Skip to main content

The role of ghrelin peptide among a sample of Egyptian patients with first episode of major depressive disorder



Major depressive disorder (MDD) is a prominent psychiatric disorder that significantly reduces living quality and increases the risk of suicide. Ghrelin influences the central nervous system (CNS) and impacts reward, inspiration, and signaling pathways in addition to acting as an appetite signal. This case-controlled comparative study focused on the association between serum ghrelin levels and MDD. The study was done during September 2021 and March 2022 on 25 people with MDD and 25 healthy controls. SCID-1 and the Ham-D 17 scales were used to evaluate the cases. The GHQ scale was used to evaluate the controls. The serum ghrelin levels of all samples were determined. The findings were presented, and statistically analyzed to perform an accurate assessment.


There were 50 subjects: 25 cases of MDD and 25 healthy matched controls with non-statistically significant difference to cases as regard gender, marital status, residence, education, age, height, weight and body mass index (BMI). Total serum ghrelin levels among our cases showed a mean value of 4.152, while the controls showed markedly low values, with a mean value of 0.436, showing a statistically significant difference between both groups with p < 0.001. Furthermore, Post Hoc analysis by least significant difference showed a significant difference between mild-severe and moderate-severe groups, although there was no statistically significant difference between mild and moderate groups.


There was a significant indirect correlation between serum ghrelin level and severity of the illness. Further investigations via longitudinal studies and on larger samples are recommended to settle specific causal paths between the two variables.


Major depressive disorder (MDD) is a common, progressive, and frequently chronic illness with poorly understood fundamental neural mechanisms that explain why certain people are more sensitive to stressors than others [1]. According to latest published statistics, 16.6% of individuals have experienced depression at some point in their lives, and the incidence of MDD is 6.6% per year. It was discovered that major depression is linked to lifetime incidences of isolated manic or hypomanic symptoms in up to 40% of patients, as well as the presence of anxiety [2, 3].

The control of mood and the expression of feelings involve many various regions of the brain. Neuroimaging and neuropathological experiments have shown that such regions including the medial prefrontal cortex, the caudolateral orbital cortex, the amygdala, the hippocampus, and the ventromedial parts of the basal ganglia are links that regulate emotional behavior, and there is proof that their role is changed in people with MDD. The above-mentioned brain regions are not only linked to MDD, but they also have major roles in eating habits and hormones associated with nutrition, such as ghrelin and leptin [4, 5].

Ghrelin is a 28-amino acid peptide, secreted by the stomach and functions as an orexigenic hormone. Other peripheral organs such as the testis, placenta, kidney, small intestine, pancreas, and in specific neuronal cells of the hypothalamus, do secrete it but at a much lower level. It is responsible for communicating the negative energy state with neuronal centers to stimulate feeding responses; moreover, it is considered the natural endogenous ligand for the growth hormone secretagogue receptor [6].

The link between ghrelin and MDD is still debatable, with several studies conducted on animals reported conflicting results, while a few have suggested that ghrelin may be an anxiety-inducing hormone, others have suggested that it might have antidepressant and anxiety-provoking effects [7]. Ghrelin levels in depression patients have also yielded conflicting results. While recent reports claim decreased ghrelin levels in depressed patients, others show no distinction in ghrelin levels among depression patients and healthy individuals. However, several investigations discovered elevated serum ghrelin levels in people with significant depression [8, 9]. This study aims to analyze the correlation between the development of ghrelin in the blood and the degree of major depressive disorder.


The study was carried out at Okasha Institute of Psychiatry, Ain Shams University, Cairo, during September 2021 and March 2022 on 25 control participants and 25 patients of both genders (males and females) with first episode of MDD and age range from 18 to 65 years old. However, cases were excluded from this study if they included a diagnosis of any co-morbid axis I or history of substance use disorder, inability to cooperate or complete the interview due to any cognitive impairment, or severe physical illness, chronic relapsing MDD, or received any medical treatment for MDD.

