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Ghrelin and leptin levels in patients with obsessive–compulsive disorder
Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 1270 – 1274 www.elsevier.com/locate/pnpbp
Ghrelin and leptin levels in patients with obsessive–compulsive disorder H. Murat Emül a , Mustafa Serteser b , Erhan Kurt c , Omer Ozbulut a , Ozkan Guler a , Omer Gecici a,⁎ a
Department of Psychiatry, School of Medical, Afyonkarahisar Kocatepe University, Afyonkarahisar, Turkey Department of Biochemistry, School of Medical, Afyonkarahisar Kocatepe University, Afyonkarahisar, Turkey Department of Psychiatry, Bakirkoy Research and Training Hospital for Psychiatry and Neurology, Istanbul, Turkey b
c
Received 9 January 2007; received in revised form 18 May 2007; accepted 19 May 2007 Available online 26 May 2007
Abstract To examine the importance of ghrelin and leptin in the pathogenesis of obsessive–compulsive disorder (OCD), we measured serum ghrelin and leptin levels, lipid profile and body mass index (BMI) in 43 patients with OCD and 20 healthy controls. The patients were divided into two subgroups according to whether DSM-IV OCD was accompanied with major depressive disorder (MDD) (OCD + MDD) or not (OCD − MDD). There was no statistically significant difference in ghrelin and leptin levels between groups. The OCD + MDD group had a trend of higher ghrelin levels and lower leptin levels than the OCD − MDD and control groups. There was a negative correlation between change in serum ghrelin and leptin levels only in the OCD + MDD group. Neither ghrelin nor leptin showed any correlation with severity of MDD and OCD. In conclusion, our results suggest that OCD is not associated with leptin or ghrelin levels. More comprehensive and detailed studies are needed to decipher the exact role of ghrelin and leptin in OCD. © 2007 Elsevier Inc. All rights reserved. Keywords: Obsessive–compulsive disorder; Depression; Ghrelin; Leptin; BMI
1. Introduction Ghrelin was discovered at the end of 1999 as an endogenous ligand for the growth hormone secretagogue receptor, and is predominantly produced by the stomach (Kojima et al., 1999), whereas substantially lower amounts are derived from the brain (Carlini et al., 2004). Recent literature demonstrated that ghrelin and leptin have inverse amplitude changes during fasting in rodents (Bagnasco et al., 2002). The ghrelin and an adiposity hormone leptin regulate food intake and energy balance, providing the hypothalamus with information on the amount of body fat (Prolo et al., 1998; Williams and Mobarhan, 2003). It has been shown that increased ghrelin concentrations may be
Abbreviations: OCD, obsessive-compulsive disorder; BMI, body mass index; MDD, major depressive disorder; Y-BOCS, Yale-Brown obsessive compulsive scale; BDI, Beck depression inventory; BAI, Beck anxiety inventory; CNS, central nerve system. ⁎ Corresponding author. Afyon Kocatepe Universitesi, Ahmet Necdet Sezer Uygulama ve Arastırma Hastanesi Psikiyatri Klinigi 03100 Afyon, Turkey. Tel.: +90 272 2142065; fax: +90 272 2133066. E-mail addresses: [email protected], [email protected] (O. Gecici). 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.05.007
associated with binge-eating and vomiting behavior in eating disorder (Tanaka et al., 2003, 2004), which is considered to be an obsessive–compulsive spectrum disorder (Claes et al., 2006). The neurotransmitter serotonin appears to be involved in the mechanism of satiety (Chebab, 1997). Drugs that enhance serotonergic neurotransmission reduce food intake by activating serotonin receptors. In contrast, drugs that inhibit serotonergic neurotransmission stimulate food intake. Brunetti et al. (2002) have shown that ghrelin inhibits serotonin release from rat hypothalamic synaptosomes. OCD is frequently associated with depressive symptoms and comorbid depressive disorder (Jenike, 1983). On the other hand, obsessions and compulsions accompany depressive disorder. While 80% of patients with OCD have comorbid depression, 30% of the patients with depressive disorders have obsessive– compulsive symptoms (Nemiah and Uhde, 1989). In addition to a high proportion of comorbidity between OCD and depressive disorders, both conditions respond favorably to selective serotonin re-uptake inhibitors, suggesting that they may share a similar neurobiological pathophysiology. Recently, these relationships have resulted in further research on the biological association of OCD and affective disorders. A limited number
H.M. Emül et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 1270–1274
of studies have focused on the leptin and ghrelin levels in depressive disorders. In patients with MDD, leptin levels have been found to be unaltered (Deuschle et al., 1996; Gecici et al., 2005a), and ghrelin to be increased (Gecici et al., 2005b). In addition, Atmaca et al. (2005) did not find a relationship between pure OCD and leptin. To our knowledge there has been no study regarding the relation between ghrelin and OCD. Therefore, we aimed to explore whether the serum ghrelin and leptin levels are associated with the etiopathogenesis of OCD. Thus we planned to evaluate serum leptin and ghrelin levels in patients with pure OCD, OCD with comorbid depressive disorder, and healthy controls. 2. Patients and methods 2.1. Subjects and designs The study included 43 outpatients with OCD (aged 18– 55 years) who were seen in the department of psychiatry. The participants were evaluated according to The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM IV) (American Psychiatric Association, 1994). The patients were drug naive or drug free for at least one month. The patients were enrolled into two subgroups according to whether DSMIV OCD was accompanied with current MDD (OCD + MDD) or not (OCD − MDD). Each patient underwent a detailed diagnostic evaluation by training psychiatrists (O.G., E.K.) by using The Structured Clinical Interview for DSM-IV (SCID) (First et al., 1997). All subjects were evaluated by a semi-structured questionnaire form, which was arranged by us in accordance with clinical experience and available information sources. All participants were asked to complete a Beck Depression Inventory (BDI) (Beck, 1961), Beck Anxiety Inventory (BAI) (Beck et al., 1988), and Yale–Brown Obsession Compulsion Scale (YBOCS) (Goodman et al., 1989). In addition, BMI was calculated by dividing the weight (in kilograms) by the squared height (in meters) (BMI = kg/m2). In each of the patients and controls, physical and neurological examinations were performed. Liver and kidney function were evaluated. Participants with normal results and without any exclusion criteria were enrolled in the study. Exclusion criteria included: a history of severe physical illness such as hypertension, diabetes mellitus, or other endocrinopathies; abnormal physical or laboratory findings; a history of alcohol and substance abuse or addiction; a history of cholesterol lowering treatment. Likewise the patients with any kind of axis I comorbidity, except MDD, were excluded. All participants were carefully assessed to rule out autoimmune, pulmonary, infectious and neoplastic diseases. The healthy control group consisted of 20 staff members; none of them fulfilled any of the exclusion criteria for the patients' group. The control group had no past or present psychiatric illness. They did not take any psychotropic drug and none of them had ever undergone a cholesterol-lowering treatment. In addition, their first-degree relatives did not have a history of major mood disorder, dementia, mental retardation, or psychosis.
