantitative systematic reviews is to combine, aggregate, or integrate empirical research to be able to generalize from a group of studies and determine the limits of generalization [27] . The focus of quantitative systematic reviews has been primarily on aggregating the results of studies evaluating the effectiveness of interventions using experimental, quasi-experimental, and more recently, observational designs. Systematic reviews can be done with or without quantitative meta-analysis but a meta-analysis always takes place within the context of a systematic review. Researchers must consider the review's purpose and the nature of their data in undertaking a quantitative synthesis; this will assist in determining the approach.
The purpose of qualitative syntheses is broadly to synthesize complex health experiences, practices, or concepts arising in healthcare environments. There may be various purposes depending on the qualitative methodology. For example, in hermeneutic studies the aim may be holistic explanation or understanding of a phenomenon [42] , which is deepened by integrating the findings from multiple studies. In grounded formal theory, the aim is to produce a conceptual framework or theory expected to be applicable beyond the original study. Although not able to generalize from qualitative research in the statistical sense [88] , qualitative researchers usually do want to say something about the applicability of their synthesis to other settings or phenomena. This notion of ‘theoretical generalization’ has been referred to as ‘transferability’ [89] – [90] and is an important criterion of rigour in qualitative research. It applies equally to the products of a qualitative synthesis in which the synthesis of multiple studies on the same phenomenon strengthens the ability to draw transferable conclusions.
The overarching purpose of emerging syntheses is challenging the more traditional types of syntheses, in part by using data from both quantitative and qualitative studies with diverse designs for analysis. Beyond this, however, each emerging synthesis methodology has a unique purpose. In meta-narrative review, the purpose is to identify different research traditions in the area, synthesize a complex and diverse body of research. Critical interpretive synthesis shares this characteristic. Although a distinctive approach, critical interpretive synthesis utilizes a modification of the analytic strategies of meta-ethnography [61] (e.g., reciprocal translational analysis, refutational synthesis, and lines of argument synthesis) but goes beyond the use of these to bring a critical perspective to bear in challenging the normative or epistemological assumptions in the primary literature [72] – [73] . The unique purpose of a realist synthesis is to amalgamate complex empirical evidence and theoretical understandings within a diverse body of literature to uncover the operative mechanisms and contexts that affect the outcomes of social interventions. In a scoping review, the intention is to find key concepts, examine the range of research in an area, and identify gaps in the literature. The purpose of a rapid review is comparable to that of a scoping review, but done quickly to meet the time-sensitive information needs of policy makers.
4.3.1. degree of systematization.
There are varying degrees of systematization across the categories of research synthesis. The most systematized are quantitative systematic reviews and meta-analyses. There are clear processes in each with judgments to be made at each step, although there are no agreed upon guidelines for this. The process is inherently subjective despite attempts to develop objective and systematic processes [91] – [92] . Mullen and Ramirez [27] suggest that there is often a false sense of rigour implied by the terms ‘systematic review’ and ‘meta-analysis’ because of their clearly defined procedures.
In comparison with some types of qualitative synthesis, concept analysis is quite procedural. Qualitative meta-synthesis also has defined procedures and is systematic, yet perhaps less so than concept analysis. Qualitative meta-synthesis starts in an unsystematic way but becomes more systematic as it unfolds. Procedures and frameworks exist for some of the emerging types of synthesis [e.g., [50] , [63] , [71] , [93] ] but are not linear, have considerable flexibility, and are often messy with emergent processes [85] . Conventional literature reviews tend not to be as systematic as the other three types. In fact, the lack of systematization in conventional literature synthesis was the reason for the development of more systematic quantitative [17] , [20] and qualitative [45] – [46] , [61] approaches. Some authors in the field [18] have clarified processes for integrative reviews making them more systematic and rigorous, but most conventional syntheses remain relatively unsystematic in comparison with other types.
Some synthesis processes are considerably more complex than others. Methodologies with clearly defined steps are arguably less complex than the more flexible and emergent ones. We know that any study encounters challenges and it is rare that a pre-determined research protocol can be followed exactly as intended. Not even the rigorous methods associated with Cochrane [81] systematic reviews and meta-analyses are always implemented exactly as intended. Even when dealing with numbers rather than words, interpretation is always part of the process. Our collective experience suggests that new methodologies (e.g., meta-narrative synthesis and realist synthesis) that integrate different data types and methods are more complex than conventional reviews or the rapid and scoping reviews.
The products of research syntheses usually take three distinct formats (see Table 1 and Additional File 1 for further details). The first representation is in tables, charts, graphical displays, diagrams and maps as seen in integrative, scoping and rapid reviews, meta-analyses, and critical interpretive syntheses. The second type of synthesis product is the use of mathematical scores. Summary statements of effectiveness are mathematically displayed in meta-analyses (as an effect size), systematic reviews, and rapid reviews (statistical significance).
The third synthesis product may be a theory or theoretical framework. A mid-range theory can be produced from formal grounded theory, meta-study, meta-ethnography, and realist synthesis. Theoretical/conceptual frameworks or conceptual maps may be created in meta-narrative and critical interpretive syntheses, and integrative reviews. Concepts for use within theories are produced in concept analysis. While these three product types span the categories of research synthesis, narrative description and summary is used to present the products resulting from all methodologies.
There are diverse ways that context is considered in the four broad categories of synthesis. Context may be considered to the extent that it features within primary studies for the purpose of the review. Context may also be understood as an integral aspect of both the phenomenon under study and the synthesis methodology (e.g., realist synthesis). Quantitative systematic reviews and meta-analyses have typically been conducted on studies using experimental and quasi-experimental designs and more recently observational studies, which control for contextual features to allow for understanding of the ‘true’ effect of the intervention [94] .
More recently, systematic reviews have included covariates or mediating variables (i.e., contextual factors) to help explain variability in the results across studies [27] . Context, however, is usually handled in the narrative discussion of findings rather than in the synthesis itself. This lack of attention to context has been one criticism leveled against systematic reviews and meta-analyses, which restrict the types of research designs that are considered [e.g., [95] ].
When conventional literature reviews incorporate studies that deal with context, there is a place for considering contextual influences on the intervention or phenomenon. Reviews of quantitative experimental studies tend to be devoid of contextual considerations since the original studies are similarly devoid, but context might figure prominently in a literature review that incorporates both quantitative and qualitative studies.
Qualitative syntheses have been conducted on the contextual features of a particular phenomenon [33] . Paterson et al. [54] advise researchers to attend to how context may have influenced the findings of particular primary studies. In qualitative analysis, contextual features may form categories by which the data can be compared and contrasted to facilitate interpretation. Because qualitative research is often conducted to understand a phenomenon as a whole, context may be a focus, although this varies with the qualitative methodology. At the same time, the findings in a qualitative synthesis are abstracted from the original reports and taken to a higher level of conceptualization, thus removing them from the original context.
Meta-narrative synthesis [67] , [84] , because it draws on diverse research traditions and methodologies, may incorporate context into the analysis and findings. There is not, however, an explicit step in the process that directs the analyst to consider context. Generally, the research question guiding the synthesis is an important factor in whether context will be a focus.
More recent iterations of concept analysis [47] , [96] – [97] explicitly consider context reflecting the assumption that a concept's meaning is determined by its context. Morse [47] points out, however, that Wilson's [98] approach to concept analysis, and those based on Wilson [e.g., [45] ], identify attributes that are devoid of context, while Rodgers' [96] , [99] evolutionary method considers context (e.g., antecedents, consequences, and relationships to other concepts) in concept development.
Realist synthesis [69] considers context as integral to the study. It draws on a critical realist logic of inquiry grounded in the work of Bhaskar [100] , who argues that empirical co-occurrence of events is insufficient for inferring causation. One must identify generative mechanisms whose properties are causal and, depending on the situation, may nor may not be activated [94] . Context interacts with program/intervention elements and thus cannot be differentiated from the phenomenon [69] . This approach synthesizes evidence on generative mechanisms and analyzes contextual features that activate them; the result feeds back into the context. The focus is on what works, for whom, under what conditions, why and how [68] .
When we began our review, we ‘assumed’ that the assumptions underlying synthesis methodologies would be a distinguishing characteristic of synthesis types, and that we could compare the various types on their assumptions, explicit or implicit. We found, however, that many authors did not explicate the underlying assumptions of their methodologies, and it was difficult to infer them. Kirkevold [101] has argued that integrative reviews need to be carried out from an explicit philosophical or theoretical perspective. We argue this should be true for all types of synthesis.
Authors of some emerging synthesis approaches have been very explicit about their assumptions and philosophical underpinnings. An implicit assumption of most emerging synthesis methodologies is that quantitative systematic reviews and meta-analyses have limited utility in some fields [e.g., in public health – [13] , [102] ] and for some kinds of review questions like those about feasibility and appropriateness versus effectiveness [103] – [104] . They also assume that ontologically and epistemologically, both kinds of data can be combined. This is a significant debate in the literature because it is about the commensurability of overarching paradigms [105] but this is beyond the scope of this review.
Realist synthesis is philosophically grounded in critical realism or, as noted above, a realist logic of inquiry [93] , [99] , [106] – [107] . Key assumptions regarding the nature of interventions that inform critical realism have been described above in the section on context. See Pawson et al. [106] for more information on critical realism, the philosophical basis of realist synthesis.
Meta-narrative synthesis is explicitly rooted in a constructivist philosophy of science [108] in which knowledge is socially constructed rather than discovered, and what we take to be ‘truth’ is a matter of perspective. Reality has a pluralistic and plastic character, and there is no pre-existing ‘real world’ independent of human construction and language [109] . See Greenhalgh et al. [67] , [85] and Greenhalgh & Wong [97] for more discussion of the constructivist basis of meta-narrative synthesis.
In the case of purely quantitative or qualitative syntheses, it may be an easier matter to uncover unstated assumptions because they are likely to be shared with those of the primary studies in the genre. For example, grounded formal theory shares the philosophical and theoretical underpinnings of grounded theory, rooted in the theoretical perspective of symbolic interactionism [110] – [111] and the philosophy of pragmatism [87] , [112] – [114] .
As with meta-narrative synthesis, meta-study developers identify constructivism as their interpretive philosophical foundation [54] , [88] . Epistemologically, constructivism focuses on how people construct and re-construct knowledge about a specific phenomenon, and has three main assumptions: (1) reality is seen as multiple, at times even incompatible with the phenomenon under consideration; (2) just as primary researchers construct interpretations from participants' data, meta-study researchers also construct understandings about the primary researchers' original findings. Thus, meta-synthesis is a construction of a construction, or a meta-construction; and (3) all constructions are shaped by the historical, social and ideological context in which they originated [54] . The key message here is that reports of any synthesis would benefit from an explicit identification of the underlying philosophical perspectives to facilitate a better understanding of the results, how they were derived, and how they are being interpreted.
The unit of analysis for each category of review is generally distinct. For the emerging synthesis approaches, the unit of analysis is specific to the intention. In meta-narrative synthesis it is the storyline in diverse research traditions; in rapid review or scoping review, it depends on the focus but could be a concept; and in realist synthesis, it is the theories rather than programs that are the units of analysis. The elements of theory that are important in the analysis are mechanisms of action, the context, and the outcome [107] .
For qualitative synthesis, the units of analysis are generally themes, concepts or theories, although in meta-study, the units of analysis can be research findings (“meta-data-analysis”), research methods (“meta-method”) or philosophical/theoretical perspectives (“meta-theory”) [54] . In quantitative synthesis, the units of analysis range from specific statistics for systematic reviews to effect size of the intervention for meta-analysis. More recently, some systematic reviews focus on theories [115] – [116] , therefore it depends on the research question. Similarly, within conventional literature synthesis the units of analysis also depend on the research purpose, focus and question as well as on the type of research methods incorporated into the review. What is important in all research syntheses, however, is that the unit of analysis needs to be made explicit. Unfortunately, this is not always the case.
In this section, we discuss the overarching strengths and limitations of synthesis methodologies as a whole and then highlight strengths and weaknesses across each of our four categories of synthesis.
With the vast proliferation of research reports and the increased ease of retrieval, research synthesis has become more accessible providing a way of looking broadly at the current state of research. The availability of syntheses helps researchers, practitioners, and policy makers keep up with the burgeoning literature in their fields without which evidence-informed policy or practice would be difficult. Syntheses explain variation and difference in the data helping us identify the relevance for our own situations; they identify gaps in the literature leading to new research questions and study designs. They help us to know when to replicate a study and when to avoid excessively duplicating research. Syntheses can inform policy and practice in a way that well-designed single studies cannot; they provide building blocks for theory that helps us to understand and explain our phenomena of interest.
The process of selecting, combining, integrating, and synthesizing across diverse study designs and data types can be complex and potentially rife with bias, even with those methodologies that have clearly defined steps. Just because a rigorous and standardized approach has been used does not mean that implicit judgements will not influence the interpretations and choices made at different stages.
In all types of synthesis, the quantity of data can be considerable, requiring difficult decisions about scope, which may affect relevance. The quantity of available data also has implications for the size of the research team. Few reviews these days can be done independently, in particular because decisions about inclusion and exclusion may require the involvement of more than one person to ensure reliability.
For all types of synthesis, it is likely that in areas with large, amorphous, and diverse bodies of literature, even the most sophisticated search strategies will not turn up all the relevant and important texts. This may be more important in some synthesis methodologies than in others, but the omission of key documents can influence the results of all syntheses. This issue can be addressed, at least in part, by including a library scientist on the research team as required by some funding agencies. Even then, it is possible to miss key texts. In this review, for example, because none of us are trained in or conduct meta-analyses, we were not even aware that we had missed some new developments in this field such as meta-regression [117] – [118] , network meta-analysis [119] – [121] , and the use of individual patient data in meta-analyses [122] – [123] .
One limitation of systematic reviews and meta-analyses is that they rapidly go out of date. We thought this might be true for all types of synthesis, although we wondered if those that produce theory might not be somewhat more enduring. We have not answered this question but it is open for debate. For all types of synthesis, the analytic skills and the time required are considerable so it is clear that training is important before embarking on a review, and some types of review may not be appropriate for students or busy practitioners.
Finally, the quality of reporting in primary studies of all genres is variable so it is sometimes difficult to identify aspects of the study essential for the synthesis, or to determine whether the study meets quality criteria. There may be flaws in the original study, or journal page limitations may necessitate omitting important details. Reporting standards have been developed for some types of reviews (e.g., systematic review, meta-analysis, meta-narrative synthesis, realist synthesis); but there are no agreed upon standards for qualitative reviews. This is an important area for development in advancing the science of research synthesis.
