Global trends of purinergic receptors and depression: A bibliometric analysis from 2003 to 2023

Abstract

BACKGROUND

Depression significantly threatens human health. Purinergic receptors are reported to be associated with depression. However, there is no bibliometric research in this field have been published.

AIM

To provide some reference for the further research in the field of purinergic receptors and depression utilizing bibliometric analysis.

METHODS

Relevant researches were retrieved from the Web of Science Core Collection database. The period of the search was from January 1, 2003 to December 31, 2023. The CiteSpace (6.2.R7) and VOSviewer (1.6.19) were applied to identify the main contributors of countries, authors, institutions, references and journals. Besides, we evaluate keywords to assess the hotspots and trends over the previous 2 decades.

RESULTS

Totally, 247 articles were identified, showing an increasing trend over time. The most productive country, institution, and journal in this field are China, Harvard University, and Biological Psychiatry, respectively. Liang SD and Rodrigues, Ana Lucia S were the most prolific authors. Burnstock G ranked first among the cited authors. The cooperation among countries and disciplines is crucial. The P2X7 receptor provides promising prospects for treating depression and further studies are warranted to validate the scope and significance of depression therapeutic strategies.

CONCLUSION

This study provides an overview of the worldwide research status and future trends in purinergic receptors and depression. P2X7 receptor is considered an appropriate target for the treatment of depression, as well as neurological diseases. It is implied that based on purinergic system, the future prospects for interventions aimed at depression treatment are promising, showing the way for both augmentation strategies and new drug treatments in the context of the pharmacology of depression.

Key Words: Depression; Purinergic receptors; Bibliometric analysis; CiteSpace; Research trend

Core Tip: The relationship between purinergic receptors and depression has not revealed through bibliometric analysis. This study is expected to provide valuable insights in this field. It uses bibliometric analysis to scrutinize factors such as publication years, countries, institutions, authors, journals, and keywords, while also revealing key areas for future research: (1) The alteration of prefrontal cortex in chronic stress-induced depression; (2) The inflammatory activation pathway in depression; and (3) The P2X7 cation channel as a potential drug target for depression. This study is expected to provide valuable insight for further depression research.

INTRODUCTION

Depression is a fundamental mental health illness that affects more than 300 million individuals worldwide[1]. Based on the statistics of the World Health Organization, depression is expected to be the primary cause of illness burden by 2030 with a prevalence ranging from 3% to 17%[2,3]. Depression also places significant financial costs on those who experience it as well as on society[4]. Many factors are frequently associated with the pathophysiology of depression, including gender, genetics, environment, and psychology[5]. Scholars point to depressed mood, attention deficit, hopelessness, lack of energy, change in appetite, anxiety, insomnia, psychomotor retardation or agitation, and, occasionally, suicidal thoughts as the major symptoms of depressive disorders[6]. The recommended first-line treatment of depression is antidepressant medication, such as selective serotonin reuptake inhibitors; however, more than 30% of patients do not react to existing antidepressants[7]. Additionally, taking antidepressants is commonly linked to adverse events such as bleeding, sexual dysfunction, hepatotoxicity, sleep disturbance and constipation[8]. Tolerating these side effects is difficult for patients, which leads to noncompliance and, typically, the cessation of medication[9]. In summary, depression has become a prevalent disease that severely impairs physical and mental health. Thus, identifying the novel pathways that underlie the pathophysiology and pharmacology of depression is imperative.

The purinergic system is now viewed as an important mechanism in regulating the mental health of patients with depression[10-12]. The neurological, circulatory, respiratory, and immunological systems, and other components of the body have widespread expressions of purinergic receptors[13]. A dysregulation in the purinoceptor function leads to various diseases, including neurological, rheumatic, and cardiovascular ones, among others[14]. Purinergic signaling interacts with other signal molecules to establish a complex system that regulates various cellular processes such as differentiation, proliferation, and death[14]. Purinergic receptors are classified into two subfamilies, namely, P1 and P2. The P2 nucleotide receptor family is further grouped into two subfamilies[15], namely, P2X [adenosine triphosphate (ATP)-gated ion channels)] and P2Y [metabotropic G protein-coupled receptors (GPCRs)]. The current research reveals that purinergic receptors are associated with the pathophysiology of depression that involves the inhibition of A1 and the activation of A2A receptors as well as P2 receptors[10]. Conversely, depression is a mental disorder accompanied by decreased self-esteem, loss of interest, abnormality in the circadian rhythm, and anxiety disorders. Presently, the available information indicates that depression is linked to the activation of cell-mediated immunity, which is a persistent, low-grade inflammatory response, and the compensatory anti-inflammatory reflex system[16]. Purinergic receptors take part in the regulation of the release of several neurotransmitters (including 5-hydroxytryptamine, noradrenaline, glutamate, γ-aminobutyric acid, and nitric oxide) and moderate the activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and the release of related inflammatory components, which are mechanisms that are consistently involved in depression[17]. In addition, common genetic variants of adenosine receptors may play a role in depression[18]. Moreover, scholars identify that purinergic receptors, especially the A2A and P2X7 receptors, are promising targets of therapy for depression[18,19].

