Relationship between Serum Ghrelin and Suicidality in patients with Depression: A Systematic review and Meta-Analysis

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Abu Bashar, Sridevi Gnanasekaran, Prabhat . This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6197084/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Ghrelin, an orexigenic peptide hormone, mainly stimulates appetite and the release of growth hormone (GH). However, beyond its metabolic roles, Ghrelin has been implicated in the neurobiological pathways associated with mood regulation, suggesting a potential link between metabolic states and psychiatric conditions such as depression. The relationship between Ghrelin and suicidality, a severe and often terminal manifestation of psychiatric disorders remains under-explored. Aim To assess the relationship between serum Ghrelin and suicidality in patients with depression. Methods A systematic review and meta-analysis following PRISMA guideline was performed using PubMed, Medline, Embase, CINHL and Google Scholar in June, 2024. Two independent reviewers systematically evaluated the studies for inclusion and any disagreement was resolved by consulting a third reviewer. Meta analysis of the included studies was performed using MetaXL software version 5.3. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale, and the risk of publication bias was assessed using a plotting funnel and Doi plots. Results Out of 249 studies identified through the database search, finally 3 studies were found eligible comprising of 302 participants. Pooling the results, the meta-analysis indicates an average increase (Effect size) of 106.01 units in serum Ghrelin levels among patients with suicidality over controls. This effect is statistically significant given the confidence interval range from 16.80 to 195.22. The heterogeneity across the studies was substantial, with an I² close to 99% and a Cochran's Q statistic of 198.77. The Funnel Plot revealed asymmetrical distribution of studies, particularly a shortage of smaller studies with negative or null outcomes. Conclusion Serum Ghrelin levels are found to be significantly elevated among individuals with suicidality compared to healthy controls. However, high heterogeneity across the studies limits the findings. Clinical Trial Number:- Not Applicable Serum Ghrelin Suicidality Case control Depression Relationship Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Ghrelin, often called as the "hunger hormone," is a multifaceted peptide produced predominantly in the stomach. 1 It is intricately involved in various physiological processes including energy homeostasis, appetite regulation, and the modulation of the growth hormone release. 2 Beyond its metabolic roles, Ghrelin has been implicated in the neurobiological pathways associated with mood regulation, suggesting a potential link between metabolic states and psychiatric conditions such as depression and anxiety. 3 , 4 Depression is a pervasive psychiatric disorder characterized by persistent sadness, loss of interest in enjoyable activities, and a heightened risk of suicidality. The complex interplay between depression and physiological factors, including hormonal imbalances, has been the subject of extensive research. Among the hormones investigated, Ghrelin has emerged as a potential biomarker due to its influence on mood and stress response systems. 5 Recent studies have indicated that ghrelin's role extends beyond simple appetite regulation, hinting at its involvement in the stress response and emotional regulation circuits within the brain. 6 This has led researchers to speculate about the hormone's potential involvement in the aetiology of psychiatric disorders, particularly depression and anxiety. The association between Ghrelin levels and depression has been noted in several studies, with some reporting lower levels of Ghrelin in depressed individuals compared to healthy controls, suggesting a potential dysregulation of appetite and energy homeostasis in depression. 7 , 8 Conversely, the relationship between Ghrelin and suicidality—a severe and often terminal manifestation of psychiatric disorders—remains under-explored. Suicidal ideation and behaviors are complex phenomena influenced by a myriad of psychological, social, and biological factors. The potential role of Ghrelin in modulating stress responses and emotional states raises questions about its involvement in suicidality among depressed patients. Furthermore, inconsistencies in the literature regarding Ghrelin levels in different psychiatric conditions highlight the hormone's complex role and the influence of various confounding factors such as age, sex, body mass index (BMI), and nutritional status. These factors can significantly impact ghrelin's secretion and action, thereby complicating the interpretation of its association with psychiatric symptoms. 9 , 10 The aim of this systematic review and meta-analysis is to synthesize existing research on the association between Ghrelin levels and suicidal ideation in patients with depression. By integrating findings from diverse studies, this review seeks to clarify the role of Ghrelin in the context of depression and suicidality, addressing the heterogeneity in previous research and exploring potential moderating factors such as demographic and lifestyle variables. In doing so, this review will contribute to a more understanding of ghrelin's role in depression and suicidality, potentially paving the way for novel diagnostic and therapeutic approaches that target the ghrelinergic system in psychiatric disorders. Material & Methods Search Strategy A comprehensive literature search was conducted across several databases, including PubMed, Medline, Google Scholar, Embase, CINHL and the Cochrane Library, to ensure a wide coverage of relevant literature. The search was performed by a combination of keywords: "Ghrelin" in conjunction with "Depression," "Depressive Disorder," "Suicide," "Suicidal ideation," or "Suicidality." The search strategy was meticulously designed to capture all pertinent studies, adhering to the protocol. The review was registered at PROSPERO with registration Id CRD42024547555 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024547555 ). Two independent reviewers systematically evaluated the studies for inclusion and exclusion, resolving any discrepancies through discussion or consultation with a third reviewer. Condition or domain being studied The digestive hormone, Ghrelin has both peripheral and cerebral effects, including the control of neurovegetative processes and reward neuronal circuits. Therefore, the physiological effects of Ghrelin may mitigate depressed symptoms such decreased appetite, sleep disturbances, and anhedonia. This review focuses on the interplay between Ghrelin levels and their potential impact on depressive symptoms and suicidal tendency, considering the hormone's dual role in metabolic and neuropsychiatric processes. The review aims to elucidate whether Ghrelin can serve as a biomarker or a therapeutic target for depression with a particular emphasis on suicidality, addressing the need for innovative treatment approaches beyond traditional modalities. Inclusion/Exclusion Criteria Original studies were selected based on their focus on patients diagnosed with depression, exhibiting suicidal tendencies, and comparisons with healthy controls. Only studies providing clear data on Ghrelin levels in these populations were considered. Exclusion criteria encompassed studies lacking direct measurement of Ghrelin levels, case reports, case series, reviews, and studies not published in English. Data Extraction method Two independent reviewers screened the titles and abstracts from the search results to identify relevant studies. Full texts of the identified studies were then accessed for detailed assessment. Data were meticulously extracted and recorded in a predefined Microsoft Excel template, capturing essential information such as authors, publication year, study design, population characteristics, sample size, interventions, comparators, Ghrelin measurement methods, and outcomes. Risk of Bias Assessment The risk of bias in individual studies was evaluated using the Newcastle–Ottawa Scale, a comprehensive tool designed for the assessment of non-randomized studies in meta-analyses. 