The conventional literature review and now the increasingly common integrative review remain important and accessible approaches for students, practitioners, and experienced researchers who want to summarize literature in an area but do not have the expertise to use one of the more complex methodologies. Carefully executed, such reviews are very useful for synthesizing literature in preparation for research grants and practice projects. They can determine the state of knowledge in an area and identify important gaps in the literature to provide a clear rationale or theoretical framework for a study [14] , [18] . There is a demand, however, for more rigour, with more attention to developing comprehensive search strategies and more systematic approaches to combining, integrating, and synthesizing the findings.
Generally, conventional reviews include diverse study designs and data types that facilitate comprehensiveness, which may be a strength on the one hand, but can also present challenges on the other. The complexity inherent in combining results from studies with diverse methodologies can result in bias and inaccuracies. The absence of clear guidelines about how to synthesize across diverse study types and data [18] has been a challenge for novice reviewers.
Quantitative systematic reviews and meta-analyses have been important in launching the field of evidence-based healthcare. They provide a systematic, orderly and auditable process for conducting a review and drawing conclusions [25] . They are arguably the most powerful approaches to understanding the effectiveness of healthcare interventions, especially when intervention studies on the same topic show very different results. When areas of research are dogged by controversy [25] or when study results go against strongly held beliefs, such approaches can reduce the uncertainty and bring strong evidence to bear on the controversy.
Despite their strengths, they also have limitations. Systematic reviews and meta-analyses do not provide a way of including complex literature comprising various types of evidence including qualitative studies, theoretical work, and epidemiological studies. Only certain types of design are considered and qualitative data are used in a limited way. This exclusion limits what can be learned in a topic area.
Meta-analyses are often not possible because of wide variability in study design, population, and interventions so they may have a narrow range of utility. New developments in meta-analysis, however, can be used to address some of these limitations. Network meta-analysis is used to explore relative efficacy of multiple interventions, even those that have never been compared in more conventional pairwise meta-analyses [121] , allowing for improved clinical decision making [120] . The limitation is that network meta-analysis has only been used in medical/clinical applications [119] and not in public health. It has not yet been widely accepted and many methodological challenges remain [120] – [121] . Meta-regression is another development that combines meta-analytic and linear regression principles to address the fact that heterogeneity of results may compromise a meta-analysis [117] – [118] . The disadvantage is that many clinicians are unfamiliar with it and may incorrectly interpret results [117] .
Some have accused meta-analysis of combining apples and oranges [124] raising questions in the field about their meaningfulness [25] , [28] . More recently, the use of individual rather than aggregate data has been useful in facilitating greater comparability among studies [122] . In fact, Tomas et al. [123] argue that meta-analysis using individual data is now the gold standard although access to the raw data from other studies may be a challenge to obtain.
The usefulness of systematic reviews in synthesizing complex health and social interventions has also been challenged [102] . It is often difficult to synthesize their findings because such studies are “epistemologically diverse and methodologically complex” [ [69] , p.21]. Rigid inclusion/exclusion criteria may allow only experimental or quasi-experimental designs into consideration resulting in lost information that may well be useful to policy makers for tailoring an intervention to the context or understanding its acceptance by recipients.
Qualitative syntheses may be the type of review most fraught with controversy and challenge, while also bringing distinct strengths to the enterprise. Although these methodologies provide a comprehensive and systematic review approach, they do not generally provide definitive statements about intervention effectiveness. They do, however, address important questions about the development of theoretical concepts, patient experiences, acceptability of interventions, and an understanding about why interventions might work.
Most qualitative syntheses aim to produce a theoretically generalizable mid-range theory that explains variation across studies. This makes them more useful than single primary studies, which may not be applicable beyond the immediate setting or population. All provide a contextual richness that enhances relevance and understanding. Another benefit of some types of qualitative synthesis (e.g., grounded formal theory) is that the concept of saturation provides a sound rationale for limiting the number of texts to be included thus making reviews potentially more manageable. This contrasts with the requirements of systematic reviews and meta-analyses that require an exhaustive search.
Qualitative researchers debate about whether the findings of ontologically and epistemological diverse qualitative studies can actually be combined or synthesized [125] because methodological diversity raises many challenges for synthesizing findings. The products of different types of qualitative syntheses range from theory and conceptual frameworks, to themes and rich descriptive narratives. Can one combine the findings from a phenomenological study with the theory produced in a grounded theory study? Many argue yes, but many also argue no.
Emerging synthesis methodologies were developed to address some limitations inherent in other types of synthesis but also have their own issues. Because each type is so unique, it is difficult to identify overarching strengths of the entire category. An important strength, however, is that these newer forms of synthesis provide a systematic and rigorous approach to synthesizing a diverse literature base in a topic area that includes a range of data types such as: both quantitative and qualitative studies, theoretical work, case studies, evaluations, epidemiological studies, trials, and policy documents. More than conventional literature reviews and systematic reviews, these approaches provide explicit guidance on analytic methods for integrating different types of data. The assumption is that all forms of data have something to contribute to knowledge and theory in a topic area. All have a defined but flexible process in recognition that the methods may need to shift as knowledge develops through the process.
Many emerging synthesis types are helpful to policy makers and practitioners because they are usually involved as team members in the process to define the research questions, and interpret and disseminate the findings. In fact, engagement of stakeholders is built into the procedures of the methods. This is true for rapid reviews, meta-narrative syntheses, and realist syntheses. It is less likely to be the case for critical interpretive syntheses.
Another strength of some approaches (realist and meta-narrative syntheses) is that quality and publication standards have been developed to guide researchers, reviewers, and funders in judging the quality of the products [108] , [126] – [127] . Training materials and online communities of practice have also been developed to guide users of realist and meta-narrative review methods [107] , [128] . A unique strength of critical interpretive synthesis is that it takes a critical perspective on the process that may help reconceptualize the data in a way not considered by the primary researchers [72] .
There are also challenges of these new approaches. The methods are new and there may be few published applications by researchers other than the developers of the methods, so new users often struggle with the application. The newness of the approaches means that there may not be mentors available to guide those unfamiliar with the methods. This is changing, however, and the number of applications in the literature is growing with publications by new users helping to develop the science of synthesis [e.g., [129] ]. However, the evolving nature of the approaches and their developmental stage present challenges for novice researchers.
Choosing an appropriate approach to synthesis will depend on the question you are asking, the purpose of the review, and the outcome or product you want to achieve. In Additional File 1 , we discuss each of these to provide guidance to readers on making a choice about review type. If researchers want to know whether a particular type of intervention is effective in achieving its intended outcomes, then they might choose a quantitative systemic review with or without meta-analysis, possibly buttressed with qualitative studies to provide depth and explanation of the results. Alternately, if the concern is about whether an intervention is effective with different populations under diverse conditions in varying contexts, then a realist synthesis might be the most appropriate.
If researchers' concern is to develop theory, they might consider qualitative syntheses or some of the emerging syntheses that produce theory (e.g., critical interpretive synthesis, realist review, grounded formal theory, qualitative meta-synthesis). If the aim is to track the development and evolution of concepts, theories or ideas, or to determine how an issue or question is addressed across diverse research traditions, then meta-narrative synthesis would be most appropriate.
When the purpose is to review the literature in advance of undertaking a new project, particularly by graduate students, then perhaps an integrative review would be appropriate. Such efforts contribute towards the expansion of theory, identify gaps in the research, establish the rationale for studying particular phenomena, and provide a framework for interpreting results in ways that might be useful for influencing policy and practice.
For researchers keen to bring new insights, interpretations, and critical re-conceptualizations to a body of research, then qualitative or critical interpretive syntheses will provide an inductive product that may offer new understandings or challenges to the status quo. These can inform future theory development, or provide guidance for policy and practice.
What is the current state of science regarding research synthesis? Public health, health care, and social science researchers or clinicians have previously used all four categories of research synthesis, and all offer a suitable array of approaches for inquiries. New developments in systematic reviews and meta-analysis are providing ways of addressing methodological challenges [117] – [123] . There has also been significant advancement in emerging synthesis methodologies and they are quickly gaining popularity. Qualitative meta-synthesis is still evolving, particularly given how new it is within the terrain of research synthesis. In the midst of this evolution, outstanding issues persist such as grappling with: the quantity of data, quality appraisal, and integration with knowledge translation. These topics have not been thoroughly addressed and need further debate.
We raise the question of whether it is possible or desirable to find all available studies for a synthesis that has this requirement (e.g., meta-analysis, systematic review, scoping, meta-narrative synthesis [25] , [27] , [63] , [67] , [84] – [85] ). Is the synthesis of all available studies a realistic goal in light of the burgeoning literature? And how can this be sustained in the future, particularly as the emerging methodologies continue to develop and as the internet facilitates endless access? There has been surprisingly little discussion on this topic and the answers will have far-reaching implications for searching, sampling, and team formation.
Researchers and graduate students can no longer rely on their own independent literature search. They will likely need to ask librarians for assistance as they navigate multiple sources of literature and learn new search strategies. Although teams now collaborate with library scientists, syntheses are limited in that researchers must make decisions on the boundaries of the review, in turn influencing the study's significance. The size of a team may also be pragmatically determined to manage the search, extraction, and synthesis of the burgeoning data. There is no single answer to our question about the possibility or necessity of finding all available articles for a review. Multiple strategies that are situation specific are likely to be needed.
While the issue of quality appraisal has received much attention in the synthesis literature, scholars are far from resolution. There may be no agreement about appraisal criteria in a given tradition. For example, the debate rages over the appropriateness of quality appraisal in qualitative synthesis where there are over 100 different sets of criteria and many do not overlap [49] . These differences may reflect disciplinary and methodological orientations, but diverse quality appraisal criteria may privilege particular types of research [49] . The decision to appraise is often grounded in ontological and epistemological assumptions. Nonetheless, diversity within and between categories of synthesis is likely to continue unless debate on the topic of quality appraisal continues and evolves toward consensus.
If research syntheses are to make a difference to practice and ultimately to improve health outcomes, then we need to do a better job of knowledge translation. In the Canadian Institutes of Health Research (CIHR) definition of knowledge translation (KT), research or knowledge synthesis is an integral component [130] . Yet, with few exceptions [131] – [132] , very little of the research synthesis literature even mentions the relationship of synthesis to KT nor does it discuss strategies to facilitate the integration of synthesis findings into policy and practice. The exception is in the emerging synthesis methodologies, some of which (e.g., realist and meta-narrative syntheses, scoping reviews) explicitly involve stakeholders or knowledge users. The argument is that engaging them in this way increases the likelihood that the knowledge generated will be translated into policy and practice. We suggest that a more explicit engagement with knowledge users in all types of synthesis would benefit the uptake of the research findings.
Research synthesis neither makes research more applicable to practice nor ensures implementation. Focus must now turn seriously towards translation of synthesis findings into knowledge products that are useful for health care practitioners in multiple areas of practice and develop appropriate strategies to facilitate their use. The burgeoning field of knowledge translation has, to some extent, taken up this challenge; however, the research-practice gap continues to plague us [133] – [134] . It is a particular problem for qualitative syntheses [131] . Although such syntheses have an important place in evidence-informed practice, little effort has gone into the challenge of translating the findings into useful products to guide practice [131] .
Our study took longer than would normally be expected for an integrative review. Each of us were primarily involved in our own dissertations or teaching/research positions, and so this study was conducted ‘off the sides of our desks.’ A limitation was that we searched the literature over the course of 4 years (from 2008–2012), necessitating multiple search updates. Further, we did not do a comprehensive search of the literature after 2012, thus the more recent synthesis literature was not systematically explored. We did, however, perform limited database searches from 2012–2015 to keep abreast of the latest methodological developments. Although we missed some new approaches to meta-analysis in our search, we did not find any new features of the synthesis methodologies covered in our review that would change the analysis or findings of this article. Lastly, we struggled with the labels used for the broad categories of research synthesis methodology because of our hesitancy to reinforce the divide between quantitative and qualitative approaches. However, it was very difficult to find alternative language that represented the types of data used in these methodologies. Despite our hesitancy in creating such an obvious divide, we were left with the challenge of trying to find a way of characterizing these broad types of syntheses.
Our findings offer methodological clarity for those wishing to learn about the broad terrain of research synthesis. We believe that our review makes transparent the issues and considerations in choosing from among the four broad categories of research synthesis. In summary, research synthesis has taken its place as a form of research in its own right. The methodological terrain has deep historical roots reaching back over the past 200 years, yet research synthesis remains relatively new to public health, health care, and social sciences in general. This is rapidly changing. New developments in systematic reviews and meta-analysis, and the emergence of new synthesis methodologies provide a vast array of options to review the literature for diverse purposes. New approaches to research synthesis and new analytic methods within existing approaches provide a much broader range of review alternatives for public health, health care, and social science students and researchers.
KSM is an assistant professor in the Faculty of Nursing at the University of Alberta. Her work on this article was largely conducted as a Postdoctoral Fellow, funded by KRESCENT (Kidney Research Scientist Core Education and National Training Program, reference #KRES110011R1) and the Faculty of Nursing at the University of Alberta.
MM's work on this study over the period of 2008-2014 was supported by a Canadian Institutes of Health Research Applied Public Health Research Chair Award (grant #92365).
We thank Rachel Spanier who provided support with reference formatting.
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Meta-Analysis shows concisely, yet comprehensively, how to apply statistical methods to achieve a literature review of a common research domain. It demonstrates the use of combined tests and measures of effect size to synthesize quantitatively the results of independent studies for both group differences and correlations. Strengths and weaknesses of alternative approaches, as well as of meta-analysis in general, are presented.
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Quantitative synthesis, or meta-analysis, is often essential for Comparative Effective Reviews (CERs) to provide scientifically rigorous summary information. Quantitative synthesis should be conducted in a transparent and consistent way with methodologies reported explicitly. This guide provides practical recommendations on conducting synthesis. The guide is not meant to be a textbook on meta-analysis nor is it a comprehensive review of methods, but rather it is intended to provide a consistent approach for situations and decisions that are commonly faced by AHRQ Evidence-based Practice Centers (EPCs). The goal is to describe choices as explicitly as possible, and in the context of EPC requirements, with an appropriate degree of confidence.