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Table 1 Demographic and clinical variables of the patients and controls OCD − MDD OCD + MDD Controls (n = 22) (n = 21) (nc = 20)
Statistical analysis
Age a
32.41 ± 10.91 32.05 ± 10.12 33.25 ± 9.54 F = 0.07, df = 2, P = 0.93 BMI (kg/m2) a 24.40 ± 4.82 24.78 ± 4.53 24.42 ± 4.90 F = 0.04, df = 2, P = 0.96 Sex (F/M) b 13/9 11/10 12/8 χ2 = 0.30, df = 2, P N 0.05 Y-BOCS c 27.18 ± 6.63 27.29 ± 8.20 – t = 0.05, P = 0.96 BDI c 12.14 ± 3.34 22.43 ± 12.06 – t = 3.78, P = 0.001 25.09 ± 11.52 23.48 ± 10.39 – t = − 0.48, P = 0.63 BAI c Dur. of illness 4.98 ± 5.29 6.45 ± 5.79 – t = 0.87, P = 0.39 (years) c Dur. = duration. a ANOVA with Tukey HSD. b χ2 test. c Student's T-test was used.
After a brief initial interview, if the subjects appeared suitable for the study, they were thoroughly informed about the research details and written informed consent to participate in the study was obtained from the subjects. The Local Ethics Committee of the Afyon Kocatepe University School of Medicine in accordance with the Declaration of Helsinki approved the research protocol. 2.2. Biochemical analysis After the patients and controls fasted overnight, venous blood samples were drawn from an antecubital vein in the morning between 8:00 and 9:00 a.m. The samples were immediately centrifuged and stored at − 20 °C for further analysis. Serum ghrelin levels were measured by using a EIA (Enzyme Immune Assay) Diagnostic kit supplied by Phoenix Pharmaceuticals, Inc. (Belmont, CA, USA) The design of this immunoassay kit is based on the principle of a competitive enzyme immunoassay. It has a sensitivity of 0.078 ng/ml, and less than 5% and less than 14% intra- and inter-assay variation, respectively. It has a detection range of 0–100 ng/ml. Serum leptin levels were determined by using a commercially available radioimmunoassay kit from Phoenix Pharmaceuticals, Inc. (Belmont, CA, USA). The assay is based upon the competition of 125 I-peptide and peptide binding to the limited quantity of antibodies specific for the peptide in each reaction mixture. This human kit is designed for the amino acids 57–92 of the human leptin molecule and gives 100% cross-reactivity. It is sensitive for leptin levels of 1–128 pg/tube. Total-cholesterol, LDLcholesterol, HDL-cholesterol, and triglyceride levels were measured in a Hitachi 917 Autoanalyzator by using Roche diagnostic kits. VLDL-cholesterol levels were calculated by using the Friedwald formula. 2.3. Statistical analysis Statistical analysis was performed using the statistical package for social sciences (SPSS). The ANOVA with Tukey HSD test was used to compare the mean levels of the hormones
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and the other biochemical parameters, and some characteristics between the patients and control groups. The chi-square test was used to compare the gender difference between groups. Correlation analysis was performed by Pearson and Spearman correlation tests. Two-tailed forms were used. Differences were considered significant at P b 0.05 for all tests. 3. Results Patients and controls did not differ with respect to sociodemographic characteristics. Our study enrolled with 43 patients (24 females and 19 males). There were 13 females and 9 males in the OCD − MDD group, and 11 females and 10 males in the OCD + MDD group. Twelve females and 8 males were included in the control group (χ2 = 0.30, df = 2, P N 0.05). The characteristics of the patients and controls are summarized in Table 1. Mean serum ghrelin levels in the OCD + MDD, the OCD − MDD and the control groups were 30.67 ± 4.88 ng/ml, 27.43 ± 5.80 ng/ml and 28.20 ± 46 ng/ml, respectively. Although the OCD + MDD group had slightly higher ghrelin levels compared with the OCD − MDD and control groups, the difference was not statistically significant. There was also no significant difference in serum ghrelin levels between OCD − MDD and controls. In the OCD + MDD group, serum leptin levels were 128.50 ± 87.24 ng/ml compared with 151.73 ± 80.29 ng/ml and 141.11 ± 99.09 ng/ml in the OCD − MDD and controls, respectively. Serum leptin levels were slightly lower in the OCD + MDD group than OCD − MDD and control groups. However, the differences were not statistically significant between the groups. Likewise, serum total cholesterol, LDLcholesterol, HDL-cholesterol, VLDL-cholesterol, and triglyceride levels were not statistically different between OCD + MDD, OCD − MDD and control groups. The results of the biochemical data are summarized in Table 2. In the OCD + MDD group, serum ghrelin levels did not show any statistically significant correlation with change in leptin levels, all lipid profiles, age, sex, BMI, or duration of illness. Also no statistically significant correlation between change in ghrelin levels and Y-BOCS, BDI or BAI was found in the OCD + MDD group. Serum leptin levels were positively correlated only with BMI in the OCD + MDD group (P b 0.05). Although there was a negative correlation between change in serum ghrelin
Table 3 Correlation analyses between parameters studied in the patients and controls Variables
Lep T-Cholesterol a Triglyceride1 HDL a LDL a VLDL a Age a BMI a Sex b Y-BOCS a BDI a BAI a Duration of illness a
OCD − MDD
OCD + MDD
Control
Ghr
Lep
Ghr
Lep
Ghr
Lep
− 0.53⁎ n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c.