11 Outcome Indicators The primary outcome of interest was serum Ghrelin levels in individuals with Suicidality/suicidal attempt in comparison to healthy controls. Statistical Analysis Raw data from the included individual studies were used in this meta-analysis. Data were entered into Microsoft Excel. Meta-analyses were performed using the software MetaXL version 5.3 using a random effect model. Relevant summary measures of efficacy were assessed using the standardized mean difference (SMD) for applicable variables along with the corresponding 95% confidence interval (CI). Statistical heterogeneity, which was quantified using the I² statistics and Publication bias was assessed by plotting funnel and Doi plots. Ethical considerations The Institute Human Ethics Committee(IEC), All India Institute of Medical Sciences, Gorakhpur(UP) waived the ethical approval for the review vide letter IHEC/AIIMS/2024/342. Results Screening Strategy The screening strategy followed the four stages outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, which encompassed identifying, screening, determining eligibility of papers, and finalizing the list of articles for inclusion in this review. Initially, a pool of 249 documents was amassed through searches on PubMed, Google Scholar, Ovid, and CINAHL databases. These documents, along with their references, were exported in CSV format and subsequently downloaded for screening. The screening process involved multiple rounds aimed at isolating relevant articles. Initially, 31 duplicate records were identified and removed, resulting in 218 unique documents. Subsequently, the titles and abstracts of these 218 documents were scrutinized to ensure alignment with the research focus on Ghrelin levels and suicide. Of these, 190 documents were deemed unrelated to the topic and were consequently excluded. The screening process continued based on predefined inclusion criteria, leading to the identification and exclusion of 18 different publication types and 7 different outcomes. Screening was carried out independently by three coauthors, with any discrepancies or controversial articles deliberated upon in team meetings to achieve consensus. Following rigorous screening and discussions, finally 3 articles were considered eligible for the review 12 – 14 (Fig. 1 ). Study Characteristics All 3 included studies were case-control studies with suicide attempters taken as the cases and healthy non-suicide attempters as controls. All other characteristics of the included studies are listed in Table 1 . Table 1 Characteristics of the studies included for meta-analysis Author/Year/Country Study Design Participants Outcome Measure Related to Suicide or Self-Harm Population/ Setting Atescelik M et al., 2017, Turkey 12 Case-control 128 patients with suicide attempts and 59 healthy controls Levels of acylated Ghrelin (AG), unacylated Ghrelin (UG), and copeptin. Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scores Emergency department patients with suicide attempts vs. healthy controls Atmaca M et al., 2006, Turkey 13 Case-control 30 patients with suicide attempts and 30 healthy controls Serum total cholesterol and Ghrelin levels Patients admitted to a university hospital with suicide attempts vs. healthy controls Kurt E et al.,2008, Turkey 14 Case-control 36 patients with suicide attempts and 25 healthy controls Serum levels of cholesterol, leptin, and Ghrelin Patients with suicide attempts admitted to the emergency unit or psychiatric clinic vs. healthy staff members Quality Assessment The quality of the included studies, assessed using the Newcastle-Ottawa Scale (NOS), indicated that the included studies were of moderate to good quality, with scores ranging from 6 to 7 out of a possible of 9 (Table 2 ). Most studies performed well in the 'Outcome' domain, suggesting that the measurement of outcomes related to suicidality and Ghrelin levels was generally robust. However, there were some limitations in the 'Selection' and 'Comparability' domains, highlighting potential areas for improvement in future research. Table 2 Quality assessment of the included studies by the Newcastle–Ottawa Scale First Author Study design Selection Comparability Outcome Total Score Atmaca M Case- control ** * *** 6 Aetscelik M Case- control *** * *** 7 Kurt E Case- control *** * *** 7 Meta analysis Pooling the results, the meta-analysis indicates an average increase of 106.01 units in Ghrelin levels in the active groups compared to the controls. This effect is statistically significant given the confidence interval range from 16.80 to 195.22, which doesn't cross the null effect line (Fig. 2 ). There is substantial heterogeneity across the studies, with an I² close to 99% and a Cochran's Q statistic of 198.77 with a p-value of zero. Such a high level of heterogeneity points towards significant variability in the effects across the studies. Publication Bias The Funnel Plot (Fig. 3) indicates possible publication bias or small-study effects, as evidenced by the asymmetrical distribution of studies, particularly a shortage of smaller studies with negative or null outcomes. This asymmetry implies concerns about the representativeness of the included studies and the potential overestimation of the effect size due to unpublished negative findings. The Doi plot displayed in Fig. 4 , with its accompanying Luis Fukuyama-Kanamori (LFK) index of 9.01, suggests significant asymmetry in the meta-analysis, indicative of major publication bias or small-study effects. This is far beyond the threshold that would signify minor asymmetry (an LFK index between 1 and 2), raising substantial concerns about the reliability of the meta-analysis results. The data points’ deviation from the expected distribution underlines the possibility that smaller or less statistically significant studies may be missing from the analysis, potentially skewing the overall effect size. Such a pronounced index value suggests a need for cautious interpretation of the findings and consideration of additional research, including unpublished studies, to achieve a more comprehensive and balanced overview of the effects being measured. Sensitivity analysis The sensitivity analysis of the meta-analysis demonstrates significant shifts in the pooled Weighted Mean Difference (WMD) and persistent heterogeneity upon the sequential exclusion of individual studies. Excluding Atescelik 2017 decreases the pooled WMD to 26.82536, with a confidence interval spanning across zero (-24.3126 to 77.96332), indicating a loss of