This guide addresses issues in the order that they are usually encountered in a synthesis, though we acknowledge that the process is not always linear. We first consider the decision of whether or not to combine studies quantitatively. The next chapter addresses how to extract and utilize data from individual studies to construct effect sizes, followed by a chapter on statistical model choice. The fourth chapter considers quantifying and exploring heterogeneity. The fifth describes an indirect evidence technique that has not been included in previous guidance – network meta-analysis, also known as mixed treatment comparisons. The final section in the report lays out future research suggestions.
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Once you have completed your analysis, you will want to both summarize and synthesize those results. You may have a qualitative synthesis, a quantitative synthesis, or both.
Qualitative Synthesis
In a qualitative synthesis, you describe for readers how the pieces of your work fit together. You will summarize, compare, and contrast the characteristics and findings, exploring the relationships between them. Further, you will discuss the relevance and applicability of the evidence to your research question. You will also analyze the strengths and weaknesses of the body of evidence. Focus on where the gaps are in the evidence and provide recommendations for further research.
Quantitative Synthesis
Whether or not your Systematic Review includes a full meta-analysis, there is typically some element of data analysis. The quantitative synthesis combines and analyzes the evidence using statistical techniques. This includes comparing methodological similarities and differences and potentially the quality of the studies conducted.
In a systematic review, researchers do more than summarize findings from identified articles. You will synthesize the information you want to include.
While a summary is a way of concisely relating important themes and elements from a larger work or works in a condensed form, a synthesis takes the information from a variety of works and combines them together to create something new.
Synthesis :
"The goal of a systematic synthesis of qualitative research is to integrate or compare the results across studies in order to increase understanding of a particular phenomenon, not to add studies together. Typically the aim is to identify broader themes or new theories – qualitative syntheses usually result in a narrative summary of cross-cutting or emerging themes or constructs, and/or conceptual models."
Denner, J., Marsh, E. & Campe, S. (2017). Approaches to reviewing research in education. In D. Wyse, N. Selwyn, & E. Smith (Eds.), The BERA/SAGE Handbook of educational research (Vol. 2, pp. 143-164). doi: 10.4135/9781473983953.n7
Data synthesis (Collaboration for Environmental Evidence Guidebook)
Interpreting findings and and reporting conduct (Collaboration for Environmental Evidence Guidebook)
Interpreting results and drawing conclusions (Cochrane Handbook, Chapter 15)
Guidance on the conduct of narrative synthesis in systematic reviews (ESRC Methods Programme)
Meta-analysis is a set of statistical techniques for synthesizing data across studies. It is a statistical method for combining the findings from quantitative studies. It evaluates, synthesizes, and summarizes results. It may be conducted independently or as a specialized subset of a systematic review. A systematic review attempts to collate empirical evidence that fits predefined eligibility criteria to answer a specific research question. Meta-analysis is a quantitative, formal, epidemiological study design used to systematically assess the results of previous research to derive conclusions about that body of research (Haidrich, 2010). Rigorously conducted meta-analyses are useful tools in evidence-based medicine . Outcomes from a meta-analysis may include a more precise estimate of the effect of a treatment or risk factor for disease or other outcomes. Not all systematic reviews include meta-analysis , but all meta-analyses are found in systematic reviews (Haidrich, 2010).
A Meta analysis is appropriate when a group of studies report quantitative results rather than qualitative findings or theory, if they examine the same or similar constructs or relationships, if they are derived from similar research designs and report the simple relationships between two variables rather than relationships that have been adjusted for the effect of additional variables (siddaway, et al., 2019).
Haidich A. B. (2010). Meta-analysis in medical research. Hippokratia , 14 (Suppl 1), 29–37.
Siddaway, A. P., Wood, A. M., & Hedges, L. V. (2019). How to do a systematic review: A best practice guide for conducting and reporting narrative reviews, meta-analyses, and meta-syntheses. Annual Review of Psychology, 70 , 747–770.
A meta synthesis is the systematic review and integration of findings from qualitative studies (Lachal et al., 2017). Reviews of qualitative information can be conducted and reported using the same replicable, rigorous, and transparent methodology and presentation. A meta-synthesis can be used when a review aims to integrate qualitative research. A meta-synthesis attempts to synthesize qualitative studies on a topic to identify key themes, concepts, or theories that provide novel or more powerful explanations for the phenomenon under review (Siddaway et al., 2019).
Lachal, J., Revah-Levy, A., Orri, M., & Moro, M. R. (2017). Metasynthesis: An original method to synthesize qualitative literature in psychiatry. Frontiers in Psychiatry, 8 , 269 .
Siddaway, A. P., Wood, A. M., & Hedges, L. V. (2019). How to do a systematic review: A best practice guide for conducting and reporting narrative reviews, meta-analyses, and meta-syntheses. Annual Review of Psychology, 70 , 747–770 .
Author Fredric M. Wolf explains how to use combined statistical tests and measures of effect size to synthesize the results of independent studies of a common research question.
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Systematic reviews.
Quantitative synthesis (meta-analysis), qualitative synthesis.
Synthesis is a stage in the systematic review process where extracted data (findings of individual studies) are combined and evaluated. The synthesis part of a systematic review will determine the outcomes of the review.
There are two commonly accepted methods of synthesis in systematic reviews:
The way the data is extracted from your studies and synthesised and presented depends on the type of data being handled.
If you have quantitative information, some of the more common tools used to summarise data include:
If you have qualitative information, some of the more common tools used to summarise data include:
Whatever tool/s you use, the general purpose of extracting and synthesising data is to show the outcomes and effects of various studies and identify issues with methodology and quality. This means that your synthesis might reveal a number of elements, including:
In a quantitative systematic review, data is presented statistically. Typically, this is referred to as a meta-analysis .
The usual method is to combine and evaluate data from multiple studies. This is normally done in order to draw conclusions about outcomes, effects, shortcomings of studies and/or applicability of findings.
Remember, the data you synthesise should relate to your research question and protocol (plan). In the case of quantitative analysis, the data extracted and synthesised will relate to whatever method was used to generate the research question (e.g. PICO method), and whatever quality appraisals were undertaken in the analysis stage.
One way of accurately representing all of your data is in the form of a f orest plot . A forest plot is a way of combining results of multiple clinical trials in order to show point estimates arising from different studies of the same condition or treatment.
It is comprised of a graphical representation and often also a table. The graphical display shows the mean value for each trial and often with a confidence interval (the horizontal bars). Each mean is plotted relative to the vertical line of no difference.
In a qualitative systematic review, data can be presented in a number of different ways. A typical procedure in the health sciences is thematic analysis .
As explained by James Thomas and Angela Harden (2008) in an article for BMC Medical Research Methodology :
"Thematic synthesis has three stages:
While the development of descriptive themes remains 'close' to the primary studies, the analytical themes represent a stage of interpretation whereby the reviewers 'go beyond' the primary studies and generate new interpretive constructs, explanations or hypotheses" (p. 45).
A good example of how to conduct a thematic analysis in a systematic review is the following journal article by Jorgensen et al. (2108) on cancer patients. In it, the authors go through the process of:
(a) identifying and coding information about the selected studies' methodologies and findings on patient care
(b) organising these codes into subheadings and descriptive categories
(c) developing these categories into analytical themes
Jørgensen, C. R., Thomsen, T. G., Ross, L., Dietz, S. M., Therkildsen, S., Groenvold, M., Rasmussen, C. L., & Johnsen, A. T. (2018). What facilitates “patient empowerment” in cancer patients during follow-up: A qualitative systematic review of the literature. Qualitative Health Research, 28(2), 292-304. https://doi.org/10.1177/1049732317721477
Thomas, J., & Harden, A. (2008). Methods for the thematic synthesis of qualitative research in systematic reviews. BMC Medical Research Methodology, 8(1), 45-54. https://doi.org/10.1186/1471-2288-8-45
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There is a growing literature exploring the placebo response within specific mental disorders, but no overarching quantitative synthesis of this research has analyzed evidence across mental disorders. We carried out an umbrella review of meta-analyses of randomized controlled trials (RCTs) of biological treatments (pharmacotherapy or neurostimulation) for mental disorders. We explored whether placebo effect size differs across distinct disorders, and the correlates of increased placebo effects. Based on a pre-registered protocol, we searched Medline, PsycInfo, EMBASE, and Web of Knowledge up to 23.10.2022 for systematic reviews and/or meta-analyses reporting placebo effect sizes in psychopharmacological or neurostimulation RCTs. Twenty meta-analyses, summarising 1,691 RCTs involving 261,730 patients, were included. Placebo effect size varied, and was large in alcohol use disorder ( g = 0.90, 95% CI [0.70, 1.09]), depression ( g = 1.10, 95% CI [1.06, 1.15]), restless legs syndrome ( g = 1.41, 95% CI [1.25, 1.56]), and generalized anxiety disorder ( d = 1.85, 95% CI [1.61, 2.09]). Placebo effect size was small-to-medium in obsessive-compulsive disorder ( d = 0.32, 95% CI [0.22, 0.41]), primary insomnia ( g = 0.35, 95% CI [0.28, 0.42]), and schizophrenia spectrum disorders (standardized mean change = 0.33, 95% CI [0.22, 0.44]). Correlates of larger placebo response in multiple mental disorders included later publication year (opposite finding for ADHD), younger age, more trial sites, larger sample size, increased baseline severity, and larger active treatment effect size. Most (18 of 20) meta-analyses were judged ‘low’ quality as per AMSTAR-2. Placebo effect sizes varied substantially across mental disorders. Future research should explore the sources of this variation. We identified important gaps in the literature, with no eligible systematic reviews/meta-analyses of placebo response in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania.
Introduction.
A placebo is an ‘inactive’ substance or ‘sham’ technique that is used as a control for assessing the efficacy of an active treatment [ 1 ]. However, study participants in a placebo control group may experience considerable symptom improvements - a ‘placebo response’ [ 1 , 2 , 3 ]. Statistical artifacts or non-specific effects account for some of the placebo response. For example, many individuals seek treatment and are enrolled in clinical trials while their symptoms are at their worst. Their symptoms will gradually return to their usual severity (‘regression to the mean’), giving the appearance of a placebo response [ 4 ]. Further, it has been suggested that the placebo response is exacerbated due to unreliable ratings as well as baseline symptom severity inflation if raters are aware of severity criteria for entry to a trial [ 5 , 6 ]. Other potential sources of apparent placebo responses include sampling biases caused by the withdrawal of the least improved patients in the placebo arm, non-specific beneficial effects resulting from interactions with staff delivering the trial, environmental effects due to inpatient care during placebo-controlled trials, or other unaccounted for factors, such as dietary or exercise changes during the trial [ 7 , 8 , 9 ]. Nonetheless, there is evidence that placebo administration results in ‘true’ - or non-artefactual - placebo effects, that is, identifiable changes in biological systems [ 1 , 10 , 11 ]. For example, placebo administration is capable of causing immunosuppression [ 12 , 13 ], placebo effects in Parkinson’s disease are driven by striatal dopamine release [ 10 , 14 ], and placebo analgesia is mediated by endogenous opioid release [ 15 , 16 ]. Furthermore, there is evidence that placebo effects in depressive and anxiety disorders are correlated with altered activity in the ventral striatum, orbitofrontal cortex, rostral anterior cingulate cortex, and the default mode network [ 17 ]. The placebo effect size can be increased through the use of verbal suggestions and conditioning procedures, thus suggesting the underlying role of psychological mechanisms including learning and expectations [ 11 , 18 ].
Across age groups, treatment modalities, and diverse mental disorders, biological treatments (pharmacotherapy or neurostimulation) do reduce symptoms [ 19 , 20 , 21 , 22 ], but only a subgroup of patients experience a clinically significant symptom response or enter remission [ 23 , 24 , 25 ]. Furthermore, current medications may also have unfavourable side effects [ 23 , 26 , 27 , 28 , 29 , 30 , 31 ]. Given the high prevalence of mental disorders and their significant socioeconomic burden [ 32 , 33 , 34 ], there is a need to develop more effective and safer psychopharmacologic and neurostimulation treatments. However, in randomized-controlled trials (RCTs), the magnitude of the placebo response may be considerable, which can affect the interpretation of their results [ 35 , 36 , 37 ]. For example, in antipsychotic trials over the past 40 years, placebo response has increased while medication response has remained consistent [ 38 , 39 ]. Consequently, the trial’s ability to statistically differentiate between an active medication and a placebo is diminished [ 40 ]. Indeed, large placebo response rates have been implicated in hindering psychotropic drug development [ 41 , 42 ]. The increased placebo response can also affect larger data synthesis approaches, such as network meta-analysis, in which assumptions about placebo responses (e.g. stability over time) might affect the validity of results [ 43 ].
Improved understanding of participant, trial, and mental disorder-related factors that contribute to placebo response might allow better clinical trial design to separate active treatment from placebo effects. There is a growing body of research, including individual studies and systematic reviews/meta-analyses, examining the placebo response within specific mental disorders [ 35 ]. However, to date, no overarching synthesis of this literature, to detect any similarities or differences across mental disorders, has been published. We therefore carried out an umbrella review of meta-analyses to address this need. We aimed to assess the placebo effect size in RCTs for a range of mental disorders, whether the effect size differs across distinct mental disorders, and identify any correlates of increased placebo effect size or response rate.
The protocol for this systematic umbrella review was pre-registered on the open science framework ( https://osf.io/fxvn4/ ) and published [ 44 ]. Deviations from this protocol, and additions to it, were: eight authors were involved in record screening rather than two; we reported effect sizes pooled across age groups and analyses comparing placebo effect sizes between age groups; and we included a meta-analysis that incorporated trials of dietary supplements as well as medications in autism. For the rationale behind these decisions, see eMethods.
Eight authors (NH, AB, VB, LE, OKF, LM, CR, SS) carried out the systematic review and data extraction independently in pairs. Discrepancies were resolved through consensus or through arbitration by a third reviewer (NH or SCo). We searched, without date or language restrictions, up to 23.10.2022, Medline, PsycInfo, EMBASE + EMBASE Classic, and Web of Knowledge for systematic reviews with or without meta-analyses of RCTs of biological treatments (psychopharmacotherapy or neurostimulation) compared with a placebo or sham treatment in individuals with mental disorders diagnosed according to standardized criteria. The full search strategy is included in eMethods. We also sought systematic reviews of RCTs conducted in patients with sleep-wake disorders, since these disorders are included in the DSM-5 and their core symptoms overlap with those of mental disorders [ 45 ]. We retained systematic reviews with or without meta-analyses that reported within-group changes in symptoms in the placebo arm.
