introduction vs literature review

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Difference Between Introduction and Literature Review

Main difference – introduction vs literature review.

Although introduction and literature review are found towards the beginning of a text, there is a difference between them in terms of their function and purpose. The main difference between introduction and literature review is their purpose; the purpose of an introduction is to briefly introduce the text to the readers whereas the purpose of a literature review is to review and critically evaluate the existing research on a selected research area. 

In this article, we will be discussing,

     1. What is an Introduction?           – Definition, Features, Characteristics

     2. What is a Literature Review?           – Definition, Features, Characteristics

What is an Introduction

An introduction is the first part of an article, paper, book or a study that briefly introduces what will be found in the following sections. An introduction basically introduces the text to the readers. It may contain various types of information, but given below some common elements that can be found in the introduction section.

• Background/context to the paper
• Outline of key issues
• Thesis statement
• Aims and purpose of the paper
• Definition of terms and concepts

Note that some introductions may not have all these elements. For example, an introduction to a short essay will only have several lines. Introductions can be found in nonfiction books, essays, research articles, thesis, etc. There can be slight variations in these various genres, but all these introductions will provide a basic outline of the whole text. 

Introduction of a thesis or dissertation will describe the background of the research, your rationale for the thesis topic, what exactly are you trying to answer, and the importance of your research.

What is a Literature Review

A literature review, which is written at the start of a research study, is essential to a research project. A literature review is an evaluation of the existing research material on a selected research area. This involves reading the major published work (both printed and online work) in a chosen research area and reviewing and critically evaluating them. A literature review should show the researcher’s awareness and insight of contrasting arguments, theories, and approaches. According to Caulley (1992) a good literature review should do the following:

• Compare and contrast different researchers’ views
• Identify areas in which researchers are in disagreement
• Group researchers who have similar conclusions
• Criticize the research methodology
• Highlight exemplary studies
• Highlight gaps in research
• Indicate the connection between your study and previous studies
• Indicate how your study will contribute to the literature in general
• Conclude by summarizing what the literature says

Literature reviews help researchers to evaluate the existing literature, to identify a gap in the research area, to place their study in the existing research and identify future research.

Introduction is at the beginning of a text.

Literature Review is located after the introduction or background.

Introduction introduces the main text to the readers.

Literature Review critically evaluates the existing research on the selected research area and identifies the research gap.

Introduction will have information such as background/context to the paper, outline of key issues, thesis statement, aims, and purpose of the paper and definition of terms and concepts. 

Literature Review will have summaries, reviews, critical evaluations, and comparisons of selected research studies.

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How to write a literature review introduction (+ examples)

The introduction to a literature review serves as your reader’s guide through your academic work and thought process. Explore the significance of literature review introductions in review papers, academic papers, essays, theses, and dissertations. We delve into the purpose and necessity of these introductions, explore the essential components of literature review introductions, and provide step-by-step guidance on how to craft your own, along with examples.

Why you need an introduction for a literature review

When you need an introduction for a literature review, what to include in a literature review introduction, examples of literature review introductions, steps to write your own literature review introduction.

A literature review is a comprehensive examination of the international academic literature concerning a particular topic. It involves summarizing published works, theories, and concepts while also highlighting gaps and offering critical reflections.

In academic writing , the introduction for a literature review is an indispensable component. Effective academic writing requires proper paragraph structuring to guide your reader through your argumentation. This includes providing an introduction to your literature review.

It is imperative to remember that you should never start sharing your findings abruptly. Even if there isn’t a dedicated introduction section .

Instead, you should always offer some form of introduction to orient the reader and clarify what they can expect.

There are three main scenarios in which you need an introduction for a literature review:

• Academic literature review papers: When your literature review constitutes the entirety of an academic review paper, a more substantial introduction is necessary. This introduction should resemble the standard introduction found in regular academic papers.
• Literature review section in an academic paper or essay: While this section tends to be brief, it’s important to precede the detailed literature review with a few introductory sentences. This helps orient the reader before delving into the literature itself.
• Literature review chapter or section in your thesis/dissertation: Every thesis and dissertation includes a literature review component, which also requires a concise introduction to set the stage for the subsequent review.

You may also like: How to write a fantastic thesis introduction (+15 examples)

It is crucial to customize the content and depth of your literature review introduction according to the specific format of your academic work.

In practical terms, this implies, for instance, that the introduction in an academic literature review paper, especially one derived from a systematic literature review , is quite comprehensive. Particularly compared to the rather brief one or two introductory sentences that are often found at the beginning of a literature review section in a standard academic paper. The introduction to the literature review chapter in a thesis or dissertation again adheres to different standards.

Here’s a structured breakdown based on length and the necessary information:

Academic literature review paper

The introduction of an academic literature review paper, which does not rely on empirical data, often necessitates a more extensive introduction than the brief literature review introductions typically found in empirical papers. It should encompass:

• The research problem: Clearly articulate the problem or question that your literature review aims to address.
• The research gap: Highlight the existing gaps, limitations, or unresolved aspects within the current body of literature related to the research problem.
• The research relevance: Explain why the chosen research problem and its subsequent investigation through a literature review are significant and relevant in your academic field.
• The literature review method: If applicable, describe the methodology employed in your literature review, especially if it is a systematic review or follows a specific research framework.
• The main findings or insights of the literature review: Summarize the key discoveries, insights, or trends that have emerged from your comprehensive review of the literature.
• The main argument of the literature review: Conclude the introduction by outlining the primary argument or statement that your literature review will substantiate, linking it to the research problem and relevance you’ve established.
• Preview of the literature review’s structure: Offer a glimpse into the organization of the literature review paper, acting as a guide for the reader. This overview outlines the subsequent sections of the paper and provides an understanding of what to anticipate.

By addressing these elements, your introduction will provide a clear and structured overview of what readers can expect in your literature review paper.

Regular literature review section in an academic article or essay

Most academic articles or essays incorporate regular literature review sections, often placed after the introduction. These sections serve to establish a scholarly basis for the research or discussion within the paper.

In a standard 8000-word journal article, the literature review section typically spans between 750 and 1250 words. The first few sentences or the first paragraph within this section often serve as an introduction. It should encompass:

• An introduction to the topic: When delving into the academic literature on a specific topic, it’s important to provide a smooth transition that aids the reader in comprehending why certain aspects will be discussed within your literature review.
• The core argument: While literature review sections primarily synthesize the work of other scholars, they should consistently connect to your central argument. This central argument serves as the crux of your message or the key takeaway you want your readers to retain. By positioning it at the outset of the literature review section and systematically substantiating it with evidence, you not only enhance reader comprehension but also elevate overall readability. This primary argument can typically be distilled into 1-2 succinct sentences.

In some cases, you might include:

• Methodology: Details about the methodology used, but only if your literature review employed a specialized method. If your approach involved a broader overview without a systematic methodology, you can omit this section, thereby conserving word count.

By addressing these elements, your introduction will effectively integrate your literature review into the broader context of your academic paper or essay. This will, in turn, assist your reader in seamlessly following your overarching line of argumentation.

Introduction to a literature review chapter in thesis or dissertation

The literature review typically constitutes a distinct chapter within a thesis or dissertation. Often, it is Chapter 2 of a thesis or dissertation.

Some students choose to incorporate a brief introductory section at the beginning of each chapter, including the literature review chapter. Alternatively, others opt to seamlessly integrate the introduction into the initial sentences of the literature review itself. Both approaches are acceptable, provided that you incorporate the following elements:

• Purpose of the literature review and its relevance to the thesis/dissertation research: Explain the broader objectives of the literature review within the context of your research and how it contributes to your thesis or dissertation. Essentially, you’re telling the reader why this literature review is important and how it fits into the larger scope of your academic work.
• Primary argument: Succinctly communicate what you aim to prove, explain, or explore through the review of existing literature. This statement helps guide the reader’s understanding of the review’s purpose and what to expect from it.
• Preview of the literature review’s content: Provide a brief overview of the topics or themes that your literature review will cover. It’s like a roadmap for the reader, outlining the main areas of focus within the review. This preview can help the reader anticipate the structure and organization of your literature review.
• Methodology: If your literature review involved a specific research method, such as a systematic review or meta-analysis, you should briefly describe that methodology. However, this is not always necessary, especially if your literature review is more of a narrative synthesis without a distinct research method.

By addressing these elements, your introduction will empower your literature review to play a pivotal role in your thesis or dissertation research. It will accomplish this by integrating your research into the broader academic literature and providing a solid theoretical foundation for your work.

Comprehending the art of crafting your own literature review introduction becomes significantly more accessible when you have concrete examples to examine. Here, you will find several examples that meet, or in most cases, adhere to the criteria described earlier.

Example 1: An effective introduction for an academic literature review paper

To begin, let’s delve into the introduction of an academic literature review paper. We will examine the paper “How does culture influence innovation? A systematic literature review”, which was published in 2018 in the journal Management Decision.

The entire introduction spans 611 words and is divided into five paragraphs. In this introduction, the authors accomplish the following:

• In the first paragraph, the authors introduce the broader topic of the literature review, which focuses on innovation and its significance in the context of economic competition. They underscore the importance of this topic, highlighting its relevance for both researchers and policymakers.
• In the second paragraph, the authors narrow down their focus to emphasize the specific role of culture in relation to innovation.
• In the third paragraph, the authors identify research gaps, noting that existing studies are often fragmented and disconnected. They then emphasize the value of conducting a systematic literature review to enhance our understanding of the topic.
• In the fourth paragraph, the authors introduce their specific objectives and explain how their insights can benefit other researchers and business practitioners.
• In the fifth and final paragraph, the authors provide an overview of the paper’s organization and structure.

In summary, this introduction stands as a solid example. While the authors deviate from previewing their key findings (which is a common practice at least in the social sciences), they do effectively cover all the other previously mentioned points.

Example 2: An effective introduction to a literature review section in an academic paper

The second example represents a typical academic paper, encompassing not only a literature review section but also empirical data, a case study, and other elements. We will closely examine the introduction to the literature review section in the paper “The environmentalism of the subalterns: a case study of environmental activism in Eastern Kurdistan/Rojhelat”, which was published in 2021 in the journal Local Environment.

The paper begins with a general introduction and then proceeds to the literature review, designated by the authors as their conceptual framework. Of particular interest is the first paragraph of this conceptual framework, comprising 142 words across five sentences:

“ A peripheral and marginalised nationality within a multinational though-Persian dominated Iranian society, the Kurdish people of Iranian Kurdistan (a region referred by the Kurds as Rojhelat/Eastern Kurdi-stan) have since the early twentieth century been subject to multifaceted and systematic discriminatory and exclusionary state policy in Iran. This condition has left a population of 12–15 million Kurds in Iran suffering from structural inequalities, disenfranchisement and deprivation. Mismanagement of Kurdistan’s natural resources and the degradation of its natural environmental are among examples of this disenfranchisement. As asserted by Julian Agyeman (2005), structural inequalities that sustain the domination of political and economic elites often simultaneously result in environmental degradation, injustice and discrimination against subaltern communities. This study argues that the environmental struggle in Eastern Kurdistan can be asserted as a (sub)element of the Kurdish liberation movement in Iran. Conceptually this research is inspired by and has been conducted through the lens of ‘subalternity’ ” ( Hassaniyan, 2021, p. 931 ).

In this first paragraph, the author is doing the following:

• The author contextualises the research
• The author links the research focus to the international literature on structural inequalities
• The author clearly presents the argument of the research
• The author clarifies how the research is inspired by and uses the concept of ‘subalternity’.

Thus, the author successfully introduces the literature review, from which point onward it dives into the main concept (‘subalternity’) of the research, and reviews the literature on socio-economic justice and environmental degradation.

While introductions to a literature review section aren’t always required to offer the same level of study context detail as demonstrated here, this introduction serves as a commendable model for orienting the reader within the literature review. It effectively underscores the literature review’s significance within the context of the study being conducted.

Examples 3-5: Effective introductions to literature review chapters

The introduction to a literature review chapter can vary in length, depending largely on the overall length of the literature review chapter itself. For example, a master’s thesis typically features a more concise literature review, thus necessitating a shorter introduction. In contrast, a Ph.D. thesis, with its more extensive literature review, often includes a more detailed introduction.

Numerous universities offer online repositories where you can access theses and dissertations from previous years, serving as valuable sources of reference. Many of these repositories, however, may require you to log in through your university account. Nevertheless, a few open-access repositories are accessible to anyone, such as the one by the University of Manchester . It’s important to note though that copyright restrictions apply to these resources, just as they would with published papers.

Master’s thesis literature review introduction

The first example is “Benchmarking Asymmetrical Heating Models of Spider Pulsar Companions” by P. Sun, a master’s thesis completed at the University of Manchester on January 9, 2024. The author, P. Sun, introduces the literature review chapter very briefly but effectively:

PhD thesis literature review chapter introduction

The second example is Deep Learning on Semi-Structured Data and its Applications to Video-Game AI, Woof, W. (Author). 31 Dec 2020, a PhD thesis completed at the University of Manchester . In Chapter 2, the author offers a comprehensive introduction to the topic in four paragraphs, with the final paragraph serving as an overview of the chapter’s structure:

PhD thesis literature review introduction

The last example is the doctoral thesis Metacognitive strategies and beliefs: Child correlates and early experiences Chan, K. Y. M. (Author). 31 Dec 2020 . The author clearly conducted a systematic literature review, commencing the review section with a discussion of the methodology and approach employed in locating and analyzing the selected records.