The utilization of antidepressants could lead to many consequences. Thus, a prospective field of study to elucidate the molecular causes and effective treatments of depression could be the purinergic system. Currently, many scientometric articles are frequently employed in the field of depression, including olfactory dysfunction with depression[20], the role of brain-derived neurotrophic factor in depression and treatment[21], and the application of artificial intelligence to the management of depressive disorders[22]. However, an overview and assessment of article features, research directions, and hot spots of purinergic receptors in depression are lacking. For this reason, evaluating and inferring the worldwide trend and evolution of purinergic receptors in relation to depression are vital to provide reference for future studies.

Developed by Dr. Chen CM, bibliometrics is currently a powerful tool for comprehending the knowledge architecture of particular academic topics[23]. Bibliographic and visual analyses provide new perspectives for the identification of development trends and projecting research directions in this field[24,25]. Bibliometric analysis can conveniently and efficiently be used to examine the contributions of authors, institutions, and countries with the use of visualization software such as CiteSpace and VOSviewer. The current study evaluates the research features of purinergic receptors in depression as listed in the Web of Science database throughout the past two decades. It analyzed and tracked the hotspots and frontier trends of purinergic receptors in depression research with a focus on high-impact countries, institutions, authors, references, journals, and keywords. This study aims to provide reference for further research in this field as well as the advancement of related disciplines.

MATERIALS AND METHODS

Data sources and search strategy

Data were derived from the Web of Science Core Collection (WoSCC) (https://www.webofscience.com/wos/woscc/). The WoSCC database is dynamically and continuously updated, which can provide comprehensive citation records and influential journals[26]. Furthermore, solely utilizing discipline-specific databases, such as PubMed, SPORTDiscus, and PsycInfo, may lead to insufficient search results, which would reduce the credibility of the current study[26]. The specific search strategy was set as follows: [TS = (Depression) OR (Depressive Symptom) OR (Depressive Disorder) OR (Emotional Depression) OR (Depressive Syndrome); AND TS = (Purinergic Signaling) OR (P1 Receptor) OR (P2 Receptor) OR (P2X) OR (P2Y) OR (Adenosine) OR (ATP) OR (ADP) OR (UTP) OR (UDP)]. The study retrieved 2965 results were retrieved after the initial screening. Given the original contribution and summary of the primary research findings, the document types were limited to articles and reviews, and the language was restricted to English. Moreover, the lack of representation of record types, such as conference abstracts and proceedings and editorial material, was omitted. Figure 1 and Table 1 illustrates the workflow of the study. Two reviewers independently collected all publications by reading the titles and abstracts and evaluated the articles. For the research content of the selected publications, the subjects of the publications were patients with depression (including depressive symptoms and disorders) and animal models of depression. Moreover, the research content must simultaneously evaluate the relationship between subjects and purinergic receptors (including P1 and P2 receptors). Any uncertainty about the qualification of the article was settled through a discussion with a third reviewer. With more experience in literature screening, the third reviewer made final decisions. Finally, 2555 articles without direct relevance were excluded after careful evaluation and filtering, which left a total of 247 articles included for analysis. CiteSpace and VOSviewer were utilized for analysis.

Figure 1 Flowchart of the article screening process and analysis methods. Three steps are shown on the left of flowchart, which are identification, screening, and included respectively. The specific progress of each step is on the right of flowchart.

Table 1 Search queries.

Set	Results	Search query
1	450751	TS = [(Depression) OR (Depressive Symptom) OR (Depressive Disorder) OR (Emotional Depression) OR (Depressive Syndrome)]
2	261873	TS = [(Purinergic Signaling) OR (P1 Receptor) OR (P2 Receptor) OR (P2X) OR (P2Y) OR (Adenosine) OR (ATP) OR (ADP) OR (UTP) OR (UDP)]
3	2965	1 AND 2

ATP: Adenosine triphosphate; ADP: Adenosine diphosphate; UTP: Uridine triphosphate; UDP: Uridine diphosphate.