Next, to prevent duplication of data, a matrix containing all eligible systematic reviews/meta-analyses for each category of mental disorder was created. Where there were multiple eligible systematic reviews/meta-analyses for the same disorder and treatment, we preferentially included meta-analyses, and if multiple eligible meta-analyses remained, then we included the one containing the largest number of studies for the same disorder and treatment, in line with recent umbrella reviews [ 46 , 47 ].
Data were extracted by at least two among six reviewers (AB, VB, LE, OKF, CR, SS) independently in pairs via a piloted form. All extracted data were further checked by a third reviewer (NH). See eMethods for a list of extracted data.
Our primary outcome was the pre-post effect size of the placebo/sham related to the condition-specific primary symptom change for each mental disorder. Secondary outcomes included any other reported clinical outcomes in eligible reviews. We report effect sizes calculated within-group from baseline and post-treatment means by meta-analysis authors, including Cohen’s d and Hedges’ g for repeated measures, which account for both mean difference and correlation between paired observations; and standardized mean change, where the average change score is divided by standard deviation of the change scores. We interpreted the effect size in line with the suggestion by Cohen [ 48 ], i.e. small (~0.2), medium (~0.5), or large (~0.8).
In addition, we extracted data regarding potential correlates of increased placebo effect size or response rate (as defined and assessed by the authors of each meta-analysis) in each mental disorder identified through correlation analyses or meta-regression. Where available, results from multivariate analyses were preferred.
The methodological quality of included reviews was assessed by at least two among six reviewers (AB, VB, LE, OKF, NH, CR) independently and in pairs using the AMSTAR-2 tool, a critical appraisal tool that enables reproducible assessments of the conduct of systematic reviews [ 49 ]. The methodological quality of each included review was rated as high, moderate, low, or critically low.
Our initial search identified 6,108 records. After screening titles and abstracts, we obtained and assessed 115 full-text reports (see eResults for a list of articles excluded following full-text assessment, with reasons). Of these, 20 were deemed eligible, and all were systematic reviews with meta-analysis (Fig. 1 ). In total, the 20 included meta-analyses synthesized data from 1,691 RCTs (median 55) involving 261,730 patients (median 5,365). These meta-analyses were published between 2007 and 2022 and involved individuals with the following mental disorders: major depressive disorder (MDD; n = 6) [ 50 , 51 , 52 , 53 , 54 , 55 ], anxiety disorders ( n = 4) [ 55 , 56 , 57 , 58 ], schizophrenia spectrum disorders ( n = 3) [ 38 , 59 , 60 ], alcohol use disorder (AUD; n = 1) [ 61 ], attention-deficit/hyperactivity disorder (ADHD; n = 1) [ 62 ], autism spectrum disorders ( n = 1) [ 63 ], bipolar depression ( n = 1) [ 64 ], intellectual disability ( n = 1) [ 65 ], obsessive-compulsive disorder (OCD; n = 1) [ 66 ], primary insomnia ( n = 1) [ 67 ], and restless legs syndrome (RLS; n = 1) [ 68 ].
Twenty meta-analyses were included.
The methodological quality of the included meta-analyses according to AMSTAR-2 ratings was high in two meta-analyses (ADHD and autism), low in four meta-analyses, and critically low in the remaining 14 meta-analyses (Table 1 ). The most common sources of bias that led to downgrading on the AMSTAR-2 were: no list of excluded full-text articles with reasons ( k = 14), no explicit statement that the protocol was pre-registered ( k = 14), and no assessment of the potential impact of risk of bias in individual studies on the results ( k = 13). The full reasoning behind our AMSTAR-2 ratings is included in eResults.
Our first objective was to determine placebo effect sizes across mental conditions. Data regarding within-group placebo efficacy were reported in sixteen of the included meta-analyses [ 38 , 50 , 52 , 53 , 55 , 56 , 57 , 58 , 60 , 61 , 62 , 63 , 65 , 66 , 67 , 68 ]. Placebo effect sizes for the primary outcomes ranged from 0.23 to 1.85, with a median of 0.64 (Fig. 2 ). Median heterogeneity across meta-analyses was I 2 = 72%, suggesting a generally high percentage of heterogeneity due to true variation across studies.
Dots represent placebo group effect size while triangles represent active effect size. CI confidence interval, MDD major depressive disorder, GAD generalized anxiety disorder, SAD social anxiety disorder, OCD obsessive-compulsive disorder, g Hedges’ g, d Cohen’s d, SMC standardized mean change, NR not reported.
A detailed description of each meta-analysis included for this objective is included in eResults. Here, we report a summary of these results in order of the greatest number of RCT’s and meta-analyses included per disorder. In MDD, a large within-group placebo effect was observed ( g = 1.10, 95% CI [1.06, 1.15]), although active medication had an even larger effect size ( g = 1.49, 95% CI [1.44, 1.53]) [ 50 ]. Similarly, in children and adolescents with MDD, placebo effect size was large ( g = 1.57, 95% CI [1.36, 1.78]), as was serotonergic medication effect size ( g = 1.85, 95% CI [1.70, 2.00]) [ 55 ]. In treatment-resistant MDD, the within-group placebo effect size was smaller than in non-treatment-resistant MDD ( g = 0.89, 95% CI [0.81, 0.98]) [ 52 ]. In neuromodulation trials for MDD, the effect size of sham was g = 0.80 (95% CI [0.65, 0.95]) [ 53 ]. In this meta-analysis, the effect size was larger for non-treatment-resistant ( g = 1.28, 95% CI [0.47, 2.97]) compared to treatment-resistant participants (g = 0.50 95% CI [0.03, 0.99]) [ 53 ]. In adults with anxiety disorders, placebo effect sizes varied across disorders, with a medium effect size in panic disorder ( d = 0.57, 95% CI [0.50, 0.64]) [ 56 ] and large effect sizes in generalized anxiety disorder (GAD) ( d = 1.85, 95% CI [1.61, 2.09]) and social anxiety disorder (SAD) ( d = 0.94, 95% CI [0.77, 1.12]) [ 57 ]. Other meta-analyses in children and adolescents and older adults pooled RCTs across anxiety disorders, and found large placebo effect sizes ( g = 1.03, 95% CI [0.84, 1.21] and d = 1.06, 95% CI [0.71, 1.42], respectively) [ 55 , 58 ]. In ADHD, placebo effect size was medium-to-large for clinician-rated outcomes (SMC = 0.75, 95% CI [0.67, 0.83]) [ 62 ]. There was additionally a significant negative relationship between placebo effect size and drug-placebo difference (−0.56, p < 0.01) for self-rated outcomes [ 62 ]. In schizophrenia spectrum disorders, placebo effect size was small-to-medium in antipsychotic RCTs (SMC = 0.33, 95% CI [0.22, 0.44]) [ 38 ] and medium in RCTs focusing specifically on negative symptoms ( d = 0.64, 95% CI [0.46, 0.83]) [ 60 ]. Placebo effect size in RLS was large when measured via rating scales ( g = 1.41, 95% CI [1.25, 1.56]), but small ( g = 0.02 to 0.24) in RCTs using objective outcomes [ 68 ]. In autism, placebo effect sizes were small (SMC ranged 0.23 to 0.36) [ 63 ]. Similarly, placebo effect size was small in OCD ( d = 0.32, 95% CI [0.22, 0.41]), although larger in children and adolescents ( d = 0.45, 95% CI [0.35, 0.56]) compared with adults ( d = 0.27, 95% CI [0.15, 0.38]) [ 66 ]. Placebo effect size was large in AUD ( g = 0.90, 95% CI [0.70, 1.09]) [ 61 ], small in primary insomnia ( g ranged 0.25 to 0.43) [ 67 ], and medium in intellectual disability related to genetic causes ( g = 0.47, 95% CI [0.18, 0.76]) [ 65 ].
Our second objective was to examine the correlates of increased placebo response. We included 14 meta-analyses that reported correlates of placebo effect size or response rate through correlation analysis or meta-regression [ 38 , 51 , 53 , 54 , 56 , 57 , 59 , 60 , 61 , 62 , 63 , 64 , 66 , 68 ]. The key correlates extracted from these studies are summarized in Table 2 .
Several variables were consistently identified across meta-analyses. Increased number of trial sites was a positive correlate of increased placebo response in MDD [ 51 , 54 ], schizophrenia spectrum disorders [ 59 ], and autism spectrum disorders [ 63 ]. Similarly, increased sample size was positively associated with placebo effect size in schizophrenia spectrum disorders [ 59 ], OCD [ 66 ], and panic disorder [ 56 ]. Later publication or study year was associated with greater placebo response in anxiety disorders [ 56 , 57 ], schizophrenia spectrum disorders [ 38 ], AUD [ 61 ], and OCD [ 66 ] but not in MDD [ 51 ], and with reduced placebo response in ADHD [ 62 ]. Younger age was associated with increased placebo responses in schizophrenia spectrum disorders [ 38 , 59 ] and OCD [ 66 ]. Increased baseline illness severity was associated with increased placebo response in schizophrenia spectrum disorders [ 38 ], ADHD [ 62 ], and AUD [ 61 ]. Increased trial or follow-up duration was positively associated with increased placebo response in MDD [ 51 ], but negatively associated with placebo response in schizophrenia spectrum disorders [ 38 , 60 ] and OCD [ 66 ]. Finally, the effect size of active treatment was positively associated with increased placebo response in neurostimulation trials for MDD [ 53 ], bipolar depression [ 64 ], autistic spectrum disorders [ 63 ], and ADHD [ 62 ].
There were also some variables associated with increased placebo response in single disorders only. Flexible dosing, rather than fixed dosing, was associated with increased placebo response in MDD [ 51 ]. Increased illness duration was associated with reduced placebo response in schizophrenia spectrum disorders [ 38 ]. In RCTs for negative symptoms of schizophrenia, a higher number of active treatment arms was associated with increased placebo response [ 60 ]. A number of treatment administrations was a positive correlate of increased placebo response in patients with AUD [ 61 ]. A low risk of bias in selective reporting was associated with increased placebo response in ADHD [ 62 ]. Finally, a low risk of bias in allocation concealment was associated with increased placebo response in autism [ 63 ].
To our knowledge, this is the first overarching synthesis of the literature exploring the placebo response in RCTs of biological treatments across a broad range of mental disorders. We found that placebo responses were present and detectable across mental disorders. Further, the placebo effect size across these disorders varied between small and large (see Fig. 3 ). Additionally, several variables appeared to be associated with increased placebo effect size or response rate across a number of disorders, while others were reported for individual disorders only.
CI confidence interval, MDD major depressive disorder, GAD generalized anxiety disorder, SAD social anxiety disorder, OCD obsessive-compulsive disorder, g Hedges’ g, d Cohen’s d, SMC standardized mean change.
Our umbrella review distinguishes itself from a recent publication on placebo mechanisms across medical conditions [ 69 ]. Only four systematic reviews of research in mental disorders were included in that recent review [ 69 ], none of which were eligible for inclusion in our umbrella review, as we focus specifically on RCTs in mental disorders. Thus, our current umbrella review synthesizes different literature and is complementary [ 69 ].
We found substantial variation in placebo effect sizes across mental disorders. In GAD, SAD, MDD, AUD, and RLS (for subjective outcomes), placebo effects were large (>0.9), while they were small (approximately 0.3) in OCD, primary insomnia, autism, RLS (for objective outcomes), and schizophrenia spectrum disorders. It is noteworthy that placebo effect size/response rate correlated with active treatment effect size/response rate in many disorders (MDD, bipolar depression, ADHD, and autism). Nonetheless, where reported, active treatment was always superior. This possibly suggests an underlying ‘treatment responsiveness’ of these disorders that can vary in size. Perhaps, the natural history of a disorder is an important factor in ‘responsiveness’, i.e., disorders in which there is greater natural fluctuation in severity will show larger placebo (and active treatment) effect sizes. Supporting this hypothesis, increased trial duration predicted a larger placebo effect size in MDD, a disorder in which the natural course includes improvement [ 31 , 51 , 70 ]. Conversely, in schizophrenia spectrum disorders where improvement (particularly of negative symptoms) is less likely [ 71 ], increased trial and illness duration predicted a smaller placebo effect size [ 38 , 60 ]. However, previous meta-analyses suggest that natural improvement, for example, measured via waiting list control, does not fully account for the placebo effect in depression and anxiety disorders [ 72 , 73 ]. Statistical artifact, therefore, does not seem to fully explain the variation in effect size.
Non-specific treatment mechanisms are likely an additional source of the observed placebo effect. For example, those with treatment-resistant illness might have reduced expectations regarding treatment. This assumption is supported by the subgroup analysis reported by Razza and colleagues showing sham neuromodulation efficacy reduced as the number of previous failed antidepressant trials increased [ 53 ]. Another factor to consider is the outcome measure chosen. For example, the placebo effect size in panic disorder was smaller when calculated with objective or self-report measures compared with clinician-rated measures [ 56 ]. A similar finding was reported in ADHD trials [ 62 ]. Why placebo effect sizes would differ with clinician-rated versus self-rated scales is unclear. This might result from ‘demand characteristics’ (i.e., cues that suggest to a patient how they ‘should’ respond), or unblinding of the rater, or a combination of the two [ 74 , 75 ].