Having absorbed all of this information, let’s recap the essential steps and offer a succinct guide on how to proceed with creating your literature review introduction:

• Contextualize your review : Begin by clearly identifying the academic context in which your literature review resides and determining the necessary information to include.
• Outline your structure : Develop a structured outline for your literature review, highlighting the essential information you plan to incorporate in your introduction.
• Literature review process : Conduct a rigorous literature review, reviewing and analyzing relevant sources.
• Summarize and abstract : After completing the review, synthesize the findings and abstract key insights, trends, and knowledge gaps from the literature.
• Craft the introduction : Write your literature review introduction with meticulous attention to the seamless integration of your review into the larger context of your work. Ensure that your introduction effectively elucidates your rationale for the chosen review topics and the underlying reasons guiding your selection.

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Introductions and Literature Reviews

• Author By Troy Mikanovich
• Publication date December 16, 2022
• Categories: Academic Publication , Research Writing
• Categories: academic journal , CARS , introduction , literature review , research , research question

Writing literature reviews is one of the trickiest things you’ll have to do in graduate school.  It is even more tricky because a lot of professors will want you to do things that are pedagogically valuable but so tailored to the specific class they are teaching that it can be hard to generalize the lessons you are meant to take away.

This page is meant to be a general overview to the goals and purposes of introductions and literature reviews (or an introduction that contains a literature review–we’ll talk about that), so even if it doesn’t exactly match what you have been asked to do in an assignment, I hope it’ll be helpful.

What is the difference between an introduction and a literature review?

As of writing this, the year is 2022 and words mean nothing. Rather than getting caught up on what these things are in some kind of objective sense, let’s look at what they are supposed to do.

The introduction and the literature review of your paper have the same job. Both are supposed to justify the question(s) you are asking about your topic and to demonstrate to your audience that the thing you are writing about is interesting and of some importance.  However, while they have the same job, they do it in two different ways.

An introduction should demonstrate that there is some broader real-world significance to the thing that you are writing about. You can do this by establishing a problem or a puzzle or by giving some background information on your topic to show why it is important.  Here’s an example from Brian E. Bride’s “Prevalence of Secondary Traumatic Stress among Social Workers” (2007, link below), where he begins by establishing a problem:

“ In the United States, the lifetime prevalence of exposure to traumatic events ranges from 40 percent to 81 percent, with 60.7 percent of men and 51.2 percent of women having been exposed to one or more traumas and 19.7 percent of men and 11.4 percent of women reporting exposure to three or more such events (Breslau, Davis, Peter-son, & Schultz, 1997; Kessler, Sonnega, Bromet, & Nelson, 1995; Stein, walker, Hazen, & Forde, 1997). Although exposure to traumatic events is high in the general population, it is even higher in subpopulations to whom social workers are likely to provide services…

Although not exhaustive of the populations with whom social workers practice, these examples illustrate that social workers face a high rate of professional contact with traumatized people. Social workers are increasingly being called on to assist survivors of childhood abuse, domestic violence, violent crime, disasters, and war and terrorism. It has become increasingly apparent that the psychological effects of traumatic events extend beyond those directly affected.”

So, Bride (2007) starts with a broad problem (lots of people with exposure to traumatic events) and narrows it to a more specific problem (social workers who work with those people are exposed to secondary trauma as they assist them) .

A literature review should demonstrate that there is some academic significance to the thing you are writing about. You can do this by establishing a scholarly problem (i.e. a “research gap”) and by demonstrating that the state of the existing scholarship on your topic needs to develop in a particular way.

As Bride (2007) transitions to talking about the scholarship on the topic of social workers and secondary trauma, he establishes what scholarship has done and identifies what it has not done .

“Figley (1999) defined secondary traumatic stress as “the natural, consequent behaviors and emotions resulting from knowledge about a traumatizing event experienced by a significant other. It is the stress resulting from helping or wanting to help a traumatized or suffering person” (p. 10). Chrestman (1999) noted that secondary traumatization includes symptoms parallel to those observed in people di-rectly exposed to trauma such as intrusive imagery related to clients’ traumatic disclosures (Courtois, 1988; Danieli, 1988; Herman, 1992; McCann & Pearlman, 1990); avoidant responses (Courtois; Haley, 1974); and physiological arousal (Figley, 1995; McCann & Pearlman, 1990). Thus, STS is a syndrome of symptoms identical to those of PTSD, the characteristic symptoms of which are intrusion, avoidance, and arousal (Figley, 1999)…

Collectively, these studies have provided empirical evidence that individuals who provide services to traumatized populations are at risk of experiencing symptoms of traumatic stress (Bride). However, the extant literature fails to document the prevalence of individual STS symptoms and the extent to which diagnostic criteria for PTSD are met as a result of work with traumatized populations.”

Taken together, Bride (2007) justifies its existence–the research that the author has undertaken in order to read the article that you are now reading–like this:

Broad real world background: Lots of people are suffering from traumatic stress.

Narrowed real world background: People who have suffered traumatic experiences often work with social workers.

Real world problem: Many social workers may through their work suffer from secondary exposure to traumatic experiences.

Broad academic background: There has been a lot of research on secondary traumatic stress

Narrowed academic background: Particularly, this research has shown that social workers are at risk of experiencing symptoms of secondary traumatic stress.

Academic problem/gap : We don’t know how prevalent individual symptoms of secondary traumatic stress are.

Introductions, then, give you space to explain why you are writing about the thing you are writing about, and literature reviews are where you explain what prior scholarship has said about the topic and what the consequences of that prior scholarship are. In an introduction you are writing about the topic; in a literature review you are writing about people writing about the topic.

So does a literature review need to be a separate section from an introduction? Or is a literature review part of an introduction?

It depends on your field, tbh. And on the expectations of the assignment/journal/outlet that you are writing for.

For instance, in the above example (Bride, 2007) the literature review is a part of the introduction. Here’s that paper and some other examples of other places where this is the case. Notice that they do not differentiate between an introductory section and a distinct “Literature Review” as they outline their topic/questions before describing their methodology:

Bride, B. E. (2007) Prevalence of secondary traumatic stress among social workers.  Social Work, 52 (1), 63-70. https://doi.org/10.1093/sw/52.1.63

Wei, X., Teng, X., Bai, J., & Ren, F. (2022). Intergenerational transmission of depression during adolescence: The mediating roles of hostile attribution bias, empathetic concern, and social self-concept.  The Journal of Psychology, 157 (1), 13-31. https://doi.org/10.1080/00223980.2022.2134276

Stephens, R., Dowber, H., Barrie, A., Sannida, A., & Atkins, K. 2022) Effect of swearing on strength: Disinhibition as a potential mediator.  Quarterly Journal of Experimental Psychology . Advance online publication. https://doi.org/10.1177/17470218221082657

However, plenty of other articles have distinct “Literature Review” sections separate from their introductions. The first two examples name it as such, while the third organizes its literature review with thematic sub-sections:

Schraedley, M.K., & Dougherty, D.S. (2021). Creating and disrupting othering during policymaking in a polarized context.  Journal of Communication, 72 (1), 111-140. https://doi.org/10.1093/joc/jqab042

Gil de Zúñiga, H., Cheng, Z., & González-González, P. (2022). Effects of the news finds me perception on algorithmic news attitudes and social media political homophily. Journal of Communication, 72 (5), 578-591. https://doi.org/10.1093/joc/jqac025

Brandão, T., Brites, R., Hipólito, J., & Nunes O. (2022) Attachment orientations and family functioning: The mediating role of emotion regulation. The Journal of Psychology , 157 (1), 1-12. https://doi.org/10.1080/00223980.2022.2128284

Whether you separate your literature review into its own distinct section is mostly a function of what you’ve been asked to do (if you are writing for a class) or what the conventions and constraints are of your field.

• UConn Library
• Literature Review: The What, Why and How-to Guide
• Introduction

Literature Review: The What, Why and How-to Guide — Introduction

• Getting Started
• How to Pick a Topic
• Strategies to Find Sources
• Evaluating Sources & Lit. Reviews
• Tips for Writing Literature Reviews
• Writing Literature Review: Useful Sites
• Citation Resources
• Other Academic Writings

What are Literature Reviews?

So, what is a literature review? "A literature review is an account of what has been published on a topic by accredited scholars and researchers. In writing the literature review, your purpose is to convey to your reader what knowledge and ideas have been established on a topic, and what their strengths and weaknesses are. As a piece of writing, the literature review must be defined by a guiding concept (e.g., your research objective, the problem or issue you are discussing, or your argumentative thesis). It is not just a descriptive list of the material available, or a set of summaries." Taylor, D.  The literature review: A few tips on conducting it . University of Toronto Health Sciences Writing Centre.

Goals of Literature Reviews

What are the goals of creating a Literature Review?  A literature could be written to accomplish different aims:

• To develop a theory or evaluate an existing theory
• To summarize the historical or existing state of a research topic
• Identify a problem in a field of research 

Baumeister, R. F., & Leary, M. R. (1997). Writing narrative literature reviews .  Review of General Psychology , 1 (3), 311-320.

What kinds of sources require a Literature Review?

• A research paper assigned in a course
• A thesis or dissertation
• A grant proposal
• An article intended for publication in a journal

All these instances require you to collect what has been written about your research topic so that you can demonstrate how your own research sheds new light on the topic.

Types of Literature Reviews

What kinds of literature reviews are written?

Narrative review: The purpose of this type of review is to describe the current state of the research on a specific topic/research and to offer a critical analysis of the literature reviewed. Studies are grouped by research/theoretical categories, and themes and trends, strengths and weakness, and gaps are identified. The review ends with a conclusion section which summarizes the findings regarding the state of the research of the specific study, the gaps identify and if applicable, explains how the author's research will address gaps identify in the review and expand the knowledge on the topic reviewed.

• Example : Predictors and Outcomes of U.S. Quality Maternity Leave: A Review and Conceptual Framework:  10.1177/08948453211037398  

Systematic review : "The authors of a systematic review use a specific procedure to search the research literature, select the studies to include in their review, and critically evaluate the studies they find." (p. 139). Nelson, L. K. (2013). Research in Communication Sciences and Disorders . Plural Publishing.

• Example : The effect of leave policies on increasing fertility: a systematic review:  10.1057/s41599-022-01270-w

Meta-analysis : "Meta-analysis is a method of reviewing research findings in a quantitative fashion by transforming the data from individual studies into what is called an effect size and then pooling and analyzing this information. The basic goal in meta-analysis is to explain why different outcomes have occurred in different studies." (p. 197). Roberts, M. C., & Ilardi, S. S. (2003). Handbook of Research Methods in Clinical Psychology . Blackwell Publishing.

• Example : Employment Instability and Fertility in Europe: A Meta-Analysis:  10.1215/00703370-9164737

Meta-synthesis : "Qualitative meta-synthesis is a type of qualitative study that uses as data the findings from other qualitative studies linked by the same or related topic." (p.312). Zimmer, L. (2006). Qualitative meta-synthesis: A question of dialoguing with texts .  Journal of Advanced Nursing , 53 (3), 311-318.

• Example : Women’s perspectives on career successes and barriers: A qualitative meta-synthesis:  10.1177/05390184221113735

Literature Reviews in the Health Sciences

• UConn Health subject guide on systematic reviews Explanation of the different review types used in health sciences literature as well as tools to help you find the right review type
• << Previous: Getting Started
• Next: How to Pick a Topic >>
• Last Updated: Sep 21, 2022 2:16 PM
• URL: https://guides.lib.uconn.edu/literaturereview

• University of Texas Libraries

Literature Reviews

• What is a literature review?
• Steps in the Literature Review Process
• Define your research question
• Determine inclusion and exclusion criteria
• Choose databases and search
• Review Results
• Synthesize Results
• Analyze Results
• Librarian Support

What is a Literature Review?

A literature or narrative review is a comprehensive review and analysis of the published literature on a specific topic or research question. The literature that is reviewed contains: books, articles, academic articles, conference proceedings, association papers, and dissertations. It contains the most pertinent studies and points to important past and current research and practices. It provides background and context, and shows how your research will contribute to the field. 

A literature review should: 

• Provide a comprehensive and updated review of the literature;
• Explain why this review has taken place;
• Articulate a position or hypothesis;
• Acknowledge and account for conflicting and corroborating points of view

From  S age Research Methods

Purpose of a Literature Review

A literature review can be written as an introduction to a study to:

• Demonstrate how a study fills a gap in research
• Compare a study with other research that's been done

Or it can be a separate work (a research article on its own) which:

• Organizes or describes a topic
• Describes variables within a particular issue/problem

Limitations of a Literature Review

Some of the limitations of a literature review are:

• It's a snapshot in time. Unlike other reviews, this one has beginning, a middle and an end. There may be future developments that could make your work less relevant.
• It may be too focused. Some niche studies may miss the bigger picture.
• It can be difficult to be comprehensive. There is no way to make sure all the literature on a topic was considered.
• It is easy to be biased if you stick to top tier journals. There may be other places where people are publishing exemplary research. Look to open access publications and conferences to reflect a more inclusive collection. Also, make sure to include opposing views (and not just supporting evidence).

Source: Grant, Maria J., and Andrew Booth. “A Typology of Reviews: An Analysis of 14 Review Types and Associated Methodologies.” Health Information & Libraries Journal, vol. 26, no. 2, June 2009, pp. 91–108. Wiley Online Library, doi:10.1111/j.1471-1842.2009.00848.x.

Meryl Brodsky : Communication and Information Studies

Hannah Chapman Tripp : Biology, Neuroscience

Carolyn Cunningham : Human Development & Family Sciences, Psychology, Sociology

Larayne Dallas : Engineering

Janelle Hedstrom : Special Education, Curriculum & Instruction, Ed Leadership & Policy ​

Susan Macicak : Linguistics

Imelda Vetter : Dell Medical School

For help in other subject areas, please see the guide to library specialists by subject .

Periodically, UT Libraries runs a workshop covering the basics and library support for literature reviews. While we try to offer these once per academic year, we find providing the recording to be helpful to community members who have missed the session. Following is the most recent recording of the workshop, Conducting a Literature Review. To view the recording, a UT login is required.