All patients were assessed by a treating team consisting of two or more psychiatrists. Subjects who fulfilled the inclusion criteria were asked to participate after explaining the study proper and to provide informed written consent. After building rapport, a detailed psychiatric interview of the available subjects was done to collect socio-demographic and clinical data including age, gender, weight, height, BMI, and mental state examination using Structured Clinical Interview for DSM-IVTM axis I disorders (SCID-I) [10]. Other scales were applied including the Hamilton Depression Scale (Ham-D 17) [11, 12] to assess the cases and General Health Questionnaire-28 (GHQ-28) for controls [13, 14] as well as Visual Analog Scale of Hunger [15]. Blood samples were collected from controls and patients. Samples were analyzed in the Central Laboratory of Ain Shams University Hospitals using the total serum ghrelin ELISA kits.

Statistical analysis

The collected data were revised, coded, tabulated, and introduced to a PC using the Statistical Package for Social Science (SPSS 20). Data were represented as means, standard deviation (± SD), and range for parametric numerical data while the median and interquartile range (IQR) was used for non-parametric numerical data as well as frequency and percentage of non-numerical data. Student’s t test, ANOVA, post hoc analysis, chi-square test, and correlation analysis were used to fully analyze the results, where p > 0.05: non-significant; p < 0.05: significant; p < 0.01: highly significant.


The goal of this case–control study, conducted in light of the fact that previous studies produced contradictory findings, is to evaluate the serum ghrelin level in cases of major depressive disorder in the first episode and its relationship to the psychopathological aspect of the illness.

Clinical and demographic information about the research participants

The total sample was divided into two major groups: “cases” and “healthy controls.” As regards our cases, demographic data illustrated that most of the cases were females (68%), married (56%), postgraduate (56%), unemployed (68%), and living in urban areas (80%), with the mean age of the cases being 34.56 ± 11.47 years and BMI 26.19 (± 4.06). Medical history showed statistically significant differences between cases and controls (p < 0.001); e.g., about 60% of cases had a positive medical history while only 8% of controls had a past medical history. Meanwhile, our results showed there were no smokers among controls while smokers constituted 16% of cases; however, there was no statistically significant difference in substance use between the groups (p = 0.118) as shown in Tables 1 and 2.

Table 1 The demographic and clinical data of cases and controls
Table 2 Serum ghrelin level among cases and controls

Total serum ghrelin in relation to demographic, anthropometric, and clinical features

Upon assessing the relationship between the total serum ghrelin level and the demographic features of the cases, a relation was found between serum ghrelin level and gender, marital status, residence, education, occupation, and medical history; all factors showed a non-statistically significant relation except substance use, which showed a statistically significant relation and where serum ghrelin level increased among those with positive history of substance use, with p = 0.006 as shown in (Table 3).

Table 3 Serum ghrelin in relation to demographic data and medical history of cases

Average total ghrelin level between various levels of depression severity

Post hoc analysis by least significant difference (LSD) showed that total serum ghrelin level to Hamilton scale scores had a statistically significant relation, with p = 0.018, being most significant between mild to severe groups and moderate to severe (p = 0.019 and 0.021, respectively) as shown in Table 4.

Table 4 Average total ghrelin level among different severity degrees of depression

Correlation analysis

Correlation of total serum ghrelin level to either age or the visual analog scale for hunger (VAS) showed an indirect correlation while being directly correlated to weight, height, and BMI; however, all values were insignificant. Moreover, upon correlating total serum ghrelin and Hamilton scores, an indirect correlation was found, which was statistically significant with p = 0.030 as shown in Table 5 and Fig. 1.