Several correlates of increased placebo response were reported in included meta-analyses. These included a larger sample size, more study sites, a later publication year (but with an opposite finding for ADHD), younger age, and increased baseline illness severity. This might reflect changes in clinical trial methods over time, the potential for increased ‘noise’ in the data with larger samples or more study sites, and, more speculatively, variables associated with increased volatility in symptoms [ 39 , 51 , 76 ]. A more extensive discussion regarding the potential reasons these variables might correlate with, or predict, placebo response is included in the eDiscussion. Although some correlates of increased placebo response were identified, perhaps more pertinently, it is unknown whether these also predict the separation between active treatment and placebo in most mental disorders. Three included meta-analyses did show that as placebo response increases, the likelihood of drug-placebo separation decreases [ 38 , 62 , 64 ]. This suggests correlates of placebo effect size are also correlates of trial success or failure, but this hypothesis needs explicit testing. In addition, few of the meta-analyses we included explored whether correlates of placebo response differed from correlates of active treatment response. For example, in clinical trials for gambling disorder, response to active treatment was predicted by weeks spent in the trial and by baseline severity, while response to placebo was predicted by baseline depressive and anxiety symptoms [ 77 ]. Furthermore, there is evidence that industry sponsorship is a specific correlate of reduced drug-placebo separation in schizophrenia spectrum disorders [ 78 ]. The largest meta-analysis that we included (conducted by Scott et al. [ 50 ]) did not explore correlates of increased placebo response through meta-regression analysis; rather, it was designed specifically to assess the impact of the use of placebo run-in periods in antidepressant trials. The authors found that use of a placebo run-in was associated with reduced placebo response. However, this effect did not enhance sensitivity to detect medication efficacy versus control groups, as trials with placebo run-in periods were also associated with a reduced medication response. Similar effects of placebo run-in were seen in univariate (but not multivariable) models in ADHD, where placebo run-in reduced placebo effect size in youth, but did not affect drug vs placebo difference [ 62 ]. Further work should be undertaken to ascertain whether trial-level correlates (including the use of placebo run-in) differentially explain active treatment or placebo response and whether controlling for these can improve drug-placebo separation.
Our results should be considered in the light of several possible limitations. First, as in any umbrella review, we were limited by the quality of the meta-analyses we included. Our AMSTAR-2 ratings suggest that confidence in the conclusions of most included meta-analyses should be critically low or low. Indeed, several meta-analyses did not assess for publication bias or for bias in included RCTs. This is relevant, as the risk of bias in selective reporting was highlighted as potentially being associated with placebo effect size in ADHD [ 62 ], and might therefore be relevant in other mental disorders. Second, our results are potentially vulnerable to biases or unmeasured confounders present in the included meta-analyses. Third, we attempted to prevent overlap and duplication of information by including only the meta-analyses with the most information. This might, however, have resulted in some data not being included in our synthesis. Fourth, an exploration of the potential clinical relevance of the placebo effect sizes reported here was outside the scope of the current review but should be considered an important question for future research. Finally, the meta-analyses we included encompassed RCTs with different levels of blinding (double-blind, single-blind). Although the majority of trials were likely double-blind, it is possible that different levels of blinding could have influenced placebo effect sizes through effects on expectations. Future analyses of placebo effects and their correlates should either focus on double-blind trials or compare results across levels of blinding. Related to this, the included meta-analyses pooled phase 2 and phase 3 trials (the latter of which will usually follow positive phase 2 trials), which might result in different expectation biases. Therefore, placebo effects should be compared between phase 2 and phase 3 trials in the future.
In this umbrella review, we found placebo effect sizes varied substantially across mental disorders. The sources of this variation remain unknown and require further study. Some variables were correlates of increased placebo response across mental disorders, including larger sample size, higher number of study sites, later publication year (opposite for ADHD), younger age, and increased baseline illness severity. There was also evidence that clinician-rated outcomes were associated with larger placebo effect sizes than self-rated or objective outcomes. We additionally identified important gaps in the literature, with no eligible systematic reviews identified in stress-related disorders, eating disorders, behavioural addictions, or bipolar mania. In relation to these disorders, some analyses have been published but they have not been included in systematic reviews/meta-analyses (e.g. analyses of individual patient data pooled across RCTs in acute mania [ 79 ] or gambling disorder [ 77 , 80 ]) and therefore were not eligible for inclusion here. We also focused on placebo response in RCTs of pharmacotherapies and neurostimulation interventions for mental disorders. We did not include placebo effects in psychosocial interventions, but such an analysis would also be valuable. Future studies should address these gaps in the literature and furthermore should compare findings in placebo arms with active treatment arms, both regarding treatment effect size and its correlates. Gaining additional insights into the placebo response may improve our ability to separate active treatment effects from placebo effects, thus paving the way for potentially effective new treatments for mental disorders.
The datasets generated during and/or analysed during the current study are available in the Open Science Framework repository, https://osf.io/fxvn4/ .
Evers AWM, Colloca L, Blease C, Annoni M, Atlas LY, Benedetti F, et al. Implications of placebo and nocebo effects for clinical practice: Expert Consensus. Psychother Psychosom. 2018;87:204–10.
Article PubMed Google Scholar
McQueen D, Cohen S, John-Smith PS, Rampes H. Rethinking placebo in psychiatry: the range of placebo effects. Adv Psychiatr Treat. 2013;19:162–70.
Article Google Scholar
Beecher HK. The powerful placebo. J Am Med Assoc. 1955;159:1602–6.
Article CAS PubMed Google Scholar
Harris I. When the placebo effect is not an effect. Acta Orthop. 2021;92:501–2.
Article PubMed PubMed Central Google Scholar
Landin R, DeBrota DJ, DeVries TA, Potter WZ, Demitrack MA. The impact of Restrictive Entry Criterion during the placebo lead-in period. Biometrics. 2000;56:271–8.
Jones BDM, Razza LB, Weissman CR, Karbi J, Vine T, Mulsant LS, et al. Magnitude of the Placebo response across treatment modalities used for treatment-resistant depression in adults: a systematic review and meta-analysis. JAMA Netw Open. 2021;4:e2125531.
Miller FG, Rosenstein DL. The nature and power of the placebo effect. J Clin Epidemiol. 2006;59:331–5.
Ashar YK, Chang LJ, Wager TD. Brain mechanisms of the Placebo effect: an affective appraisal account. Annu Rev Clin Psychol. 2017;13:73–98.
Ernst E, Resch KL. Concept of true and perceived placebo effects. BMJ. 1995;311:551–3.
Article CAS PubMed PubMed Central Google Scholar
De La Fuente-Fernandez R. Expectation and Dopamine release: mechanism of the Placebo effect in Parkinson’s disease. Science. 2001;293:1164–6.
Benedetti F, Carlino E, Pollo A. How Placebos change the patient’s brain. Neuropsychopharmacology. 2011;36:339–54.
Goebel MU, Trebst AE, Steiner J, Xie YF, Exton MS, Frede S, et al. Behavioral conditioning of immunosuppression is possible in humans. FASEB J. 2002;16:1869–73.
Albring A, Wendt L, Benson S, Witzke O, Kribben A, Engler H, et al. Placebo effects on the immune response in humans: the role of learning and expectation. PloS One. 2012;7:e49477.
Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, et al. Effects of expectation on placebo-induced Dopamine release in Parkinson disease. Arch Gen Psychiatry. 2010;67:857–65.
Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci. 1999;19:484–94.
Amanzio M, Pollo A, Maggi G, Benedetti F. Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain. 2001;90:205–15.
Huneke NTM, Aslan IH, Fagan H, Phillips N, Tanna R, Cortese S, et al. Functional neuroimaging correlates of placebo response in patients with depressive or anxiety disorders: A systematic review. Int J Neuropsychopharmacol. 2022;25:433–47.
Vase L, Riley JL, Price DD. A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain. 2002;99:443–52.
Solmi M, Croatto G, Piva G, Rosson S, Fusar-Poli P, Rubio JM, et al. Efficacy and acceptability of psychosocial interventions in schizophrenia: systematic overview and quality appraisal of the meta-analytic evidence. Mol Psychiatry. 2023;28:354–68.
Monteleone AM, Pellegrino F, Croatto G, Carfagno M, Hilbert A, Treasure J, et al. Treatment of eating disorders: A systematic meta-review of meta-analyses and network meta-analyses. Neurosci Biobehav Rev. 2022;142:104857.
Rosson S, de Filippis R, Croatto G, Collantoni E, Pallottino S, Guinart D, et al. Brain stimulation and other biological non-pharmacological interventions in mental disorders: An umbrella review. Neurosci Biobehav Rev. 2022;139:104743.
Correll CU, Cortese S, Croatto G, Monaco F, Krinitski D, Arrondo G, et al. Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review. World Psychiatry. 2021;20:244–75.
Gaynes BN, Warden D, Trivedi MH, Wisniewski SR, Fava M, Rush AJ. What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression. Psychiatr Serv. 2009;60:1439–45.
Stone MB, Yaseen ZS, Miller BJ, Richardville K, Kalaria SN, Kirsch I. Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis. BMJ. 2022;378:e067606.
Hendriks SM, Spijker J, Licht CMM, Hardeveld F, de Graaf R, Batelaan NM, et al. Long-term disability in anxiety disorders. BMC Psychiatry. 2016;16:248.
Dragioti E, Solmi M, Favaro A, Fusar-Poli P, Dazzan P, Thompson T, et al. Association of antidepressant use with adverse health outcomes: a systematic umbrella review. JAMA Psychiatry. 2019;76:1241–55.
Croatto G, Vancampfort D, Miola A, Olivola M, Fiedorowicz JG, Firth J, et al. The impact of pharmacological and non-pharmacological interventions on physical health outcomes in people with mood disorders across the lifespan: An umbrella review of the evidence from randomised controlled trials. Mol Psychiatry. 2023;28:369–90.
Papola D, Ostuzzi G, Gastaldon C, Morgano GP, Dragioti E, Carvalho AF, et al. Antipsychotic use and risk of life-threatening medical events: umbrella review of observational studies. Acta Psychiatr Scand. 2019;140:227–43.
Linden M. How to define, find and classify side effects in psychotherapy: from unwanted events to adverse treatment reactions. Clin Psychol Psychother. 2013;20:286–96.
Reynolds GP, Kirk SL. Metabolic side effects of antipsychotic drug treatment – pharmacological mechanisms. Pharmacol Ther. 2010;125:169–79.
Cuijpers P, Karyotaki E, Weitz E, Andersson G, Hollon SD, van Straten A. The effects of psychotherapies for major depression in adults on remission, recovery and improvement: A meta-analysis. J Affect Disord. 2014;159:118–26.
Bloom DE, Cafiero E, Jané-Llopis E, Abrahams-Gessel S, Bloom LR, Fathima S, et al. The global economic burden of noncommunicable diseases. PGDA Work Pap. (2012).
Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396:1204–22.
Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. The Lancet. 2013;382:1575–86.
Huneke NTM, van der Wee N, Garner M, Baldwin DS. Why we need more research into the placebo response in psychiatry. Psychol Med. 2020;50:2317–23.
Huneke NTM. Is superiority to placebo the most appropriate measure of efficacy in trials of novel psychotropic medications? Eur Neuropsychopharmacol. 2022;62:7–9.
Khan A, Brown WA. Antidepressants versus placebo in major depression: An overview. World Psychiatry. 2015;14:294–300.
Agid O, Siu CO, Potkin SG, Kapur S, Watsky E, Vanderburg D, et al. Meta-regression analysis of placebo response in antipsychotic trials, 1970–2010. Am J Psychiatry. 2013;170:1335–44.
Leucht S, Leucht C, Huhn M, Chaimani A, Mavridis D, Helfer B, et al. Sixty years of placebo-controlled antipsychotic drug trials in acute schizophrenia: systematic review, bayesian meta-analysis, and meta-regression of efficacy predictors. Am J Psychiatry. 2017;174:927–42.
Enck P, Bingel U, Schedlowski M, Rief W. The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov. 2013;12:191–204.
Correll CU, Solmi M, Cortese S, Fava M, Højlund M, Kraemer HC, et al. The future of psychopharmacology: a critical appraisal of ongoing phase 2/3 trials, and of some current trends aiming to de-risk trial programmes of novel agents. World Psychiatry. 2023;22:48–74.
Stahl SM, Greenberg GD. Placebo response rate is ruining drug development in psychiatry: why is this happening and what can we do about it? Acta Psychiatr Scand. 2019;139:105–7.
Nikolakopoulou A, Chaimani A, Furukawa TA, Papakonstantinou T, Rücker G, Schwarzer G. When does the placebo effect have an impact on network meta-analysis results? BMJ Evid-Based Med. 2023. https://doi.org/10.1136/bmjebm-2022-112197 .
Huneke NTM, Amin J, Baldwin DS, Chamberlain SR, Correll CU, Garner M, et al. Placebo effects in mental health disorders: protocol for an umbrella review. BMJ Open. 2023;13:e073946.
Gauld C, Lopez R, Morin CM, Maquet J, Mcgonigal A, Geoffroy P-A, et al. Why do sleep disorders belong to mental disorder classifications? A network analysis of the “Sleep-Wake Disorders” section of the DSM-5. J Psychiatr Res. 2021;142:153–9.
Köhler-Forsberg O, Stiglbauer V, Brasanac J, Chae WR, Wagener F, Zimbalski K, et al. Efficacy and safety of antidepressants in patients with comorbid depression and medical diseases: an umbrella systematic review and meta-Analysis. JAMA Psychiatry. 2023. https://doi.org/10.1001/jamapsychiatry.2023.2983 .
Belbasis L, Bellou V, Ioannidis JPA. Conducting umbrella reviews. BMJ Med. 2022;1:e000071.
Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; (1988).
Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008.
Scott AJ, Sharpe L, Quinn V, Colagiuri B. Association of Single-blind Placebo Run-in Periods With the Placebo Response in Randomized Clinical Trials of Antidepressants: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2022;79:42.
Furukawa TA, Cipriani A, Atkinson LZ, Leucht S, Ogawa Y, Takeshima N, et al. Placebo response rates in antidepressant trials: a systematic review of published and unpublished double-blind randomised controlled studies. Lancet Psychiatry. 2016;3:1059–66.
Scott F, Hampsey E, Gnanapragasam S, Carter B, Marwood L, Taylor RW, et al. Systematic review and meta-analysis of augmentation and combination treatments for early-stage treatment-resistant depression. J Psychopharmacol. 2023;37:268–78.
Razza LB, Moffa AH, Moreno ML, Carvalho AF, Padberg F, Fregni F, et al. A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials. Prog Neuropsychopharmacol Biol Psychiatry. 2018;81:105–13.
Meister R, Abbas M, Antel J, Peters T, Pan Y, Bingel U, et al. Placebo response rates and potential modifiers in double-blind randomized controlled trials of second and newer generation antidepressants for major depressive disorder in children and adolescents: a systematic review and meta-regression analysis. Eur Child Adolesc Psychiatry. 2020;29:253–73.
Locher C, Koechlin H, Zion SR, Werner C, Pine DS, Kirsch I, et al. Efficacy and safety of selective Serotonin reuptake inhibitors, Serotonin-Norepinephrine Reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. Jama Psychiatry. 2017;74:1011–20.