– n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c.
n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c.
– n.c. n.c. n.c. n.c. n.c. n.c. 0.51⁎ n.c. n.c. n.c. n.c. n.c.
n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. – – – –
– n.c. n.c. n.c. n.c. n.c. n.c. n.c. 0.60⁎⁎ – – – –
Ghr = Ghrelin, Lep = Leptin, n.c. = no correlation. ⁎P b 0.05, ⁎⁎P b 0.001. a Pearson. b Spearman correlation tests were used.
levels and leptin levels (P b 0.05), no correlation was observed among all biochemical and other data in the OCD − MDD group. Additionally, serum ghrelin levels did not reveal any significant correlation with any parameters in the control group. There was also no statistically significant correlation between serum leptin levels and the other parameters, except a significant positive correlation between leptin levels and sex in the control group (P b 0.01) (Table 3). 4. Discussion It has been suggested that there should be links between metabolic control and higher brain functions (Moran and Gao, 2006; Shannon and Cummings, 2006). Some recent research suggested that some executive dysfunctions in OCD represent an epiphenomenon of comorbid depressive symptoms (Moritz et al., 2003). This study is significant in that it was designed to search for a relationship between metabolic features and MDD + OCD and pure OCD, although it was a negative study in that it revealed no group differences. Brunetti et al. (2002) have shown that depolarizationstimulated serotonin release is inhibited by ghrelin. An interaction between leptinergic and serotonergic systems also
Table 2 The levels of serum ghrelin, leptin and lipid profile in DD and the control group
I II III Statistics a I–II–III I–II I–III II–III
Ghrelin (ng/ml)
Leptin (ng/ml)
T-Chol (mg/dl)
Trig (mg/dl)
HDL (mg/dl)
VLDL (mg/dl)
27.43 ± 580 30.67 ± 4.88 28.20 ± 4.46
151.73 ± 80.29 128.50 ± 87.24 141.11 ± 90.09
167.09 ± 27.80 177.43 ± 35.39 179.70 ± 37.64
104.64 ± 58.51 122.10 ± 67.21 137.15 ± 96.39
45.18 ± 10.30 46.48 ± 12.16 44.50 ± 11.68
34.69 ± 37.19 30.13 ± 29.09 31.92 ± 32.01
F = 0.07, P = 0.93 P = 0.10 P = 0.88 P = 0.28
F = 0.07, P = 0.93 P = 0.67 P = 0.92 P = 0.89
F = 0.07, P = 0.93 P = 0.58 P = 0.45 P = 0.98
F = 0.07, P = 0.93 P = 0.73 P = 0.35 P = 0.80
F = 0.07, P = 0.93 P = 0.93 P = 0.98 P = 0.84
F = 0.07, P = 0.93 P = 0.89 P = 0.96 P = 0.98
I = OCD − MDD, II = OCD + MDD, III = control. a Performed by ANOVA with Tukey HSD.
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has been demonstrated in the central nerve system (Leibowitz and Alexander, 1998). The conditions regulated by leptin, e.g. food intake, sexual behavior, locomotion, and sleep–wake regulation are considerably affected in MDD (Chebab, 1997; Pelleymounter et al., 1995). On the other hand, diminished serotonergic neurotransmission has been implicated in OCD and MDD. Serotonin modulates different neuronal activities in the CNS and, as a result, many physiological and behavioral dysfunctions frequently occur in depressive disorders or OCD. A previous study revealed that ghrelin has powerful stimulatory effects on feeding (Asakawa et al., 2001). Atmaca et al. (2005) have found high serum leptin levels in pure OCD compared with OCD with comorbid depression and controls, and suggested that hyperactivity of the HPA axis in depression, but not in pure OCD, might cause inhibition of leptin levels. In contrast, we have found no difference in mean serum leptin or ghrelin levels between the groups. In this study, the OCD with comorbid MDD group had a trend of higher ghrelin levels, but also had a trend of lower leptin levels compared to the pure OCD and control groups. We proposed that these trends may be due to depressive co-morbidity rather than pure OCD. It has been demonstrated that ghrelin and leptin have inverse amplitude changes during fasting in rodents (Bagnasco et al., 2002). Consistent with these findings, Tschop et al. (2001) have described that plasma ghrelin was negatively correlated with leptin and percent body fat in lean and obese humans. In contrast, Guillen et al. (2004) have proposed that there was no correlation between ghrelin and leptin in obese children, adolescents with anorexia nervosa and control group. In our study, ghrelin was negatively correlated with serum leptin levels in the OCD with comorbid MDD group, but not in pure OCD and control groups. In addition there was no correlation between ghrelin and BMI in patients or controls. To interpret these results, we need further in vivo studies with large samples. Ghrelin administration was reported to increase adipogenesis and adiposity (Barazzoni et al., 2006). It was also reported that leptin affected intracellular lipid concentration by decreasing fatty acid and triglyceride levels and increasing lipid oxidation (Auwerx and Steals, 1998). Additionally leptin had a positive correlation with total cholesterol, LDL-cholesterol, triglyceride and body fat ratio (Kaplan et al., 1998). Likewise a few studies showed a significant positive correlation between serum leptin and cholesterol values (Atmaca et al., 2002a,b). In spite of these observations, there is no significant change in lipid levels in patients with leptin insufficiency, and this situation is interpreted as central rather than peripheral leptin resistance. In this study total-cholesterol, HDL-cholesterol, LDLcholesterol, VLDL-cholesterol, and triglyceride levels did not show any significant difference among the patients and controls. There was also no correlation between the lipid profile and ghrelin and leptin. It is worth noting that the present study has several limitations. First, a relatively small sample size might not be representative of the patients. Furthermore, leptin secretion has diurnal variation (Kaplan et al., 1998), but leptin level was measured only once. However all samples were obtained between 8.00 and 9.00 a.m. after 12 h of fasting. Likewise the
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female and male individuals were not divided into different groups, but matched for all groups. In the present study, the OCD with comorbid MDD group had a trend of higher ghrelin levels and lower leptin levels compared to the pure OCD and control groups. The comorbidity of OCD and depressive disorder is frequently observed. Under these circumstances, two questions remain for us: (1) whether trend changes in the ghrelin and leptin levels are associated with only MDD in this study; (2) whether the possible relationship of ghrelin and leptin in OCD and MDD relate to neurotransmitters in the CNS or only to patients' attitudes toward eating. In conclusion, we proposed only a suggestion which needs to be assessed in the light of more comprehensive and detailed studies. References American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, et al. A role of ghrelin is neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 2001;74:143–7. Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Gecici O, Fridin B. Serum leptin and cholesterol values in the suicide attempters. Neuropsychobiology 2002a;45(3):124–7. Atmaca M, Kuloglu M, Tezcan E, Gecici O, Ustundag B. Serum cholesterol and leptin levels in patients with borderline personality disorder. Neuropsychobiology 2002b;45:167–71. Atmaca M, Tezcan E, Kuloglu M, Ustundag B. Serum leptin levels in obsessive–compulsive disorder. Psychiatry Clin Neurosci 2005;59:189–93. Auwerx J, Steals B Leptin. Lancet 1998;351:737–42. Bagnasco M, Kalraa P, Kalra S. Ghrelin and leptin pulse discharge in fed and fasted rats. Endocrinology 2002;143:726–9. Barazzoni R, Bosutti A, Stebel M, Cattin MR, Roder E, Visintin L, et al. Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution favoring triglyceride deposition in liver but not skeletal muscle. Am J Physiol Endocrinol Metab 2006;291(2):E428. Beck At. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–71. Beck At, Epstein N, Brown G, Steer Ra. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56:893–7. Brunetti L, Recinella L, Orlando G, Michelotto B, Di Nisio C, Vacca M. Effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release in the hypothalamus. Eur J Pharmacol 2002;454:189–92. Carlini VP, Varas MM, Cragnolini AB, Schioth 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;313:635–41. Chebab FF. The reproductive side of leptin. Nat Med 1997;3:952–3. Claes L, Nederkoorn C, Vandereycken W, Guerrieri R, Vertommen H. Impulsiveness and lack of inhibitory control in eating disorders. Eat Behav 2006;7(3):196–203. Deuschle M, Blum WF, Englaro P, Schweiger U, Weber B, Pflaum CD, et al. Plasma leptin in depressed patients and healthy controls. Horm Metab Res 1996;28:714–7. First MB, Spitzer RL, Gibbon M., Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders. First published in United States by American Psychiatric Press, Inc, Washington, 1997. Gecici O, Kuloglu M, Atmaca M, Tezcan AE, Tunckol H, Emul HM, et al. High serum leptin levels in depressive disorders with atypical features. Psychiatry Clin Neurosci 2005a;59:734–6. Gecici O, Serteser M, Emül M, Demirel R. Serum ghrelin and leptin levels in major depressive disorders. Neurol Psychiatry Brain Res 2005b;12:47–52.
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Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale–Brown Obsessive Compulsive Scale. Arch Gen Psychiatry 1989;46:1006–16. Guillen LS, Barrıos V, Barros AC, Argente J. Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr 2004;144:36–42. Jenike MA. Obsessive compulsive disorder. Compr Psychiatry 1983;24:99115. Kaplan LM. Leptin, obesity, and liver disease. Gastroenterology 1998;115: 9971001. Kojima M, Hosoda H, Matsuo H, et al. Ghrelin is a growth-hormone-releasing acylated peptide from the stomach. Nature 1999;402:656–60. Leibowitz SF, Alexander JT. Hypothalamic serotonin in control of eating behavior, meal size, and body weight. Biol Psychiatry 1998;44:851–64. Moran TH, Gao S. Looking for food in all the right places? Cell Metab 2006;3:233–4. Moritz S, Kloss M, Jahn H, et al. Impact of comorbid depressive symptoms on nonverbal memory and visuospatial performance in obsessive–compulsive disorder. Cogn Neuropsychiatry 2003;8(4):261–72.
Nemiah JC, Uhde TW. Obsessive–compulsive disorder. In: Kaplan HI, Sadock BJ, editors. Comprehensive textbook of psychiatry. 5th edn. Baltimore: Williams & Wilkins; 1989. p. 9841000. Pelleymounter MA, Cullen MJ, Baker MB, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540–3. Prolo P, Wong ML, Leptin J Licino. Int J Biochem Cell Biol 1998;30:1285–90. Shannon MH, Cummings DE. Hunger and memory: can Ghrelin help us remember where to find dinner? Cell Sci Rev 2006:3 [Commentary]. Tanaka M, Naruo T, Nagai N, Kuroki N, Shiiya T, Nakazato M, et al. Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders. J Psychiatr Res 2003;37: 17–22. Tanaka M, Nakahara T, Kojima S, Nakano T, Muranaga T, Nagai N, et al. Effect of nutritional rehabilitation on circulating ghrelin and growth hormone levels in patients with anorexia nervosa. Regul Pept 2004;122:163–8. Tschop M, Weyer C, Tataranni A, Devanarayan V, Ravussin E, Heiman M. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50:707–9. Williams J, Mobarhan S. A critical interaction: leptin and ghrelin. Nutr Rev 2003;61(11):391–3.
Ghrelin and leptin levels in patients with obsessive–compulsive disorder H. Murat Emül a , Mustafa Serteser b , Erhan Kurt c , Omer Ozbulut a , Ozkan Guler a , Omer Gecici a,⁎ a
Department of Psychiatry, School of Medical, Afyonkarahisar Kocatepe University, Afyonkarahisar, Turkey Department of Biochemistry, School of Medical, Afyonkarahisar Kocatepe University, Afyonkarahisar, Turkey Department of Psychiatry, Bakirkoy Research and Training Hospital for Psychiatry and Neurology, Istanbul, Turkey b
c
Received 9 January 2007; received in revised form 18 May 2007; accepted 19 May 2007 Available online 26 May 2007
Abstract To examine the importance of ghrelin and leptin in the pathogenesis of obsessive–compulsive disorder (OCD), we measured serum ghrelin and leptin levels, lipid profile and body mass index (BMI) in 43 patients with OCD and 20 healthy controls. The patients were divided into two subgroups according to whether DSM-IV OCD was accompanied with major depressive disorder (MDD) (OCD + MDD) or not (OCD − MDD). There was no statistically significant difference in ghrelin and leptin levels between groups. The OCD + MDD group had a trend of higher ghrelin levels and lower leptin levels than the OCD − MDD and control groups. There was a negative correlation between change in serum ghrelin and leptin levels only in the OCD + MDD group. Neither ghrelin nor leptin showed any correlation with severity of MDD and OCD. In conclusion, our results suggest that OCD is not associated with leptin or ghrelin levels. More comprehensive and detailed studies are needed to decipher the exact role of ghrelin and leptin in OCD. © 2007 Elsevier Inc. All rights reserved. Keywords: Obsessive–compulsive disorder; Depression; Ghrelin; Leptin; BMI
1. Introduction Ghrelin was discovered at the end of 1999 as an endogenous ligand for the growth hormone secretagogue receptor, and is predominantly produced by the stomach (Kojima et al., 1999), whereas substantially lower amounts are derived from the brain (Carlini et al., 2004). Recent literature demonstrated that ghrelin and leptin have inverse amplitude changes during fasting in rodents (Bagnasco et al., 2002). The ghrelin and an adiposity hormone leptin regulate food intake and energy balance, providing the hypothalamus with information on the amount of body fat (Prolo et al., 1998; Williams and Mobarhan, 2003). It has been shown that increased ghrelin concentrations may be
Abbreviations: OCD, obsessive-compulsive disorder; BMI, body mass index; MDD, major depressive disorder; Y-BOCS, Yale-Brown obsessive compulsive scale; BDI, Beck depression inventory; BAI, Beck anxiety inventory; CNS, central nerve system. ⁎ Corresponding author. Afyon Kocatepe Universitesi, Ahmet Necdet Sezer Uygulama ve Arastırma Hastanesi Psikiyatri Klinigi 03100 Afyon, Turkey. Tel.: +90 272 2142065; fax: +90 272 2133066. E-mail addresses: [email protected], [email protected] (O. Gecici). 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.05.007
associated with binge-eating and vomiting behavior in eating disorder (Tanaka et al., 2003, 2004), which is considered to be an obsessive–compulsive spectrum disorder (Claes et al., 2006). The neurotransmitter serotonin appears to be involved in the mechanism of satiety (Chebab, 1997). Drugs that enhance serotonergic neurotransmission reduce food intake by activating serotonin receptors. In contrast, drugs that inhibit serotonergic neurotransmission stimulate food intake. Brunetti et al. (2002) have shown that ghrelin inhibits serotonin release from rat hypothalamic synaptosomes. OCD is frequently associated with depressive symptoms and comorbid depressive disorder (Jenike, 1983). On the other hand, obsessions and compulsions accompany depressive disorder. While 80% of patients with OCD have comorbid depression, 30% of the patients with depressive disorders have obsessive– compulsive symptoms (Nemiah and Uhde, 1989). In addition to a high proportion of comorbidity between OCD and depressive disorders, both conditions respond favorably to selective serotonin re-uptake inhibitors, suggesting that they may share a similar neurobiological pathophysiology. Recently, these relationships have resulted in further research on the biological association of OCD and affective disorders. A limited number
H.M. Emül et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 1270–1274