Fig. 1
figure 1

The significant inverse relationship between severity of depression and serum ghrelin level

Table 5 Study correlations with serum ghrelin level


The concentration of total serum ghrelin in depression has lately been studied and numerous researchers have demonstrated a connection between it and major depressive disorder, either as a risk factor or a protective factor. To the best of our knowledge, no studies on Egyptian participants have looked at blood ghrelin levels in depression. To illustrate this topic of study, we conducted a case-controlled study at the Okasha Institute of Psychiatry, Ain Shams University, Cairo, Egypt. We evaluated the hypothesis that there is a relationship between serum ghrelin and MDD, and if there is, whether or not it is linked to the incidence of MDD.

In terms of demographics, our findings revealed that roughly 70% of the patients were female. This is consistent with the research on ghrelin in Japan [16] and how it impacts depressive status, where females made up about two-thirds of the study participants, and given the WHO’s announcement that depression is more common in women globally in 2021. These results may be explained by the fact that women are more susceptible to disease because of the way their hormonal system affects pathophysiology [17]. Additionally, the findings of this study indicated that major depressive disorder was more common among young people, correlating with findings in China [18], which noted that the incidence of depression in adolescents was 24–34%. Additionally, these findings are consistent with the global statistics of the illness, which may be described by the presence of various environmental triggers in this age category. Additionally, our study revealed that the majority of patients were unemployed and from urban areas, demonstrating the critical role that social and environmental stressors play in the pathology of depression in accordance with other published work [19]. As a result, depression is more common in low- and middle-income, densely populated communities as noted in numerous studies, including those by investigators in the USA [20] and in Iran [21].

According to the DSM-IV diagnostic criteria, our study found statistically significant elevations in serum total ghrelin levels in clinically depressed patients, with a mean value of 4.152 (± 1.424) ng/mL compared to 0.436 (± 0.155) ng/mL in the healthy control group (p = 0.001). In reports published by Turkish groups [22, 23], total ghrelin levels in depressive patients were assessed. The mean value for the cases was 1.76 ng/mL, whereas the mean value for the controls was 0.601 ng/mL. Ghrelin levels were measured in depressed workers in Japan [24,25,26], revealing that total ghrelin levels are higher in depressed people. Auto-regulatory mechanisms that increase serum ghrelin levels to treat depressive status could account for elevated serum levels in depression. In addition to being the hunger hormone, ghrelin is thought to be neuroprotective, reducing cellular death and aging. In an attempt to prevent disease development, it is raised in MDD as a result of chronic stress and a malfunctioning HPA axis in depression. It also has a demonstrated involvement in hippocampus neurogenesis, which may be mediated through estrogen and BDNF [7, 27]. For further investigation and confirmation of these findings, other population studies are required.

Ghrelin was found to have a depressogenic effect in long-term research by van Andel and her colleagues in The Netherlands in [28]. Median total ghrelin levels were found to be 0.93 ng/mL for the cases and 0.89 ng/mL for the controls, with no statistically significant difference between the two groups. These conclusions might have been reached as a result of the various study designs, older age groups, and diverse ethnicities. A possible explanation is that prolonged ghrelin release under chronic stress activates the HPA axis, leading to depressive-like behaviors.

This study confirmed that total ghrelin level is not related to gender or prior medical history. Despite this, our research showed a relationship between smoking and serum ghrelin, with a p-value of 0.006, indicating a substantial association between tobacco use and higher ghrelin levels. A research group in the USA reported similar findings among a group of smokers, finding that relapsers had greater ghrelin levels than non-smokers, with a -value of 0.05 [29]. Additionally, Chao et al. [30] in the USA investigated the relationship between cigarette smoking and depression symptoms, and came to the conclusion that chronic smokers with depressive symptoms had raised total ghrelin levels when compared to non-smokers and ex-smokers. This could be explained by the mesolimbic system function of ghrelin, its link to impulsive behavior, and its activation of the reward circuits, all of which boost drug seeking behavior. Another factor is the interference with hormone control brought on by long-term tobacco usage [31]. Moreover, our study demonstrated an indirect relationship between total serum ghrelin levels and depression severity, with serum ghrelin levels falling as depression severity elevated. Numerous study teams found a significant link between rising serum ghrelin levels and growing depression severity [32]. Other research found no link between ghrelin levels and the degree of depression [26, 33, 34]. These differences could be explained by patients’ varying depressive symptomatology, the study’s smaller sample size, the use of various scales to gauge the severity of the depression, or perhaps a different method of sample collection.