• October 26, 2022 recording
• Last Updated: Oct 26, 2022 2:49 PM
• URL: https://guides.lib.utexas.edu/literaturereviews

Research Skills

Introduction and literature review.

This section is the beginning of the article, but don’t expect it to contain any sort of position or argument. In academic articles, this section has one, overarching purpose: to demonstrate that the authors are familiar with all previous relevant research on the issue they are writing about. Therefore, this section is usually the most “citation-heavy” section of the paper. It is not uncommon to have one or more citations at the end of each sentence. You will likely also encounter a number of compound citations: parentheticals in which not one source, but two or more are cited at one time. Each sentence that precedes a citation in this section is typically a very brief paraphrase of the relevant methods or applicable findings of the other articles that have come before. This review of prior studies is a very important exercise for scholars because it demonstrates the depth of their understanding. None of the articles you read occur in a vacuum; they are usually part of an evolving web of scholarship. Each new article picks up the thread (or, usually, several threads) left by articles published recently. Another important thing to realize is that, in a very real sense, the authors have not really begun; they do not make an argument or say much that is new in this section. It is designed to provide an academic history and theoretical context for the topic of discussion.

At the very end of every literature review section, however, the authors do something important. After having demonstrated their familiarity with previous research, authors indicate that, even though much research has been done, there are still gaps in the research that need filling. You should try to find language such as, “While many studies have examined this subject, no one has looked at this particular issue in this way.” The authors then announce their intention to address that gap in knowledge with the research that follows. This rhetorical move always appears at the end of this section, and often gives the reader the clearest and most detailed description of what exactly the authors are looking at—and why. This is not a thesis, however. Academic articles are not like the essays you may be used to writing, in which the thesis appears at the end of the introduction. The research gap is more akin to a hypothesis than a thesis. It does not make an argument, which comes much later—usually in the discussion or conclusion.

There are also articles that are stand-alone literature reviews; these are sometimes called “Review Articles” or “Meta-analyses.” Rather than engaging in original research, these articles, if they are recent and on point, can provide you with the bibliographic information of all the important, recent sources on your topic. There are many ways to find sources that don’t involve a search engine of any kind. Look at your articles’ references lists to see if they contain any relevant-sounding articles that you haven’t found by other means. You can save a great deal of time this way.

• Parts of An Article. Authored by : Kerry Bowers. Provided by : The University of Mississippi. Project : WRIT 250 Committee OER Project. License : CC BY-SA: Attribution-ShareAlike

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Ten Simple Rules for Writing a Literature Review

Marco pautasso.

1 Centre for Functional and Evolutionary Ecology (CEFE), CNRS, Montpellier, France

2 Centre for Biodiversity Synthesis and Analysis (CESAB), FRB, Aix-en-Provence, France

Literature reviews are in great demand in most scientific fields. Their need stems from the ever-increasing output of scientific publications [1] . For example, compared to 1991, in 2008 three, eight, and forty times more papers were indexed in Web of Science on malaria, obesity, and biodiversity, respectively [2] . Given such mountains of papers, scientists cannot be expected to examine in detail every single new paper relevant to their interests [3] . Thus, it is both advantageous and necessary to rely on regular summaries of the recent literature. Although recognition for scientists mainly comes from primary research, timely literature reviews can lead to new synthetic insights and are often widely read [4] . For such summaries to be useful, however, they need to be compiled in a professional way [5] .

When starting from scratch, reviewing the literature can require a titanic amount of work. That is why researchers who have spent their career working on a certain research issue are in a perfect position to review that literature. Some graduate schools are now offering courses in reviewing the literature, given that most research students start their project by producing an overview of what has already been done on their research issue [6] . However, it is likely that most scientists have not thought in detail about how to approach and carry out a literature review.

Reviewing the literature requires the ability to juggle multiple tasks, from finding and evaluating relevant material to synthesising information from various sources, from critical thinking to paraphrasing, evaluating, and citation skills [7] . In this contribution, I share ten simple rules I learned working on about 25 literature reviews as a PhD and postdoctoral student. Ideas and insights also come from discussions with coauthors and colleagues, as well as feedback from reviewers and editors.

Rule 1: Define a Topic and Audience

How to choose which topic to review? There are so many issues in contemporary science that you could spend a lifetime of attending conferences and reading the literature just pondering what to review. On the one hand, if you take several years to choose, several other people may have had the same idea in the meantime. On the other hand, only a well-considered topic is likely to lead to a brilliant literature review [8] . The topic must at least be:

• interesting to you (ideally, you should have come across a series of recent papers related to your line of work that call for a critical summary),
• an important aspect of the field (so that many readers will be interested in the review and there will be enough material to write it), and
• a well-defined issue (otherwise you could potentially include thousands of publications, which would make the review unhelpful).

Ideas for potential reviews may come from papers providing lists of key research questions to be answered [9] , but also from serendipitous moments during desultory reading and discussions. In addition to choosing your topic, you should also select a target audience. In many cases, the topic (e.g., web services in computational biology) will automatically define an audience (e.g., computational biologists), but that same topic may also be of interest to neighbouring fields (e.g., computer science, biology, etc.).

Rule 2: Search and Re-search the Literature

After having chosen your topic and audience, start by checking the literature and downloading relevant papers. Five pieces of advice here:

• keep track of the search items you use (so that your search can be replicated [10] ),
• keep a list of papers whose pdfs you cannot access immediately (so as to retrieve them later with alternative strategies),
• use a paper management system (e.g., Mendeley, Papers, Qiqqa, Sente),
• define early in the process some criteria for exclusion of irrelevant papers (these criteria can then be described in the review to help define its scope), and
• do not just look for research papers in the area you wish to review, but also seek previous reviews.

The chances are high that someone will already have published a literature review ( Figure 1 ), if not exactly on the issue you are planning to tackle, at least on a related topic. If there are already a few or several reviews of the literature on your issue, my advice is not to give up, but to carry on with your own literature review,

The bottom-right situation (many literature reviews but few research papers) is not just a theoretical situation; it applies, for example, to the study of the impacts of climate change on plant diseases, where there appear to be more literature reviews than research studies [33] .

• discussing in your review the approaches, limitations, and conclusions of past reviews,
• trying to find a new angle that has not been covered adequately in the previous reviews, and
• incorporating new material that has inevitably accumulated since their appearance.

When searching the literature for pertinent papers and reviews, the usual rules apply:

• be thorough,
• use different keywords and database sources (e.g., DBLP, Google Scholar, ISI Proceedings, JSTOR Search, Medline, Scopus, Web of Science), and
• look at who has cited past relevant papers and book chapters.

Rule 3: Take Notes While Reading

If you read the papers first, and only afterwards start writing the review, you will need a very good memory to remember who wrote what, and what your impressions and associations were while reading each single paper. My advice is, while reading, to start writing down interesting pieces of information, insights about how to organize the review, and thoughts on what to write. This way, by the time you have read the literature you selected, you will already have a rough draft of the review.

Of course, this draft will still need much rewriting, restructuring, and rethinking to obtain a text with a coherent argument [11] , but you will have avoided the danger posed by staring at a blank document. Be careful when taking notes to use quotation marks if you are provisionally copying verbatim from the literature. It is advisable then to reformulate such quotes with your own words in the final draft. It is important to be careful in noting the references already at this stage, so as to avoid misattributions. Using referencing software from the very beginning of your endeavour will save you time.

Rule 4: Choose the Type of Review You Wish to Write

After having taken notes while reading the literature, you will have a rough idea of the amount of material available for the review. This is probably a good time to decide whether to go for a mini- or a full review. Some journals are now favouring the publication of rather short reviews focusing on the last few years, with a limit on the number of words and citations. A mini-review is not necessarily a minor review: it may well attract more attention from busy readers, although it will inevitably simplify some issues and leave out some relevant material due to space limitations. A full review will have the advantage of more freedom to cover in detail the complexities of a particular scientific development, but may then be left in the pile of the very important papers “to be read” by readers with little time to spare for major monographs.

There is probably a continuum between mini- and full reviews. The same point applies to the dichotomy of descriptive vs. integrative reviews. While descriptive reviews focus on the methodology, findings, and interpretation of each reviewed study, integrative reviews attempt to find common ideas and concepts from the reviewed material [12] . A similar distinction exists between narrative and systematic reviews: while narrative reviews are qualitative, systematic reviews attempt to test a hypothesis based on the published evidence, which is gathered using a predefined protocol to reduce bias [13] , [14] . When systematic reviews analyse quantitative results in a quantitative way, they become meta-analyses. The choice between different review types will have to be made on a case-by-case basis, depending not just on the nature of the material found and the preferences of the target journal(s), but also on the time available to write the review and the number of coauthors [15] .

Rule 5: Keep the Review Focused, but Make It of Broad Interest

Whether your plan is to write a mini- or a full review, it is good advice to keep it focused 16 , 17 . Including material just for the sake of it can easily lead to reviews that are trying to do too many things at once. The need to keep a review focused can be problematic for interdisciplinary reviews, where the aim is to bridge the gap between fields [18] . If you are writing a review on, for example, how epidemiological approaches are used in modelling the spread of ideas, you may be inclined to include material from both parent fields, epidemiology and the study of cultural diffusion. This may be necessary to some extent, but in this case a focused review would only deal in detail with those studies at the interface between epidemiology and the spread of ideas.

While focus is an important feature of a successful review, this requirement has to be balanced with the need to make the review relevant to a broad audience. This square may be circled by discussing the wider implications of the reviewed topic for other disciplines.

Rule 6: Be Critical and Consistent

Reviewing the literature is not stamp collecting. A good review does not just summarize the literature, but discusses it critically, identifies methodological problems, and points out research gaps [19] . After having read a review of the literature, a reader should have a rough idea of:

• the major achievements in the reviewed field,
• the main areas of debate, and
• the outstanding research questions.

It is challenging to achieve a successful review on all these fronts. A solution can be to involve a set of complementary coauthors: some people are excellent at mapping what has been achieved, some others are very good at identifying dark clouds on the horizon, and some have instead a knack at predicting where solutions are going to come from. If your journal club has exactly this sort of team, then you should definitely write a review of the literature! In addition to critical thinking, a literature review needs consistency, for example in the choice of passive vs. active voice and present vs. past tense.

Rule 7: Find a Logical Structure

Like a well-baked cake, a good review has a number of telling features: it is worth the reader's time, timely, systematic, well written, focused, and critical. It also needs a good structure. With reviews, the usual subdivision of research papers into introduction, methods, results, and discussion does not work or is rarely used. However, a general introduction of the context and, toward the end, a recapitulation of the main points covered and take-home messages make sense also in the case of reviews. For systematic reviews, there is a trend towards including information about how the literature was searched (database, keywords, time limits) [20] .

How can you organize the flow of the main body of the review so that the reader will be drawn into and guided through it? It is generally helpful to draw a conceptual scheme of the review, e.g., with mind-mapping techniques. Such diagrams can help recognize a logical way to order and link the various sections of a review [21] . This is the case not just at the writing stage, but also for readers if the diagram is included in the review as a figure. A careful selection of diagrams and figures relevant to the reviewed topic can be very helpful to structure the text too [22] .

Rule 8: Make Use of Feedback

Reviews of the literature are normally peer-reviewed in the same way as research papers, and rightly so [23] . As a rule, incorporating feedback from reviewers greatly helps improve a review draft. Having read the review with a fresh mind, reviewers may spot inaccuracies, inconsistencies, and ambiguities that had not been noticed by the writers due to rereading the typescript too many times. It is however advisable to reread the draft one more time before submission, as a last-minute correction of typos, leaps, and muddled sentences may enable the reviewers to focus on providing advice on the content rather than the form.

Feedback is vital to writing a good review, and should be sought from a variety of colleagues, so as to obtain a diversity of views on the draft. This may lead in some cases to conflicting views on the merits of the paper, and on how to improve it, but such a situation is better than the absence of feedback. A diversity of feedback perspectives on a literature review can help identify where the consensus view stands in the landscape of the current scientific understanding of an issue [24] .

Rule 9: Include Your Own Relevant Research, but Be Objective

In many cases, reviewers of the literature will have published studies relevant to the review they are writing. This could create a conflict of interest: how can reviewers report objectively on their own work [25] ? Some scientists may be overly enthusiastic about what they have published, and thus risk giving too much importance to their own findings in the review. However, bias could also occur in the other direction: some scientists may be unduly dismissive of their own achievements, so that they will tend to downplay their contribution (if any) to a field when reviewing it.

In general, a review of the literature should neither be a public relations brochure nor an exercise in competitive self-denial. If a reviewer is up to the job of producing a well-organized and methodical review, which flows well and provides a service to the readership, then it should be possible to be objective in reviewing one's own relevant findings. In reviews written by multiple authors, this may be achieved by assigning the review of the results of a coauthor to different coauthors.

Rule 10: Be Up-to-Date, but Do Not Forget Older Studies

Given the progressive acceleration in the publication of scientific papers, today's reviews of the literature need awareness not just of the overall direction and achievements of a field of inquiry, but also of the latest studies, so as not to become out-of-date before they have been published. Ideally, a literature review should not identify as a major research gap an issue that has just been addressed in a series of papers in press (the same applies, of course, to older, overlooked studies (“sleeping beauties” [26] )). This implies that literature reviewers would do well to keep an eye on electronic lists of papers in press, given that it can take months before these appear in scientific databases. Some reviews declare that they have scanned the literature up to a certain point in time, but given that peer review can be a rather lengthy process, a full search for newly appeared literature at the revision stage may be worthwhile. Assessing the contribution of papers that have just appeared is particularly challenging, because there is little perspective with which to gauge their significance and impact on further research and society.

Inevitably, new papers on the reviewed topic (including independently written literature reviews) will appear from all quarters after the review has been published, so that there may soon be the need for an updated review. But this is the nature of science [27] – [32] . I wish everybody good luck with writing a review of the literature.