of studies have focused on the leptin and ghrelin levels in depressive disorders. In patients with MDD, leptin levels have been found to be unaltered (Deuschle et al., 1996; Gecici et al., 2005a), and ghrelin to be increased (Gecici et al., 2005b). In addition, Atmaca et al. (2005) did not find a relationship between pure OCD and leptin. To our knowledge there has been no study regarding the relation between ghrelin and OCD. Therefore, we aimed to explore whether the serum ghrelin and leptin levels are associated with the etiopathogenesis of OCD. Thus we planned to evaluate serum leptin and ghrelin levels in patients with pure OCD, OCD with comorbid depressive disorder, and healthy controls. 2. Patients and methods 2.1. Subjects and designs The study included 43 outpatients with OCD (aged 18– 55 years) who were seen in the department of psychiatry. The participants were evaluated according to The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM IV) (American Psychiatric Association, 1994). The patients were drug naive or drug free for at least one month. The patients were enrolled into two subgroups according to whether DSMIV OCD was accompanied with current MDD (OCD + MDD) or not (OCD − MDD). Each patient underwent a detailed diagnostic evaluation by training psychiatrists (O.G., E.K.) by using The Structured Clinical Interview for DSM-IV (SCID) (First et al., 1997). All subjects were evaluated by a semi-structured questionnaire form, which was arranged by us in accordance with clinical experience and available information sources. All participants were asked to complete a Beck Depression Inventory (BDI) (Beck, 1961), Beck Anxiety Inventory (BAI) (Beck et al., 1988), and Yale–Brown Obsession Compulsion Scale (YBOCS) (Goodman et al., 1989). In addition, BMI was calculated by dividing the weight (in kilograms) by the squared height (in meters) (BMI = kg/m2). In each of the patients and controls, physical and neurological examinations were performed. Liver and kidney function were evaluated. Participants with normal results and without any exclusion criteria were enrolled in the study. Exclusion criteria included: a history of severe physical illness such as hypertension, diabetes mellitus, or other endocrinopathies; abnormal physical or laboratory findings; a history of alcohol and substance abuse or addiction; a history of cholesterol lowering treatment. Likewise the patients with any kind of axis I comorbidity, except MDD, were excluded. All participants were carefully assessed to rule out autoimmune, pulmonary, infectious and neoplastic diseases. The healthy control group consisted of 20 staff members; none of them fulfilled any of the exclusion criteria for the patients' group. The control group had no past or present psychiatric illness. They did not take any psychotropic drug and none of them had ever undergone a cholesterol-lowering treatment. In addition, their first-degree relatives did not have a history of major mood disorder, dementia, mental retardation, or psychosis.
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Table 1 Demographic and clinical variables of the patients and controls OCD − MDD OCD + MDD Controls (n = 22) (n = 21) (nc = 20)
Statistical analysis
Age a
32.41 ± 10.91 32.05 ± 10.12 33.25 ± 9.54 F = 0.07, df = 2, P = 0.93 BMI (kg/m2) a 24.40 ± 4.82 24.78 ± 4.53 24.42 ± 4.90 F = 0.04, df = 2, P = 0.96 Sex (F/M) b 13/9 11/10 12/8 χ2 = 0.30, df = 2, P N 0.05 Y-BOCS c 27.18 ± 6.63 27.29 ± 8.20 – t = 0.05, P = 0.96 BDI c 12.14 ± 3.34 22.43 ± 12.06 – t = 3.78, P = 0.001 25.09 ± 11.52 23.48 ± 10.39 – t = − 0.48, P = 0.63 BAI c Dur. of illness 4.98 ± 5.29 6.45 ± 5.79 – t = 0.87, P = 0.39 (years) c Dur. = duration. a ANOVA with Tukey HSD. b χ2 test. c Student's T-test was used.
After a brief initial interview, if the subjects appeared suitable for the study, they were thoroughly informed about the research details and written informed consent to participate in the study was obtained from the subjects. The Local Ethics Committee of the Afyon Kocatepe University School of Medicine in accordance with the Declaration of Helsinki approved the research protocol. 2.2. Biochemical analysis After the patients and controls fasted overnight, venous blood samples were drawn from an antecubital vein in the morning between 8:00 and 9:00 a.m. The samples were immediately centrifuged and stored at − 20 °C for further analysis. Serum ghrelin levels were measured by using a EIA (Enzyme Immune Assay) Diagnostic kit supplied by Phoenix Pharmaceuticals, Inc. (Belmont, CA, USA) The design of this immunoassay kit is based on the principle of a competitive enzyme immunoassay. It has a sensitivity of 0.078 ng/ml, and less than 5% and less than 14% intra- and inter-assay variation, respectively. It has a detection range of 0–100 ng/ml. Serum leptin levels were determined by using a commercially available radioimmunoassay kit from Phoenix Pharmaceuticals, Inc. (Belmont, CA, USA). The assay is based upon the competition of 125 I-peptide and peptide binding to the limited quantity of antibodies specific for the peptide in each reaction mixture. This human kit is designed for the amino acids 57–92 of the human leptin molecule and gives 100% cross-reactivity. It is sensitive for leptin levels of 1–128 pg/tube. Total-cholesterol, LDLcholesterol, HDL-cholesterol, and triglyceride levels were measured in a Hitachi 917 Autoanalyzator by using Roche diagnostic kits. VLDL-cholesterol levels were calculated by using the Friedwald formula. 2.3. Statistical analysis Statistical analysis was performed using the statistical package for social sciences (SPSS). The ANOVA with Tukey HSD test was used to compare the mean levels of the hormones
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and the other biochemical parameters, and some characteristics between the patients and control groups. The chi-square test was used to compare the gender difference between groups. Correlation analysis was performed by Pearson and Spearman correlation tests. Two-tailed forms were used. Differences were considered significant at P b 0.05 for all tests. 3. Results Patients and controls did not differ with respect to sociodemographic characteristics. Our study enrolled with 43 patients (24 females and 19 males). There were 13 females and 9 males in the OCD − MDD group, and 11 females and 10 males in the OCD + MDD group. Twelve females and 8 males were included in the control group (χ2 = 0.30, df = 2, P N 0.05). The characteristics of the patients and controls are summarized in Table 1. Mean serum ghrelin levels in the OCD + MDD, the OCD − MDD and the control groups were 30.67 ± 4.88 ng/ml, 27.43 ± 5.80 ng/ml and 28.20 ± 46 ng/ml, respectively. Although the OCD + MDD group had slightly higher ghrelin levels compared with the OCD − MDD and control groups, the difference was not statistically significant. There was also no significant difference in serum ghrelin levels between OCD − MDD and controls. In the OCD + MDD group, serum leptin levels were 128.50 ± 87.24 ng/ml compared with 151.73 ± 80.29 ng/ml and 141.11 ± 99.09 ng/ml in the OCD − MDD and controls, respectively. Serum leptin levels were slightly lower in the OCD + MDD group than OCD − MDD and control groups. However, the differences were not statistically significant between the groups. Likewise, serum total cholesterol, LDLcholesterol, HDL-cholesterol, VLDL-cholesterol, and triglyceride levels were not statistically different between OCD + MDD, OCD − MDD and control groups. The results of the biochemical data are summarized in Table 2. In the OCD + MDD group, serum ghrelin levels did not show any statistically significant correlation with change in leptin levels, all lipid profiles, age, sex, BMI, or duration of illness. Also no statistically significant correlation between change in ghrelin levels and Y-BOCS, BDI or BAI was found in the OCD + MDD group. Serum leptin levels were positively correlated only with BMI in the OCD + MDD group (P b 0.05). Although there was a negative correlation between change in serum ghrelin
Table 3 Correlation analyses between parameters studied in the patients and controls Variables
Lep T-Cholesterol a Triglyceride1 HDL a LDL a VLDL a Age a BMI a Sex b Y-BOCS a BDI a BAI a Duration of illness a
OCD − MDD
OCD + MDD
Control
Ghr
Lep
Ghr
Lep
Ghr
Lep
− 0.53⁎ n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c.
– n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c.
n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c.
– n.c. n.c. n.c. n.c. n.c. n.c. 0.51⁎ n.c. n.c. n.c. n.c. n.c.
n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. n.c. – – – –
– n.c. n.c. n.c. n.c. n.c. n.c. n.c. 0.60⁎⁎ – – – –
Ghr = Ghrelin, Lep = Leptin, n.c. = no correlation. ⁎P b 0.05, ⁎⁎P b 0.001. a Pearson. b Spearman correlation tests were used.
levels and leptin levels (P b 0.05), no correlation was observed among all biochemical and other data in the OCD − MDD group. Additionally, serum ghrelin levels did not reveal any significant correlation with any parameters in the control group. There was also no statistically significant correlation between serum leptin levels and the other parameters, except a significant positive correlation between leptin levels and sex in the control group (P b 0.01) (Table 3). 4. Discussion It has been suggested that there should be links between metabolic control and higher brain functions (Moran and Gao, 2006; Shannon and Cummings, 2006). Some recent research suggested that some executive dysfunctions in OCD represent an epiphenomenon of comorbid depressive symptoms (Moritz et al., 2003). This study is significant in that it was designed to search for a relationship between metabolic features and MDD + OCD and pure OCD, although it was a negative study in that it revealed no group differences. Brunetti et al. (2002) have shown that depolarizationstimulated serotonin release is inhibited by ghrelin. An interaction between leptinergic and serotonergic systems also
Table 2 The levels of serum ghrelin, leptin and lipid profile in DD and the control group
I II III Statistics a I–II–III I–II I–III II–III
Ghrelin (ng/ml)
Leptin (ng/ml)
T-Chol (mg/dl)
Trig (mg/dl)
HDL (mg/dl)
VLDL (mg/dl)
27.43 ± 580 30.67 ± 4.88 28.20 ± 4.46
151.73 ± 80.29 128.50 ± 87.24 141.11 ± 90.09
167.09 ± 27.80 177.43 ± 35.39 179.70 ± 37.64
104.64 ± 58.51 122.10 ± 67.21 137.15 ± 96.39
45.18 ± 10.30 46.48 ± 12.16 44.50 ± 11.68
34.69 ± 37.19 30.13 ± 29.09 31.92 ± 32.01
F = 0.07, P = 0.93 P = 0.10 P = 0.88 P = 0.28
F = 0.07, P = 0.93 P = 0.67 P = 0.92 P = 0.89
F = 0.07, P = 0.93 P = 0.58 P = 0.45 P = 0.98
F = 0.07, P = 0.93 P = 0.73 P = 0.35 P = 0.80
F = 0.07, P = 0.93 P = 0.93 P = 0.98 P = 0.84
F = 0.07, P = 0.93 P = 0.89 P = 0.96 P = 0.98
I = OCD − MDD, II = OCD + MDD, III = control. a Performed by ANOVA with Tukey HSD.
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has been demonstrated in the central nerve system (Leibowitz and Alexander, 1998). The conditions regulated by leptin, e.g. food intake, sexual behavior, locomotion, and sleep–wake regulation are considerably affected in MDD (Chebab, 1997; Pelleymounter et al., 1995). On the other hand, diminished serotonergic neurotransmission has been implicated in OCD and MDD. Serotonin modulates different neuronal activities in the CNS and, as a result, many physiological and behavioral dysfunctions frequently occur in depressive disorders or OCD. A previous study revealed that ghrelin has powerful stimulatory effects on feeding (Asakawa et al., 2001). Atmaca et al. (2005) have found high serum leptin levels in pure OCD compared with OCD with comorbid depression and controls, and suggested that hyperactivity of the HPA axis in depression, but not in pure OCD, might cause inhibition of leptin levels. In contrast, we have found no difference in mean serum leptin or ghrelin levels between the groups. In this study, the OCD with comorbid MDD group had a trend of higher ghrelin levels, but also had a trend of lower leptin levels compared to the pure OCD and control groups. We proposed that these trends may be due to depressive co-morbidity rather than pure OCD. It has been demonstrated that ghrelin and leptin have inverse amplitude changes during fasting in rodents (Bagnasco et al., 2002). Consistent with these findings, Tschop et al. (2001) have described that plasma ghrelin was negatively correlated with leptin and percent body fat in lean and obese humans. In contrast, Guillen et al. (2004) have proposed that there was no correlation between ghrelin and leptin in obese children, adolescents with anorexia nervosa and control group. In our study, ghrelin was negatively correlated with serum leptin levels in the OCD with comorbid MDD group, but not in pure OCD and control groups. In addition there was no correlation between ghrelin and BMI in patients or controls. To interpret these results, we need further in vivo studies with large samples. Ghrelin administration was reported to increase adipogenesis and adiposity (Barazzoni et al., 2006). It was also reported that leptin affected intracellular lipid concentration by decreasing fatty acid and triglyceride levels and increasing lipid oxidation (Auwerx and Steals, 1998). Additionally leptin had a positive correlation with total cholesterol, LDL-cholesterol, triglyceride and body fat ratio (Kaplan et al., 1998). Likewise a few studies showed a significant positive correlation between serum leptin and cholesterol values (Atmaca et al., 2002a,b). In spite of these observations, there is no significant change in lipid levels in patients with leptin insufficiency, and this situation is interpreted as central rather than peripheral leptin resistance. In this study total-cholesterol, HDL-cholesterol, LDLcholesterol, VLDL-cholesterol, and triglyceride levels did not show any significant difference among the patients and controls. There was also no correlation between the lipid profile and ghrelin and leptin. It is worth noting that the present study has several limitations. First, a relatively small sample size might not be representative of the patients. Furthermore, leptin secretion has diurnal variation (Kaplan et al., 1998), but leptin level was measured only once. However all samples were obtained between 8.00 and 9.00 a.m. after 12 h of fasting. Likewise the
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female and male individuals were not divided into different groups, but matched for all groups. In the present study, the OCD with comorbid MDD group had a trend of higher ghrelin levels and lower leptin levels compared to the pure OCD and control groups. The comorbidity of OCD and depressive disorder is frequently observed. Under these circumstances, two questions remain for us: (1) whether trend changes in the ghrelin and leptin levels are associated with only MDD in this study; (2) whether the possible relationship of ghrelin and leptin in OCD and MDD relate to neurotransmitters in the CNS or only to patients' attitudes toward eating. In conclusion, we proposed only a suggestion which needs to be assessed in the light of more comprehensive and detailed studies. References American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, et al. A role of ghrelin is neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 2001;74:143–7. Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Gecici O, Fridin B. Serum leptin and cholesterol values in the suicide attempters. Neuropsychobiology 2002a;45(3):124–7. Atmaca M, Kuloglu M, Tezcan E, Gecici O, Ustundag B. Serum cholesterol and leptin levels in patients with borderline personality disorder. Neuropsychobiology 2002b;45:167–71. Atmaca M, Tezcan E, Kuloglu M, Ustundag B. Serum leptin levels in obsessive–compulsive disorder. Psychiatry Clin Neurosci 2005;59:189–93. Auwerx J, Steals B Leptin. Lancet 1998;351:737–42. Bagnasco M, Kalraa P, Kalra S. Ghrelin and leptin pulse discharge in fed and fasted rats. Endocrinology 2002;143:726–9. Barazzoni R, Bosutti A, Stebel M, Cattin MR, Roder E, Visintin L, et al. Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution favoring triglyceride deposition in liver but not skeletal muscle. Am J Physiol Endocrinol Metab 2006;291(2):E428. Beck At. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561–71. Beck At, Epstein N, Brown G, Steer Ra. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988;56:893–7. Brunetti L, Recinella L, Orlando G, Michelotto B, Di Nisio C, Vacca M. Effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release in the hypothalamus. Eur J Pharmacol 2002;454:189–92. Carlini VP, Varas MM, Cragnolini AB, Schioth 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;313:635–41. Chebab FF. The reproductive side of leptin. Nat Med 1997;3:952–3. Claes L, Nederkoorn C, Vandereycken W, Guerrieri R, Vertommen H. Impulsiveness and lack of inhibitory control in eating disorders. Eat Behav 2006;7(3):196–203. Deuschle M, Blum WF, Englaro P, Schweiger U, Weber B, Pflaum CD, et al. Plasma leptin in depressed patients and healthy controls. Horm Metab Res 1996;28:714–7. First MB, Spitzer RL, Gibbon M., Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders. First published in United States by American Psychiatric Press, Inc, Washington, 1997. Gecici O, Kuloglu M, Atmaca M, Tezcan AE, Tunckol H, Emul HM, et al. High serum leptin levels in depressive disorders with atypical features. Psychiatry Clin Neurosci 2005a;59:734–6. Gecici O, Serteser M, Emül M, Demirel R. Serum ghrelin and leptin levels in major depressive disorders. Neurol Psychiatry Brain Res 2005b;12:47–52.
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