Our study had a number of limitations. First, it was a cross-sectional study so it was difficult to draw any firm conclusions on the causal relationship between the two variables. The healthy people were chosen and no more tests were performed to look for any ailments that had not yet been detected. The exclusion criteria were only met by a person’s medical history. There were more female participants in the sample. To investigate any potential effect of gender differences, it would be advantageous to obtain a larger sample with more male participants. It was difficult to determine whether acylated or des-acylated ghrelin was involved in the pathophysiology of major depressive disorder because only total serum ghrelin was measured.


According to the current investigation, major depressive disorder patients’ serum ghrelin levels are noticeably higher than those of comparable healthy controls. In addition, our research revealed an indirect link between serum ghrelin levels and the severity of major depressive disorder.

Availability of data and materials

All generated or analyzed data during this study are included in the published work.



Major depressive disorder


Body mass index


Structured Clinical Interview for DSM-IVTM axis I disorders Hamilton Depression

Ham-D 17:

Hamilton Depression Scale


General Health Questionnaire-28


Least significant difference


Visual analog scale for hunger


Standard deviation


Enzyme-linked immunosorbent assay


  1. Trivedi MH (2020) Major depressive disorder in primary care: strategies for identification. J Clin Psychiatry 81(2):UT17042BR1C.

    Article  Google Scholar 

  2. Boku S, Nakagawa S, Toda H, Hishimoto A (2018) Neural basis of major depressive disorder: Beyond monoamine hypothesis. Psychiatry Clin Neurosci 72(1):3–12.

    Article  CAS  Google Scholar 

  3. Kennedy SH, Ceniti AK (2018) Unpacking major depressive disorder: from classification to treatment selection. Can J Psychiatry 63(5):308–313.

    Article  Google Scholar 

  4. Schiller M, Ben-Shaanan TL, Rolls A (2021) Neuronal regulation of immunity: why, how and where? Nat Rev Immunol 21(1):20–36.

    Article  CAS  Google Scholar 

  5. Wen X, Liu Y, Zhao P, Liu Z, Li H, Li W, Zhu Z, Wu X (2021) Disrupted communication of the temporoparietal junction in patients with major depressive disorder. Cogn Affect Behav Neurosci 21(6):1276–1296.

    Article  Google Scholar 

  6. Naufel MF, Pedroso AP, Oyama LM, Telles MM, Hachul H, Ribeiro EB (2021) Preliminary evidence of acylated ghrelin association with depression severity in postmenopausal women. Sci Rep 11(1):5319.

    Article  CAS  Google Scholar 

  7. Ozsoy S, Besirli A, Abdulrezzak U, Basturk M (2014) Serum ghrelin and leptin levels in patients with depression and the effects of treatment. Psychiatry Investig 11(2):167–172.

    Article  CAS  Google Scholar 

  8. Wang P, Li B, Fan J, Zhang K, Yang W, Ren B, Cui R (2019) Additive antidepressant-like effects of fasting with β-estradiol in mice. J Cell Mol Med 23(8):5508–5517.

    Article  CAS  Google Scholar 

  9. Choi W, Kim JW, Kang HJ, Kim HK, Kang HC, Lee JY, Kim SW, Stewart R, Kim JM (2021) Synergistic effects of resilience and serum ghrelin levels on the 12-week pharmacotherapeutic response in patients with depressive disorders. J Affect Disord 295:1489–1493.

    Article  CAS  Google Scholar 

  10. First MB, Spitzer RL, Gibbon M, Williams JBW et al (1995) The structured clinical interview for DSM-III-R personality disorders (SCID-II): II. Multi-site test-retest reliability study. J Personal Disord 9(2):92–104.

