Increased Ghrelin Levels and Unchanged Adipocytokine Levels in Major Depressive Disorder

Abstract

Objective:

One of the hypotheses of the pathophysiology of major depressive disorder (MDD) proposes that there is a relationship between adipocytokine and ghrelin levels and depression.

Methods:

Patients with major depression with a BMI ≤25 kg/m² between the ages of 11 and 18 years (n = 30) were compared with a healthy control group (n = 30). Both groups were evaluated across a pretreatment period (MD-PT) and an improved period (MD-I). We measured serum leptin, adiponectin, resistin, and ghrelin levels and other parameters related to metabolic syndrome, such as glucose, insulin, insulin resistance (homeostasis model assessment [HOMA]), triglycerides (TG), and total cholesterol (TCHOL).

Results:

Leptin, adiponectin, and resistin levels did not differ across groups; however, ghrelin levels were increased in the MD-I group compared with the control and MD-PT groups (p < 0.05). HOMA levels were also higher in the MD-PT group than in the control group (p < 0.05). After treatment, there was no difference in this measurement.

Conclusions:

The relationship between adipocytokines and major depression may be dependent on ghrelin levels as a result of antidepressant treatment and subsequent obesity.

Introduction

Major depressive disorder (MDD) is a common disease that ranks high in the global burden of disease classification because of obesity, metabolic syndrome, and other associated diseases in MDD patients (Marazziti et al. 2014). Studies have shown that patients with a previous history of MDD were more obese than the general population (Simon et al. 2006). Those with MDD in adolescence are susceptible to increased body mass index (BMI) in adulthood (Pine et al. 1997); however, the relation between MDD and obesity is bidirectional (Luppino et al. 2010). Some studies have shown that obesity in patients without baseline depression is associated with an increased risk of depression 5 years later even after controlling for covariates, such as age, gender, physical health problems, and functional limitations (Roberts et al. 2003). The prevalence of metabolic syndrome is also relatively higher in MDD patients compared with the general population (Heiskanen et al. 2006; Teixeira and Rocha 2007). It has been suggested that this prevalence is not affected by age, marital status, education, smoking, alcohol use, physical activity, or duration of depressive symptoms (Heiskanen et al. 2006), although cardiovascular disease related to metabolic syndrome is the most common cause of early death in MDD patients (after suicide) (Osby et al. 2001). MDD patients also have a higher risk of developing diabetes mellitus, and patients with diabetes are more susceptible to developing MDD (Lang and Borgwardt 2013). The relationship among MDD, obesity, and metabolic syndrome is still not entirely clear. One hypothesis concerning this relationship proposes that there is a relationship between adipocytokines (leptin, adiponectin, and resistin) and ghrelin with MDD that is caused by inflammation (Soczynska et al. 2011).

Leptin is an anorexigenic peptide whose release is regulated by adipose tissue (Ouchi et al. 2011). Leptin receptors are expressed by dopamine neurons in the ventricular tegmental area. These receptors regulate eating habits by reducing the firing rate of dopamine neurons (Hommel et al. 2006). Studies have demonstrated that patients with a history of depression had higher levels of leptin and that these higher levels were a predictor of future episodes of depression (Pasco et al. 2008). The relationship between leptin and depression may be attributed to the effects of leptin on the hypothalamic pituitary adrenal (HPA) axis and the inflammatory process mediated by tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 (Taylor and MacQueen, 2010; Soczynska et al. 2011; Marazziti et al. 2014). A recent study, however, has suggested that the relationship between leptin and depression is mainly the result of low leptin signaling (leptin resistance), which may represent a new potential mechanism (Milaneschi et al. 2014).

Adiponectin release is regulated by adipose tissue, and its levels decrease as the amount of adipose tissue increases (Ryo et al. 2004). Adiponectin, in contrast to leptin, is anti-inflammatory and increases insulin sensitivity (Kwon and Pessin 2013). Adiponectin reduces the level of TNF-α (Ferńandez-Real et al. 2003) and increases the production of anti-inflammatory cytokines, such as IL-10 and IL-1 receptor antagonists (Wolf et al. 2004). The relationship between depression and adiponectin may have an inflammation basis, but it is not clear whether this relationship is affected by increases in weight over time or by antidepressant treatment (Taylor and MacQueen 2010). Another important factor is that adiponectin receptors are expressed in the hippocampus, which plays a role in mood regulation. Intracerebroventricular administration of exogenous adiponectin produces antidepressant-like behavioral effects (Liu et al. 2012).