statistical significance and persistent high heterogeneity (I²= 97.40335%, p < 0.00001). When Atmaca et al., 2016, is omitted, the WMD jumps to 137.0769, yet with a confidence interval (-130.507 to 404.6607) so wide that it questions the precision of this estimate, alongside extreme heterogeneity (I² = 99.37655%, p = 0). The exclusion of Kurt et al., 2008, yields a WMD of 163.1353 but with a similarly wide confidence interval (-53.2915 to 379.5622), including zero, hinting at potential chance findings and again high heterogeneity (I² = 98.90262%, p = 0). The high levels of I² in all cases point to a considerable variance between the studies, regardless of which individual study is excluded, which underscores the instability of the overall effect size and calls into question the robustness of the meta-analysis findings Table 3 ). Table 3 Sensitivity analysis Excluded study Pooled WMD LCI 95% HCI 95% Cochran Q p I 2 I 2 LCI 95% Atescelik 2017, Turkey 26.82536 -24.3126 77.96332 38.51121 5.44E-10 97.40335 93.48293 Atmaca et al, 2016, Turkey 137.0769 -130.507 404.6607 160.398 0 99.37655 98.87699 Kurt et al,2008, Turkey 163.1353 -53.2915 379.5622 91.12577 0 98.90262 97.7735 Discussion The potential link between Ghrelin levels and suicidality in people with depression is an emerging field of research in psychoneuroendocrinology. The study of the biological underpinnings of suicidal behaviors has sparked an interest in the involvement of Ghrelin, a hormone involved in hunger regulation and energy balance. This systematic review and meta-analysis examine the complex association between Ghrelin levels and suicidality. The meta-analysis suggests a potential link between heightened Ghrelin levels and suicidal ideation among depression patients. This association, indicated by the positive WMD, supports the notion that Ghrelin, beyond its metabolic roles, may influence neuropsychiatric processes associated with depression and suicidality. Nevertheless, the pronounced heterogeneity and indications of publication bias necessitate a prudent approach to interpreting these findings. The heterogeneity could be attributed to variations in study designs, participant populations, and Ghrelin measurement methodologies, highlighting the need for more uniform research in this field. The potential publication bias shown in the Funnel Plot complicates interpretation, suggesting the actual effect size might be overestimated. The current meta-analysis shows that Ghrelin may have a role in suicidal ideation, in addition to its established metabolic roles. This emphasizes the complexities of depression and suicidal ideation, implying the necessity for a multidimensional approach to understanding and treating these problems. The consequences for medical treatment and research are considerable. Identifying Ghrelin as a potential signal or target for treating depression and suicidal ideation could tremendously assist physicians in decision making. Monitoring Ghrelin levels in depressed people, particularly those at risk of suicide, may help guide therapy decisions and measure efficacy. Furthermore, research into the processes by which Ghrelin acts in the body may pave the way for novel approaches to treating depression in the future. Researchers have explored Ghrelin's role as a potential sensor for Deep Brain Stimulation in addressing obesity. 15 Further research is needed to determine ghrelin's role as a mediator of stress and fertility, as well as its therapeutic implications. 16 More research is needed to understand the role of Ghrelin in Alcohol Use Disorder (AUD) before it is considered a possible target for customized therapy. 17 The age-related attributes of Ghrelin may play an important role in degenerative musculoskeletal diseases. 18 Differences in study design, participant demographics, and Ghrelin measuring methods may affect the generalizability of our findings. While our study provides useful insights, these variations should be considered when interpreting our findings. Overall, while Ghrelin levels in the blood can be useful as an outcome measure in some cases, it is important to carefully consider the limitations of using this measure and to interpret the results of studies that use Ghrelin levels as an outcome measure with caution. There are several potential ways in which future research on Ghrelin and suicidality may benefit patients with suicidal thoughts or behaviors. One possibility is that Ghrelin may serve as a biomarker for suicidality, which could help identify individuals at risk for developing suicidal thoughts or behaviors. This could potentially allow for earlier identification and intervention, which may reduce the likelihood of suicidal thoughts or behaviors occurring. Another possibility is that Ghrelin may be used as a target for the development of new treatments for suicidality. For example, researchers may investigate whether modulating Ghrelin levels through medications or other interventions may be effective in reducing suicidal thoughts or behaviors. Limitations Potential biases in the papers we analyzed, such as publication bias or selective inclusion of studies, may have influenced our overall conclusions. Furthermore, sensitivity analysis revealed that excluding specific studies could modify our findings, implying that our results may be insufficiently robust. Our review included studies only from 4 major databases and articles without full text availability were excluded. Another limitation is that serum Ghrelin levels can be influenced by a variety of factors, including age, sex, body weight, and diet, which can make it difficult to interpret the results of studies that use Ghrelin levels as an outcome measure. For example, if a study is comparing the effects of two different interventions on Ghrelin levels, it may be difficult to determine whether any differences in Ghrelin levels are due to the interventions or to other factors that are not being controlled for. Conclusion Serum Ghrelin levels are significantly higher among patients with suicidality compared to healthy non-suicidal individuals. Higher Ghrelin levels may act as a biomarker for suicidality in patients with depressive disorder. However, further research studies are needed to determine the extent to which Ghrelin may be involved in the development or maintenance of suicidal thoughts or behaviors. Abbreviations GH- Growth hormone BMI- Body mass index WMD- Weighted Mean difference PRISMA- Preferred Reporting Items for Systematic reviews and Meta-Analyses Declarations Ethics approval and consent to participate Not applicable as it was a review of published literature Consent for publication Not applicable Availability of data and material All data generated or analysed during this study are included in this manuscript. Funding The authors received no financial support for the research, authorship and/or publication of this article Competing interests None declared Authors' contributions MAB conceived the idea of the manuscript. MAB & SG performed literature search and performed the analysis. PP acted as third reviewer in helping finalizing the inclusion of the studies in the SRMA and critically analyzed the manuscript. SG wrote the first draft which was subsequently revised by MAB & PP. All authors approved the final manuscript for submission. Acknowledgements Nil Declaration regarding the use of generative AI “The author(s) attest that there was no use of generative artificial intelligence (AI) technology in the generation of text, figures, or other informational content of this manuscript.” References Pradhan G, Samson SL, Sun Y. Ghrelin: much more than a hunger hormone. Curr Opin Clin Nutr Metab Care. 2013;16:619–24. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;9:656–60. Lutter M, Elmquist JK. (2009). Depression and metabolism: Linking changes in leptin and ghrelin to mood. *F1000 Biology Reports*, 1, 63. Schellekens H, Finger BC, Dinan TG, Cryan JF. Ghrelin signalling and obesity: at the interface of stress, mood and food reward. Pharmacol Ther. 2012;135:316–26. Carlini VP, Varas MM, Cragnolini AB, Schiöth HB, Scimonelli TN, de Barioglio SR. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun. 2004;16:635–41. Lis M, Miłuch T, Majdowski M, Zawodny T. A link between ghrelin and major depressive disorder: a mini review. Front Psychiatry. 2024;13:1367523. Chuang JC, Zigman JM. Ghrelin's Roles in Stress, Mood, and Anxiety Regulation. Int J Pept. 20102010,460549. Gajewska A, Strzelecki D, Gawlik-Kotelnicka O. Ghrelin as a Biomarker of Immunometabolic Depression and Its Connection with Dysbiosis. Nutrients. 2023;13:3960. St-Pierre DH, Karelis AD, Coderre L, et al. Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women. J Clin Endocrinol Metab. 2007;92:264–9. Kluge M, Schussler P, Schmid D, Uhr M, Kleyer S, Yassouridis A, Steiger A. Ghrelin plasma levels are not altered in major depression. Neuropsychobiology. 2009;59:199–204. Atescelik M, Yilmaz M, Korkmaz S, Goktekin MC, Gurger M, Ilhan N. The Relationship between Ghrelin and Copeptin Levels, and Anxiety and Depression Levels in Suicide Attempts. Clin Psychopharmacol Neurosci. 2017;31:256–60. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5. Atmaca M, Tezcan E, Parmaksiz S, Saribas M, Ozler S, Ustundag B. Serum ghrelin and cholesterol values in suicide attempters. Neuropsychobiology. 2006;54:59–63. 10.1159/000096039 . Kurt E, Güler Ö, Ozbulut O, Altinbaş K, Işingör M, Serteser M, Gecici O. Evaluation of serum ghrelin and leptin levels in suicide attempters. J Psychophysiol. 2008;22:76–80. Formolo DA, Gaspar JM, Melo HM, et al. Deep Brain Stimulation for Obesity: A Review and Future Directions. Front Neurosci. 2019;18:323. Sominsky L, Hodgson DM, McLaughlin EA et al. Linking Stress and Infertility: A Novel Role for Ghrelin. Endocr Rev 20171, 38:432–67. Morris LS, Voon V, Leggio L, Stress. Motivation, and the Gut-Brain Axis: A Focus on the Ghrelin System and Alcohol Use Disorder. Alcohol Clin Exp Res 2018 May 24: 10.1111/acer.13781 Sun J, Tan Y, Su J, Mikhail H, Pavel V, Deng Z, Li Y. Role and molecular mechanism of ghrelin in degenerative musculoskeletal disorders. J Cell Mol Med. 2023, 107. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6197084","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":437199551,"identity":"0d5c075a-f6f6-474d-a8d5-0e815db9d38b","order_by":0,"name":"MD. 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flow diagram showing the study selection process\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6197084/v1/96650c41ff8dab05ef634a33.png"},{"id":81198517,"identity":"d5af5d18-5b67-4225-b7a0-b8377de8ffba","added_by":"auto","created_at":"2025-04-23 10:48:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":24753,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForrest Plot of the included studies\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6197084/v1/c900c4dc11716d03915dbf03.png"},{"id":81197693,"identity":"093f810f-0fb0-430c-b2d6-edca9cf1fa22","added_by":"auto","created_at":"2025-04-23 10:40:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":36375,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe Funnel Plot of the studies assessing publication bias\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6197084/v1/5c5aa7e56be16dcbf6e99214.png"},{"id":81197694,"identity":"77078c20-72f9-4be2-ac6e-d3b0e23c77ec","added_by":"auto","created_at":"2025-04-23 10:40:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":10951,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDoi Plot showing Publication bias among the included studies\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6197084/v1/08774eef50e365becb2c8b64.png"},{"id":81199296,"identity":"ad37f6ec-04c7-4821-be27-edb3a7886290","added_by":"auto","created_at":"2025-04-23 10:56:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":828792,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6197084/v1/1052f58a-2fc2-46cf-a932-8a6d69bcd054.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Relationship between Serum Ghrelin and Suicidality in patients with Depression: A Systematic review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGhrelin, often called as the \"hunger hormone,\" is a multifaceted peptide produced predominantly in the stomach.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e It is intricately involved in various physiological processes including energy homeostasis, appetite regulation, and the modulation of the growth hormone release.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Beyond its metabolic roles, Ghrelin has been implicated in the neurobiological pathways associated with mood regulation, suggesting a potential link between metabolic states and psychiatric conditions such as depression and anxiety.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDepression is a pervasive psychiatric disorder characterized by persistent sadness, loss of interest in enjoyable activities, and a heightened risk of suicidality. The complex interplay between depression and physiological factors, including hormonal imbalances, has been the subject of extensive research. Among the hormones investigated, Ghrelin has emerged as a potential biomarker due to its influence on mood and stress response systems.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRecent studies have indicated that ghrelin's role extends beyond simple appetite regulation, hinting at its involvement in the stress response and emotional regulation circuits within the brain.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e This has led researchers to speculate about the hormone's potential involvement in the aetiology of psychiatric disorders, particularly depression and anxiety. The association between Ghrelin levels and depression has been noted in several studies, with some reporting lower levels of Ghrelin in depressed individuals compared to healthy controls, suggesting a potential dysregulation of appetite and energy homeostasis in depression.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Conversely, the relationship between Ghrelin and suicidality\u0026mdash;a severe and often terminal manifestation of psychiatric disorders\u0026mdash;remains under-explored. Suicidal ideation and behaviors are complex phenomena influenced by a myriad of psychological, social, and biological factors. The potential role of Ghrelin in modulating stress responses and emotional states raises questions about its involvement in suicidality among depressed patients.