    Article  Google Scholar 

  11. Alhadi AN, Alarabi MA, Alshomrani AT, Shuqdar RM, Alsuwaidan MT, McIntyre RS (2018) Arabic translation, validation and cultural adaptation of the 7-item Hamilton Depression Rating Scale in two community samples. Sultan Qaboos Univ Med J 18(2):e167–e172.

    Article  Google Scholar 

  12. Bagby RM, Ryder AG, Schuller DR, Marshall MB (2004) The Hamilton Depression Rating Scale: has the gold standard become a lead weight? Am J Psychiatry 161(12):2163–2177.

    Article  Google Scholar 

  13. Okasha A (1988) Okasha’s clinical psychiatry (Arabic version of General Health Questionnaire). Anglo Egyptian Bookshop, Cairo

    Google Scholar 

  14. Goldberg DP, Hillier VF (1979) A scaled version of the General Health Questionnaire. Psychol Med 9(1):139–145.

    Article  CAS  Google Scholar 

  15. Flint A, Raben A, Blundell JE, Astrup A (2000) Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab Disord 24(1):38–48.

    Article  CAS  Google Scholar 

  16. Agawa S, Futagami S, Yamawaki H, Ikeda G, Noda H, Kirita K, Higuchi K, Murakami M, Kodaka Y, Ueki N, Akamizu T, Iwakiri K (2019) Acylated ghrelin levels were associated with depressive status, physical quality of life, endoscopic findings based on Kyoto classification in Japan. J Clin Biochem Nutr 65(1):65–70.

    Article  CAS  Google Scholar 

  17. Slavich GM, Sacher J (2019) Stress, sex hormones, inflammation, and major depressive disorder: Extending Social Signal Transduction Theory of Depression to account for sex differences in mood disorders. Psychopharmacology 236(10):3063–3079.

    Article  CAS  Google Scholar 

  18. Akhtar P, Ma L, Waqas A, Naveed S, Li Y, Rahman A, Wang Y (2020) Prevalence of depression among university students in low and middle income countries (LMICs): a systematic review and meta-analysis. J Affect Disord 274:911–919.

    Article  Google Scholar 

  19. Nurmela K, Mattila A, Heikkinen V, Uitti J, Ylinen A, Virtanen P (2018) Identification of major depressive disorder among the long-term unemployed. Soc Psychiatry Psychiatr Epidemiol 53(1):45–52.

    Article  Google Scholar 

  20. Mossakowski KN (2009) The influence of past unemployment duration on symptoms of depression among young women and men in the United States. Am J Public Health 99(10):1826–1832.

    Article  Google Scholar 

  21. Amiri S (2021) Unemployment associated with major depression disorder and depressive symptoms: a systematic review and meta-analysis. Int J Occup Saf Ergon 5:1–13.

    Article  Google Scholar 

  22. Algul S, Ozcelik O (2018) Evaluating the Levels of Nesfatin-1 and Ghrelin Hormones in Patients with Moderate and Severe Major Depressive Disorders. Psychiatry Investig 15(2):214–218.

    Article  CAS  Google Scholar 

  23. Ergul Erkec O, Algul S, Kara M (2018) Evaluation of ghrelin, nesfatin-1 and irisin levels of serum and brain after acute or chronic pentylenetetrazole administrations in rats using sodium valproate. Neurol Res 40(11):923–929.

    Article  CAS  Google Scholar 

  24. Ishitobi Y, Kohno K, Kanehisa M, Inoue A, Imanaga J, Maruyama Y, Ninomiya T, Higuma H, Okamoto S, Tanaka Y, Tsuru J, Hanada H, Isogawa K, Akiyoshi J (2012) Serum ghrelin levels and the effects of antidepressants in major depressive disorder and panic disorder. Neuropsychobiology 66(3):185–192.