Ahmadzad-Asl M, Davoudi F, Mohamadi S, Hadi F, Nejadghaderi SA, Mirbehbahani SH, et al. Systematic review and meta-analysis of the placebo effect in panic disorder: Implications for research and clinical practice. Aust N Z J Psychiatry. 2022;56:1130–41.
Bandelow B, Reitt M, Röver C, Michaelis S, Görlich Y, Wedekind D. Efficacy of treatments for anxiety disorders: a meta-analysis. Int Clin Psychopharmacol. 2015;30:183–92.
Pinquart M, Duberstein PR. Treatment of anxiety disorders in older adults: a meta-analytic comparison of behavioral and pharmacological interventions. Am J Geriatr Psychiatry. 2007;15:639–51.
Leucht S, Chaimani A, Leucht C, Huhn M, Mavridis D, Helfer B, et al. 60 years of placebo-controlled antipsychotic drug trials in acute schizophrenia: Meta-regression of predictors of placebo response. Schizophr Res. 2018;201:315–23.
Czobor P, Kakuszi B, Bitter I. Placebo response in trials of negative symptoms in Schizophrenia: A critical reassessment of the evidence. Schizophr Bull. 2022;48:1228–40.
Del Re AC, Maisel N, Blodgett J, Wilbourne P, Finney J. Placebo group improvement in trials of pharmacotherapies for alcohol use disorders: a multivariate meta-analysis examining change over time. J Clin Psychopharmacol. 2013;33:649.
Faraone SV, Newcorn JH, Cipriani A, Brandeis D, Kaiser A, Hohmann S, et al. Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis. Mol Psychiatry. 2022;27:212–9.
Siafis S, Çıray O, Schneider-Thoma J, Bighelli I, Krause M, Rodolico A, et al. Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis. Mol Autism. 2020;11:66.
Iovieno N, Nierenberg AA, Parkin SR, Hyung Kim DJ, Walker RS, Fava M, et al. Relationship between placebo response rate and clinical trial outcome in bipolar depression. J Psychiatr Res. 2016;74:38–44.
Curie A, Yang K, Kirsch I, Gollub RL, des Portes V, Kaptchuk TJ, et al. Placebo responses in genetically determined intellectual disability: a meta-analysis. PloS One. 2015;10:e0133316.
Mohamadi S, Ahmadzad-Asl M, Nejadghaderi SA, Jabbarinejad R, Mirbehbahani SH, Sinyor M, et al. Systematic review and meta-analysis of the placebo effect and its correlates in obsessive compulsive disorder. Can J Psychiatry. 2023;68:479–94.
Winkler A, Rief W. Effect of placebo conditions on polysomnographic parameters in primary insomnia: a meta-analysis. Sleep. 2015;38:925–31.
PubMed PubMed Central Google Scholar
Silva MA, Duarte GS, Camara R, Rodrigues FB, Fernandes RM, Abreu D, et al. Placebo and nocebo responses in restless legs syndrome: A systematic review and meta-analysis. Neurology. 2017;88:2216–24.
Frisaldi E, Shaibani A, Benedetti F, Pagnini F. Placebo and nocebo effects and mechanisms associated with pharmacological interventions: an umbrella review. BMJ Open. 2023;13:e077243.
Cuijpers P, Stringaris A, Wolpert M. Treatment outcomes for depression: challenges and opportunities. Lancet Psychiatry. 2020;7:925–7.
Bromet EJ, Fennig S. Epidemiology and natural history of schizophrenia. Biol Psychiatry. 1999;46:871–81.
Rutherford BR, Mori S, Sneed JR, Pimontel MA, Roose SP. Contribution of spontaneous improvement to placebo response in depression: A meta-analytic review. J Psychiatr Res. 2012;46:697–702.
Fernández-López R, Riquelme-Gallego B, Bueno-Cavanillas A, Khan KS. Influence of placebo effect in mental disorders research: A systematic review and meta-analysis. Eur J Clin Invest. 2022;52:e13762.
Goodwin GM, Croal M, Marwood L, Malievskaia E. Unblinding and demand characteristics in the treatment of depression. J Affect Disord. 2023;328:1–5.
Coles NA, Gaertner L, Frohlich B, Larsen JT, Basnight-Brown DM. Fact or artifact? Demand characteristics and participants’ beliefs can moderate, but do not fully account for, the effects of facial feedback on emotional experience. J Pers Soc Psychol. 2023;124:287–310.
Weimer K, Colloca L, Enck P. Placebo eff ects in psychiatry: mediators and moderators. Lancet Psychiatry. 2015;2:246–57.
Huneke NTM, Chamberlain SR, Baldwin DS, Grant JE. Diverse predictors of treatment response to active medication and placebo in gambling disorder. J Psychiatr Res. 2021;144:96–101.
Leucht S, Chaimani A, Mavridis D, Leucht C, Huhn M, Helfer B, et al. Disconnection of drug-response and placebo-response in acute-phase antipsychotic drug trials on schizophrenia? Meta-regression analysis. Neuropsychopharmacology. 2019;44:1955–66.
Welten CCM, Koeter MWJ, Wohlfarth T, Storosum JG, van den Brink W, Gispen-de Wied CC, et al. Placebo response in antipsychotic trials of patients with acute mania. Eur Neuropsychopharmacol. 2015;25:1018–26.
Grant JE, Chamberlain SR. The placebo effect and its clinical associations in gambling disorder. Ann Clin Psychiatry. 2017;29:167.
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Dr Nathan TM Huneke is an NIHR Academic Clinical Lecturer. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS, or the UK Department of Health and Social Care. For the purpose of open access, the author has applied a Creative Commons Attribution License (CC BY) to any Author Accepted Manuscript version arising from this submission.
NTMH, JA, DSB, SRC, CUC, MG, CMH, RH, ODH, JMAS, MS, and SCo conceptualized the study. NTMH, AB, VB, LE, CJG, OKF, LM, CR, SS, and SCo contributed to data collection, data curation, or data analysis. NTMH, MS, and SCo wrote the first draft of the manuscript. All authors had access to the raw data. All authors reviewed and edited the manuscript and had final responsibility for the decision to submit it for publication.
These authors contributed equally: Marco Solmi, Samuele Cortese.
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
Nathan T. M. Huneke, Jay Amin, David S. Baldwin, Samuel R. Chamberlain, Matthew Garner, Catherine M. Hill, Ruihua Hou, Konstantinos Ioannidis, Julia M. A. Sinclair & Samuele Cortese
Southern Health NHS Foundation Trust, Southampton, UK
Nathan T. M. Huneke, Jay Amin, David S. Baldwin, Samuel R. Chamberlain, Konstantinos Ioannidis & Satneet Singh
University Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa
David S. Baldwin
School of Psychology, University of Nottingham Malaysia, Semenyih, Malaysia
Alessio Bellato
Centre for Innovation in Mental Health, School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK
Alessio Bellato, Valerie Brandt, Matthew Garner, Corentin J. Gosling, Claire Reed, Marco Solmi & Samuele Cortese
Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hanover, Germany
Valerie Brandt
Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany
Christoph U. Correll
Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA
Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA
Faculty of Education and Psychology, University of Navarra, Pamplona, Spain
Luis Eudave
School of Psychology, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, UK
Matthew Garner
Université Paris Nanterre, DysCo Lab, F-92000, Nanterre, France
Corentin J. Gosling
Université de Paris, Laboratoire de Psychopathologie et Processus de Santé, F-92100, Boulogne-Billancourt, France
Department of Sleep Medicine, Southampton Children’s Hospital, Southampton, UK
Catherine M. Hill
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
Oliver D. Howes
H Lundbeck A/s, Iveco House, Watford, UK
Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
Ole Köhler-Forsberg
Psychosis Research Unit, Aarhus University Hospital–Psychiatry, Aarhus, Denmark
Department of Translational Biomedicine and Neuroscience (DIBRAIN), University of Studies of Bari “Aldo Moro”, Bari, Italy
Lucia Marzulli
Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada
Marco Solmi
Department of Mental Health, Ottawa Hospital, Ottawa, ON, Canada
Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ottawa, ON, Canada
School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
Solent NHS Trust, Southampton, UK
Samuele Cortese
DiMePRe-J-Department of Precision and Regenerative Medicine-Jonic Area, University “Aldo Moro”, Bari, Italy
Hassenfeld Children’s Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA
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Correspondence to Nathan T. M. Huneke .
Competing interests.
DSB is President of the British Association for Psychopharmacology, Editor of the Human Psychopharmacology journal (for which he receives an editor’s honorarium), and has received royalties from UpToDate. CMH has acted on an expert advisory board for Neurim Pharmaceuticals. ODH is a part-time employee and stockholder of Lundbeck A/s. He has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/Mylan. ODH has a patent for the use of dopaminergic imaging. All other authors declare no competing interests. MS has received honoraria/has been a consultant for Angelini, Lundbeck, and Otsuka. SCo has received honoraria from non-profit associations (BAP, ACAMH, CADDRA) for educational activities and an honorarium from Medice. KI has received honoraria from Elsevier for editorial work. SRC receives honoraria from Elsevier for associate editor roles at comprehensive psychiatry and NBR journals. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic.
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PLACEBO EFFECTS IN RANDOMIZED TRIALS OF PHARMACOLOGICAL AND NEUROSTIMULATION INTERVENTIONS FOR MENTAL DISORDERS: AN UMBRELLA REVIEW SUPPLEMENTARY APPENDIX
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Huneke, N.T.M., Amin, J., Baldwin, D.S. et al. Placebo effects in randomized trials of pharmacological and neurostimulation interventions for mental disorders: An umbrella review. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02638-x
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The pandemic exacerbated student absenteeism.
Chronic student absenteeism, characterized as missing at least 10 percent of the school year, has increased markedly in the U.S. since the COVID-19 pandemic. According to the Annie E. Casey Foundation, it doubled from 15% in 2018–19 to 30% in the 2021–22 school year. Chronic absenteeism can have profound effects on student academic performance, social development, and overall well-being. To help students attend school regularly, policymakers and school leaders need to identify and implement evidence-based approaches that work in diverse contexts.
NORC will synthesize data from multiple studies to estimate the effectiveness of absenteeism interventions.
NORC will conduct a comprehensive literature review of absenteeism interventions that are used in the U.S. from preschool through high school. It will include studies published in English between 2016 through the present day. That period follows the passage of the Every Student Succeeds Act in 2015, which shone a light on school attendance by requiring states to include an additional “non-achievement” indicator in their accountability reporting. Currently, more than 80 percent of states have chosen an attendance metric as the additional indicator.
NORC’s review includes the following factors from the studies:
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Invasive freshwater aquatic plants can have adverse ecological effects on the systems to which they are introduced, changing ecosystem function, threatening native plant species and causing billions of dollars in damage to infrastructure. Additionally, once established, invasive aquatic plants are often difficult to eradicate or control. Given the importance of managing invasive aquatic plants, and the high associated economic costs of doing so, it is essential to determine the relative effectiveness of different control methods. Here, we present a protocol for a systematic review that will estimate the effectiveness of various biological, chemical, habitat manipulations and/or manual/mechanical methods for eradicating or controlling invasive plant abundance and biomass. This systematic review will use published and grey literature, without date restriction, that determines the effectiveness of invasive plant control methods. English‑language searches will be performed using five bibliographic databases, Google Scholar, and networking tools to find relevant literature. Eligibility screening will be conducted at two stages: (1) title and abstract and (2) full text. Studies that evaluate the effectiveness of methods for controlling the abundance or biomass or eradicating invasive plants will be included. A list of plant species currently, or potentially, in Canadian freshwater systems and of management concern will be considered. Included studies will undergo critical appraisal of internal study validity. We will extract information on study characteristics, intervention and comparator details, measured outcomes (abundance and biomass, broadly defined) and effect modifiers (e.g., plant growth pattern or timing of treatments). A narrative synthesis will be used to describe the quantity and characteristics of the evidence base, while quantitative synthesis (i.e., meta‑analysis) will be conducted to estimate an overall mean and variance of effect when sufficient numbers of similar studies are available.
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Latin America (LATAM) encompasses a vast region with diverse populations. Despite publicly funded health care systems providing universal coverage, significant socioeconomic and ethno-racial disparities persist in health care access across the region. Breast cancer (BC) incidence and mortality rates in Brazil are comparable to those in other LATAM countries, supporting the relevance of Brazilian data, with Brazil’s health care policies and expenditures often serving as models for neighboring countries. We evaluated the impact of mobility on oncological outcomes in LATAM by analyzing studies of patients with BC reporting commuting routes or travel distances to receive treatment or diagnosis.
We searched MEDLINE (PubMed), Embase, Cochrane CENTRAL, LILACS, and Google Scholar databases. Studies eligible for inclusion were randomized controlled trials and observational studies of patients with BC published in English, Portuguese, or Spanish and conducted in LATAM. The primary outcome was the impact of mobility or travel distance on oncological outcomes. Secondary outcomes included factors related to mobility barriers and access to health services. For studies meeting eligibility, relevant data were extracted using standardized forms. Risk of bias was assessed using the Newcastle-Ottawa Scale. Quantitative and qualitative evidence synthesis focused on estimating travel distances based on available data. Heterogeneity across distance traveled or travel time was addressed by converting reported travel time to kilometers traveled and estimating distances for unspecified locations.
Of 1142 records identified, 14 were included (12 from Brazil, 1 from Mexico, and 1 from Argentina). Meta-analysis revealed an average travel distance of 77.8 km (95% CI, 49.1-106.48) to access BC-related diagnostic or therapeutic resources. Nonetheless, this average fails to precisely encapsulate the distinct characteristics of each region, where notable variations persist in travel distance, ranging from 88 km in the South to 448 km in the North.
The influence of mobility and travel distance on access to BC care is multifaceted and should consider the complex interplay of geographic barriers, sociodemographic factors, health system issues, and policy-related challenges. Further research is needed to comprehensively understand the variables impacting access to health services, particularly in LATAM countries, where the challenges women face during treatment remain understudied.
CRD42023446936.
Peer Review reports
Limited geographic access to health facilities is a major factor contributing to reduced utilization of health services, resulting in poorer health outcomes [ 1 ]. This issue is particularly critical in the context of patients with cancer, as their treatment typically involves a combination of surgery, radiotherapy, and/or chemotherapy, often requiring multiple visits to health facilities. Geographic barriers that impede access may delay treatment initiation, leading to suboptimal outcomes or even premature and preventable deaths. The burden of travel demands on patients with cancer has been linked to more advanced disease at diagnosis, flawed treatment, a grimmer prognosis, and diminished quality of life [ 2 ].
Brazil’s breast cancer (BC) incidence and mortality rates are comparable to those of other Latin American countries. For instance, the age-standardized incidence rates of BC per 100,000 women are 62.9 in Brazil, 61.1 in Argentina, and 49.6 in Mexico, illustrating that Brazil’s epidemiological data are within the regional range [ 3 ]. This epidemiological consistency supports the relevance of Brazilian data to the broader Latin American context. As Latin America’s largest economy, Brazil’s health care policies and expenditures influence regional trends and often serve as models for neighboring countries [ 4 ].
In Brazil, a country of continental dimensions, more than half of patients with cancer are required to travel from their hometown to another city to receive treatment, with persistent disparities in regional accessibility despite the shorter travel distances recently observed in some states [ 2 , 5 , 6 , 7 ]. For example, there are 359 dedicated public treatment centers with asymmetric geographical distribution, where approximately 80% are located in 2 of the 5 Brazilian regions and 20% in the remaining regions [ 8 , 9 ]. Patients with cancer who must commute for treatment face considerable challenges, including fatigue, long waiting times for their return trip, inadequate nourishment, financial constraints due to travel expenses, and disruption to daily life [ 10 ]. Radiotherapy and chemotherapy are of particular concern as they require frequent visits to cancer care facilities.
Low- and middle-income countries find themselves in diverse circumstances with respect to workforce capacity, regulation of private health care, public sector investment, care pathways, and the ineffectiveness of comprehensive national strategies for the development, management, sustainable financing, and accreditation of cancer care centers. Therefore, identifying issues of geographic mobility for patients with cancer in Latin America is important to ensure equitable access to care.
In this systematic review and meta-analysis, we aimed to evaluate the impact of mobility on oncological outcomes in Latin America by analyzing studies of patients with BC reporting their commuting routes or travel distances to receive treatment or diagnosis. We addressed 2 knowledge gaps: (1) whether BC treatment or screening programs have been made geographically accessible to patients in Latin American countries, and (2) whether the existing literature can provide regional estimates of travel distances to health facilities. The paper contributes to the worldwide debate on how to widen access to BC care and may pave the way for further developments and studies on the topic, while providing relevant data to the strategic planning of cancer care services.
We developed this systematic review according to the PRISMA 2020 guidelines [ 11 ] and the recommendations proposed by the Cochrane Collaboration [ 12 ]. A detailed review protocol is available at PROSPERO (CRD42023446936).
We searched MEDLINE (via PubMed), Embase, Cochrane Central Register of Controlled Trials (Cochrane CENTRAL), Latin American and Caribbean Health Sciences Literature (LILACS, via Virtual Health Library), and Google Scholar databases for articles published from inception to June 28, 2023, by entering the following keywords and terms individually, including index terms (MeSH and Emtree terms), subject indexes, and synonyms, or by combining them with Boolean operators (“AND” and “OR”): “Breast cancer,” “Breast neoplasm,” “Mobility,” “Access to healthcare,” and “Latin America.” Terms related to intervention or study design were not used to improve the search sensitivity. Although no language restrictions were imposed, we only considered articles published in English, Portuguese, or Spanish. We hand searched the reference lists of the included studies and of all reviews published to date on the topic to cover potential additional studies within the intended scope. The complete search strategy is provided in Additional Table 1 . A cross-reference check to locate and eliminate duplicates complemented the search strategy.
Studies eligible for inclusion in this review were published in English, Portuguese, or Spanish and recruited patients with BC in Latin American countries. The study designs considered for inclusion were randomized controlled trials and observational studies (cohort, cross-sectional, case control, case series, or ecological studies) with or without a comparison group, regardless of the intervention used. We excluded conference abstracts, guidelines, editorials, book chapters, commentaries, letters, notes, and study protocols.
We limited the scope of the review to Latin America because we intended to explore mobility-related factors alongside health care resource utilization in Latin American populations. Furthermore, this decision stemmed from the shared health patterns observed in Latin American countries, characterized by popular-collective health care, recurrent discontinuity in public policies—an inherent feature of the region—and a prevailing culture of prioritizing urgency in professional endeavors.
Studies were considered for inclusion if they clearly reported the travel distance (in kilometers or other units) or time (in hours, minutes) required to access BC-related health care. The primary outcome of this review was the impact of mobility or travel distance on oncological outcomes such as mortality, time to treatment initiation, and time to diagnosis. Secondary outcomes included mobility-related factors such as geographic barriers, access to municipal transportation, and travel time.
After removal of duplicates, 2 reviewers (AFA and BSZ) independently screened titles and abstracts, and then screened potentially eligible or candidate full-text articles for selection based on the inclusion and exclusion criteria. A third independent reviewer was consulted to settle any disagreements between reviewers that had not been resolved by consensus. From studies of overlapping populations, we included only the one with the largest sample size.
The same 2 reviewers (AFA and BSZ) independently extracted data from eligible studies using a standardized form. Disagreements were resolved with discussion and, if required, consensus was reached by consulting a third independent reviewer. The following data were extracted: study characteristics (e.g., author, year, study setting, study design, and study context), sample characteristics (e.g., number of participants, age of participants, and sample size), characteristics of the tools used to measure mobility or access, and comparison groups (if available).
The same reviewers (AFA and BSZ) independently assessed the risk of bias of each included study. The original Newcastle-Ottawa Scale (NOS) was used to assess cohort studies comparing treatment options. It consists of 8 items that classify methodological quality across 3 categories by a star rating system: participant selection (maximum 4 stars), comparability (maximum 2 stars), and assessment of outcome (maximum 3 stars) [ 13 ]. In the NOS adapted for cross-sectional studies, a maximum of 10 stars can be awarded to each study: selection (maximum 5 stars), comparability (maximum 2 stars), and outcome (maximum 3 stars). Studies reaching 75% or more of the maximum number of stars are considered to be at low risk of bias, while those reaching 50–75% are considered to be at moderate risk of bias.
We performed a synthesis of qualitative and quantitative evidence. We collected data on the main findings and consequences of mobility as assessed in each study and the related oncological outcomes. Given the heterogeneity among study results regarding distance traveled or travel time, we decided to use the distance traveled instead of travel time given the relatively deficient and expensive transport systems in Latin American countries. When the outcomes were reported in travel time instead of distance traveled, the study authors were contacted. If there was no response or the data were unavailable, a conversion technique was used. To address this issue, when a study reported data on travel time, we converted the data to kilometers traveled based on the estimates provided by INRIX (vehicle monitoring and software company), which assumes an average city traffic of 30.2 km/h [ 14 , 15 ]. If necessary, we used WebPlotDigitalizer [ 16 ] to extract data from figures and graphs. For studies reporting parameters such as ‘outside the city,’ we estimated the average distance from the capital city to nearby cities using Google Maps.
Based on the data presented in the included studies, we estimated the average distance traveled by people to access BC screening services and by patients with BC to access treatment facilities. Since most studies did not provide sufficient data to estimate the standard error of the distance traveled, we calculated standard errors for the set of average distances estimated for the different studies (imputation-driven meta-analysis). We attributed the standard errors to all studies so that all of them had the same weight in the meta-analysis, as calculated using the inverse variance method. We used R software (meta package v 6.0–0) for data analysis [ 17 ].
The study selection process is shown in Fig. 1 . The database searches provided a total of 1142 records. After adjusting for duplicates, 1117 remained. After title and abstract screening, a total of 36 studies were retrieved for full-text review, 14 of which met the inclusion criteria.
PRISMA flow diagram
Table 1 provides the main characteristics of each included study, an outline of the individual characteristics of each study population, and the context in which the impact of mobility was studied. Regarding mobility outcomes, 4 studies reported travel distance [ 6 , 7 , 18 , 19 ], 3 studies reported travel time [ 20 , 21 , 22 ], and 7 studies reported any effect measure such as mammograms not performed or effect on access to cancer screening [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. To facilitate understanding of the results, the following sections are divided into the impact of mobility on BC screening and the impact of mobility on BC treatment.
Three studies evaluated BC screening. The study of Agudelo Botero et al. [ 23 ] used secondary data from 3 Mexican databases to explain factors that can impact BC screening for women. In all databases, the sociodemographic variables that together could explain the strongest relationship with breast self-examination were level of education, age group, and type of area (urban vs. rural). The other 2 studies were conducted in Brazil by Rodrigues et al. [ 24 ] and Amaral et al. [ 25 ] and found results similar to those of the Mexican study. Rodrigues et al. [ 24 ] reported that the spatial coverage of mammography machines, using 60 km as a parameter for the maximum distance between an individual’s home and a mammography machine, was fully achieved in the South and Southeast regions and several states in the Northeast but not in the North and Midwest regions.
Several studies investigated the association between travel burden and BC treatment. de Almeida et al. [ 20 ] reported an increased likelihood of advanced BC stage at diagnosis in patients who traveled to another city for BC care. Ferreira et al. [ 26 ] evaluated over 150,000 women with BC and concluded that those categorized as non-white with a low level of education living in the North of Brazil had to wait longer from diagnosis to treatment than women in other groups, in addition to being more likely to wait over 60 days to start BC treatment. Oliveira et al. [ 7 ] highlighted that a high percentage of women receiving treatment through the Brazilian publicly funded health care system lived more than 150 km away from the place of care. Knowing that treatment is based on frequent procedures, the authors noted that a large proportion of women receiving care had to face a number of difficulties other than the disease itself due to long travel distances.
Saldanha et al. [ 6 ] reported that commuting can affect 51.34% of BC patients negatively, with over half requiring journeys of more than 3 h in half of the cases. The proportion of patients who need to travel outside their hometown for chemotherapy and radiotherapy is similar to that for hospital admissions. However, given that these therapies require multiple visits to health facilities during the treatment cycle, their potential impact on the quality of life of women undergoing treatment is of particular concern. In a prospective study conducted in Brazil, Medeiros et al. [ 21 ] showed that living outside the city of Rio de Janeiro and older age were associated with a time interval between diagnosis and treatment initiation exceeding 60 days, despite the ‘60-day law’ in place since 2013 establishing that treatment for any type of cancer in the public health system must start within 60 days of the diagnosis. In a study comparing private and public hospitals in the city of Buenos Aires, Argentina, regarding BC treatment, Recondo et al. [ 27 ] found that patients receiving treatment in public hospitals used public transport more often (69.3%) than those treated in private hospitals (29.3%), resulting in significantly longer commutes for those treated in public hospitals. In southern Brazil, Romeiro Lopes et al. [ 28 ] found a mean time to diagnosis of 102.5 (SD 165.5) days, with treatment delay in 63.4% ( n = 52) of cases, where 60% of patients with a delay in treatment > 30 days lived more than 100 km from the cancer care center. Although without statistical significance, this finding draws attention as a factor influencing treatment adherence over time.
Unlike the previous findings, 2 studies [ 24 , 29 ] did not report geographic distance or commuting as the main access barriers. Evaluating barriers to access to health care as perceived by women with BC in northeastern Brazil, Gonçalves et al. [ 29 ] reported that geographic barriers were rarely mentioned by women during treatment, but this factor requires attention because transfer to another city and difficulty accessing transport provided by the municipal health department were mentioned by the participants, capturing the reality of the Northeast region. Also in the Northeast of Brazil, de Sousa et al. [ 18 ] demonstrated that, despite important data on geographic distance and time to treatment, treatment delay was not linked to geographic barriers but rather to a fragmentation of health services, that is, to a need to shift the points of care from primary to specialized care with a well-defined patient flow. Finally, Aguiar et al. [ 22 ] reported that work commutes of 1 to 2 h were negatively associated with BC mortality in the city of São Paulo, Brazil, and that these findings were important to guide cancer prevention policies.
Table 2 provides the quantitative results of individual studies and the impact of mobility on the related oncological outcomes. Regarding quantitative data analysis, the heterogeneity was notably high (I 2 = 93%), and the number of studies that provided sufficient information for a meta-analysis was limited to 7, rendering the meta-analysis inadequate for reporting the primary outcome [ 6 , 7 , 19 , 20 , 22 , 26 ]. We performed an exploratory subgroup analysis to investigate the regions of Brazil where the studies had been conducted as a potential source of heterogeneity. Indeed, this analysis revealed that a portion of the observed heterogeneity stemmed from variations in the regions where the studies had been conducted.
The average distances traveled are shown in the forest plot in Fig. 2 . For hypothesis generation purposes only, the average distances traveled to BC-related diagnostic or therapeutic resources in the 5 administrative regions of Brazil were estimated via a random-effects meta-analysis (Additional Fig. 1 ), yielding the following results: 448 km (95% CI, 383.87–512.13) in the North; 323 km (95% CI, 258.87–387.13) in the Midwest; 239.8 km (95% CI, 58.78–419.02) in the Northeast; 104.8 km (95% CI, 70.93–138.82) in the Southeast; and 88 km (95% CI, 23.87–152.13) in the South. Four studies reported results for Brazil as a whole, without specifying a region. For description purposes, these results indicate an average travel distance of 77.8 km (95% CI, 49.1–106.48) to a BC-related diagnostic or therapeutic resource. Even though we acknowledge the limitations and regional disparities both within and between countries, our findings align with the existing literature, indicating an equivalent of 3–4 h of commute on a national average [ 30 ].
Forest plot of average travel distances reported in the studies
Overall, the risk of bias was moderate to low. The 12 cross-sectional non-comparative studies were rated with a median of 7.5 stars on the adapted NOS (maximum 10 stars). The 2 cohort studies were also rated as having a moderate to low risk of bias (7 and 8 out of 9 stars, respectively) on the original NOS (Additional Table 2 ). Particularly in this analysis, the risk of bias had an impact on the interpretability of the studies.
Access to and affordability of appropriate diagnosis and care represent critical limiting factors in health care [ 31 ]. The establishment of national BC plans, whether of a general or specific nature, plays a pivotal role in facilitating organized governance, financing, and health care delivery [ 20 , 31 ]. In this regard, evidence-based treatment guidelines have been disseminated by government authorities, cancer institutes, or scientific associations in numerous countries. Nevertheless, the principal challenge lies in the effective implementation of policies and mechanisms designed to ensure consistent compliance with these guidelines over the entire population.