\u003c/p\u003e \u003cp\u003eFurthermore, inconsistencies in the literature regarding Ghrelin levels in different psychiatric conditions highlight the hormone's complex role and the influence of various confounding factors such as age, sex, body mass index (BMI), and nutritional status. These factors can significantly impact ghrelin's secretion and action, thereby complicating the interpretation of its association with psychiatric symptoms. \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe aim of this systematic review and meta-analysis is to synthesize existing research on the association between Ghrelin levels and suicidal ideation in patients with depression. By integrating findings from diverse studies, this review seeks to clarify the role of Ghrelin in the context of depression and suicidality, addressing the heterogeneity in previous research and exploring potential moderating factors such as demographic and lifestyle variables. In doing so, this review will contribute to a more understanding of ghrelin's role in depression and suicidality, potentially paving the way for novel diagnostic and therapeutic approaches that target the ghrelinergic system in psychiatric disorders.\u003c/p\u003e"},{"header":"Material \u0026 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch Strategy\u003c/h2\u003e \u003cp\u003eA comprehensive literature search was conducted across several databases, including PubMed, Medline, Google Scholar, Embase, CINHL and the Cochrane Library, to ensure a wide coverage of relevant literature. The search was performed by a combination of keywords: \"Ghrelin\" in conjunction with \"Depression,\" \"Depressive Disorder,\" \"Suicide,\" \"Suicidal ideation,\" or \"Suicidality.\" The search strategy was meticulously designed to capture all pertinent studies, adhering to the protocol. The review was registered at PROSPERO with registration Id CRD42024547555 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024547555\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024547555\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Two independent reviewers systematically evaluated the studies for inclusion and exclusion, resolving any discrepancies through discussion or consultation with a third reviewer.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCondition or domain being studied\u003c/h3\u003e\n\u003cp\u003eThe digestive hormone, Ghrelin has both peripheral and cerebral effects, including the control of neurovegetative processes and reward neuronal circuits. Therefore, the physiological effects of Ghrelin may mitigate depressed symptoms such decreased appetite, sleep disturbances, and anhedonia. This review focuses on the interplay between Ghrelin levels and their potential impact on depressive symptoms and suicidal tendency, considering the hormone's dual role in metabolic and neuropsychiatric processes. The review aims to elucidate whether Ghrelin can serve as a biomarker or a therapeutic target for depression with a particular emphasis on suicidality, addressing the need for innovative treatment approaches beyond traditional modalities.\u003c/p\u003e\n\u003ch3\u003eInclusion/Exclusion Criteria\u003c/h3\u003e\n\u003cp\u003eOriginal studies were selected based on their focus on patients diagnosed with depression, exhibiting suicidal tendencies, and comparisons with healthy controls. Only studies providing clear data on Ghrelin levels in these populations were considered. Exclusion criteria encompassed studies lacking direct measurement of Ghrelin levels, case reports, case series, reviews, and studies not published in English.\u003c/p\u003e\n\u003ch3\u003eData Extraction method\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers screened the titles and abstracts from the search results to identify relevant studies. Full texts of the identified studies were then accessed for detailed assessment. Data were meticulously extracted and recorded in a predefined Microsoft Excel template, capturing essential information such as authors, publication year, study design, population characteristics, sample size, interventions, comparators, Ghrelin measurement methods, and outcomes.\u003c/p\u003e\n\u003ch3\u003eRisk of Bias Assessment\u003c/h3\u003e\n\u003cp\u003eThe risk of bias in individual studies was evaluated using the Newcastle\u0026ndash;Ottawa Scale, \u003cem\u003ea\u003c/em\u003e comprehensive tool designed for the assessment of non-randomized studies in meta-analyses.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eOutcome Indicators\u003c/h2\u003e \u003cp\u003eThe primary outcome of interest was serum Ghrelin levels in individuals with Suicidality/suicidal attempt in comparison to healthy controls.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eRaw data from the included individual studies were used in this meta-analysis. Data were entered into Microsoft Excel. Meta-analyses were performed using the software MetaXL version 5.3 using a random effect model. Relevant summary measures of efficacy were assessed using the standardized mean difference (SMD) for applicable variables along with the corresponding 95% confidence interval (CI). Statistical heterogeneity, which was quantified using the I\u0026sup2; statistics and Publication bias was assessed by plotting funnel and Doi plots.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthical considerations\u003c/h3\u003e\n\u003cp\u003eThe Institute Human Ethics Committee(IEC), All India Institute of Medical Sciences, Gorakhpur(UP) waived the ethical approval for the review vide letter IHEC/AIIMS/2024/342.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eScreening Strategy\u003c/h2\u003e \u003cp\u003eThe screening strategy followed the four stages outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework, which encompassed identifying, screening, determining eligibility of papers, and finalizing the list of articles for inclusion in this review. Initially, a pool of 249 documents was amassed through searches on PubMed, Google Scholar, Ovid, and CINAHL databases. These documents, along with their references, were exported in CSV format and subsequently downloaded for screening. The screening process involved multiple rounds aimed at isolating relevant articles. Initially, 31 duplicate records were identified and removed, resulting in 218 unique documents. Subsequently, the titles and abstracts of these 218 documents were scrutinized to ensure alignment with the research focus on Ghrelin levels and suicide. Of these, 190 documents were deemed unrelated to the topic and were consequently excluded. The screening process continued based on predefined inclusion criteria, leading to the identification and exclusion of 18 different publication types and 7 different outcomes. Screening was carried out independently by three coauthors, with any discrepancies or controversial articles deliberated upon in team meetings to achieve consensus. Following rigorous screening and discussions, finally 3 articles were considered eligible for the review \u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStudy Characteristics\u003c/h2\u003e \u003cp\u003eAll 3 included studies were case-control studies with suicide attempters taken as the cases and healthy non-suicide attempters as controls. All other characteristics of the included studies are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the studies included for meta-analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor/Year/Country\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy Design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eParticipants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOutcome Measure Related to Suicide or Self-Harm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePopulation/ Setting\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtescelik M et al., 2017, Turkey\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e128 patients with suicide attempts and 59 healthy controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLevels of acylated Ghrelin (AG), unacylated Ghrelin (UG), and copeptin. Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) scores\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEmergency department patients with suicide attempts vs. healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtmaca M et al., 2006, Turkey\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 patients with suicide attempts and 30 healthy controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum total cholesterol and Ghrelin levels\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatients admitted to a university hospital with suicide attempts vs. healthy controls\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKurt E et al.,2008, Turkey\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase-control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 patients with suicide attempts and 25 healthy controls\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSerum levels of cholesterol, leptin, and Ghrelin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatients with suicide attempts admitted to the emergency unit or psychiatric clinic vs. healthy staff members\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eQuality Assessment\u003c/h2\u003e \u003cp\u003eThe quality of the included studies, assessed using the Newcastle-Ottawa Scale (NOS), indicated that the included studies were of moderate to good quality, with scores ranging from 6 to 7 out of a possible of 9 (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Most studies performed well in the 'Outcome' domain, suggesting that the measurement of outcomes related to suicidality and Ghrelin levels was generally robust. However, there were some limitations in the 'Selection' and 'Comparability' domains, highlighting potential areas for improvement in future research.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eQuality assessment of the included studies by the Newcastle\u0026ndash;Ottawa Scale\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst Author\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSelection\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eComparability\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal Score\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtmaca M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase- control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAetscelik M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase- control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKurt E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase- control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eMeta analysis\u003c/h2\u003e \u003cp\u003ePooling the results, the meta-analysis indicates an average increase of 106.01 units in Ghrelin levels in the active groups compared to the controls. This effect is statistically significant given the confidence interval range from 16.80 to 195.22, which doesn't cross the null effect line (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThere is substantial heterogeneity across the studies, with an I\u0026sup2; close to 99% and a Cochran's Q statistic of 198.77 with a p-value of zero. Such a high level of heterogeneity points towards significant variability in the effects across the studies.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003ePublication Bias\u003c/h2\u003e \u003cp\u003eThe Funnel Plot (Fig.\u0026nbsp;3) indicates possible publication bias or small-study effects, as evidenced by the asymmetrical distribution of studies, particularly a shortage of smaller studies with negative or null outcomes. This asymmetry implies concerns about the representativeness of the included studies and the potential overestimation of the effect size due to unpublished negative findings.\u003c/p\u003e \u003cp\u003eThe Doi plot displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, with its accompanying Luis Fukuyama-Kanamori (LFK) index of 9.01, suggests significant asymmetry in the meta-analysis, indicative of major publication bias or small-study effects. This is far beyond the threshold that would signify minor asymmetry (an LFK index between 1 and 2), raising substantial concerns about the reliability of the meta-analysis results. The data points\u0026rsquo; deviation from the expected distribution underlines the possibility that smaller or less statistically significant studies may be missing from the analysis, potentially skewing the overall effect size. Such a pronounced index value suggests a need for cautious interpretation of the findings and consideration of additional research, including unpublished studies, to achieve a more comprehensive and balanced overview of the effects being measured.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eThe sensitivity analysis of the meta-analysis demonstrates significant shifts in the pooled Weighted Mean Difference (WMD) and persistent heterogeneity upon the sequential exclusion of individual studies. Excluding Atescelik 2017 decreases the pooled WMD to 26.82536, with a confidence interval spanning across zero (-24.3126 to 77.96332), indicating a loss of statistical significance and persistent high heterogeneity (I\u0026sup2;= 97.40335%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). When Atmaca et al., 2016, is omitted, the WMD jumps to 137.0769, yet with a confidence interval (-130.507 to 404.6607) so wide that it questions the precision of this estimate, alongside extreme heterogeneity (I\u0026sup2; = 99.37655%, p\u0026thinsp;=\u0026thinsp;0). The exclusion of Kurt et al., 2008, yields a WMD of 163.1353 but with a similarly wide confidence interval (-53.2915 to 379.5622), including zero, hinting at potential chance findings and again high heterogeneity (I\u0026sup2; = 98.90262%, p\u0026thinsp;=\u0026thinsp;0). The high levels of I\u0026sup2; in all cases point to a considerable variance between the studies, regardless of which individual study is excluded, which underscores the instability of the overall effect size and calls into question the robustness of the meta-analysis findings Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitivity analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExcluded study\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePooled WMD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLCI 95%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHCI 95%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCochran Q\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eI\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eI\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e LCI 95%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtescelik 2017, Turkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26.82536\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-24.3126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e77.96332\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e38.51121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.44E-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e97.40335\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e93.48293\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtmaca et al, 