    Article  CAS  Google Scholar 

  25. Akter S, Pham NM, Nanri A, Kurotani K, Kuwahara K, Jacka FN, Yasuda K, Sato M, Mizoue T (2014) Association of serum leptin and ghrelin with depressive symptoms in a Japanese working population: a cross-sectional study. BMC Psychiatry 14:203.

    Article  CAS  Google Scholar 

  26. Matsuo K, Nakano M, Nakashima M, Watanuki T, Egashira K, Matsubara T, Watanabe Y (2012) Neural correlates of plasma acylated ghrelin level in individuals with major depressive disorder. Brain Res 1473:185–192.

    Article  CAS  Google Scholar 

  27. Ozsoy S, Besirli A, Unal D, Abdulrezzak U, Orhan O (2015) The association between depression, weight loss and leptin/ghrelin levels in male patients with head and neck cancer undergoing radiotherapy. Gen Hosp Psychiatry 37(1):31–35.

    Article  Google Scholar 

  28. van Andel M, van Schoor NM, Korten NC, Heijboer AC, Drent ML (2022) Ghrelin, leptin and high-molecular-weight adiponectin in relation to depressive symptoms in older adults: Results from the Longitudinal Aging Study Amsterdam. J Affect Disord 296:103–110.

    Article  CAS  Google Scholar 

  29. al’Absi M, DeAngelis B, Nakajima M, Hatsukami D, Allen S (2021) Early life adversity and appetite hormones: The effects of smoking status, nicotine withdrawal, and relapse on ghrelin and peptide YY during smoking cessation. Addict Behav. 118:106866.

    Article  Google Scholar 

  30. Chao AM, White MA, Grilo CM, Sinha R (2017) Examining the effects of cigarette smoking on food cravings and intake, depressive symptoms, and stress. Eat Behav 24:61–65.

    Article  Google Scholar 

  31. Lemieux AM, al’Absi M (2018) Changes in circulating peptide YY and ghrelin are associated with early smoking relapse. Biol Psychol 131:43–48.

    Article  Google Scholar 

  32. Ricken R, Bopp S, Schlattmann P, Himmerich H, Bschor T, Richter C, Elstner S, Stamm TJ, Schulz-Ratei B, Lingesleben A, Reischies FM, Sterzer P, Borgwardt S, Bauer M, Heinz A, Hellweg R, Lang UE, Adli M (2017) Ghrelin Serum Concentrations Are Associated with Treatment Response During Lithium Augmentation of Antidepressants. Int J Neuropsychopharmacol 20(9):692–697.

    Article  CAS  Google Scholar 

  33. Tunçel ÖK, Akbas S, Bilgici B (2016) Increased ghrelin levels and unchanged adipocytokine levels in major depressive disorder. J Child Adolesc Psychopharmacol 26:733–739.

    Article  CAS  Google Scholar 

  34. Simmons WK, Burrows K, Avery JA, Kerr KL, Taylor A, Bodurka J, Potter W, Teague TK, Drevets WC (2020) Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states. Mol Psychiatry 25(7):1457–1468.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations



T.O. contributed to the study concept and design, analysis and interpretation of data, and critical revision of the manuscript. D.M.E. contributed to the study concept and design, analysis and interpretation of data. F.F.G contributed to the interpretation of results and writing and editing the manuscript. M.H.A recruited and studied the patients and gathered all data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Fiby F. Gabrielle.

Ethics declarations

Ethics approval and consent to participate

All patients gave written informed consent after being briefed about the purpose and parameters of the trial. The investigation was carried out in compliance with the recommendations of the Institute of Psychiatry's Research and Ethics Committee at Ain Shams University. FMASU MS 453 / 2021 is the reference number for the committee.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Okasha, T.A., El-Gabry, D.A., Ali, M.H. et al. The role of ghrelin peptide among a sample of Egyptian patients with first episode of major depressive disorder. Middle East Curr Psychiatry 29, 99 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: