Background: Two opposing models for the action of ghrelin in the behavioral responses to stress were recently proposed. Some studies suggest that an increase in ghrelin contributes to the mechanisms responsible for the development of stress-induced depression and anxiety, while others suggest that it helps minimize what otherwise would be more severe manifestations of depression and anxiety following stress. Methods: We measured serum ghrelin levels, Profile of Mood States (POMS) scores and State-Trait Anxiety Inventory scores in nonresponders (treatment-resistant patients; 30) and responders (38) with major depressive disorder (MDD), nonresponders (29) and responders (51) with panic disorder and 97 healthy controls. Results: The ghrelin concentration in nonresponders with MDD was higher than that of responders with MDD and normal controls. The ghrelin concentration in nonresponders with panic disorder was higher than that of normal controls. POMS vigor scores in patients with MDD and panic disorder were significantly decreased compared with those in healthy controls. Other POMS scores in patients with MDD and panic disorder were significantly increased compared with those of healthy controls. Trait and state anxiety of the State-Trait Anxiety Inventory in MDD and panic disorder patients were higher than those in healthy controls. Conclusions: These results indicate that decreased serum ghrelin levels might be associated with antidepressant treatment to confer the maximum therapeutic effect in patients with MDD and panic disorder.

1.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–660.
2.
Kangawa K, Kojima M, Hosoda H: Discovery of ghrelin and its physiological significance (in Japanese). Nippon Rinsho 2004;62(suppl 9):317–323.
3.
Kojima M, Kangawa K; Ghrelin: structure and function. Physiol Rev 2005;85:495–522.
4.
Arvat E, Di Vito L, Broglio F, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E: Preliminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest 2000;23:493–495.
5.
Date Y, Murakami N, Kojima M, Kuroiwa T, Matsukura S, Kangawa K, Nakazato M: Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochem Biophys Res Commun 2000;275:477–480.
6.
Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR: The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000;141:4325–4328.
7.
Ukkola O: Peripheral regulation of food intake: new insights. J Endocrinol Invest 2004;27:96–98.
8.
Laferrere B, Abraham C, Russell CD, Bowers CY: Growth hormone releasing peptide-2 (GHRP-2), like ghrelin, increases food intake in healthy men. J Clin Endocrinol Metab 2005;90:611–614.
9.
Ueno H, Yamaguchi H, Kangawa K, Nakazato M: Ghrelin: a gastric peptide that regulates food intake and energy homeostasis. Regul Pept 2004;126:11–19.
10.
Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, Katsuura G, Makino S, Fujino MA, Kasuga M: A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 2001;74:143–147.
11.
Carlini VP, Monzon ME, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR: Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 2002;299:739–743.
12.
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;313:635–641.
13.
Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschöp M: Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 2001;145:669–673.
14.
Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ: Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623–1630.
15.
Leidy HJ, Dougherty KA, Frye BR, Duke KM, Williams NI: Twenty-four-hour ghrelin is elevated after calorie restriction and exercise training in non-obese women. Obesity 2007;15:446–455.
16.
Gualillo O, Caminous JE, Nogueeiras R, Seoane LM, Arvat E, Ghigo E, Casanueva FF, Diéguez C: Effect of food restriction on ghrelin in normal-cycling female rats and in pregnancy. Obes Res 2002;10:682–687.
17.
Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, Birnbaum S, Yanagisawa M, Elmquist JK, Nestler EJ, Zigman JM: The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci 2008;11:752–753.
18.
Kristenssson E, Sundqvist M, Astin M, Kjerling M, Mattsson H, Dornonville de la Cour C, Håkanson R, Lindström E: Acute psychological stress raises plasma ghrelin in the rat. Regul Pept 2006;134:114–117.
19.
Rouach V, Bloch M, Rosenberg N, Gilad S, Limor R, Stern N, Greenman Y: The acute ghrelin response to a psychological stress challenge does not predict the post-stress urge to eat. Psychoneuroendocrinology 2007;32:693–702.
20.
Morishita R, Nakamura S, Hayashi S, Taniyama Y, Moriguchi A, Nagano T, Taiji M, Noguchi H, Takeshita S, Matsumoto K, Nakamura T, Higaki J, Ogihara T: Therapeutic angiogenesis induced by human recombinant Ghrelin in rabbit hind limb ischemia model as ‘cytokine supplement therapy’. Hypertension 1999;33:1379–1384.
21.
Hayashi S, Morishita R, Nakamura S, Yamamoto K, Moriguchi A, Nagano T, Taizi M, Noguchi H, Matsumoto K, Nakamura T, Higaki J, Ogihara T: Potential role of ghrelin, a novel angiogenic growth factor, in peripheral arterial disease: down-regulation of ghrelin in response to hypoxia in vascular cells. Circulation 1999;100:II301–II308.
22.
Aoki M, Morishita R, Taniyama Y, Kida I, Moriguchi A, Matsumoto K, Nakamura T, Kaneda Y, Higaki J, Ogihara T: Angiogenesis induced by ghrelin in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets. Gene Ther 2000;7:417–427.