Acknowledgments

Many thanks to M. Barbosa, K. Dehnen-Schmutz, T. Döring, D. Fontaneto, M. Garbelotto, O. Holdenrieder, M. Jeger, D. Lonsdale, A. MacLeod, P. Mills, M. Moslonka-Lefebvre, G. Stancanelli, P. Weisberg, and X. Xu for insights and discussions, and to P. Bourne, T. Matoni, and D. Smith for helpful comments on a previous draft.

Funding Statement

This work was funded by the French Foundation for Research on Biodiversity (FRB) through its Centre for Synthesis and Analysis of Biodiversity data (CESAB), as part of the NETSEED research project. The funders had no role in the preparation of the manuscript.

Introduction vs. Literature Review — What's the Difference?

Difference Between Introduction and Literature Review

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Introduction vs Literature Review

Introduction is at the beginning of a text while literature review is located after the introduction or background.

Introduction is the part that introduces the main text to the readers while literature review critically evaluates the existing research on the selected research area and identifies the research gap.

Introduction have elements such as background, outline of key issues, thesis statement, aims and purpose of the paper and definition of terms and concepts while literature review have summaries, reviews, critical evaluations, and comparisons of selected research studies.

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Literature Review for Introduction Vs. Discussion

A literature review presents a summary of studies related to a particular area of research. It identifies and summarizes all the relevant research conducted on a particular topic. Literature reviews are used in the  introduction  and  discussion sections of your  manuscripts . However, there are differences in how you can present literature reviews in each section. This smartshort describes how to effectively use literature reviews in these sections. You can also read a detailed article on this topic here.

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• Open access
• Published: 02 June 2024

Neuroleptic malignant syndrome and serotonin syndrome: a comparative bibliometric analysis

• Waleed M. Sweileh 1  

Orphanet Journal of Rare Diseases volume  19 , Article number:  221 ( 2024 ) Cite this article

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This study aimed to analyze and map scientific literature on Neuroleptic Malignant Syndrome (NMS) and Serotonin Syndrome (SS) from prestigious, internationally indexed journals. The objective was to identify key topics, impactful articles, prominent journals, research output, growth patterns, hotspots, and leading countries in the field, providing valuable insights for scholars, medical students, and international funding agencies.

A systematic search strategy was implemented in the PubMed MeSH database using specific keywords for NMS and SS. The search was conducted in the Scopus database, renowned for its extensive coverage of scholarly publications. Inclusion criteria comprised articles published from 1950 to December 31st, 2022, restricted to journal research and review articles written in English. Data were analyzed using Microsoft Excel for descriptive analysis, and VOSviewer was employed for bibliometric mapping.

The search yielded 1150 articles on NMS and 587 on SS, with the majority being case reports. Growth patterns revealed a surge in NMS research between 1981 and 1991, while SS research increased notably between 1993 and 1997. Active countries and journals differed between NMS and SS, with psychiatry journals predominating for NMS and pharmacology/toxicology journals for SS. Authorship analysis indicated higher multi-authored articles for NMS. Top impactful articles focused on review articles and pathogenic mechanisms. Research hotspots included antipsychotics and catatonia for NMS, while SS highlighted drug interactions and specific medications like linezolid and tramadol.

Conclusions

NMS and SS represent rare but life-threatening conditions, requiring detailed clinical and scientific understanding. Differential diagnosis and management necessitate caution in prescribing medications affecting central serotonin or dopamine systems, with awareness of potential drug interactions. International diagnostic tools and genetic screening tests may aid in safe diagnosis and prevention. Reporting rare cases and utilizing bibliometric analysis enhance knowledge dissemination and research exploration in the field of rare drug-induced medical conditions.

Introduction

Neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) are drug-induced, potentially life-threatening conditions that are infrequently encountered in medical practice, necessitating prompt intervention [ 1 , 2 , 3 , 4 ]. Neuroleptic Malignant Syndrome is characterized by a decrease in dopamine activity in the brain, often associated with the use of dopamine antagonists, primarily neuroleptic or antipsychotic medications [ 5 , 6 ]. While the exact pathophysiology of NMS remains incompletely understood, it is believed to involve dopamine dysregulation in the basal ganglia and hypothalamus. This dysregulation, particularly the blockade of dopamine receptors, especially D2 receptors, leads to a state of dopamine deficiency, manifesting in symptoms such as muscle rigidity, hyperthermia, and autonomic instability. Furthermore, withdrawal from dopamine agonists, such as L-Dopa, can also precipitate NMS in susceptible individuals. Serotonin Syndrome is characterized by an excess of serotonin (5-HT) in the central nervous system, typically stemming from the use of serotonergic medications or substances that elevate serotonin levels [ 7 , 8 ]. These drugs encompass antidepressants, notably selective serotonin reuptake inhibitors (SSRIs), opioids, specific psychedelics, serotonin agonists, and herbal supplements. The pathophysiology of SS revolves around the excessive stimulation of serotonin receptors, particularly the 5-HT2A receptors. This heightened stimulation precipitates a spectrum of symptoms, ranging from agitation, confusion, hyperthermia, muscle rigidity, to autonomic dysfunction. The severity of SS can vary widely, from mild manifestations to life-threatening conditions, contingent upon the extent of serotonin excess and individual susceptibility factors.

Both NMS and SS exhibit shared clinical manifestations, including hyperthermia, hypertension, hypersalivation, diaphoresis, and altered mental status [ 4 ], with instances of coexistence reported in some patients [ 9 ]. However, they diverge in their etiologies and clinical presentations. For instance, individuals with NMS typically display hyporeflexia, normal pupil size, and normal bowel sounds, contrasting with SS patients who often present with hyperreflexia, dilated pupils, and hyperactive bowel activity [ 10 ]. NMS is typified by lead-pipe muscle rigidity, whereas SS manifests with increased muscle tone, particularly in the lower extremities [ 11 , 12 ]. Given these distinctions, treatment strategies for NMS and SS diverge based on their underlying causes [ 2 ]. The mechanisms driving these syndromes differ significantly; while NMS involves diminished dopamine activity in the brain, SS is characterized by elevated serotonin levels [ 13 ]. Dopamine antagonists, such as neuroleptics or antipsychotics, are commonly implicated in NMS [ 14 , 15 , 16 ], although other triggers like withdrawal from dopamine agonists, like L-Dopa, can also induce NMS [ 17 , 18 ]. Conversely, SS can result from various drug classes, including antidepressants, opioids, psychedelics, serotonin agonists, and certain herbs [ 7 , 19 , 20 , 21 , 22 , 23 ]. Consequently, distinct medications are employed for their management; benzodiazepines and serotonin antagonists are standard therapy for SS, whereas dopaminergic agents and dantrolene are preferred for NMS [ 10 ]. While the incidence of NMS remains low, particularly among patients receiving newer generation antipsychotics [ 24 , 25 ], recent studies on SS incidence are lacking. However, a 1999 study reported an incidence of 0.4 cases per 1000 patient-months with nefazodone [ 26 ], while SS incidence reaches 14–16% in cases of selective serotonin reuptake inhibitor (SSRI) overdose [ 27 ].

Research context and objectives

The landscape of psychiatric pharmacotherapy has evolved over time, witnessing a surge in the number of approved drugs and the introduction of novel classes into clinical practice [ 28 , 29 , 30 , 31 ]. This trend is particularly notable in the treatment of depression and schizophrenia, where the absence of universally safe and effective drugs persists [ 32 , 33 , 34 , 35 , 36 ]. Additionally, off-label utilization of antidepressants and antipsychotics has been observed among patients with dementia and other neuro-cognitive disorders [ 37 , 38 , 39 , 40 , 41 ], contributing to an upward trajectory in psychiatric drug consumption [ 42 , 43 ]. The risk of SS is linked to any medication or herb augmenting the central serotonergic pathway, necessitating vigilant monitoring by healthcare professionals due to the potential for adverse effects, whether as a primary mechanism or side effect [ 20 ]. A concerning trend of unsupported polypharmacy in psychiatric medications has also emerged [ 44 ], along with significant prescribing of antidepressants and antipsychotics to dementia patients without documented indications of depression or psychosis [ 45 , 46 ], mirroring similar trends among individuals with intellectual disabilities [ 47 ]. The escalating demand for psychiatric therapy raises apprehensions regarding the likelihood of adverse medication effects [ 48 ], exacerbated by increased prescribing rates, polypharmacy, and off-label usage, which heighten the incidence of drug-induced toxicities, including NMS and SS. Analyzing published literature on drug-induced NMS and SS provides valuable insights into these rare yet severe toxicities, aligning with the pressing global public health burden of depression, schizophrenia, and related conditions, accentuated by the fatal toxicities associated with specific psychiatric medications. This scientific literature on NMS and SS is ripe for analysis and mapping to delineate current research hotspots [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ], addressing the gap in the literature. Accordingly, the present study aims to analyze and map scientific research on NMS and SS published in prestigious, internationally indexed journals. Through this analysis, the study seeks to identify key topics, impactful articles, prominent journals, research output, growth patterns, hotspots, and leading countries in the field, providing valuable insights for scholars, medical students, and international funding agencies to discern research trajectories, bibliographic trends, and knowledge structures pertaining to NMS and SS. Ultimately, this endeavor aims to invigorate scholarly discourse and inform clinical practice in the field.

Database and keywords

In this study, we employed a systematic search strategy to extract relevant scientific literature on NMS and SS from the PubMed MeSH database. Specifically, we utilized the following keywords:

Malignant neuroleptic syndrome: “malignant neuroleptic syndrome”.

Serotonin syndrome: “serotonin syndrome” or “serotonin toxicity”.

To ensure comprehensive coverage, we conducted our search in Scopus, a prestigious scientific database owned by Elsevier, which has previously been utilized for analyzing research in psychiatry [ 56 , 57 ]. Scopus is renowned for its extensive coverage, encompassing a vast array of scholarly publications in the field. Notably, Scopus encompasses over 95% of the content included in other databases such as PubMed and Web of Science, rendering it an ideal platform for our study [ 58 ].

Inclusion and exclusion criteria

We restricted our search to articles published from 1950 to December 31st, 2022, and focused exclusively on journal research and review articles written in English. Excluded from our analysis were editorials, notes, letters, and conference abstracts. Additionally, articles pertaining to non-human subjects were excluded, ensuring the relevance of our findings. We meticulously reviewed the titles and abstracts of over 100 articles to eliminate irrelevant publications, such as those mentioning NMS or SS only marginally, thereby refining the scope of our analysis.

Our search strategy yielded results indicative of its validity, as evidenced by the prominent presence of leading scientists and journals in the fields of psychiatry and pharmacology. This reaffirmed the robustness of our search criteria and the relevance of the retrieved literature to our study objectives.

Data management, analysis, and mapping

The dataset comprising the retrieved articles was subjected to descriptive analysis using Microsoft Excel. Subsequently, we employed VOSviewer, a freely available online tool, for bibliometric mapping purposes [ 59 ]. VOSviewer maps offer researchers a visual tool for exploring bibliometric data, revealing patterns, relationships, and trends within a dataset. Interpretation of these maps involves understanding several key elements. Firstly, node size indicates the prominence or frequency of an item, with larger nodes representing more significant themes or influential publications. Secondly, node color categorizes items into clusters, with similar colors indicating thematic groupings. Thirdly, the thickness of connecting lines between nodes signifies the strength of associations, with thicker lines indicating stronger connections. Lastly, the distance between nodes reflects the similarity or dissimilarity between items, with closer nodes indicating stronger relationships. Overall, VOSviewer maps provide a comprehensive visual overview of bibliometric data, enabling researchers to identify clusters, influential publications, and emerging trends within their field of study by considering the interplay between node size, color, line thickness, and spatial relationships. Within the descriptive analysis, we presented lists of active countries and journals, alongside a linear graph illustrating the growth of publications over time. In the keyword visualization map generated using VOSviewer, node size corresponded to the frequency of occurrence of each keyword, enabling visual identification of prominent themes. Similarly, in the journal visualization map, node size reflected the normalized citation count received by each journal, providing insights into publication impact within the field.

Number of publications

The search strategy yielded a total of 1150 articles on NMS and 587 on SS. Among the articles on NMS, 791 (68.8%) were case reports, while 384 (65.4%) of the articles on SS took the form of case reports.

Growth of publications

The earliest scientific publication on NMS dates back to 1973 [ 60 ], while publications on SS emerged in 1979 [ 61 ]. Research on NMS experienced a notable surge between 1981 and 1991, followed by a fluctuating decline. Conversely, research on SS saw a steep increase between 1993 and 1997, followed by a fluctuating rise. Figure  1 illustrates the growth trends of research on NMS and SS.

Annual growth of publications of NMS (blue line) and SS (green line). The Figure was created by SPSS program

Active countries and journals

Table  1 outlines the top five countries contributing articles on NMS and SS. Japan ranked second in NMS publications but fifth in SS publications. Table  2 presents the top five active journals for both NMS and SS, with NMS publications primarily within psychiatry journals and SS publications within pharmacology/toxicology journals.

Authorship analysis

Articles on NMS involved 3820 authors (mean = 3.1 authors per article), with 89 (7.3%) single-authored and 171 (14.1%) multi-authored articles. Similarly, articles on SS included 2105 authors (mean = 3.0 authors per article), with 102 (16.0%) single-authored and 41 (7.1%) multi-authored articles.

Most impactful articles

The top five impactful articles on NMS comprised mainly review articles and a research article focusing on the pathogenic role of dopamine antagonists [ 62 ]. For SS, the top five impactful articles included review articles and research articles discussing the Hunter diagnostic criteria [ 63 ] and the role of monoamine oxidase inhibitors (MAO-I) and opioid analgesics in serotonin toxicity [ 64 ].