2016, Turkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e137.0769\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-130.507\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e404.6607\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e160.398\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e99.37655\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e98.87699\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKurt et al,2008, Turkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e163.1353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-53.2915\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e379.5622\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e91.12577\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e98.90262\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e97.7735\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe potential link between Ghrelin levels and suicidality in people with depression is an emerging field of research in psychoneuroendocrinology. The study of the biological underpinnings of suicidal behaviors has sparked an interest in the involvement of Ghrelin, a hormone involved in hunger regulation and energy balance. This systematic review and meta-analysis examine the complex association between Ghrelin levels and suicidality.\u003c/p\u003e \u003cp\u003eThe meta-analysis suggests a potential link between heightened Ghrelin levels and suicidal ideation among depression patients. This association, indicated by the positive WMD, supports the notion that Ghrelin, beyond its metabolic roles, may influence neuropsychiatric processes associated with depression and suicidality. Nevertheless, the pronounced heterogeneity and indications of publication bias necessitate a prudent approach to interpreting these findings. The heterogeneity could be attributed to variations in study designs, participant populations, and Ghrelin measurement methodologies, highlighting the need for more uniform research in this field. The potential publication bias shown in the Funnel Plot complicates interpretation, suggesting the actual effect size might be overestimated.\u003c/p\u003e \u003cp\u003eThe current meta-analysis shows that Ghrelin may have a role in suicidal ideation, in addition to its established metabolic roles. This emphasizes the complexities of depression and suicidal ideation, implying the necessity for a multidimensional approach to understanding and treating these problems. The consequences for medical treatment and research are considerable. Identifying Ghrelin as a potential signal or target for treating depression and suicidal ideation could tremendously assist physicians in decision making. Monitoring Ghrelin levels in depressed people, particularly those at risk of suicide, may help guide therapy decisions and measure efficacy. Furthermore, research into the processes by which Ghrelin acts in the body may pave the way for novel approaches to treating depression in the future.\u003c/p\u003e \u003cp\u003eResearchers have explored Ghrelin's role as a potential sensor for Deep Brain Stimulation in addressing obesity.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e Further research is needed to determine ghrelin's role as a mediator of stress and fertility, as well as its therapeutic implications.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e More research is needed to understand the role of Ghrelin in Alcohol Use Disorder (AUD) before it is considered a possible target for customized therapy.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e The age-related attributes of Ghrelin may play an important role in degenerative musculoskeletal diseases. \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDifferences in study design, participant demographics, and Ghrelin measuring methods may affect the generalizability of our findings. While our study provides useful insights, these variations should be considered when interpreting our findings. Overall, while Ghrelin levels in the blood can be useful as an outcome measure in some cases, it is important to carefully consider the limitations of using this measure and to interpret the results of studies that use Ghrelin levels as an outcome measure with caution.\u003c/p\u003e \u003cp\u003eThere are several potential ways in which future research on Ghrelin and suicidality may benefit patients with suicidal thoughts or behaviors. One possibility is that Ghrelin may serve as a biomarker for suicidality, which could help identify individuals at risk for developing suicidal thoughts or behaviors. This could potentially allow for earlier identification and intervention, which may reduce the likelihood of suicidal thoughts or behaviors occurring. Another possibility is that Ghrelin may be used as a target for the development of new treatments for suicidality. For example, researchers may investigate whether modulating Ghrelin levels through medications or other interventions may be effective in reducing suicidal thoughts or behaviors.\u003c/p\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003ePotential biases in the papers we analyzed, such as publication bias or selective inclusion of studies, may have influenced our overall conclusions. Furthermore, sensitivity analysis revealed that excluding specific studies could modify our findings, implying that our results may be insufficiently robust. Our review included studies only from 4 major databases and articles without full text availability were excluded.\u003c/p\u003e \u003cp\u003eAnother limitation is that serum Ghrelin levels can be influenced by a variety of factors, including age, sex, body weight, and diet, which can make it difficult to interpret the results of studies that use Ghrelin levels as an outcome measure. For example, if a study is comparing the effects of two different interventions on Ghrelin levels, it may be difficult to determine whether any differences in Ghrelin levels are due to the interventions or to other factors that are not being controlled for.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSerum Ghrelin levels are significantly higher among patients with suicidality compared to healthy non-suicidal individuals. Higher Ghrelin levels may act as a biomarker for suicidality in patients with depressive disorder. However, further research studies are needed to determine the extent to which Ghrelin may be involved in the development or maintenance of suicidal thoughts or behaviors.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGH- Growth hormone\u003c/p\u003e\n\u003cp\u003eBMI- Body mass index\u003c/p\u003e\n\u003cp\u003eWMD- Weighted Mean difference\u003c/p\u003e\n\u003cp\u003ePRISMA- Preferred Reporting Items for Systematic reviews and Meta-Analyses\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate Not applicable as it was a review of published literature\u003c/p\u003e\n\u003cp\u003eConsent for publication Not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and material All data generated or analysed during this study are included in this manuscript.\u003c/p\u003e\n\u003cp\u003eFunding The authors received no financial support for the research, authorship and/or publication of this article\u003c/p\u003e\n\u003cp\u003eCompeting interests None declared\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions MAB conceived the idea of the manuscript. MAB \u0026amp; SG performed literature search and performed the analysis. PP acted as third reviewer in helping finalizing the inclusion of the studies in the SRMA and critically analyzed the manuscript. SG wrote the first draft which was subsequently revised by MAB \u0026amp; PP. All authors approved the final manuscript for submission.