Resistin is a proinflammatory adipocytokine that increases insulin resistance (Steppan et al. 2001). It is found in two quarternary forms, and its trimer structure is responsible for hepatic insulin resistance (Patel et al. 2004). Resistin in human mononuclear cells also increases the expression of TNF-α and IL-6 (Bokarewa et al. 2005) and increased levels of this cytokine are related to insulin levels and Type 2 diabetes (Ouchi et al. 2011).

Ghrelin is a peptide that consists of 28 amino acids and is primarily released from oxyntic cells found in the stomach mucosa (Kojima et al. 1999). Ghrelin also exists in acylated and des-acylated forms in the blood. Although the des-acylated form is predominant in plasma, acylated ghrelin form is biologically active. Acylated ghrelin enhances appetite and increases weight gain; these effects are revealed by the growth hormone secretagogue-receptor (GHSR-1a) that is found in the hypothalamus (Frago et al. 2011). It has been proposed that ghrelin increases dopamine, which in turn increases appetite (Shin et al. 2009); however, there is an inverse relationship between body weight and ghrelin (Tschöp et al. 2001). Lutter et al. (2008) found that chronic stress produced hyperphagia because of an increase in ghrelin levels that resulted in anxiolytic and antidepressant-like responses.

To the best of our knowledge, a limited number of studies have investigated the relationship among adipocytokines and ghrelin levels and MDD. Because BMI is a potential confound, it must be taken into consideration (Carvalho et al. 2014). Several questions related to this relationship are: Is there a direct relationship between depression and these parameters? Or does this relationship emerge secondarily as a result of causes leading to weight gain in patients with depression (chronic stress, lifestyle, drugs)? Therefore, in this study, we investigated whether leptin, adiponectin, resistin, and ghrelin levels and insulin, glucose, homeostasis model assessment (HOMA), triglycerides (TG), and total cholesterol (TCHOL) levels are associated with metabolic disorder in nonobese patients diagnosed with MDD.

Methods

Subjects

This study used a naturalistic design and was conducted on a total of 30 patients, with an age range between 11 and 18 years who were diagnosed with MDD at Ondokuz Mayıs University, Child and Adolescent Psychiatry Clinic, in addition to 30 healthy participants as a control group. Both groups were age and sex matched. MDD was diagnosed by a child psychiatry specialist using Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children- Present and Lifetime Version-Turkish Version (K-SADS-PL-T) (Gökler et al. 2004) and these patients were included as the major depression pretreatment (MD-PT) group. Of these patients, those scoring “very much improved” or “much improved” according to The Clinical Global Impressions Scale (CGI) and ≤19 according to Child Depression Inventory after the treatment were considered to be improved, and were classified into the major depression improved (MD-I) group. Treatment was provided according to the clinical picture of the patients, independent from the study. The control group was randomly selected from individuals who had not been diagnosed after the K-SADS-PL-T interview. These individuals had not had a psychiatric disease, and there was no history of a psychiatric disease in their families. The patients completed the Children's Depression Inventory (CDI) twice, once during the MD-PT period and once during the MD-I period, whereas the control group completed it only once. Both the patients and the control group had a BMI ≤25 kg/m² and had no chronic disease (inflammatory disease, diabetes, cardiovascular disease, hypertension, neurological disorders, or cancer) and were nonsmokers. A total of 37 major depression patients were originally included in the study, but 7 of these patients (3 male, 4 female) were later excluded from the study because they did not respond to antidepressant treatment (because they did not use drugs regularly and did not come to interview at the hospital for control of the process of the illness). Twenty of the patients were in their first episode and had not received any previous treatment. The remaining 10 patients had received depression treatment before but had not used any medication at least 1 month prior to the study.

This study was conducted with the permission of Ondokuz Mayıs University, Ethical Committee (No: B.30.2.ODM.0.20.08/144, No: 2012/53). All participants and their parents were informed both orally and in writing. All participants and their parents gave written informed consent, and all procedures were arranged in accordance with the World Medical Association Declaration of Helsinki.

A total of 8 mL of blood was taken into the biochemical tube with gel from each subject in the patient group during the MD-PT period and from those in the control group between 8:00 a.m. and 9:00 a.m. after overnight fasting. Blood was drawn from the same patient group for the second time during the MD-I period. We meticulously ensured that none of the participants had acute infections as their blood was drawn. Similarly, none of the female participants were menstruating during the process. Blood drawn was centrifuged (Jouan C4i Cat no: 11177560) at 3000g, + 4°C for 5 minutes, and the serum separated, and was stored at −80°C (NUAIRE Ultra-Low Freezer Model no: Nu-6420E) until it were evaluated.

Biochemical parameters

The serum stored at −80°C was melted at room temperature on the day the study was initiated. We ensured that all serum and kits reached room temperature before the measurements were conducted. Prior to the measurements, the serum was stirred with a vortex. Leptin levels were measured using a Leptin EASIA kit (DIAsource, Louvain-la-Neuva, Belgium Cat No: KAP2281, Lot No: 140101/A). The assay-detection limit was 0.04 ng/mL and the intra-assay and interassay coefficient variations were 10% and 10.2% for leptin. Adiponectin levels were measured using a Human Adiponectın ELISA kit (Biovendor, Heidelberg Germany, Cat No: RD191023100, Lot No: E14-039). The assay-detection limit was 0.47 ng/mL and intra-assay and interassay coefficient variations were 4.4% and 5.8% for adiponectin. Resistin levels were measured using a Human Resistin ELISA kit (Biovendor, Heidelberg Germany, Cat No: RD191016100, Lot No:E14-009). The assay-detection limit was 0.012 ng/mL and the intra-assay and interassay coefficient variations were 5.2% and 7.0% for resistin. Ghrelin levels were measured using an Acylated Ghrelin (human) EIA kit (SPI-BIO, Montıgny Le Bretennoux, France, Batch No: 0113). The assay-detection limit was 4 pg/mL and the intra-assay and interassay coefficient variations were 6.2% and 6.7% for ghrelin, respectively. Glucose, TG, and TCHO levels were measured spectrophotometrically in serum using Roche/Hitachi Modular Analytic System Cobas 8000. The serum insulin levels were examined using the chemiluminescence method in a Siemens/İmmulite 2000 autoanalyzer. HOMA was calculated using the formula (insulinxglucose)/405.

Statistical analyses

SPSS for Windows 15.0. was used for statistical analyses. The Kolmogorov–Smirnov normality test was used to test the normal distribution of the data. We compared the grouped data using a χ² test. The measured values with normal distribution were compared using an independent samples t test; those without a normal distribution were compared with a Mann–Whitney U test. As for the dependent groups, paired-samples t test and Wilcoxon signed rank tests were used. Pearson correlation and Spearman correlation methods were used for correlation analysis. A value of p < 0.05 was considered significant in statistical analysis. Results are expressed as means ± standard deviation.

Results

There was no significant difference among study groups with respect to age, sex, BMI, or education. The CDI score of the MD-PT group was higher than those for both the control group and the MD-I group (p < 0.05). There was no difference between the control group and the MD-I group with respect to CDI. There was a statistically significant difference between the patient group and the control group with regard to socioeconomic status and history of any psychiatric disease in the family (p < 0.05) (Table 1). The insulin level and HOMA were higher in the MD-PT group compared with those of the control group (p < 0.05). There was no statistically significant difference between the control group and the MD-I group with respect to these parameters. As for the ghrelin level, the MD-PT group did not differ from the control group, but it was higher in the MD-I group than in the control group and the MD-PT group (p < 0.05). Leptin, adiponectin, resistin, glucose, TG, and TCHOL levels were not significant (p > 0.05) (Table 2).

Table 1.

Subject Characteristics

		MDD patients (n = 30)
Features	Control (n = 30)	MD-PT	MD-I	p
Age, mean ± SD (years)	14.7 ± 2.03	14.7 ± 2.03		>0.05
Sex, n (%)
Male	7 (23.3)	7 (23.3)		>0.05
Female	23 (76.7)	23 (76.7)
BMI (kg/m²), mean ± SD	20.02 ± 2.06	21.24 ± 2.61	21.98 ± 2.96	>0.05
Education, mean ± SD (years)	9.5 ± 1.8	8.8 ± 1.9		>0.05
Socioeconomical status, n (%)
Low	1 (3.3)	8(26.7)		<0.05^a
Middle	28 (93.3)	22 (73.3)
High	1 (3.3)	0(0)
CDI, mean ± SD	7.10 ± 4.63	25.17 ± 5.22^b	9.60 ± 4.67	<0.05
Family psychiatric history, No(%)
No	30(100.0)	12(40.0)		<0.0001^a
Yes	0	18(60.0)
Medicines used, n (%)
Sertraline		28(93.3)
Fluoxetine		2(6.7)
Improvement time (day), mean ± SD			91.17 ± 65.09

Bold indicates statistical significance.

Chi square tests: p = 0.028.

Wilcoxon signed rank test, MD-PT versus MD-I, p < 0.001; Mann–Whitney U test, control versus MD-PT, p < 0.0001.

BMI, body mass index; CDI, Child Depression Inventory; MDD, major depressive disorder; MD-I, major depression improved group; MD-PT, major depression pretreatment group.

Table 2.

Biochemical Parameters

		MDD patients
Parameters	Control	MD-PT	MD-I	p
Leptin (ng/mL)	2.71 ± 0.26	2.87 ± 0.48	3.09 ± 0.96	>0.05
Adiponectin (ng/mL)	8850.31 ± 4012.28	8763.40 ± 2808.54	8103.75 ± 2983.54	>0.05
Resistin (ng/mL)	5.453 ± 3.55	5.72 ± 2.91	5.28 ± 1.54	>0.05
Ghrelin (pg/mL)	25.46 ± 11.26	28.76 ± 19.58	36.99 ± 16.91^a,b	<0.05
Glucose (mg/dL)	88.36 ± 12.15	93.54 ± 6.45	90.38 ± 5.38	>0.05
Insulin (μU/mL)	7.30 ± 3.74	10.25 ± 4.58^c	8.34 ± 6.28	<0.05
HOMA	1.56 ± 0.78	2.35 ± 1.04^d	1.90 ± 1.52	<0.05
TG (mg/dL)	72.77 ± 31.85	79.83 ± 32.76	82.80 ± 44.91	>0.05
TCHOL (mg/dL)	146.21 ± 25.59	155.03 ± 23.30	155.87 ± 22.05	>0.05

Bold indicates statistical significance.

Results are expressed as means ± standard deviation.

Mann–Whitney U test, control versus MD-I, p = 0.014.

Wilcoxon signed rank test, MD-PT versus MD-I, p = 0.004.

Independent samples test, control versus MD-PT, p = 0.011.

Independent samples test, control versus MD-PT, p = 0.002.

HOMA, homeostasis model assessment (insulin resistance); MDD, major depressive disorder; MD-I, major depression improved group; MD-PT, major depression pretreatment group; TG, triglycerides; TCHOL, total cholesterol.

There was no correlation among the biochemical parameters themselves. There was no correlation between these biochemical parameters and the characteristics of the patients either.

Discussion

Previous studies have found differing results on the relationship between adipocytokines and MDD. Some studies have found that leptin levels were increased (Antonijevic et al. 1998; Cizza et al. 2010), some found them to be decreased (Kraus et al. 2001; Jow et al. 2006), and some found that they remained unchanged (Deuschle et al. 1996; Kotan et al. 2012); moreover, it has been proposed that leptin levels are higher in women (Antonijevic et al. 1998; Rubin et al. 2002; Pasco et al. 2008). It has also been proposed that adiponectin levels are lower in male than in female MDD patients (Cizza et al. 2010; Diniz et al. 2012) and are even lower in men (Leo et al. 2006); however, a study conducted on 3289 subjects revealed that there was no relationship between adiponectin and depression after adjusting for potential confounding variables (Pan et al. 2008). The number of studies on the relationship between resistin levels and MDD is limited. It has been reported that resistin levels were reduced after antidepressant treatment and remained unchanged in patients who had not shown any improvement (Weber-Hamann et al. 2007); however, the argument that there is no relationship between resistin and MDD remains prominent (Pan et al. 2008; Lehto et al. 2010; Papakostas et al. 2013).

One of the most important confounding factors in studies conducted on the relationship between adipocytokines and MDD is BMI, because the amount of adipocytokine in circulation proportionally changes with that of adipose tissue (Ouchi et al. 2011). We evaluated patients between 11 and 18 years of age, in order to avoid BMI and other confounding factors (diabetes, inflammatory disease, hypertension, cardiovascular disease age, smoking). We found that there was no difference across the groups with respect to adipocytokines. A recent study also found that the relationship between severe and moderate depression and leptin persisted after multivariate adjustments for age, gender, race, history of hypertension and diabetes, blood pressure, lipids, glucose, and c-reactive protein (CRP) but that it ceased after further adjustment for BMI (Morris et al. 2012), which supports the importance of BMI and its relation to leptin. In addition, a meta-analysis conducted by Carvalho et al. (2014) revealed the effect of BMI on studies conducted, and, therefore, the standardization of BMI, severity of depression, and measurement methods were recommended. In this study, we found higher insulin resistance in the MD-PT group than in the control group (unlike the MD-I group). This analysis did not reveal any correlation among insulin resistance and leptin and adiponectin and resistin. Many studies have cited the development of insulin resistance and type 2 diabetes in patients with depression (Knol et al. 2006; Austin et al. 2014) and it has been shown that depression contributes to immune dysregulation and that the level of TNF-α, a proinflammatory cytokine, is increased in depression (Dowlati et al. 2010). It is known that an increase in TNF-α level results in insulin resistance (Nieto-Vazquez et al. 2008). Another factor that may result in insulin resistance is an increase in cortisol levels, which is a result of changes in the hypothalamic pituitary adrenal axis (Marazziti et al. 2014). These two factors, cortisol and TNF-α, may have affected the insulin resistance in patients in our study.

The most important finding in our study was increased levels of ghrelin in the MD-I group, which was not different in the MD-PT group compared with the control group. Previous studies have found that ghrelin levels did not change during the pretreatment period of depression (Emül et al. 2007; Kluge et al. 2009; Paslakis et al. 2014), which is parallel to our findings. Ghrelin promotes appetite by activating the dopaminergic neurons found in the ventricular tegmental area responsible for mood and reward (Abizaid et al. 2006, Chuang et al. 2011); however, it has been reported that ghrelin and the ventricular tegmental area are negatively correlated with gray volume, despite the fact that plasma ghrelin levels did not change in MDD (Matsuo et al. 2012). Moreover, it was found that ghrelin levels remained high in mice after terminating chronic social defeat stress (CSDS). Mice without ghrelin receptors were more adversely affected by CSDS, such that release of ghrelin might be an indicator of adaptation to stress (Lutter et al. 2008). Similarly, a study conducted by Ishitobi et al. (2012) reported that ghrelin levels were higher in nonresponder MDD patients than in responder patients. Assuming that increased ghrelin levels in the remission period might represent a response to prolonged stress, we examined the correlation between ghrelin levels and improvement time, and did not find any correlation between the two after controlling for CDI as a confounding factor.

Another factor contributing to ghrelin levels may be the type of antidepressant medication used; however, there is no consensus on the subject (Zarouna et al. 2015). In addition, the number of studies on the effect of selective serotonin reuptake inhibitors (SSRIs) on ghrelin levels is limited. Although it has been reported that citalopram treatment did not affect ghrelin levels (Barim et al. 2009), another study conducted by Kumar et al. (2013) showed that fluoxetine decreased ghrelin levels. In our study, 28 patients were taking sertraline and 2 were taking fluoxetine. When we examined ghrelin levels after excluding these two patients taking fluoxetine, we found that the ghrelin levels were higher in the MD-I group than in the other groups. We have not found any study in the literature on the relationship between sertraline and ghrelin. Therefore, this is the first study revealing that ghrelin levels are higher in patients using sertraline. It has been reported that the most common side effects of SSRIs are decreased sexual function and sleepiness, followed by weight gain (Cascade et al. 2009). Although SSRIs cause weight loss in the short term, they also result in weight gain in the long term (Sussman et al. 2001). The weight gain induced by SSRIs may result from increased ghrelin followed by increased adipose tissue, which may result in high leptin and resistin levels and low adiponectin (Fig. 1).

FIG. 1.

Possible mechanism of relationship among adipocytokines, ghrelin, and major depressive disorder.

Limitations

The major limitation of this study was the relatively small sample size of patients, which should have been at least 24 in each group as calculated by power analysis with Minitab 15.0 (90% power, 5% type I error, and d = 4.7). Another limitation was that we did not evaluate different subtypes of depression, such as atypical/undifferentiated depression and melancholic depression. Atypical/undifferentiated depression patients are prone to metabolic syndrome compared with melancholic depression patients (Cizza et al. 2012)

Conclusions

The relationship between adipocytokines and major depressive disorder may be the result of increased levels of ghrelin as a result of treatment and the weight gain resulting from it. However, this is a preliminary study, and further studies with larger sample sizes are required to further evaluate the bidirectional relation between major depressive disorder and obesity, and effect of medication on ghrelin levels.

Clinical Significance

Ghrelin levels increase with antidepressant treatment. There is insulin resistance before the treatment of the disease. Insulin resistance ceases with this treatment.

Footnotes

Acknowledgment

We thank Dr. Ebru Kaynar Tunçel, Public Health Center, Bafra, Samsun for statistical consultation.

Disclosures

No competing financial interests exist.

References

Abizaid

, Liu

, Andrews

, Shanabrough

, Borok

, Elsworth

, Roth

, Sleeman

, Picciotto

, Tschöp

, Gao

, Horvath

: Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest, 116:3229–3239, 2006.

Antonijevic

, Murck

, Frieboes

, Horn

, Brabant

, Steiger

: Elevated nocturnal profiles of serum leptin in patients with depression. J Psychiatr Res, 32:403–410, 1998.

Austin

, Gordon

, Lavoie

, Arsenault

, Dasgupta

, Bacon

: Differential association of insulin resistance with cognitive and somatic symptoms of depression. Diabet Med, 31:994–1000, 2014.

Barim

, Aydin

, Colak

, Dag

, Deniz

, Sahin

: Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment. Clin Biochem, 42:1076–1081, 2009.

Bokarewa

, Nagaev

, Dahlberg

, Smith

, Tarkowski

: Resistin, an adipokine with potent proinflammatory properties. J Immunol, 174:5789–5795, 2005.

Carvalho

, Rocha

DQC

, McIntyre

, Mesquita

, Kohler

, Hyphantis

T N

, Sales

PMG

, Machado–Vieira

, Berk

: Adipokines as emerging depression biomarkers: A systematic review and meta-analysis. J Psychiatr Res, 59:28–37, 2014.

Cascade

, Kalali

, Kennedy

: Real-world data on SSRI antidepressant side effects. Psychiatry (Edgmont), 6:16–18, 2009.

Chuang

, Perello

, Sakata

, Osborne–Lawrence

, Savitt

, Lutter

, Zigman

: Ghrelin mediates stress-induced food-reward behavior in mice. J Clin Invest, 121:2684–2692, 2011.

Cizza

, Nguyen

, Eskandari

, Duan

, Wright

, Reynolds

, Ahima

, Blackman

: Low 24-hour adiponectin and high nocturnal leptin concentrations in a case-control study of community-dwelling premenopausal women with major depressive disorder: The Premenopausal, Osteopenia/Osteoporosis, Women, Alendronate, Depression (POWER) study. J Clin Psychiatry, 71:1079–1087, 2010.

10.

Cizza

, Ronsaville

, Kleitz

, Eskandari

, Mistry

, Torvik

, Sonbolian

, Reynolds

, Blackman

, Gold

, Martinez

: Clinical subtypes of depression are associated with specific metabolic parameters and circadian endocrine profiles in women. PloS One, 7:e28912, 2012.

11.

Deuschle

, Blum

, Englaro

, Schweiger

, Weber

, Pflaum

, Heuser

: Plasma leptin in depressed patients and healthy controls. Horm Metab Res, 28:714–717, 1996.

12.

Diniz

, Teixeira

, Campos

, Miranda

, Rocha

, Talib

, Gattaz

, Forlenza

: Reduced serum levels of adiponectin in elderly patients with major depression. J Psychiatr Res, 46:1081–1085, 2012.

13.

Dowlati

, Herrmann

, Swardfager

, Liu

, Sham

, Reim

, Lanctôt

: A meta analysis of cytokines in major depression. Biol Psychiatry, 67:446–457, 2010.

14.

Emül

, Serteser

, Kurt

, Ozbulut

, Guler

, Gecici

: Ghrelin and leptin levels in patients with obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry, 31:1270–1274, 2007.

15.

Ferńandez–Real

, Ĺopez–Bermejo

, Casamitjana

, Ricart

: Novel interactions of adiponectin with the endocrine system and inflammatory parameters. J Clin Endocrinol Metab, 88:2714–2718, 2003.

16.

Frago

, Baquedano

, Argente

, Chowen

: Neuroprotective actions of ghrelin and growth hormone secretagogues. Front Mol Neurosci, 4:23, 2011.

17.

Gökler

, Ünal

, Pehlivantürk

, Kültür

EÇ

, Akdemir

, Taner

: Reliability and validity of Schedule for Affective Disorders and Schizophrenia for School Age Children–Present and Lifetime Version–Turkish Version (K-SADS-PL-T) [in Turkish]. Turk J Child Adolesc Ment Health, 11:109–116, 2004.

18.

Heiskanen

, Niskanen

, Hintikka

, Koivumaa–Honkanen

, Honkalampi

, Haatainen

, Viinamäki

: Metabolic syndrome and depression: A cross–sectional analysis. J Clin Psychiatry, 67:1422–1427, 2006.

19.

Hommel

, Trinko

, Sears

, Georgescu

, Liu

, Gao

, Thurmon

, Marinelli

, DiLeone

: Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron, 51:801–810, 2006.

20.

Ishitobi

, Kohno

, Kanehisa

, Inoue

, Imanaga

, Maruyama

, Ninomiya

, Higuma

, Okamoto

, Tanaka

, Tsuru

, Hanada

, Isogawa

, Akiyoshi

: Serum ghrelin levels and the effects of antidepressants in major depressive disorder and panic disorder. Neuropsychobiology, 66:185–192, 2012.

21.

Jow

, Yang

, Chen

: Leptin and cholesterol levels are low in major depressive disorder, but high in schizophrenia. J Affect Disord, 90:21–27, 2006.

22.

Kluge

, Schussler

, Schmid

, Uhr

, Kleyer

, Yassouridis

, Steiger

: Ghrelin plasma levels are not altered in majordepression. Neuropsychobiology, 59:199–204, 2009.

23.

Knol

, Twist

, Beekam

, Heine

, Snoek

, Power

: Depression as a risk factor for the onset of type 2 diabetes mellitus. A meta-analysis Diabetologia, 49:837–845, 2006.

24.

Kojima

, Hosoda

, Date

, Nakazato

, Matsuo

, Kangawa

: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 402:656–660, 1999.

25.

Kotan

, Sarandol

, Kirhan

, Ozkaya

, Kirli

: Serum brain-derived neurotrophic factor, vascular endothelial growth factor and leptin levels in patients with a diagnosis of severe major depressive disorder with melancholic features. Ther Adv Psychopharmacol, 2:65–74, 2012.

26.

Kraus

, Haack

, Schuld

, Hinze–Selch

, Pollmächer

: Low leptin levels but normal body mass indices in patients with depression or schizophrenia. Neuroendocrinology, 73:243–247, 2001.

27.

Kumar

, Chuang

, Na

, Kuperman

, Gillman

, Mukherjee

, Zigman

, McClung

, Lutter

: Differential effects of chronic social stress and fluoxetine on meal patterns in mice. Appetite, 64:81–88, 2013.

28.

Kwon

, Pessin

: Adipokines mediate inflammation and insulin resistance. Front Endocrinol, 4:71, 2013.

29.

Lang

, Borgwardt

: Molecular mechanisms of depression: Perspectives on new treatment strategies. Cell Physiol Biochem, 31:761–777, 2013.

30.

Lehto

, Huotari

, Niskanen

, Tolmunen

, Koivumaa–Honkanen

, Honkalampi

, Ruotsalainen

, Herzig

, Viinamäki

, Hintikka

: Serum adiponectin and resistin levels in major depressive disorder. Acta Psychiatr Scand, 121:209–215, 2010.

31.

Leo

, Di Lorenzo

, Tesauro

, Cola

, Fortuna

, Zanasi

, Troisi

, Siracusano

, Lauro

, Romeo

: Decreased plasma adiponectin concentration in major depression. Neurosci Lett, 407:211–213, 2006.

32.

Liu

, Guo

, Zhang

, Cheng

, Liu

, Ding

, Scherer

, Liu

, Lu

: Adiponectin is critical in determining susceptibility to depressive behaviors and has antidepressant–like activity. Proc Natl Acad Sci U S A, 109:12,248–12,253, 2012.

33.

Luppino

, de Wit

, Bouvy

, Stijnen

, Cuijpers

, Penninx

, Zitman

: Overweight, obesity, and depression: A systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry, 67:220–229, 2010.

34.

Lutter

, Sakata

, Osborne–Lawrence

, Rovinsky

, Anderson

, Jung

, Birnbaum

, Yanagisawa

, Elmquist

, Nestler

, Zigman

: The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci, 11:752–753, 2008.

35.

Marazziti

, Rutigliano

, Baroni

, Landi

, Dell'Osso

: Metabolic syndrome and major depression. CNS Spectr, 19:293–304, 2014.

36.

Matsuo

, Nakano

, Nakashima

, Watanuki

, Egashira

, Matsubara

, Watanabe

: Neural correlates of plasma acylated ghrelin level in individuals with major depressive disorder. Brain Res, 1473:185–192, 2012.

37.

Milaneschi

, Sutin

, Terracciano

, Canepa

, Gravenstein

, Egan

, Vogelzangs

, Guralnik

, Bandinelli

, Penninx

, Ferrucci

: The association between leptin and depressive symptoms is modulated by abdominal adiposity. Psychoneuroendocrinology, 42:1–10, 2014.

38.

Morris

, Ahmed

, Stoyanova

, Hooper

, De Staerke

, Gibbons

, Quyyumi

, Vaccarino

: The association between depression and leptin is mediated by adiposity. Psychosom Med, 74:483–488, 2012.

39.

Nieto–Vazquez

, Fernandez–Veledo

, Kramer

D K

, Vila–Bedmar

, Garcia–Guerra

, Lorenzo

: Insulin resistance associated to obesity: The link TNF-alpha. Arch Physiol Biochem, 114:183–194, 2008.

40.

Osby

, Brandt

, Correia

, Ekbom

, Sparen

: Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry, 58:844–850, 2001.

41.

Ouchi

, Parker

, Lugus

, Walsh

: Adipokines in inflammation and metabolic disease. Nat Rev Immunol, 11:85–97, 2011.

42.

Pan

, Ye

, Franco

, Li

, Yu

, Wang

, Qi

, Gu

, Pang

, Liu

, Lin

: The association of depressive symptoms with inflammatory factors and adipokines in middle-aged and older Chinese. Plos One, 3:e1392, 2008.

43.

Papakostas

, Shelton

, Kinrys

, Henry

, Bakow

, Lipkin

, Pi

, Thurmond

, Bilello

: Assessment of a multiassay, serum-based biological diagnostic test for major depressive disorder: A pilot and replication study. Mol Psychiatry, 18:332–329, 2013.

44.

Pasco

, Jacka

, Williams

, Henry

, Nicholson

, Kotowicz

, Berk

: Leptin in depressed women: Cross-sectional and longitudinal data from an epidemiologic study. J Affect Disord, 107:221–225, 2008.

45.

Paslakis

, Westphal

, Hamann

, Gilles

, Lederbogen

, Deuschle

: Unstimulated and glucose-stimulated ghrelin in depressed patients and controls. J Psychopharmacol, 28:582–586, 2014.

46.

Patel

, Rajala

, Rossetti

, Scherer

, Shapiro

: Disulfide-dependent multimeric assembly of resistin family hormones. Science, 304:1154–1158, 2004.

47.

Pine

, Cohen

, Brook

, Coplan

: Psychiatric symptoms in adolescence as predictors of obesity in early adulthood: A longitudinal study. Am J Public Health, 87:1303–1310, 1997.

48.

Roberts

, Deleger

, Strawbridge

, Kaplan

: Prospective association between obesity and depression: evidence from the Alameda County Study. Int J Obes Relat Metab Disord, 27: 514–521, 2003.

49.

Rubin

, Rhodes

, Czambel

: Sexual diergism of baseline plasma leptin and leptin suppression by arginine vasopressin in major depressives and matched controls. Psychiatry Res, 113:255–268, 2002.

50.

Ryo

, Nakamura

, Kihara

, Kumada

, Shibazaki

, Takahashi

, Nagai

, Matsuzawa

, Funahashi

: Adiponectin as a biomarker of the metabolic syndrome. Circ J, 68:975–981, 2004.

51.

Shin

, Zheng

, Berthoud

: An expanded view of energy homeostasis: Neural integration of metabolic, cognitive and emotional drives to eat. Physiol Behav, 97:572–580, 2009.

52.

Simon

, Von Korff

, Saunders

, Miglioretti

, Crane

, van Belle

, Kessler

: Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry, 63:824–830, 2006.

53.

Soczynska

, Kennedy

, Woldeyohannes

, Liauw

, Alsuwaidan

, Yim

, McIntyre

: Mood disorders and obesity: Understanding inflammation as a pathophysiological nexus. Neuromol Med, 13:93–116, 2011.

54.

Steppan

, Bailey

, Bhat

, Brown

, Banerjee

, Wright

, Patel

, Ahima

, Lazar

: The hormone resistin links obesity to diabetes. Nature, 409:307–312, 2001.

55.

Sussman

, Ginsberg

, Bikoff

: Effects of nefazodone on body weight: a pooled analysis of selective serotonin reuptake inhibitor- and imipramine-controlled trials. J Clin Psychiatry, 62:256–260, 2001.

56.

Taylor

, MacQueen

: The role of adipokines in understanding the associations between obesity and depression. J Obes, 2010:748048, 2010.

57.

Teixeira

, Rocha

: The prevalence of metabolic syndrome among psychiatric inpatients in Brazil. Rev Bras Psiquiatr, 29:330–336, 2007.

58.

Tschöp

, Weyer

, Tataranni

, Devanarayan

, Ravussin

, Heiman

: Circulating ghrelin levels are decreased in human obesity. Diabetes, 50:707–709, 2001.

59.

Weber–Hamann

, Kratzsch

, Kopf

, Lederbogen

, Gilles

, Heuser

, Deuschle

: Resistin and adiponectin in major depression: The association with free cortisol and effects of antidepressant treatment. J Psychiatr Res, 41:344–350, 2007.

60.

Wolf

A M

, Wolf

, Rumpold

, Enrich

, Tilg

: Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1 RA in human leukocytes. Biochem Biophys Res Commun, 323:630–635, 2004.

61.

Zarouna

, Wozniak

, Papachristou

: Mood disorders: A potential link between ghrelin and leptin on human body?. World J Exp Med, 5:103–109, 2015.