Research hotspots

Research hotspots were identified by mapping author keywords with a minimum occurrence of five times (Figs.  2 and 3 ). Notable hotspots for SS included antidepressants, SSRIs, tramadol, linezolid, cyproheptadine, and drug interactions. For NMS, hotspots included antipsychotics (various drug names), catatonia, and rhabdomyolysis.

Network visualization map of author keywords with minimum occurrences of five times. Large nodes represent research hotspots on NMS. The term NMS was not shown to make other keywords more visible

Network visualization map of author keywords with minimum occurrences of five times. Large nodes represent research hotspots on SS. The term SS was not shown to make other keywords more visible

Journal citation analysis

The top 15 active journals in publishing articles on NMS and SS were mapped (Figs.  4 and 5 ). Notably, articles on NMS published in the American Journal of Psychiatry and the Journal of Clinical Psychiatry received the highest number of citations per article. Similarly, articles on SS published in Clinical Toxicology and the Annals of Pharmacotherapy garnered the most citations per article.

Network visualization map of the top 15 journals in the field of NMS. Large node sized indicates higher normalized citation count

Network visualization map of the top 15 journals in the field of SS. Large node sized indicates higher normalized citation count

Geographic mapping

The geographic distribution of research publications on NMS and SS was illustrated on a worldwide map (Fig.  6 ), with the majority of contributions originating from the US. Several countries in specific regions showed minimal to no research output on either NMS or SS.

Worldwide distribution of research publications on NMS and SS. Figure was created by Microsoft Excel

Molecular genetics

The retrieved literature on NMS has 20 articles that discussed the potential link between NMS and certain genetics. Ten articles discussed the potential linkage between Cytochrome 2D6 and potential risk for NMS [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ]. Five articles discussed the potential linkage between dopamine receptor 2 gene polymorphism and NMS [ 75 , 76 , 77 , 78 , 79 ]. Four articles discussed the linkage between ryanodine receptor gene mutations and susceptibility to NMS [ 80 , 81 , 82 , 83 ]. No association was found between NMS and serotonin receptor gene variation [ 84 ]. The literature on SS has few articles that discussed the genetic predisposition of patients to SS such as the 5-HT receptor gene or the CYP 2D6 gene polymorphism [ 85 , 86 ].

Drug interactions

Serious drug-drug interactions leading to NMS were mentioned in a limited number of articles and involved the administration of two dopamine antagonists [ 87 ] or two atypical antipsychotic drugs [ 88 ]. However, there were many articles discussing potential SS caused by drug-drug interactions, which included SSRI–methylene blue [ 89 ], SSRI–metoclopramide [ 89 ], sertraline–phenelzine [ 90 ], anti-depressants–opioids [ 91 ], citalopram-fentanyl [ 92 ], a combination of two anti-depressants [ 93 ], SSRI-linezolid [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ], sertraline–phenelzine [ 90 ], citalopram-buspirone [ 103 ], venlafaxine-tranylcypromine [ 104 ], and many others [ 92 , 105 , 106 , 107 , 108 , 109 ].

Non-psychiatric causative agents

The retrieved literature on SS, showed that several drugs and drug classes not related to antidepressants can induce SS. Examples of such drugs included Linezolid, CNS stimulants (amphetamine), hallucinogens (LSD), opioids (fentanyl), ondansetron, sumatriptan, and certain herbs (St. John’s wort), metoclopramide, ritonavir, and others [ 5 , 20 , 110 , 111 ]. The retrieved literature on NMS showed that drug-induced NMS is limited to antipsychotics and withdrawal of dopamine agonists [ 112 , 113 , 114 ].

Diagnostic criteria

For NMS, there were 30 articles that discussed issues related to diagnosis. In 2011, an international panel tried to develop NMS diagnostic criteria [ 115 , 116 ]. The neutrophil-lymphocyte ratio was suggested by certain researchers as a diagnostic test for NMS [ 117 , 118 ]. The differential diagnosis for NMS compared to SS and catatonia was also published [ 13 , 118 , 119 ]. For SS, there were 17 articles that discussed issues related to diagnosis of SS. The Hunter diagnostic criteria was one of these articles [ 63 ]. Other articles discussed controversies and the importance of differential diagnosis in SS [ 120 ].

The current study analyzed and compared the scientific literature on two rare drug-induced conditions with certain overlapping clinical features. Both syndromes are mainly caused by medications used in psychiatry, such as those for schizophrenia and depression. The name “NMS” implies that the syndrome is correlated with the use of neuroleptic medications, while the name “SS” implies that it is correlated with any medication or herb that raises serotonin centrally.

The analysis showed that the volume of research publications on NMS was larger and started earlier than research publications on SS. The NMS is associated with the use of dopamine antagonists (neuroleptics). The history of using old-generation antipsychotics for the treatment of schizophrenia dates back to the 1950s [ 121 , 122 , 123 , 124 , 125 ]. On the other hand, the introduction of the SSRI drug class, the main causative agent of SS, dates back to the late 1980s [ 126 ]. The difference in the history of introduction into clinical practice explains the differences between SS and NMS in growth patterns. The difference in the volume of literature between the two syndromes could be due to diagnostic uncertainty [ 127 ] for NMS versus SS, the seriousness of medical complications, or debate regarding whether an atypical antipsychotic drug class causes NMS in a similar way to conventional antipsychotics [ 13 , 30 , 128 , 129 , 130 ]. The current study showed that the number of research publications on NMS started to decline after 1991 but the number of publications on SS started to increase after 1997. The introduction of atypical antipsychotics with lesser dopaminergic side effects than conventional antipsychotics decreased the incidence of NMS and therefore decreased the number of publications with time. On the other hand, the increased number of SS publications after 1997 could be explained by the many reported drug interactions at serotonin level leading to more cases of SS with time.

The current study showed that journals in the field of psychiatry ranked highest in publishing articles on NMS, while those in the field of pharmacology/toxicology ranked highest in publishing articles on SS. The reason for this difference is difficult to explain. However, NMS is primarily limited to schizophrenia patients taking antipsychotic drugs, while SS might occur in normal people taking SSRIs for depression or any other condition. Furthermore, the potentially large numbers of drug- or drug-herb interactions make the SS interesting to pharmacology/toxicology journals [ 22 ]. Actually, SS has been termed “serotonin toxicity” implying relatedness to toxicology [ 131 ].

The findings of the current study regarding active countries were not surprising. The English-speaking countries, the US, the UK, Australia, and Canada showed leading roles in many scientific disciplines and ranked first in several studies that analyzed research activity [ 132 , 133 , 134 , 135 ]. This is due to advancements in technology, medicine, clinical practice, and research funding in high-income countries relative to other countries. However, there are also reasons related to the nature of journals indexed in Scopus. The vast majority of Scopus-indexed journals publish articles in English, and the vast majority of the journals are issued by publishers and institutions based in the US, Europe, or Australia. Therefore, Scopus might be biased toward scholars in English-speaking countries. The finding that research articles on NMS tend to be multi-authored while those on SS are not is not easy to explain. However, it is possible that cases of NMS tend to involve a larger medical team due to the nature of complications that might involve renal and blood complications. Furthermore, the treatment of NMS requires medications and follow-up. All this makes the number of authors in a case study of NMS higher than those involved in SS cases [ 13 , 136 , 137 ].

Of the retrieved articles on SS and NMS, the research article “The hunter serotonin toxicity criteria: Simple and accurate diagnostic decision rules for serotonin toxicity” [ 63 ] received the highest number of citations excluding the review articles. The diagnosis of SS is based on the clinical symptoms and the medical history of the patient. Harvey Sternbach introduced the first diagnostic criteria for SS in 1991 and the Hunter Diagnostic Criteria tool was introduced in 2003 [ 63 , 138 ].

Mapping the retrieved literature on NMS showed that rhabdomyolysis and catatonia constituted distinct research hotspots in addition to those related to antipsychotic medications and schizophrenia. However, mapping the author keywords of SS research publications showed that linezolid, drug interactions, and tramadol constituted research hotspots in addition to antidepressants and SSRIs. Rhabdomyolysis has been reported as a consequence of NMS even among children and adolescents [ 139 , 140 ]. However, reports of rhabdomyolysis among patients taking antipsychotics were published, suggesting that rhabdomyolysis could be a side effect of antipsychotics even in the absence of NMS [ 139 , 140 ]. Catatonia is, as NMS, a consequence of neuroleptic drugs, and there is an overlap in clinical features between the symptoms of catatonia and those of NMS, which makes the distinction between them difficult [ 141 ]. Linezolid is an antibiotic that was originally designed to be used as an anti-depressant by virtue of its MAO enzyme inhibition property [ 142 ]. This explains the many cases of SS induced by drug interactions with Linezolid [ 141 ]. The relatively higher number of research articles on drug/herb interactions leading to SS is attributed to the presence of many and different drug classes that affect and increase serotonergic pathways in the brain [ 90 , 105 , 109 , 143 ]. The scientific controversy about the potential ability of tramadol to cause SS received a high number of citations. Current scientific evidence supports the ability of tramadol to cause SS due to its molecular pharmacological effects on both the opioid and serotonergic systems [ 105 , 107 , 144 , 145 , 146 , 147 ]. Cyproheptadine was also a research hotspot in the field of SS. Cyproheptadine has anti-histaminic, anticholinergic, and anti-serotonergic properties and that is why it has been used to counter the symptoms of SS [ 148 , 149 , 150 ].

The current study showed that SS has a wide range of possible drug/herb interactions due to the many drugs that affect the serotonin system. Of particular interest is the one with opioid analgesics, since they are commonly used in hospital settings. Opioids, including fentanyl and even dextromethorphan in cough syrups, were reported to increase serotonin levels, and therefore caution should be practiced when given to patients with SSRIs in their medical records [ 19 , 22 , 109 , 151 ].

Limitations

Limitations arise in this study from various factors. Firstly, the reliance on the Scopus database for literature retrieval could potentially limit the inclusivity of articles from low- and middle-income countries. Although Scopus offers extensive coverage, the possibility exists that some relevant journals from these regions may not be indexed, thereby leading to a potential underestimation of publications from certain geographic areas. Secondly, despite efforts to employ a comprehensive search strategy, the use of a title-abstract search method might have resulted in the retrieval of some false-positive results. While validation tests were conducted to mitigate this issue, the possibility of false positives cannot be entirely ruled out. Thirdly, the analysis focused solely on articles published in English-language journals, which could introduce a language bias and limit the generalizability of findings. This exclusion of literature published in other languages may have led to the omission of relevant data from non-English sources. Lastly, diagnostic uncertainty poses a challenge in distinguishing between neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) due to overlapping clinical features and the absence of definitive diagnostic tests. Misdiagnosis or underreporting of cases may have occurred, potentially impacting the accuracy of the literature analysis and conclusions drawn from it.

In conclusion, NMS and SS represent rare but potentially life-threatening conditions associated with drug-induced dysregulation of dopamine and serotonin systems, respectively. The study analyzed and compared the scientific literature on these syndromes, revealing distinct growth patterns, research hotspots, and publication trends. The findings underscored the evolving landscape of psychiatric pharmacotherapy and the complexities involved in diagnosing and managing NMS and SS. While NMS research exhibited a longer history and a decline in publications over time, SS research witnessed a notable increase in publications, reflecting advancements in pharmacological understanding and the recognition of SS as a significant clinical entity. Identified research hotspots provided valuable insights into emerging areas of interest, including drug interactions, molecular genetics, and diagnostic criteria. Understanding these trends is essential for informing clinical practice, guiding future research endeavors, and promoting collaboration among scholars and healthcare professionals. Despite the study’s contributions, several limitations warrant consideration, including database restrictions, potential publication bias, and diagnostic uncertainties. Addressing these limitations through expanded literature search strategies, international collaboration, and improved diagnostic tools is crucial for advancing knowledge and enhancing patient care in the field of rare drug-induced syndromes. Moving forward, efforts to develop standardized diagnostic criteria, genetic screening tools, and international reporting mechanisms for NMS and SS are warranted. Additionally, continued bibliometric analysis and mapping of literature on rare medical conditions can facilitate ongoing research and contribute to the dissemination of knowledge across global healthcare communities.

Data availability

All data present in this article can be retrieved from Scopus using keywords listed in the methodology.

Abbreviations

• Neuroleptic malignant syndrome

Serotonin Syndrome/ Serotonin toxicity

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Sweileh, W.M. Neuroleptic malignant syndrome and serotonin syndrome: a comparative bibliometric analysis. Orphanet J Rare Dis 19 , 221 (2024). https://doi.org/10.1186/s13023-024-03227-5

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Treatment-resistant depression (TRD) affects approximately 2.8 million people in the U.S. with estimated annual healthcare costs of $43.8 billion. Deep brain stimulation (DBS) is currently an investigational intervention for TRD. We used a decision-analytic model to compare cost-effectiveness of DBS to treatment-as-usual (TAU) for TRD. Because this therapy is not FDA approved or in common use, our goal was to establish an effectiveness threshold that trials would need to demonstrate for this therapy to be cost-effective. Remission and complication rates were determined from review of relevant studies. We used published utility scores to reflect quality of life after treatment. Medicare reimbursement rates and health economics data were used to approximate costs. We performed Monte Carlo (MC) simulations and probabilistic sensitivity analyses to estimate incremental cost-effectiveness ratios (ICER; USD/quality-adjusted life year [QALY]) at a 5-year time horizon. Cost-effectiveness was defined using willingness-to-pay (WTP) thresholds of $100,000/QALY and $50,000/QALY for moderate and definitive cost-effectiveness, respectively. We included 274 patients across 16 studies from 2009–2021 who underwent DBS for TRD and had ≥12 months follow-up in our model inputs. From a healthcare sector perspective, DBS using non-rechargeable devices (DBS-pc) would require 55% and 85% remission, while DBS using rechargeable devices (DBS-rc) would require 11% and 19% remission for moderate and definitive cost-effectiveness, respectively. From a societal perspective, DBS-pc would require 35% and 46% remission, while DBS-rc would require 8% and 10% remission for moderate and definitive cost-effectiveness, respectively. DBS-pc will unlikely be cost-effective at any time horizon without transformative improvements in battery longevity. If remission rates ≥8–19% are achieved, DBS-rc will likely be more cost-effective than TAU for TRD, with further increasing cost-effectiveness beyond 5 years.

Introduction

Neuropsychiatric disorders are a major cause of morbidity and mortality worldwide, yet treatment options for many of these conditions are limited in their specificity and long-term efficacy. Major depressive disorder (MDD), in particular, has an estimated annual prevalence of 8.3% among US adults [ 1 ] and is the leading cause of disability as well as death from suicide, globally [ 2 , 3 ]. MDD is characterized by the presence of a persistently depressed mood and/or anhedonia, as well as a number of debilitating somatic and psychological symptoms [ 4 ]. Clinical severity is measured using a variety of questionnaires, including the Hamilton Depression Rating Scale (HDRS) [ 5 ] and the Montgomery-Åsberg Depression Rating Scale (MADRS) [ 6 ]. The treatment of MDD is complicated by its multifactorial nature, high degree of comorbidity, and phenotypic heterogeneity [ 7 ].

Conventional treatment for MDD consists of psychotherapy and pharmacotherapy, but a significant proportion (up to 30%) of patients fail to respond to these treatment modalities [ 8 ]. While the definition of treatment-resistant depression (TRD) has not been standardized [ 9 ], patients whose symptoms do not adequately improve after multiple treatment trials are classified as having TRD [ 10 , 11 ]. TRD is associated with increased health care costs, reduced quality of life (QoL), high rates of unemployment, and high suicidality [ 12 ]. The poor prognosis and limited recourse for patients with TRD demonstrates a need for the development of new therapeutic methods.

In the last decade, more targeted treatment approaches that modulate specific networks in the brain have emerged as promising therapeutic candidates for decreasing symptom burden and improving QoL in individuals with TRD. In some developed countries, additional treatment options for TRD now include transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and vagus nerve stimulation (VNS). These non-invasive (TMS, ECT) and invasive (VNS) neurmodulatory treatments have been shown to be highly effective and even reduce medical costs for TRD [ 13 , 14 , 15 ]. However, some patients with depression do not attain meaningful improvement even with these additional therapies. Deep brain stimulation (DBS) is a neurosurgical intervention that involves stereotactically implanting electrodes to deliver continuous, yet adjustable, electrical stimulation to specific anatomic targets in the brain. The procedure has gained FDA approval for movement disorders, epilepsy, and obsessive-compulsive disorder, but is still experimental for TRD. Several DBS targets for TRD have been studied, including the subcallosal cingulate (SCC) [ 16 , 17 , 18 , 19 , 20 , 21 ], nucleus accumbens (NAcc) [ 22 , 23 ], ventral capsule/ventral striatum (VC/VS) or anterior limb of the internal capsule (ALIC) [ 24 , 25 , 26 ], bed nucleus of the stria terminalis (BNST) [ 27 , 28 ], and medial forebrain bundle (MFB) [ 29 , 30 , 31 ]. Although open-label trials showed encouraging response rates (20–92%), two randomized-controlled trials (RCTs) [ 17 , 32 ] were aborted by their industry sponsors out of concern that they would fail to demonstrate effectiveness relative to sham stimulation. Developments in targeting strategies since these trials have demonstrated significant promise in more recent open-label studies [ 33 , 34 ] and a pivotal new industry-sponsored RCT is being planned with FDA breakthrough therapy designation [ 35 ].

As this therapy is further investigated, it is worth considering its potential position within the health economic marketplace. We therefore used existing literature to conduct a cost-effectiveness analysis (CEA) of DBS compared to treatment-as-usual (TAU) for TRD. This CEA is unique in that DBS for TRD is not yet approved or commonly utilized, so our analyses determined effectiveness thresholds that would need to be demonstrated by future trials in order for the therapy to be cost-effective should it receive FDA approval. Specifically, we calculated the remission rates necessary to achieve acceptable incremental cost-effectiveness ratios (ICER) relative to TAU and propose future improvements that could increase its cost-effectiveness.

Using a decision analytic model [ 36 , 37 ], we compared DBS to TAU, which was defined as maintenance antidepressant medication (with or without augmentation therapies) along with concomitant non-pharmacologic treatments (i.e. psychotherapy, TMS, and/or ECT). Our base case for the model is an adult (age 22–70) diagnosed with a severe major depressive episode (HDRS-17 ≥ 18 or MADRS > 22), who has received at least 2 years of TAU without treatment response. Since patients who are eligible for DBS represent a particularly severe form of TRD, we chose to follow more thorough criteria for treatment-resistance compared to the standard definition including: lack of antidepressant response to 1) at least 3 medications from 3 different classes, 2) an adequate course of psychotherapy (>6 weeks), and 3) an adequate trial (>6 bilateral sessions) of ECT. The time horizon is 5 years following DBS, as is typical for novel surgical cost-effectiveness analyses [ 38 , 39 ]. All model inputs were derived from a retrospective review of relevant literature.

Literature review – efficacy

A PubMed search to identify clinical trials establishing the efficacy of DBS for TRD was conducted using the following terms: “Deep Brain Stimulation” AND “Treatment Resistant” AND “Depression” AND “Trial”. The search was completed in March 2023. We selected studies with original patient data that had at least 1 year of follow-up with response, remission, and complication rates and excluded any studies that were not either patient-blinded, sham-controlled, or included target-optimization. Open-label trials with fewer than 3 patients were also excluded. Data collected from selected studies included study design, patient inclusion/exclusion criteria, sample size, patient sex, patient age, follow-up time, patient-level pre-operative HDRS-17 or MADRS scores, 12- and 24-month post-operative HDRS-17 or MADRS scores, response/remission criteria, response/remission rates, and complication rates.

We presumed that the probability of remission from TAU in our model patients would be particularly low, given the rigorous eligibility criteria for classification as extremely treatment-resistant and for consideration as a neurosurgical candidate. In the patient sample we analyzed, for example, the average duration of TRD was approximately 20 years without clinical benefit, making spontaneous remission highly unlikely. However, in an effort to make as rigorous a model as possible, we sought to include some non-zero probability in the TAU treatment arm. As such, we conducted a general search of the literature for longitudinal studies (≥5 years follow-up) focusing on outcomes of patients with TRD on TAU [ 40 , 41 , 42 ].

Complications

Serious adverse events were limited to those related to DBS and were divided into three categories based on management strategy: lead revision/replacement, implantable pulse generator (IPG) revision/replacement, and short-hospitalization (e.g., 3–7 days for infection, skin erosion, etc.). Only complications that significantly added to costs or detracted from effectiveness were considered for our model, so self-limited complications were not included. No complications were considered for the TAU arm as these would fall into the self-limited category and would not affect model outputs.

Effectiveness – the utility model

Utility is a quantitative measure of a patient’s subjective improvement in QoL and ranges from 1 (perfect health) to 0 (death). In cost-effectiveness analyses, effectiveness is calculated by multiplying the net gain in utility by the duration (in years). The product is reported in quality-adjusted life-years (QALYs), where 1 QALY equals 1 year in perfect health [ 43 ]. Because the HDRS and MADRS are not designed to specifically measure QoL, and due to the paucity of available QoL data in our selected studies, we employed a utility model. Using published utility values for remission and non-remission in TRD [ 44 ], remission status was converted to a utility value for each patient in our sample and averaged to reflect mean QoL after treatment. A separate disutility value from the literature was assigned to complications to approximate the negative impact of post-operative DBS complications on QoL [ 45 ].

We conducted our analysis from both healthcare sector and societal perspectives. The healthcare sector approach accounts for all monetary costs of healthcare associated with an intervention (DBS or TAU), regardless of who bears the cost: the third-party payer (i.e., Medicare), the hospital, or the patient (out-of-pocket expenses). It does not consider costs of transportation, patient and caregiver time, productivity loss, or non-monetary costs—all of which are instead included in the societal perspective. While the societal perspective was previously considered the gold standard for cost-effectiveness analyses, recommendations from the Second Panel on Cost-Effectiveness in Health and Medicine have moved to include analyses from two perspectives [ 46 ]. Additionally, we created separate models to account for the varying costs of DBS using non-rechargeable (DBS-pc) versus rechargeable (DBS-rc) devices. While there was considerable variability between specific protocols, most of our selected studies used DBS-pc at initial implantation and switched patients to DBS-rc at the first IPG replacement. To estimate cost-effectiveness with this combined approach, we ran additional analyses using costs of DBS-pc with one battery replacement for the first 18 months and DBS-rc for the following 42 months.

The aggregate cost of DBS was defined as a sum of the cost of one pre-operative assessment, one pre-operative magnetic resonance imaging (MRI), one pre- and one post-operative computed tomography (CT), one bilateral stereotactic DBS lead and neurostimulator device implantation procedure, fifty-four follow-up programming office visits, and any hospital (facility) fees or additional out-of-pocket expenses. Additionally, the 5-year cost for DBS-pc included three IPG replacements. Costs associated with TAU included costs of pharmacotherapy (e.g. selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic antidepressants, monoamine oxidase inhibitors, atypical antipsychotics, esketamine), cognitive-behavioral therapy (CBT), and TMS or ECT with a wide range and standard error to account for variability in individual treatment plans. Under the assumption that most remitters with either DBS or TAU would remain on some form of pharmacological therapy while discontinuing additional neuromodulation therapies, we defined a separate variable for the cost of pharmacotherapy alone and designated it as an incremental cost each year after remission. All cost data, including costs associated with complications, were collected from the 2023 Centers for Medicare & Medicaid Services (CMS) Physician Fee Schedule (based on HCPCS/CPT codes) [ 47 ] and from published health economics literature [ 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ].

Decision analytic model

We created our model using TreeAge Pro Healthcare 2023 (TreeAge Software, Williamstown, MA). The model placed patients in one of two treatment arms: DBS or TAU. Patients undergoing DBS had the opportunity to become remitters at 1, 2, 3, 4, and 5 years. The 5-year time horizon was chosen to capture the longer-term trajectory of DBS treatment response in our patient sample, including an initial 6–12 month optimization phase, 1–3 years of varying response, and a period of follow-up beyond 3 years with relatively sustained remission rates (see Fig. 1 for the time to remission in our analyzed sample). When a DBS patient remitted, their subsequent incremental cost per year after surgery transitioned from the costs of TAU to the cost of pharmacotherapy alone. Those who did not respond to DBS within the first year remained on TAU, thus accumulating the costs of TAU for each year of non-remission in addition to the initial costs of DBS. On the other hand, patients on TAU alone were given 1 year to remit. This decision was made based on prior studies, which showed that ~80–90% of patients with MDD who recover with TAU do so within the first 2 years of initiating treatment [ 61 , 62 , 63 , 64 , 65 ], with earlier response (typically within the first 4 weeks of initial treatment) predicting positive treatment outcomes [ 66 , 67 ]. Previous prospective studies found that after 5 years, the probability of MDD recovery with each additional year is only between 2% and 15% [ 40 , 68 ]. In TRD patients, particularly the severely treatment-resistant population eligible for DBS, the likelihood of response to TAU is inevitably even lower with each passing year [ 41 , 69 ].

Shows the cumulative percentage of total patients in our sample that achieved remission over 5 years of follow-up. The majority (79.7%) of TRD patients who achieved remission with DBS did so within the first year. Only 1% of patients who achieved remission within 5 years of DBS did so after year 3.

For DBS patients, all post-operative complications throughout the 5-year treatment period were assigned prior to year 1 on the model for simplicity. By extension, costs and disutilities associated with complications were factored into final calculations once and did not accumulate over time. For both treatment arms, there was no incremental utility or disutility for continuing as a non-remitter, as the utility of non-remission was applied to those who failed to remit at the end of each treatment arm. Finally, mortality rate was not considered in our model given the relatively short time horizon and negligible added mortality risk of either treatment [ 70 , 71 , 72 , 73 , 74 , 75 ].

We analyzed our model using TreeAge Pro Healthcare 2023 (TreeAge Software, Williamstown, MA). To account for uncertainty and variability, model inputs were parametrized using pooled means and standard deviations, and a Monte Carlo (MC) simulation ( n  = 100,000) was performed. We examined the primary model output, the incremental cost-effectiveness ratio (ICER), using a willingness-to-pay (WTP) threshold approach. The ICER ($/QALY) is calculated by dividing incremental cost – the difference in net cost ($) between two treatment arms – by incremental effectiveness – the difference in QALYs gained between two treatment arms. Based on current accepted definitions of cost-effectiveness, unequivocal cost-effectiveness was considered an ICER less than $0/QALY, definitive cost-effectiveness was achieved at less than $50,000/QALY, moderate cost-effectiveness between $50,000 and $100,000/QALY, and cost-ineffectiveness at greater than $100,000/QALY gained [ 76 ]. Results of the MC simulation were further analyzed using both probabilistic and deterministic sensitivity analyses. Finally, using one-way sensitivity analyses, we analyzed the minimum 1-year remission rate necessary to achieve cost-effectiveness at each WTP threshold.