Data analysis

This study uses bibliometrics and data visualization as analytical methods. The results were presented as graphics composed of nodes and lines. The cited journals, keywords, and co-cited references were represented as nodes in a network map created using CiteSpace. The color of a node represents various clusters or years, while its size denotes the frequency of its occurrence or citation. The color of a network edge on the map indicates the year in which the cooperation, co-occurrence, or co-citation link was initially established. Network edges stand for cooperation, co-occurrence, and co-citation interactions[27]. Nodes with the same color correspond to the same cluster in the visualization results produced by VOSviewer. One node represents one keyword (i.e., institution or author). The linked lines of the network symbolize collaboration between countries, institutions, and authors in which line thickness indicates the strength of cooperation[28]. Moreover, different colors represent different meanings in VOSviewer. In the network visualization, colors represent classifications, and the same color (e.g., green, yellow, or blue) pertains to the keywords of a cluster category. The size of an element is dependent on the degree of the node, strength of a line, and number of citation, among others. In addition, the color of the element represents the cluster to which it belongs, and different colors denote clusters. In the overlay visualization, colors represent time. The default values are blue and yellow with the order of occurrence from blue to yellow.

CiteSpace was configured with the following parameters: Years per slice (one), source terms (all options), node type (one at a time), selection criterion (top 50 items), pruning (Pathfinder and Pruning sliced networks), and time slicing (2003-2023). Evaluation measures, including modularity Q and mean silhouette, were included in cluster analysis. Credible clustering results are indicated by a mean silhouette value of > 0.5, while a Q-value of > 0.3 implies a substantial clustering structure[29,30]. These two important evaluation indicators can effectively measure the drawing effect of the knowledge graph. In this study, Q > 0.3 and mean silhouette > 0.5 in the chart indicate that the clustering requirements are fully met. The keyword cluster structure is significant and has high confidence, which can establish reliability for this study on purinergic receptors and depression.

RESULTS

Analysis of annual publications

A total of 247 literature (199 articles and 48 reviews) were identified in the WoSCC from January 2003 to December 2023. The annual number of articles in a field can be utilized to estimate its trends. Figure 2 depicts that only four papers on the relationship between purinergic receptors and depression were published in 2003. By 2021, however, two decades later, there were seven times as many articles annually. The number of publications produced in the year peaked in 2019 and 2023 (n = 28). The annual number of studies exhibited a steady increase over the past two decades, which indicates that scholarly attention to purinergic signaling in depression has increased.

Figure 2 Trends of the related annual publications. The horizontal axis shows the year of publication, and the vertical axis shows the annual number of publications.

Analysis of countries

A total of 40 countries conducted research on the roles of purinergic receptors in depression. Table 2 indicates that the country with the largest number of publications was China [89 (36.03%)] followed by the United States [42 (17.00%)], and Germany [32 (12.96%)]. Figure 3A illustrates that the articles in this field mainly come from East Asia, North America, and Europe. According to the cooperation network between countries (Figure 3B), the United Kingdom exhibited the highest cooperation intensity (37); in other words, it engaged in closer cooperation with other countries. The top five countries by centrality were the United Kingdom (0.45), the United States (0.40), Germany (0.36), China (0.15), and Australia (0.14). Developed countries, such as the United Kingdom and the United States, featured advanced medical research institutions, excellent scientific scholars, and sufficient financial support. Moreover, the research results of these countries frequently exert a comparatively significant impact. Notably, the United Kingdom displayed the highest centrality (0.45), which points to its leading role in the study on purinergic receptors in depression. This result may be related to the strong and mature research capability and continued investment in the United Kingdom, which has led to extensive connections with other nations and solid international cooperation. As a developing country, China has been increasing its number of publications, and the total number of articles quickly exceeded. This result may be attributed to the large population base and the significant proportion of patients with depression as well as the rapid growth of the national gross domestic product and increased funding on scientific research. Although Chinese academics produced a sizable amount of relevant research in this field, they are nevertheless expected to place a high value on the enhancement of the quality of future publications.

Figure 3 Cooperation between countries. A: World map of the intensity of cooperation between countries; B: Circle diagram of international collaboration between countries. In these two visual maps, each node is a country, and the links between countries represent cooperative relations. The size of each node is proportional to the total number of publications. The red nodes indicate that there are more cooperative publications between the country and other countries, while the thicker connecting lines between the nodes indicate that the cooperation between the two countries is closer.

Table 2 Top 10 Countries with the most publications and centrality related to purinergic receptors in depression, n (%).

Rank	Countries	Publications (%)	Rank	Countries	Centrality
1	China	89 (36.03)	1	United Kingdom	0.45
2	United States	42 (17.00)	2	United States	0.4
3	Germany	32 (12.96)	3	Germany	0.36
4	Brazil	25 (10.12)	4	China	0.15
5	United Kingdom	22 (8.91)	5	Australia	0.14
6	Australia	14 (5.67)	6	Brazil	0.13
7	Italy	11 (4.45)	7	Italy	0.12
8	Hungary	8 (3.24)	8	Iran	0.09
9	Japan	8 (3.24)	9	Canada	0.06
10	Spain	8 (3.24)	10	Austria	0.03

Analysis of institutions

From 2003 to 2023, a total of 329 institutions participated in purinergic receptors and depression research. Table 3 shows the top ten institutions. Among them, institutions with a publication volume greater than 7 articles include Southern Medical University China (n = 11), Max Planck Society (n = 10), Universidade Federal de Santa Catarina (n = 9), Nanchang University (n = 8), and Semmelweis University (n = 8). Particularly, Southern Medical University China was the institution with the most number of publications (11) and the highest centrality (0.13), demonstrating that it had lay a solid foundation for the development of purinergic receptors and depression. Figure 4A displays the collaborative network between major publishing institutions in this topic.

Figure 4 Cooperative network of according to VOSviewer. A: Top 50 institutions. In this network visualization map, each node is an institution. The size of the node indicates the volume of publications, and the colors of nodes represent different institutions, and the connecting lines represent the cooperative relationship between individual institutions; B: Authors contributed to the field of purinergic receptors in depression; C: Co-cited authors contributed to the field of purinergic receptors in depression. In these two network visualization maps (B and C), each node is an author, and the links between the authors represent the cooperative relationship. The size of each node is proportional to the total number of publications, the colors of nodes represent different authors, and the connecting lines represent the cooperative relationship between individual authors.

Table 3 Top 10 frequency and centrality of institutions associated with purinergic receptors in depression.

Rank	Institutions	Frequency	Rank	Institutions	Centrality
1	Southern Medical University China	11	1	Southern Medical University China	0.13
2	Max Planck Society	10	2	Jinan University	0.11
3	Universidade Federal de Santa Catarina	9	3	National Institutes of Health United States	0.1
4	Nanchang University	8	4	Max Planck Society	0.09
5	Semmelweis University	8	5	Academy of Military Medical Sciences China	0.09
6	Chengdu University of Traditional Chinese Medicine	7	6	RWTH Aachen University	0.09
7	Universidade de Sao Paulo	7	7	Helmholtz Association	0.07
8	National Institutes of Health United States	7	8	Universidade de Coimbra	0.06
9	Aarhus University	6	9	Harvard University	0.04
10	University of Manchester	6	10	Harvard Medical School	0.04

Analysis of authors and co-cited authors

A total of 1559 authors were involved in this field in which different colors represented clusters. The relevant scientific framework in a certain topic can be reflected in the scholarship efforts of outstanding authors (30). Out of the 1559 authors, 59 produced approximately three documents (Figure 4B). Among them, Liang SD, and Rodrigues, Ana Lucia S were the most prolific authors with publications of six papers each, followed by Deussing, Jan M, and Tang Y. Among the 9942 co-cited authors, 30 had approximately 30 citations (Figure 4C). According to the co-citation analysis (Table 4), the study found that the top three most cited authors were Burnstock and Geoffrey (162 times), Kaster and Pinto (91 times), and Maes and Michael (68 times). The results indicate that Burnstock and Geoffrey exerted a greater influence on research, which provided favorable conditions for further research in the field of purinergic receptors in depression.

Table 4 Top 10 authors and co-cited authors in the field of purinergic receptors in depression.

Rank	Authors	Publications	Rank	Authors	Citations
1	Liang SS	6	1	Burnstock G	162
2	Rodrigues, Ana Lucia S	6	2	Kaster MP	91
3	Deussing, Jan M	5	3	Maes M	68
4	Tang Y	5	4	Cunha RA	65
5	Poleszak E	4	5	Bhattacharya A	65
6	Serchov T	4	6	Salamone JD	63
7	Szopa A	4	7	Csolle C	61
8	Li SJ	4	8	Fredholm BB	60
9	Cunha RA	4	9	Illes P	59
10	Szekely A	4	10	Iwata M	50

Analysis of cited journals

As illustrated in Figure 5 and Table 5, the study found that Biological Psychiatry ranked highest in citation frequency (172) followed by the Journal of Neuroscience (165), Molecular Psychiatry (144), and the Proceedings of the National Academy of Sciences of the United States of America (144). The journal citation reports (JCR) 2022 classified five of the top 10 cited journals, namely, Biological Psychiatry, Molecular Psychiatry, Proceedings of the National Academy of Sciences of the United States of America, Neuroscience, Nature, and Neuropsychopharmacology. In addition, the journal with the greatest impact factor (IF) in 2022 was Nature (IF = 64.8) followed by the Proceedings of the National Academy of Sciences of the United States of America (IF = 11.1) and Molecular Psychiatry (IF = 11).

Figure 5 Cited journal maps related to purinergic receptors in depression. In this network visualization map, each node represents a journal, and the links between the journals represent the cooperative relationship. The size of each node is proportional to the total number of publications, the colors of nodes represent different journals, and the connecting lines represent the cooperative relationship between individual journals.

Table 5 Top 10 cited journals in the field of purinergic receptors in depression.

Rank	Journal	Frequency	JCR	IF (2022)
1	Biological Psychiatry	172	Q1	10.6
2	Journal of Neuroscience	165	Q2	5.3
3	Proceedings of the National Academy of Sciences of the United States of America	144	Q1	11.1
4	Molecular Psychiatry	144	Q1	11
5	Neuroscience	131	Q3	3.3
6	Journal of Affective Disorders	129	Q2	6.6
7	Nature	124	Q1	64.8
8	Neuropsychopharmacology	123	Q1	7.6
9	Behavioural Brain Research	119	Q3	2.7
10	Neuropharmacology	115	Q2	4.7

IF: Impact factor; JCR: Journal citation reports.

Analysis of references

In general, the study generated 3102 references in this topic. An assessment of co-citation references enables the identification of valuable resources and analysis of the links between references. According to the frequency ranking of cited references (Figure 6A), the most cited article was “Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors” by Yue et al[31], which was published in J Neuroinflammation in 2017 (Table 6). This article revealed that the activation of P2X7 receptor and the NLRP3 inflammasome in hippocampus microglial cells mediate depressive-like behaviors, which offers a potential therapeutic target for the prevention and treatment of depression. Frequently referenced literature over time can demonstrate the evolution of a field of knowledge through references with citation bursts[5]. Figure 6B displays a total of 25 references with citation bursts. The strongest reference for citation bursts since 2006 is that of Iwata (“Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor”) in 2016.

Figure 6 Cited references. A: Cited references map related to the research of purinergic receptors in depression; B: Top 25 references with the strongest citation bursts. Each node represents a reference, and the links between the references represent the cooperative relationship. The size of each node is proportional to the total number of publications, the colors of nodes represent different references, and the connecting lines represent the cooperative relationship between individual references. The red bars represent the starting and ending, and the duration of citation bursts.

Table 6 Top 10 frequently cited references about purinergic receptors in depression.

Rank	Title of reference	Frequency	Author	Year	Journal
1	Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors	24	Yue N	2017	J Neuroinflamm
2	Psychological Stress Activates the Inflammasome via Release of Adenosine Triphosphate and Stimulation of the Purinergic Type 2X7 Receptor	23	Iwata M	2016	Biol Psychiat
3	Emerging role of the P2X7-NLRP3-IL1β pathway in mood disorders	17	Bhattacharya A	2018	Psychoneuroendocrino
4	Pathological ATPergic Signaling in Major Depression and Bipolar Disorder	16	Illes P	2020	Front Mol Neurosci
5	P2X7 Receptor: A Potential Therapeutic Target for Depression?	16	Deussing JM	2018	Trends Mol Med
6	Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress	15	Kaster MP	2015	P Natl Acad Sci
7	P2X7 Receptor Signaling in Stress and Depression	14	Ribeiro DE	2019	Int J Mol Sci
8	Depression	13	Malhi GS	2018	Lancet
9	Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors	13	Csölle C	2013	Plos One
10	P2X7 receptor: An emerging target in central nervous system diseases	13	Sperlágh B	2014	Trends Pharmacol Sci

Analysis of keywords

Reflecting on the topic of research and identifying hotspots and frontiers by analyzing keywords in a certain field[32] are feasible. According to the co-occurrence network of keywords (Figure 7A and Table 7), those with high frequencies were “major depressive disorder”, “major depression”, “expression”, “depression”, “brain”, “prefrontal cortex”, and “p2x (7) receptor”. Thus, determining whether or not a subject of study is hot for a specific period of time is possible by identifying keywords with citation bursts[33]. Among the top 25 keywords, “bipolar affective disorder”, “mutation”, and “DNA” covered the entire time span of 2003-2023, which indicates that scholarly attention was continuous (Figure 7B). In addition, we found that “p2x7 receptor”, “inflammasome”, “meta-analysis”, and “chronic stress” were keywords with the strongest citation bursts from 2020 to 2023. In other words, they have received increasing attention and development in the field of purinergic receptors in depression.

Figure 7 Keywords. A: Network map of keywords related to the research of purinergic receptors in depression. Each node represents a keyword, and the links between the keywords represent the cooperative relationship. The size of each node is proportional to the total number of publications, and purple nodes represent references with high centrality; B: Top 25 keywords with the strongest citation bursts. Red horizontal lines indicate the importance and attention of the references in the field. A longer red line length indicates greater popularity for reference.

Table 7 Top 10 keywords related to migraine and sleep disorders.

Rank	Keywords	Frequency
1	Major depressive disorder	36
2	Major depression	36
3	Expression	35
4	Depression	33
5	Brain	33
6	Prefrontal cortex	29
7	P2x (7) receptor	29
8	Stress	26
9	Activation	25
10	Bipolar disorder	22

DISCUSSION

General information

The study conducted an overall and scientific bibliometric analysis in the field of purinergic receptors in depression from January 1, 2003 to December 31, 2023. To the best of our knowledge, this study is the first bibliometric one to comprehensively summarize hot topics and emerging trends in this field. The findings demonstrated a growing trend in publication over the past two decades and that purinergic receptors in depression are receiving more scholarly attention toward this research sphere, which is progressively becoming a research hotspot. The upward trend may be due to the enhanced knowledge on the role of purinergic receptors in depression and increased research funding. Thus, the study predicted that the quantity of yearly publications will continue to increase in the following years, which could lead to further development in the field.

The results also revealed a wide network of worldwide collaboration through the analysis of international academic cooperation (Figure 3B). According to the analysis of countries (Figure 3A), the leading research forces in this area are China, the United States, and Germany. This finding may be due to more affiliations or prominent academics in these countries, which strengthens their global impact in this field. Furthermore, international collaboration in the research on purinergic receptors and depression was mainly centered in the United Kingdom (Figure 3B), which took the lead in fostering collaboration among other countries. In terms of centrality, the top three countries were the United kingdom (0.45), the United States (0.4), and Germany (0.36), which reflects high levels of collaboration. The majority of the most prolific institutions and authors were from China, but they were unable to provide sufficiently impactful studies or global cooperation in the research process. Consequently, further global scientific collaboration is needed between nations and organizations in China. Table 4 indicates that Liang SD, and Rodrigues, Ana Lucia S, from Nanchang University and Universidade Federal de Santa Catarina, respectively, were the most productive authors. However, the international cooperation of the authors was not interrelated. To enhance international collaboration in this sphere, authors should eliminate linguistic obstacles and build bridges for communication. Burnstock was the leading contributor with the highest citation frequency. In 1976, Burnstock[34] first described purinergic receptors and identified the P1 and P2 receptors based on their pharmacological differences. In 1985, the author postulated that the latter included the P2X (ion channel) and P2Y (G protein-coupled) subtypes[35,36]. The author also demonstrated the exceptional research that he and his colleagues conducted in this field, which laid a solid foundation for the development of the molecular mechanisms of depression[16,37,38]. Based on purinergic signaling, Zou et al[39] summarized the potential molecular mechanisms mediated by different purinergic receptors and concluded that purinergic receptors A1, A2A, P2X3, P2X4, P2X7, and P2Y(6), P2Y(1), and P2Y(12) may be potential common therapeutic targets in the comorbid mechanism of depression and chronic pain. This finding may promote a thorough comprehension of purinergic receptors and provide directions for the improvement of treatments for depression and chronic pain.

A total of 464 journals were included such as Biological Psychiatry, Molecular Psychiatry, and Neuropsychopharmacology. Ranking according to journal IF, which are separated into four quartiles [e.g., from the most (Q1) to the least (Q4) influential journals], for the basis of the JCR. It is commonly used to assess the universal impact of journals[40]. The study found that 50% of the top 10 most cited journals obtained an IF of more than 7. In this regard, Nature was the most influential journal in the field of purinergic receptors in depression with the highest IF (64.8).

The frequently cited journals, such as Biological Psychiatry, Molecular Psychiatry, and Neuropsychopharmacology, are high-quality journals in the field of molecular, biology, and medicine, which contributes to the investigation on the role of purinergic receptors in depression. Biological Psychiatry publishes novel results of original basic and clinical mechanistic studies that advance the understanding of depression and provide new perspectives for treatment. Neuropsychopharmacology focuses on clinical and basic science contributions that advance the understanding of depressive symptoms, especially in relation to the molecular, cellular, physiological, and psychological properties of agents that act within the central nervous system. This understanding includes the identification of new molecular targets for the development of the next generation of drugs. Moreover, Molecular Psychiatry publishes work that aims to elucidate the biological mechanisms that underlie depression and its treatment. It emphasizes studies at the interface of preclinical and clinical research, including those at the cellular, molecular, integrative, clinical, and psychopharmacology levels. The fact that these journals are highly valued and regarded in the academic domain implies that clinical research published in these journals is of excellent quality and is typical of the discipline. These publications offer valuable information that helps scholars expand horizons and stimulate innovative ideas. In terms of the analysis of institutions, Southern Medical University-China leads the world in the field of purinergic receptors in depression in terms of the total number of publications and important implications. This finding may be related to the outstanding scholars and substantial funding of the country.

Scientific studies need to be based on rooted facts, which are frequently discussed in cited resources. In other words, the cited references effectively express the discipline frameworks of a certain topic. The article entitled “Activation of P2X7 receptor and NLRP3 inflammasome assembly in hippocampal glial cells mediates chronic stress-induced depressive-like behaviors”, which was published in the Journal of Neuroinflammation, was the most cited article. It proposed that chronic stress promotes the activation of P2X7 receptor and the subsequent NLRP3 inflammasome in hippocampal microglial cells, which can trigger depressive-like behaviors[31]. It then proposed that the P2X7/NLRP3 axis could be a potential therapeutic target for the prevention and treatment of depression. The strongest reference for citation burst since 2006 is the article entitled “Psychological stress activates the inflammasome via release of ATP and stimulation of the purinergic type 2X7 receptor” by Iwata in 2016. With regard to the treatment of stress-related mood disorders and concomitant diseases, the author provided new therapeutic targets and demonstrated that the innate immune system of the brain can detect psychological stress through the ATP/P2X7 receptor-NLRP3 inflammasome cascade[41]. Both references contributed to the further development of the pathogenesis and treatment of depression, which hold significant positions and exert a broad influence in the field of purinergic receptors and depression.

Hotspots and frontiers

The most frequent keywords are “major depressive disorder”, “major depression”, “expression”, “depression”, “brain”, “prefrontal cortex”, “p2x (7) receptor,” “stress,” “activation,” and “bipolar disorder.” Furthermore, “inflammasome,” “chronic stress” and “P2X7 receptor” were the keywords with the strongest citation bursts. Thus, scholars can effectively elucidate research hotspots and identify potential research priorities in the future according to the study of keywords and burst words.

The alteration of the prefrontal cortex in chronic stress-induced depression: A major contributing factor to depression is chronic stress[42]. Various forms of social stress and survival pressure, including childhood trauma, abortion, and economic burden, eventually lead to depression[43]. The prefrontal cortex (PFC) is a specific region of the brain that is involved in a broad range of complicated activities such as working memory, behavioral regulation, and emotional control[44]. In major depressive disorder (MDD), the PFC has become one of the areas that is most persistently impaired[45]. It is extremely sensitive to the impacts of environmental stress. Abnormal prefrontal activation and reduced executive performance frequently characterize mood and anxiety disorders[46]. Alternatively, ATP has been proven to influence various behaviors, including mood and cognition, and learning and memory via P2X receptors or P2Y receptors[47]. Scholars found that chronic stress evaluated P2X2 levels in the medial prefrontal cortex (mPFC), and P2X2 bidirectionally mediated the vulnerability of stress through the regulation of neuronal plasticity. This research identified P2X2 as an important mechanism that underlies depression, which represents a potential therapeutic target for the treatment of stress-related MDD[48]. Evidence depicted that long-term stress exposure is related to a decrease in prefrontal volume[49], which was associated with a longer duration of sickness and a reduction in the expression of synaptic markers, both of which are directly identified in the PFC[50]. A purinergic receptor that is only expressed by microglia in the brain, P2Y12 regulates the manner in which purine released by neurons attracts microglial processes. In addition to the prevention of microglia-mediated neuronal remodeling and the reduction of synapse loss in the mPFC, the genetic deletion or pharmacological blockage of microglial P2Y12 also decreased changes in working memory function and stress coping behavior[51]. The characteristics of P2Y12 in driving microglia-neuron interaction in stress and microglial intervention in stress-linked disorders may provide genetic or pharmacological strategies for the treatment of depression.

The inflammatory activation pathway of depression: The results revealed that MDD and mood disorders have been associated with the purinergic system[37,52]. Moreover, neuroinflammation may be a factor that leads to psychiatric disorders. Many mental disorders, such as MDD, bipolar disorder, schizophrenia, and autism spectrum disorder, are seemingly caused by the stimulation of the P2X7 receptor/NLRP3/Capase-1/interleukin (IL)-1β-pathway via ATP[53].

Inflammation is associated with depression, and the degree of inflammation can influence depressive symptoms[54]. High levels of proinflammatory cytokines, such as interferon-γ, tumor necrosis factor-α, IL-1, and IL-6, induce constant neuroinflammation, which ultimately results in depression[33]. The inflammasome is a significant component of neuroinflammation[55], which is formed by family members of nucleotide-binding and oligomerization domain-like receptors (NLRs), adaptor apoptosis-associated speck-like protein containing a CARD and pro-caspase-1[56]. Among the NLRs, NLRP3 is stimulated by the greatest variety of danger signals[57]. The NLRP3 inflammasome plays a crucial role in the pathophysiology and behavioral symptomatology of stress-induced depression by mediating the production of IL-1β protein in the serum and hippocampus[58]. Accumulating evidence has proven that the activation of the NLRP3 inflammasome may be a significant component of depression[59-61]. Iwata proposed an inflammasome hypothesis of depression: Psychological stress can activate the NLRP3 inflammasome, which elevates IL-1β and contributes to depressive symptoms[62]. Therefore, efficient NLRP3 inflammasome inhibitors could be novel therapeutic agents for depression. At the same time, individuals with NLRP3-related systemic diseases, such as diabetes and cardiovascular and inflammatory diseases, were more likely to exhibit depressive symptoms. This result implies that the inflammasome is a central mediator that connects depression with systemic diseases, and it may serve as a novel target for the advancement of therapy for depression[63].

The P2X7 cation channel as a potential drug target for depression: In the context of the pharmacology of depression, scholarly interest in the purinergic system is increasing, which is related to the exploration of augmentation techniques and novel medication therapies[64]. One of the main drivers of neuroinflammation is the ATP-gated ion channel P2X7 receptor, which is highly expressed in microglia[65]. Moreover, the P2X7 receptor is the most relevant out of the seven P2X subtypes in terms of the role it plays in the regulation of neuroinflammation[66]. The genetic deletion of P2X7 receptors is associated with antidepressant effects[18]. Four studies conducted by various groups examine the impact of the genetic deletion of P2X7 on behavior in mice using the tail suspension and forced swim tests, which are two common tests for depression[18]. In addition, transgenic mice deficient in P2X7 (P2X7-/-) displayed a prominent reduction in immobility time in the four tests, which is a characteristic associated with antidepressive behavior[67]. Researchers found that P2X7 receptor knockout mice exhibited an antidepressant-like profile and displayed higher levels of responsivity to an antidepressant drug[68]. The literature has also identified that the human P2X7 gene exhibits a large number of defective single nucleotide polymorphism (SNPs) that significantly impact receptor transportation or receptor function[69]. Evidence provided proof that SNPs in the gene P2RX7, specifically rs2230912, were closely associated with major depressive symptoms and the intensity of depressive symptoms[70]. Although several clinical studies on inflammatory disorders reported failure, P2X7 receptor antagonists (compounds that cross the blood-brain barrier) are being developed to treat depression[71]. As a high-affinity (and high-potency) P2X7 antagonist, JNJ-54175446 binds to human, rat, and dog brain sections and inhibits P2X7-dependent IL-1β production in human blood. Additionally, JNJ54175446 has undergone a clinical evaluation for the treatment of major depression[72].

The articles highlight the importance of the P2X7 cation channel as a potential drug target for depression, but further studies are required to strengthen the evidence for pharmacological purposes. Purinergic receptors are more widely distributed throughout the body compared with many other GPCRs or ion channels. The therapeutic value of novel small molecule modulators for a wide range of diseases and conditions becomes possible through this ubiquity. Therefore, revealing specific molecular mechanisms between purinergic receptors and depression in the future, as well as molecular targets for the treatment of clinical disorders related to depression, may become major research hotspots and potential directions for future development.

Limitations

This study has its limitations. Initially, the publications were obtained only from the WoSCC database, and the publication language was limited to English. Although the WoSCC database contains major data sources, the study may have overlooked a few valuable papers published in PubMed and Scopus or those published in other languages. Second, only reviews and articles were selected as the type of paper. Consequently, analysis may fail to include several crucial conference abstracts, which omits other relevant studies. Finally, bias is inevitable despite the designation of two researchers to evaluate the preliminary data.

CONCLUSION

To the best of our knowledge, this study is the first bibliometric one conducted to comprehensively summarize hot topics and emerging trends in purinergic receptors and depression. In summary, it provides an overview of the worldwide research status while identifying key areas for future research: (1) The alteration of PFC in chronic stress-induced depression; (2) The inflammatory activation pathway of depression, and (3) The P2X7 cation channel as a potential drug target for depression. This study is expected to provide valuable insights for further research on depression.

ACKNOWLEDGEMENTS

We appreciate the availability of data via the Web of Science Core Ensemble Data as well as the cooperation of all authors.