Consistent with the existing literature, our research findings underscore the presence of regional disparities across the health care landscape of Brazil [ 31 ]. Specifically, our analysis revealed that patients living in the North and Midwest of the country must travel longer distances to access cancer care than their counterparts in the South, Southeast, and Northeast [ 30 ]. It is worth noting that, despite the existence of Law No. 12,732, which mandates a 60-day time frame for initiating cancer treatment after the disease has been diagnosed, there is a lack of empirical evidence to define what constitutes a reasonable travel distance for such treatment [ 32 ], since approximately 40% of patients experience a delay in starting their treatment of more than 60 days, and this delay is longer in the SUS than in the private health insurance system [ 26 , 33 ]. In other words, the law addresses the number of days for initiating treatment but does not establish what distance is considered to be reasonable for patients to obtain such treatment. de Almeida et al. [ 20 ] showed that women traveling to another city to receive BC care were more likely to have advanced disease at the time of diagnosis and that late diagnosis increases the cost of treatment and compromises the patient’s clinical outcome. Despite the ‘60-day law’ and health care policy initiatives in Brazil, there appears to be a gap between policy intentions and their actual implementation, particularly for patients living outside major urban centers [ 22 , 23 , 27 , 29 ]. Some studies have highlighted the underrepresentation of geographic barriers in patients’ perceptions, emphasizing the need for a nuanced contextual understanding.
In the context of BC screening, the health care system should be designed to ensure an adequate number of mammography machines, with due consideration for a maximum distance of 60 km between the machine and the residences of the target population [ 25 , 34 ]. However, although this spatial proximity is deemed essential to facilitate timely and accessible screening services for BC detection, women continue to face difficulties in accessing appropriate screening, and by the time they do, they often present at an advanced disease stage [ 20 ]. Nonetheless, in addition to distance, Bretas et al. [ 35 ] pointed out the lack of a well-defined strategy to receive women with self-detected breast abnormalities in the primary health care unit. Strategies may encompass procedures such as enhancement of clinical breast examination, breast biopsy, and accurate pathology as well as BC surveillance and telehealth. Such actions take place occasionally in one-stop clinics, although patients will often be transferred to different locations [ 35 ]. Therefore, patient navigation programs and integration between primary and tertiary care need to be further improved.
Long travel distances to radiotherapy centers have been associated with diminished utilization of radiotherapy services, elevated mastectomy rates in patients with BC, reduced probability of radiotherapy utilization among individuals with BC and other cancers, and infrequent recourse to palliative radiotherapy [ 30 ]. While it is important to acknowledge that patient travel distance is not the only determinant of access to cancer services, it remains a pivotal factor to be addressed in endeavors to enhance health equity and achieve a broader health coverage [ 7 ].
The concentration of specialized cancer care to centers located in the Southeast of Brazil highlights the need to narrow the gap between supply and demand for this type of care. Providing broad coverage of cancer treatment requires improved planning and regulation, in addition to ensuring the activation of the highly complex infrastructure and qualified human resources that are needed to support treatment [ 30 , 31 ].
The obstacles to mobility and access to BC screening and treatment identified in Brazil, such as geographic barriers, socioeconomic inequalities, and health care infrastructure limitations, resonate with challenges faced by other Latin American countries. Practical solutions to overcome these barriers include implementing telemedicine services and mobile health units [ 36 ] and expanding the role of community health workers to provide education, support, and navigation services [ 37 ]. Policymakers can leverage Brazil’s experiences to inform regional strategies, such as the Brazilian National Policy of Comprehensive Women’s Health Care, which provides a framework for addressing women’s health issues, including BC, adaptable by other Latin American countries to improve outcomes [ 38 ].
The heterogeneity of the studies renders the meta-analytic estimates not representative of the overall travel distances observed in the included studies. Even though our objective was to conduct a comprehensive literature review within a Latin American perspective, there were only 2 studies outside Brazil. It was expected that Brazil, Mexico, and Argentina, the largest Latin American countries, would be better represented in the literature, but the lack of studies from other countries in Latin America makes generalization difficult. While concerns about the regional representativeness of Brazilian studies are valid, the similarities in demographics, socioeconomic status, health care structures, and epidemiological trends across Latin America support the relevance of Brazilian data. By addressing practical implications and proposing evidence-based solutions, we aim to improve BC screening and treatment accessibility throughout the region. Besides that, the fact that a sensitive search strategy was unable to retrieve studies from a more diverse group of countries shows a wide gap in the scientific literature on this topic in other countries in Latin America. Furthermore, our analyses and results were limited by the need to convert travel time to travel distance when data were not available even after contacting authors, which could have underestimated or overestimated some results especially in remote areas where the transportation infrastructure is poor. However, this approach allowed the comparison of travel distances in diverse settings.
The collective evidence from these studies underscores the multifaceted and pervasive influence of mobility and travel distance on access to BC care. It also emphasizes the importance of not only addressing geographic barriers but also considering sociodemographic factors, health system issues, and policy-related challenges in the pursuit of equitable BC care. The scarce information on this topic in Latin American countries, especially on the complications and challenges women face before and during treatment, indicates that travel distance alone may not serve as the only determinant of mobility. Therefore, additional research is imperative to comprehensively elucidate the multifaceted variables that underlie the impact of mobility on access to health services.
All data analyzed during this study are included in this published article and its supplementary information files.
breast cancer
Newcastle-Ottawa Scale
Brazilian national public health care system
Hierink F, Okiro EA, Flahault A, Ray N. The winding road to health: a systematic scoping review on the effect of geographical accessibility to health care on infectious diseases in low- and middle-income countries. PLoS ONE. 2021;16:e0244921.
Article CAS PubMed PubMed Central Google Scholar
Ambroggi M, Biasini C, Giovane CD, Fornari F, Cavanna L. Distance as a barrier to cancer diagnosis and treatment: review of the literature. Oncologist. 2015;20:1378–85.
Article PubMed PubMed Central Google Scholar
GLOBOCAN. 2020. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. https://gco.iarc.who.int/today . Accessed 15 July 2023.
Nunes L, Silva JD, Vieira MT. Health financing in Brazil: trends and challenges. Saude Debate. 2020;44:105–20.
Google Scholar
Rocha-Brischiliari SC, Andrade L, Nihei OK, Brischiliari A, Hortelan MDS, Carvalho MDB, et al. Spatial distribution of breast cancer mortality: socioeconomic disparities and access to treatment in the state of Parana, Brazil. PLoS ONE. 2018;13:e0205253.
Saldanha RF, Xavier DR, Carnavalli KM, Lerner K, Barcellos C. [Analytical study of the breast cancer patient flow network in Brazil from 2014 to 2016]. Cad Saude Publica. 2019;35:e00090918.
Article PubMed Google Scholar
Oliveira EX, Melo ECP, Pinheiro RS, Noronha CP, Carvalho MS. [Access to cancer care: mapping hospital admissions and high- complexity outpatient care flows. The case of breast cancer]. Cad Saude Publica. 2011;27:317–26.
Atlas dos Centros de Cuidados do Câncer. https://atlas.oncoguia.org.br/#em_numeros . Accessed 15 July 2023.
Brasil. Saúde e Vigilância Sanitária: Habilitar hospitais em alta complexidade em oncologia. https://www.gov.br/pt-br/servicos/habilitar-hospitais-em-alta-complexidade-em-oncologia . Accessed 15 July 2023.
Teston EF, Fukumori EFC, Benedetti GMS, Spigolon DN, Costa MAR, Marcon SS. Feelings and difficulties experienced by cancer patients along the diagnostic and therapeutic itineraries. Esc Anna Nery. 2018;22:e20180017.
Article Google Scholar
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane. 2022. www.training.cochrane.org/handbook . Accessed 20 Aug 2023.
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta- analyses. Ottawa: The Ottawa Hospital. 2013. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp . Accessed 8 Sept 2020.
INRIX. 2022 INRIX Global Traffic Scorecard. https://inrix.com/scorecard/ . Accessed 15 July 2023.
Companhia de Engenharia de Tráfego do Rio de Janeiro - CET-RIO. https://carioca.rio/orgao/companhia-de-engenharia-de-trafego-do-rio-de-janeiro-cet-rio/#:~:text=Missão%3A,o%20bem%2Destar%20da%20população . Accessed 23 June 2023.
Rohatgi A, WebPlotDigitizer. https://automeris.io/WebPlotDigitizer. 2022. Accessed 13 May 2023.
Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health. 2019;22:153–60.
de Souza BC, Dos Santos Figueiredo FW, de Alcantara Sousa LV, da Silva Maciel E, Adami F. Regional disparities in the flow of access to breast cancer hospitalizations in Brazil in 2004 and 2014. BMC Womens Health. 2020;20:37.
Sousa SMMT, Carvalho MGFM, Santos Júnior LA, Mariano SBC. Acesso Ao Tratamento Da mulher com câncer de mama. Saúde Debate. 2019;43:727–41.
de Almeida RJ, de Moraes Luizaga CT, Eluf-Neto J, de Carvalho Nunes HR, Pessoa EC, Murta-Nascimento C. Impact of educational level and travel burden on breast cancer stage at diagnosis in the state of Sao Paulo, Brazil. Sci Rep. 2022;12:8357.
Medeiros GC, Thuler LCS, Bergmann A. Determinants of delay from cancer diagnosis to treatment initiation in a cohort of Brazilian women with breast cancer. Health Soc Care Community. 2021;29:1769–78.
Aguiar BS, Pellini ACG, Rebolledo EAS, Ribeiro AG, Diniz CSG, Bermudi PMM, et al. Intra-urban spatial variability of breast and cervical cancer mortality in the city of São Paulo: analysis of associated factors. Rev Bras Epidemiol. 2023;26:e230008.
PubMed PubMed Central Google Scholar
Agudelo Botero M. [Sociodemographic determinants of access to breast cancer screening in Mexico: a review of national surveys]. Salud Colect. 2013;9:79–90.
Rodrigues DCN, Freitas-Junior R, Rahal RMS, Correa RDS, Peixoto JE, Ribeiro NV, et al. Difficult Access and Poor Productivity: Mammography Screening in Brazil. Asian Pac J Cancer Prev. 2019;20(6):1857–64.
Amaral P, Luz L, Cardoso F, Freitas R. Distribuição Espacial De equipamentos de mamografia no Brasil. RBEUR. 2017;19:326.
Ferreira NAS, Schoueri JHM, Sorpreso ICE, Adami F, Dos Santos Figueiredo FW. Waiting time between breast cancer diagnosis and treatment in Brazilian women: an analysis of cases from 1998 to 2012. Int J Environ Res Public Health. 2020;17:4030.
Recondo G, Cosacow C, Cutuli HJ, Cermignani L, Straminsky S, Naveira M, et al. Access of patients with breast and lung cancer to chemotherapy treatment in public and private hospitals in the city of Buenos Aires. Int J Qual Health Care. 2019;31(9):682–90.
Romeiro Lopes TC, Gravena AAF, Demitto MO, Borghesan DHP, Dell`Agnolo CM, Brischiliari SCR, et al. Delay in diagnosis and treatment of breast Cancer among women attending a Reference Service in Brazil. Asian Pac J Cancer Prev. 2017;18:3017–23.
PubMed Google Scholar
Gonçalves LL, Travassos GL, Maria de Almeida A, Guimaraes AM, Gois CF. [Barriers in health care to breast cancer: perception of women]. Rev Esc Enferm USP. 2014;48:394–400.
Fonseca BP, Albuquerque PC, Saldanha RF, Zicker F. Geographic accessibility to cancer treatment in Brazil: a network analysis. Lancet Reg Health Am. 2022;7:100153.
Cazap E. Breast Cancer in Latin America: a map of the Disease in the region. Am Soc Clin Oncol Educ Book. 2018;38:451–6.
Brasil. Lei Nº 12732 de 22 de Novembro de 2012. Dispõe sobre o primeiro tratamento de paciente com neoplasia maligna comprovada e estabelece prazo para seu início (60 dias). Brasília, DF: Diário Oficial da União. 2012. https://www.planalto.gov.br/ccivil_03/_ato2011-2014/2012/lei/l12732.htm . Accessed 10 Sept 2023.
Resende H, Aguiar VQ, Jacob LFP, Renó ALCA, Cunha AP, Assis BR, et al. The journey of breast cancer patient from self-perception of breast abnormalities to first cancer treatment- a sectional study in Sul Fluminense region-RJ-Brazil. Med Res Arch. 2023;11:10.
Brasil. Ministério da Saúde. Gabinete do Ministro. Portaria N.o 1.631 de 1 de outubro de 2015. Aprova critérios e parâmetros para o planejamento e programação de ações e serviços de saúde no âmbito do SUS. DF: Diário Oficial da União, no. 189, Seção 1, p. 38. 2015. https://www.as.saude.ms.gov.br/wp-content/uploads/2016/08/Portaria-parametros-revoga-a-Portaria-1101.pdf . Accessed 12 Apr 2023.
Bretas G, Renna NL, Bines J. Practical considerations for expediting breast cancer treatment in Brazil. Lancet Reg Health Am. 2021;2:100028.
Leite H, Hodgkinson IR, Gruber T. New development: ‘Healing at a distance’—telemedicine and COVID-19. Public Money Manag. 2021;41:65–8.
Nascimento ALB, de Souza Santos I, Andrade FM. The role of community health workers in promoting mental health and connecting with primary care in Brazil. Int J Ment Health. 2018;47:122–34.
Brasil. Ministério Da Saúde. Política Nacional De Atenção Integral à Saúde Da Mulher. Editora MS; 2011.
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AFA, BSZ, FM, NN, RA, and CM: Concept and design; AFA, BSZ: Acquisition of data; AFA and BSZ: Analysis and interpretation of data; AFA and BSZ: Drafting of the manuscript; AFA, BSZ, FM, NN, RA, and CM: Critical revision of the paper for important intellectual content; CM: Obtaining funding; FM, NN, and RA: Administrative, technical, or logistic support; NN and CM: Supervision. All authors read and approved the final manuscript.
Correspondence to Clarissa Medeiros .
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FM, RA, NN, and CM were Roche S/A employees at the time of the analysis. BSZ and AFA were working on behalf of Roche S/A on the project.
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Azeredo-da-Silva, A.F., Zanotto, B.S., Martins, F. et al. Health care accessibility and mobility in breast cancer: a Latin American perspective. BMC Health Serv Res 24 , 764 (2024). https://doi.org/10.1186/s12913-024-11222-6
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