Literature review

Our PubMed search yielded 76 initial results (see Fig. 2 for our PRISMA [ 77 ] flowchart). From the 16 studies selected for data collection (published 2009–2021), we found a total of 274 unique patients who underwent DBS for TRD [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Six additional studies (three narrative reviews [ 25 , 78 , 79 ] and three systematic reviews and meta-analyses [ 80 , 81 , 82 ]) were used to cross-reference data and eliminate duplicates. Across all patients, mean baseline (pre-operative) MADRS and HDRS-17 scores were 34.09 (±5.11) and 23.68 (±3.96), respectively. Based on the established remission criteria of MADRS score ≤10 or HDRS-17 score ≤7, overall remission rate was 24.2% at 1 year (n = 260). Mean follow-up time was 33.17 (±26.65) months. Using observed-case analysis from studies that included long-term follow-up data, remission rates were 23.7% at 2 years (n = 177), 40% at 3 years (n = 60), 33.3% at 4 years (n = 39), and 36.7% at 5 years (n = 30). Comprehensive outcomes and complications data from our systematic review can be found in Table 1 .

Data added to the PRISMA template (from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6[7]:e1000097) under the terms of the Creative Commons Attribution License.

For an overview of our completed model, see Fig. 3 . All base case model inputs and distributions are included in Table 2 . The average 5-year cost of DBS-rc, which included one pre-operative office visit ($167.40), one pre-operative MRI ($160.63), one pre-operative and one post-operative CT ($81.34), electrodes and neurostimulator device ($2,731.31), IPG implant ($20,378.78), estimated hospital fees ($2,607.00), and post-operative follow-up ($3,397.59) was $29,524.05 (±$817.66). The average 5-year cost of DBS-pc, which included all of the same costs as DBS-rc plus 3 IPG replacements ($91,042.80), was $120,566.85 (±$817.66). The standard deviation represents the variability in hospital fees and number of follow-up programming visits required (other values in this calculation are fixed and based on Medicare reimbursement amounts). Estimated costs from complications were $27,066.84 (lead revision/replacement), $30,347.60 (IPG revision/replacement), and $13,035.00 (short hospitalization). Mean yearly cost of TAU, which was calculated as the average of either psychotherapy and medications alone ($7,721.84), psychotherapy and medications with ECT ($17,097.84) and psychotherapy and medications with ECT and TMS ($23,277.84) was $16,032.51 (±$7,832.53) from a healthcare sector perspective and $38,575.86 (±$5,722.14) from a societal perspective. The annual cost of pharmacotherapy alone was $1,576 (±$1,174.00). Using published utility scores [ 44 ], we included the following utility values in our model: 0.84 (±0.15) for remission, and 0.54 (±0.25) for non-remission.

Compares cost-effectiveness of DBS versus TAU for TRD over a 5-year time horizon. Variable definitions, probabilities, and individual payoff formulas at terminal branches were omitted for simplicity.

MC simulation

Based on the results of our MC simulation (n = 100,000), after 5 years DBS-pc was less cost-effective than TAU from both healthcare sector (ICER = $254,719.81/QALY) and societal (ICER = $178,949.98/QALY) perspectives. DBS-rc, however, was definitively more cost-effective than TAU from a healthcare sector perspective (ICER = $31,878.61/QALY) and unequivocally more cost-effective than TAU from a societal perspective (ICER = −$43,924.23/QALY). See Table 3 for a summary of cost-effectiveness rankings. A combined approach (DBS-pc switched to DBS-rc at first IPG replacement) was just shy of being moderately more cost-effective than TAU (ICER = $105,831.71/QALY) from the healthcare sector perspective and was definitively more cost-effective than TAU (ICER = $30,195.12/QALY) from the societal perspective.

Net cost for TAU over 5 years was approximately $79,500.00 from the healthcare sector perspective and $191,000.00 from the societal perspective. Net cost of DBS-pc over 5 years was $183,529.00 from the healthcare sector perspective and $264,039.00 from the societal perspective. Net cost of DBS-rc over 5 years was $92,549.00 from the healthcare sector perspective and $173,065.00 from the societal perspective. Net effectiveness of DBS over 5 years was 3.12 QALYs, compared to 2.71 QALYs for TAU. The incremental effectiveness of DBS was therefore 0.41 QALYs.

Sensitivity analyses

Using probabilistic sensitivity analysis, outputs from the MC simulation were plotted on cost-effectiveness acceptability curves (Fig. 4 ). MC simulation revealed that TAU was more cost-effective than DBS-pc (Fig. 4A ) in 100% (at $50,000/QALY) and 100% (at $100,000/QALY) of iterations from the healthcare sector perspective and in 100% (at $50,000/QALY) and 97% (at $100,000/QALY) of iterations from the societal perspective. Conversely, DBS-rc (Fig. 4B ) was more cost-effective than TAU in 72.8% (at $50,000/QALY) and 100% (at $100,000/QALY) of iterations from the healthcare sector perspective and in 100% (at $50,000/QALY) and 100% (at $100,000/QALY) of iterations from the societal perspective.

Show results from Monte Carlo simulation (n = 100,000) and probabilistic sensitivity analysis. For DBS-pc ( A ), the TAU (red) curves dominate the DBS (blue) curves. TAU is thus shown to be more cost-effective than DBS-pc in 100% of iterations from both the healthcare sector (dark red) and societal sector (light red) perspectives at $50,000/QALY. For DBS-rc ( B ), the DBS (blue) curves dominate the TAU (red) curves. DBS-rc is thus shown to be more cost-effective than TAU in 72.8% of iterations from the healthcare sector perspective (dark blue) and 100% of iterations from the societal sector perspective (light blue) at $50,000/QALY. The black vertical line marks the broadly-accepted WTP threshold of $50,000 per QALY.

Using 1-way sensitivity analyses, we determined the minimum 1-year remission rates needed to achieve acceptable ICERs at WTP thresholds of $50,000 (for definitive cost-effectiveness) and $100,000 (for moderate cost effectiveness) per QALY (Fig. 5 ). DBS-pc (Fig. 5A ) requires 55% remission for moderate cost-effectiveness and 85% remission for definitive cost-effectiveness from a healthcare sector perspective. From a societal perspective, DBS-pc requires 35% and 46% remission for moderate and definitive cost-effectiveness, respectively. DBS-rc (Fig. 5B ) requires 11% and 19% remission for moderate and definitive cost-effectiveness, respectively, from a healthcare sector perspective. From a societal perspective, DBS-rc requires 8% and 10% remission for moderate and definitive cost-effectiveness, respectively. A combined approach (DBS-pc switched to DBS-rc at first IPG replacement) requires 26% and 41% remission for moderate and definitive cost-effectiveness, respectively, from a healthcare sector perspective. From a societal perspective, DBS with this approach requires 16% and 21% remission for moderate and definitive cost-effectiveness, respectively.

Show minimum 1-year remission rates necessary for DBS for TRD to achieve acceptable incremental cost-effectiveness ratios (ICER) at accepted willingness-to-pay (WTP) thresholds of $50,000 (for moderate cost-effectiveness) and $100,000 (for definitive cost-effectiveness) per QALY. DBS-pc ( A ) requires 55% remission for moderate cost-effectiveness and 85% remission for definitive cost-effectiveness from a healthcare sector perspective (dark blue), and 35% remission for moderate cost-effectiveness and 46% remission for definitive cost-effectiveness from a societal perspective (light blue). DBS-rc ( B ) requires 11% remission for moderate cost-effectiveness and 19% remission for definitive cost-effectiveness from a healthcare sector perspective (dark blue), and 8% remission for moderate cost-effectiveness and 10% remission for definitive cost-effectiveness from a societal perspective (light blue).

Finally, deterministic sensitivity analyses were used to create tornado diagrams (Fig. 6 ) that illustrate the effects of varying each parametrized input in our decision analytic model on the overall ICER for non-rechargeable (Fig. 6A ) and rechargeable (Fig. 6B ) DBS for TRD, from both healthcare sector and societal perspectives. All costs, probabilities, and utilities were varied within sensitivity ranges 20% above and below mean values. For all four scenarios, the parameter (with sensitivity ranges) that had the greatest impact on ICER variance was utility of remission (0.67 to 0.99). Other parameters with the greatest impact for all four scenarios included: utility of non-remission (0.43 to 0.65), cost of DBS ($96,453.48 to $144,680.22 for non-rechargeable; $23,619.24 to $35,428.86 for rechargeable), probability of remission in year 1 (0.19 to 0.29), and cost of TAU ($12,826.01 to $19,239.01 for the healthcare sector perspective; $30,860.69 to $46,291.03 for the societal perspective). For utility of remission, cost of TAU, and probability of remission in year 1, lower values increased the ICER. Conversely, for utility of non-remission and cost of DBS, higher values increased the ICER.

Displays the effect of varying each parametrized input on the ICER for DBS with non-rechargeable ( A ) and rechargeable ( B ) devices from both the healthcare sector (top) and societal sector (bottom) perspectives. All costs, probabilities, and utilities were varied within a sensitivity range 20% above and below mean values. Red bars show the impact of an increase and blue bars show the impact of a decrease in the variable value on overall ICER.

Importantly, none of the parameters in any of the scenarios affected the ICER in a way that impacted the cost-effectiveness of DBS at a WTP threshold of $100 K. Only in the scenario of DBS-rc from the healthcare sector perspective, a utility of remission lower than 0.735 and a utility of non-remission above 0.648 would increase the ICER beyond a WTP threshold of $50 K. Based on previously published literature [ 44 ], the lower limit for utility of remission was 0.76, while the upper limit for utility of non-remission was 0.58, so these parameter values would be outside the expected range and are unlikely to impact our cost-effectiveness results. Overall, DBS-pc did not reach cost-effectiveness compared to TAU, while DBS-rc remained cost-effective compared to TAU (from both healthcare sector and societal perspectives) under a broad range of cost and effectiveness values.

This study, which to our knowledge is the first economic evaluation comparing DBS to TAU for TRD, shows that regardless of economic perspective, DBS-pc would not be more cost-effective than TAU. However, with a 1-year remission rate of at least 20%, DBS-rc would be more cost-effective than TAU for TRD, particularly when considering the large societal costs of TRD. With a mean 1-year remission of 24.2% in our sample, DBS-rc had a higher probability of being cost-effective, even despite having higher upfront costs compared to TAU from either economic perspective. From a healthcare sector perspective, under the broadly accepted WTP threshold of $50,000/QALY, DBS-rc had a 72.8% probability of being cost-effective after 5 years, reaching 100% probability of cost-effectiveness at a WTP of $100,000/QALY. From a societal perspective, DBS-rc had a 100% probability of being cost-effective after 5 years at both WTP thresholds.

As this is the first cost-effectiveness study of DBS for TRD, there are no directly comparable analyses, however the cost-effectiveness of DBS for non-psychiatric indications has been explored in several studies. In a cost-utility analysis of DBS vs long-term medical management for Parkinson’s disease, Dams et al. [ 83 ] found the average 5-year cost of treatment with DBS to be €67,374.12 (~$75,693.81) with an average 5-year incremental cost-utility ratio (ICUR) of €36,065.82/QALY (~$40,483.70/QALY) from a healthcare provider perspective, adapted to 2023 values. It is likely that the total DBS costs presented in that study are lower than those we used for DBS-pc because battery replacement costs were only included every 4 years, rather than every 1.5 years as in our study. DBS battery depletion is assumed to be quicker in TRD due to the higher amplitudes typically required for TRD than for Parkinson’s disease [ 84 ], but if battery life for non-rechargeable IPGs can be extended to 4 years or more, it is likely that the cost-effectiveness of DBS-pc would increase substantially.

Chan et al. [ 85 ] compared the cost-effectiveness of DBS vs. VNS for patients with refractory epilepsy and found the cost of DBS over 5 years to be €72,251 (~$81,129.93) with an expected effectiveness of 3.42 QALYs (5-year ICER = €21,126.02, ~$23,728.53) from a healthcare sector perspective. In this study, the authors also only accounted for costs of IPG replacement every 5 years (compared to 1.5 years in our study) and used response (defined as ≥50% reduction in seizure frequency) rather than remission status as the primary outcome, resulting in both lower costs and higher effectiveness for DBS-pc. As previously discussed, a longer battery life would improve the cost-effectiveness of DBS-pc for any indication. While we chose to employ remission as a more stringent outcome metric, it is likely that the threshold for cost-effectiveness of DBS for TRD would also be lower if response (defined as ≥50% reduction in symptom severity) was considered instead.

Growing evidence has suggested the potential of DBS for treating other highly debilitating and costly medical conditions such as chronic pain, obesity, and dementia, with several clinical trials now underway [ 86 ]. Mahajan et al. [ 38 ] examined the cost-effectiveness of DBS compared to laparoscopic Roux-en-Y gastric bypass (LRYGB) for obesity using a societal perspective and calculated the overall 5-year cost of DBS to be $29,951. While the study did not specify between rechargeable and non-rechargeable devices, this value is very similar to our average 5-year cost of $29,524.05 for DBS-rc.

DBS has been used off-label for a variety of other psychiatric conditions including Tourette’s, bipolar disorder, post-traumatic stress disorder, eating disorders, and substance use disorders, yet economic evaluations have been limited by low case numbers and lack of published clinical trial data. Taking a societal perspective and using Medicare reimbursement as a proxy for direct costs, Kuijper et al. [ 39 ] conducted a threshold and cost-effectiveness analysis of DBS compared to contingency management for cocaine use disorder. The 1-year cost of DBS-rc for cocaine use disorder was calculated to be $27,988.45, which is very close to our 1-year cost of DBS-rc at $28,071.09.

Finally, cost-effectiveness analyses of DBS vs TAU for treatment-resistant obsessive-compulsive disorder (TROCD) offer perhaps the most relevant comparison for our findings. Separate studies from Ooms et al. [ 87 ] and Moon et al. [ 88 ] both compared the cost-effectiveness of DBS vs TAU for patients with TROCD. While each of these models were applied to countries outside of the United States (the Netherlands, Korea, and the U.K.) and used different time horizons (4, 10, and 2 years) as well as different effect measures (area under the curve analysis and response status) than our study, their results are nonetheless informative and allow for a reasonable comparison of direct and indirect costs. Ooms et al. [ 87 ]. found the cost of DBS-pc (including battery changes every 14 months) over 4 years to be €127,112.74 from a societal perspective. Moon et al. [ 88 ] found the cost of DBS-pc over 10 years (including battery replacements every 3 years) to be $44,672 in Korea and $42,322 in the U.K., from a healthcare payer perspective. In the former study, the costs for DBS-pc are very close to those in our study, likely due to a similar frequency of battery replacements. In the latter study, a lower frequency (every 3 years) and substantially lower cost ($2,232 in Korea and $760 in the U.K.) of battery replacements account for the overall lower costs of DBS-pc compared to our findings. The longer time horizon of 10 years in the Moon et al. [ 88 ] study highlights the increasing cost-effectiveness of DBS over time relative to TAU. Unlike Parkinson’s patients, those receiving DBS for psychiatric conditions are relatively young with fewer surgical risk factors [ 72 , 89 , 90 ] and therefore have a longer time horizon to benefit from DBS treatment. Extending the time horizon for economic analyses of DBS for psychiatric indications would better capture the true cost-effectiveness of this intervention. Relatedly, the area under the curve (AUC) approach for measuring antidepressant effect over time in the Ooms et al. [ 87 ] study may better capture overall symptom improvement throughout the course of treatment and is likely more representative of the patient’s subjective gain in QoL [ 31 ]. While our selected studies lacked sufficient patient-level QoL data for this approach, this method of calculating QALYs would improve future economic evaluations and underscores the need to include QoL measures in clinical trials.

Considering the lack of consistency in reported costs for DBS across multiple indications, our study highlights the need for greater public access to healthcare economics data. Though societal costs are highly variable and difficult to estimate, and exact healthcare costs may not be readily accessible in a complex system such as that in the U.S., accurate cost data are nonetheless imperative for future cost-effectiveness analyses to capture the full economic burden of disease. Ideally, in addition to safety and efficacy data, large prospective trials would collect cost and utility data across multiple institutions to account for cost differences. For DBS, in particular, it is important for studies to also provide patient-level data on specific stimulation targets and parameters, as well as effects on battery life to most accurately compare costs and efficacy across studies. This approach would enable more generalizable conclusions, and results of these studies would influence medical decision making not only at the physician and patient levels, but also for hospital administrators, insurance companies, and government healthcare programs such as Medicare and Medicaid [ 91 ]. Despite promising preliminary results for multiple conditions, public acceptance of and insurance coverage for surgical treatment of psychiatric illness is still disproportionately lower than for other non-psychiatric indications [ 92 , 93 , 94 ]. As the field of psychiatric neurosurgery develops, there is a growing need for high-quality cost-effectiveness analyses.

It is important to remember that TRD patients who meet eligibility criteria for DBS are a smaller percentage of all patients with TRD, as they must have also failed to respond to additional treatments such as augmentation strategies with ketamine and non-invasive neuromodulation. Furthermore, considering the high incidence of treatment-resistance in MDD and the low probability of response to TAU after 3 years in this population, it is possible that the criteria for surgical treatment of TRD are overly stringent in terms of disease duration. At least 5 years since MDD onset is commonly required for DBS eligibility, but there is evidence that it would be reasonable to enroll patients sooner, as long as they have significant symptom severity and have proven to be treatment-refractory (multiple failed SSRIs, adjunctive medication trials, CBT, and either TMS or ECT). Multiple studies have found that longer duration of untreated disease is a major prognostic factor for poor treatment response and worse long-term outcomes [ 95 , 96 , 97 , 98 ]. Compared to MDD, TRD patients utilize twice the number of outpatient healthcare resources, triple the number of inpatient stays, and have 23% higher all-cause mortality [ 99 ]. Additionally, rates of intentional self-harm and suicide are significantly higher in TRD [ 100 ], further increasing the risk of negative outcomes in these refractory patients while they wait to fulfill DBS eligibility criteria. Thus, continued TAU may unnecessarily prolong suffering with severe disease and simultaneously increase cost burden to patients, caregivers, healthcare systems, and society at large. Given these results, earlier treatment of TRD with DBS may be both clinically and economically more effective.

With rising incidence and high rates of untreated depression [ 101 , 102 ], the economic impact of TRD on society at large cannot be overstated. In addition to decreased quality of life, higher healthcare resource utilization, and increased all-cause mortality for patients themselves [ 12 ], TRD also has a wide sphere of impact on others including family members, caregivers, and employers [ 103 ]. Mrazek et al. [ 49 ]. found that the societal burden of major depressive disorder for the United States in 2012 was $188 billion-- $57 billion dollars more than the societal cost of cancer and $15 billion dollars more than that of diabetes. Providing new cost-effective treatment options to patients with TRD would provide substantial benefit in diminishing not only their TRD-related healthcare costs, but also other non-TRD healthcare costs, while also allowing them to return to work and reengage in society in meaningful ways. According to society preferences, willingness-to-pay is higher for patients with a higher level of disease, younger age, and larger QOL gains [ 104 ]. Since TRD patients have a high disease burden, are relatively young in age, and benefit from substantial increases in QOL with remission, raising WTP thresholds in accordance to society preferences would make DBS for TRD more cost-effective even with higher total costs and lower remission rates. As new treatments for highly prevalent and debilitating conditions like TRD become available and their safety is established, the economic threshold for their approval should be adjusted in the broader context of societal impact.

Several important limitations apply to this study. One limitation was the high variability of TAU costs between patients. These costs vary widely depending on the specific combination of medications, psychotherapy, TMS, and ECT that any given patient may be using prior to DBS, as well as on the high variability in costs attributed to transportation, lost productivity, and healthcare utilization unrelated to depression for each patient. To account for this variability, we included very large standard deviations for these parameters.

Second, we chose to only include remission and non-remission as outcomes, as response rates likely do not accurately reflect meaningful patient outcomes due to the arbitrary nature of a 50% reduction criterium and high rates of return to non-response status [ 31 ]. Further, it is unlikely that a single utility value could accurately represent the range in QoL changes associated with varying levels of treatment response. For refractory illnesses, such as TRD, it is likely that even small sub-threshold reductions in symptoms could still provide considerable improvement in QoL. As such, response status may likely underestimate effectiveness and therefore inflate ICERs.

Additionally, we did not include relapse as a possible outcome in our model, though up to 80% of TRD patients experience relapse within 5 years of response despite continued maintenance treatment [ 63 , 105 , 106 , 107 ]. Remission, on the other hand, is the ideal outcome of depression treatment with a low risk of relapse [ 108 , 109 , 110 ]. Thus, we assumed that remitters in either treatment arm would remain remitters for the duration of the model. This was supported by previous literature and the data reported in our selected studies. Although most patients in our sample who achieved remission with DBS did so by year 3, we still included non-zero probability for remission with DBS in years 4 and 5, the same as was used to represent a non-zero probability of remission with TAU. This small but non-zero value reflects stability of remission status in either treatment arm. Nevertheless, it is possible that some patients, particularly those with residual symptoms, would relapse despite remission [ 111 , 112 ]. Due to a lack of longitudinal data on residual symptoms or utility values associates with these symptoms, it is impossible to include these variables in this analysis. While considerably more complex, a Markov model that accounts for patient response, relapse, and remission at each year of the decision tree could more fully account for every possible outcome in depression treatment and would allow for a more thorough analysis. At this time, a paucity of detailed individual patient-level data reflecting the transitions between these outcomes limits the feasibility of accurately using such an approach.

Third, our utility model is based on prior prospective cohort studies and cost-effectiveness analyses that collected direct measures of health-related quality-of-life (HRQoL) scores and health utilities. Thus, utilities associated with remission status and disutilities associated with complications are indirect derivations for our cohort and should be interpreted as approximations of true utility. Importantly, two main sources from which utility values in these studies were derived are based on MDD [ 113 , 114 ]. For TRD, the transition from non-remission to remission is likely associated with an even greater improvement in health utility, so our utility values are likely conservative. Further, we assumed that non-remission in this context did not necessarily mean non-response, so we included a wider range of values for our estimate—from severe depression (~0.2–0.55) on the lower end to response without remission (0.67–0.72) on the higher end [ 44 ]. As there is no prior literature defining the disutility of DBS complications in TRD specifically, we assumed that the disutility of complications related to DBS would be similar across psychiatric disorders. Clinical trials for TRD should move to include direct measures of QoL (e.g., EQ-5D, SF-36, etc.) in addition to standard efficacy measures (e.g., HDRS, MADRS, etc.) to assess for these potential differences between indications and ensure that future health economics studies have sufficient data to support more generalizable claims of cost-effectiveness.

Our 5-year time horizon restricts complications to those occurring up to 60 months after surgery. In our aggregate sample, this captured greater than 99% of all complications. Previous work has found that the majority of DBS-related complications occur within the first 5 years and complication rates with DBS do not increase in the long-term [ 115 , 116 ]. While recent reports have published outcomes of DBS for TRD for up to 8 years of follow-up, we found that available data were still insufficient to carry the model past 5 years without adding significant uncertainty. Additionally, there was significant variation in the timepoint of the last observation (range = 0.50–142.92 months) where such an analysis would inappropriately represent the efficacy of DBS treatment and the confidence interval would be much too large for meaningful interpretation. As more data become available, it will be important to assess cost-effectiveness with this additional efficacy and complication information in the long-term. In our study, we assumed a non-staged approach for initial implantation and that all complications occurred after initial implantation for model simplicity. Although we did not include the probability of additional post-operative complications for each IPG replacement, it is important to note that non-rechargeable devices incur extra costs, not only for the new IPG itself, but also for the associated surgical procedure, hospitalization, and any post-operative complications, such as infection or hemorrhage, which further increase the incremental cost of DBS-pc each year.

Finally, though there is a well-documented risk of suicidality in TRD patients, this outcome was not included in our model for several reasons. First, estimates of the monetary cost or specific disutility associated with either suicidal ideation or suicide attempt (e.g., emergency psychiatric hospitalization, medication changes, intensive inpatient therapy, various medical and neurologic sequelae, etc.) are limited by lack of available data. Second, while 11% (n = 29) of patients in our DBS sample experienced suicidality and 4% (n = 12) completed suicide, there is no evidence to support that these adverse events were directly related to DBS. Suicide is unfortunately common in TRD, regardless of treatment approach, so it was assumed that any additional costs incurred due to suicide would be the same for each treatment arm and would therefore not affect the model.

While the efficacy of DBS for TRD has not yet been definitively established, prior studies report remission rates of approximately 25–45% [ 20 , 21 , 26 , 32 , 80 , 81 , 107 , 117 , 118 , 119 , 120 , 121 ]. From our analyses, DBS-pc is unlikely to be cost-effective compared to TAU even at remission rates at the higher end of this range. DBS-rc, however, would only need remission rates in the 10–20% range to reach cost-effectiveness compared to TAU. Based on outcomes from 274 patients with TRD across 16 studies showing an average 1-year remission rate of 24.2%, we found that DBS with a rechargeable device would be more cost-effective than treatment as usual for treatment-resistant depression, under a range of possible cost and effectiveness values.

DBS with rechargeable devices is particularly well suited for psychiatric indications. Patients report increased satisfaction with rechargeable IPGs [ 122 ], psychiatric indications require high amplitude stimulation settings for treatment compared to other DBS conditions and therefore more quickly deplete battery life [ 84 ], and the longer time horizon of treatment in these relatively young patients allows for the extended benefits of DBS to outweigh high upfront costs. Our analyses show that an approach of initial implantation with a non-rechargeable device and subsequent transition to a rechargeable IPG in patients who experience response at the time of first battery replacement would reach both moderate and definitive cost-effectiveness at 5 years, with increasing cost-effectiveness each following year.

Our results demonstrate that, using current estimates of treatment efficacy, DBS with rechargeable devices for TRD already represents a cost-effective approach compared to current treatments. As DBS strategies continue to improve, so will justification for its use as an effective treatment for patients with TRD.

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Acknowledgements

This work was funded by the McNair Foundation (SAS) as well as the National Institutes of Health (NIH) under award number T32GM136611 and by BRASS: Baylor Research Advocates for Student Scientists (KEK).

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Katherine E. Kabotyanski, Garrett P. Banks, Himanshu Sharma, Nicole R. Provenza, Benjamin Y. Hayden & Sameer A. Sheth

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KK, RN, and SS contributed to conceptualization of the study. KK and RN contributed to article selection and data collection. KK conducted quantitative analysis and figure preparation. KK prepared the initial manuscript. All authors contributed to manuscript editing and critical review.

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Dr. Sheth is a consultant for Boston Scientific, Neuropace, Zimmer Biomet, Koh Young, Sensoria Therapeutics, and Varian Medican and is co-founder of Motif Neurotech. Dr. Mathew has served as a consultant for Abbott, Almatica Pharma, Biohaven, BioXcel Therapeutics, Boehringer-Ingelheim, Brii Biosciences, Clexio Biosciences, COMPASS Pathways, Delix Therapeutics, Douglas Pharmaceuticals, Eleusis, Engrail Therapeutics, Freedom Biosciences, Janssen, Liva Nova, Levo Therapeutics, Merck, Neumora, Neurocrine, Perception Neurosciences, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, Sunovion, Xenon Pharmaceuticals, and XW Pharma.

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Kabotyanski, K.E., Najera, R.A., Banks, G.P. et al. Cost-effectiveness and threshold analysis of deep brain stimulation vs. treatment-as-usual for treatment-resistant depression. Transl Psychiatry 14 , 243 (2024). https://doi.org/10.1038/s41398-024-02951-7

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Received : 13 November 2023

Revised : 14 May 2024

Accepted : 20 May 2024

Published : 07 June 2024

DOI : https://doi.org/10.1038/s41398-024-02951-7

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