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgements Nil\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDeclaration regarding the use of generative AI \u0026ldquo;The author(s) attest that there was no use of generative artificial intelligence (AI) technology in the generation of text, figures, or other informational content of this manuscript.\u0026rdquo;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePradhan G, Samson SL, Sun Y. Ghrelin: much more than a hunger hormone. Curr Opin Clin Nutr Metab Care. 2013;16:619\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;9:656\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLutter M, Elmquist JK. (2009). Depression and metabolism: Linking changes in leptin and ghrelin to mood. *F1000 Biology Reports*, 1, 63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchellekens H, Finger BC, Dinan TG, Cryan JF. Ghrelin signalling and obesity: at the interface of stress, mood and food reward. Pharmacol Ther. 2012;135:316\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarlini VP, Varas MM, Cragnolini AB, Schi\u0026ouml;th HB, Scimonelli TN, de Barioglio SR. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun. 2004;16:635\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLis M, Miłuch T, Majdowski M, Zawodny T. A link between ghrelin and major depressive disorder: a mini review. Front Psychiatry. 2024;13:1367523.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChuang JC, Zigman JM. Ghrelin's Roles in Stress, Mood, and Anxiety Regulation. Int J Pept. 20102010,460549.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGajewska A, Strzelecki D, Gawlik-Kotelnicka O. Ghrelin as a Biomarker of Immunometabolic Depression and Its Connection with Dysbiosis. Nutrients. 2023;13:3960.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSt-Pierre DH, Karelis AD, Coderre L, et al. Association of acylated and nonacylated ghrelin with insulin sensitivity in overweight and obese postmenopausal women. J Clin Endocrinol Metab. 2007;92:264\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKluge M, Schussler P, Schmid D, Uhr M, Kleyer S, Yassouridis A, Steiger A. Ghrelin plasma levels are not altered in major depression. Neuropsychobiology. 2009;59:199\u0026ndash;204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtescelik M, Yilmaz M, Korkmaz S, Goktekin MC, Gurger M, Ilhan N. The Relationship between Ghrelin and Copeptin Levels, and Anxiety and Depression Levels in Suicide Attempts. Clin Psychopharmacol Neurosci. 2017;31:256\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAtmaca M, Tezcan E, Parmaksiz S, Saribas M, Ozler S, Ustundag B. Serum ghrelin and cholesterol values in suicide attempters. Neuropsychobiology. 2006;54:59\u0026ndash;63. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000096039\u003c/span\u003e\u003cspan address=\"10.1159/000096039\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKurt E, G\u0026uuml;ler \u0026Ouml;, Ozbulut O, Altinbaş K, Işing\u0026ouml;r M, Serteser M, Gecici O. Evaluation of serum ghrelin and leptin levels in suicide attempters. J Psychophysiol. 2008;22:76\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFormolo DA, Gaspar JM, Melo HM, et al. Deep Brain Stimulation for Obesity: A Review and Future Directions. Front Neurosci. 2019;18:323.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSominsky L, Hodgson DM, McLaughlin EA et al. Linking Stress and Infertility: A Novel Role for Ghrelin. Endocr Rev 20171, 38:432\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorris LS, Voon V, Leggio L, Stress. Motivation, and the Gut-Brain Axis: A Focus on the Ghrelin System and Alcohol Use Disorder. Alcohol Clin Exp Res 2018 May 24: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/acer.13781\u003c/span\u003e\u003cspan address=\"10.1111/acer.13781\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun J, Tan Y, Su J, Mikhail H, Pavel V, Deng Z, Li Y. Role and molecular mechanism of ghrelin in degenerative musculoskeletal disorders. J Cell Mol Med. 2023, 107.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Serum Ghrelin, Suicidality, Case control, Depression, Relationship","lastPublishedDoi":"10.21203/rs.3.rs-6197084/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6197084/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGhrelin, an orexigenic peptide hormone, mainly stimulates appetite and the release of growth hormone (GH). However, beyond its metabolic roles, Ghrelin has been implicated in the neurobiological pathways associated with mood regulation, suggesting a potential link between metabolic states and psychiatric conditions such as depression. The relationship between Ghrelin and suicidality, a severe and often terminal manifestation of psychiatric disorders remains under-explored.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the relationship between serum Ghrelin and suicidality in patients with depression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA systematic review and meta-analysis following PRISMA guideline was performed using PubMed, Medline, Embase, CINHL and Google Scholar in June, 2024. Two independent reviewers systematically evaluated the studies for inclusion and any disagreement was resolved by consulting a third reviewer. Meta analysis of the included studies was performed using MetaXL software version 5.3. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale, and the risk of publication bias was assessed using a plotting funnel and Doi plots.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOut of 249 studies identified through the database search, finally 3 studies were found eligible comprising of 302 participants. Pooling the results, the meta-analysis indicates an average increase (Effect size) of 106.01 units in serum Ghrelin levels among patients with suicidality over controls. This effect is statistically significant given the confidence interval range from 16.80 to 195.22. The heterogeneity across the studies was substantial, with an I² close to 99% and a Cochran's Q statistic of 198.77. The Funnel Plot revealed asymmetrical distribution of studies, particularly a shortage of smaller studies with negative or null outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum Ghrelin levels are found to be significantly elevated among individuals with suicidality compared to healthy controls. However, high heterogeneity across the studies limits the findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Number:-\u003c/strong\u003eNot Applicable\u003c/p\u003e","manuscriptTitle":"Relationship between Serum Ghrelin and Suicidality in patients with Depression: A Systematic review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-23 10:40:44","doi":"10.21203/rs.3.rs-6197084/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"27fd6444-9e6c-4e6d-b650-9866e0c18c3f","owner":[],"postedDate":"April 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-04-23T10:40:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-23 10:40:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6197084","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6197084","identity":"rs-6197084","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}