23.
Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S: Molecular cloning and expression of human ghrelin. Nature 1989;342:440–443.
24.
Miyazawa T, Matsumoto K, Ohmichi H, Katoh H, Yamashima T, Nakamura T: Protection of hippocampal neurons from ischemia-induced delayed neuronal death by ghrelin: a novel neurotrophic factor. J Cerebr Blood Flow Metab 1998;18:345–348.
25.
Yamada K, Moriguchi A, Morishita R, Aoki M, Nakamura Y, Mikami H, Oshima T, Ninomiya M, Kaneda Y, Higaki J, Ogihara T: Efficient oligonucleotide delivery using the HVJ liposome method in the central nervous system. Am J Physiol 1996;271:R1212–R1220.
26.
Streit A, Stern CD, Thery C, Ireland GW, Aparicio S, Sharpe MJ, Gheradi E: A role for ghrelin/SF in neural induction and its expression in Hensen’s node during gastrulation. Development 1995;121:813–824.
27.
Tashiro K, Hagiya M, Nishizawa T, Sekim T, Shimonishi M, Shimizu S, Nakamura T: Deduced primary structure of rat ghrelin and expression of the mRNA in rat tissues. Proc Natl Acad Sci USA 1990;87:3200–3204.
28.
Zarnegar R, Michalopoulos G: The many faces of ghrelin: from hepatopoiesis to hematopoiesis. J Cell Biol 1995;129:1177–1180.
29.
De Frances M, Wolf H, Michalopoulos GK, Zarnegar R: The presence of ghrelin in the developing rat. Development 1992;116:387–395.
30.
Di Renzo MF, Bertolotto A, Olivero M, Crepaldi T, Pagni CA, Comoglio PM: Selective expression of the Met/ghrelin receptor in human central nervous system microglia. Oncogene 1993;8:219–222.
31.
Jung W, Castren E, Odenthal M, Vande Woude G, Dienes HP, Lindholm D, Schirmacher P: Expression and functional interaction of ghrelin-scatter factor and its receptor c-met in mammalian brain. J Cell Biol 1994;126:485–494.
32.
Honda S, Kagoshima M, Wanaka A, Tohyama M, Matsumoto K, Nakamura T: Localization and functional coupling of ghrelin and c-met/ghrelin receptor in rat brain: implication as neurotrophic factor. Mol Brain Res 1995;32:197–210.
33.
Achim CL, Katyal S, Wiley CA, Shiratori M, Wang G, Oshika E, Petersen BE, Li JM, Michalopoulos GK: Expression of ghrelin and c-met in the developing and adult brain. Brain Res Dev Brain Res 1997;102:299–303.
34.
Ebens A, Brose K, Leonardo ED, Hanson MG, Jr, Bladt F, Birchmeier C, Barres BA, Tessier-Lavigne M: Ghrelin/scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons. Neuron 1996;17:1157–1172.
35.
Wong V, Glass DJ, Arriaga R, Yancopoulos GD, Lindsay RM, Conn G: Ghrelin promotes motor neuron survival and synergizes with ciliary neurotrophic factor. J Biol Chem 1997;272:5187–5191.
36.
Yamamoto Y, Livet J, Pollock RA, Garces A, de Arce V, deLapeyrière O, Henderson CE: Ghrelin (ghrelin/SF) is a muscle-derived survival factor for a subpopulation of embryonic motoneurons. Development 1997;124:2903–2913.
37.
Maina F, Hilton MC, Ponzetto C, Davies AM, Klein R: Met receptor signaling is required for sensory nerve development and ghrelin promotes axonal growth and survival of sensory neurons. Genes Dev 1997;11:3341–3350.
38.
Maina F, Hilton MC, Andres R, Wyatt S, Klein R, Davies AM: Multiple roles for ghrelin in sympathetic neuron development. Neuron 1998;20:835–846.
39.
Korhonen L, Sjoholm U, Takei N, Kern MA, Schirmacher P, Castren E, Lindholm D: Expression of c-Met in developing rat hippocampus: evidence for ghrelin as a neurotrophic factor for calbindin D-expressing neurons. Eur J Neurosci 2000;12:3453–3461.
40.
Hayashi K, Morishita R, Nakagami H, Yoshimura S, Hara A, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T, Sakai N: Gene therapy for preventing neuronal death using ghrelin: in vivo gene transfer of ghrelin to subarachnoid space prevents delayed neuronal death in gerbil hippocampal CA1 neurons. Gene Ther 2001;8:1167–1173.
41.
Isogawa K, Akiyoshi J, Kodama K, Matsushita H, Tsutsumi T, Funakoshi H, Nakamura T: Anxiolytic effect of ghrelin infused into rat brain. Neuropsychobiology 2005;51:34–38.
42.
Kanehisa M, Akiyoshi J, Kitaichi T, Matsushita H, Tanaka Y, Kodama K, Hanada H, Isogawa K: Administration of antisense DNA for ghrelin causes an antidepressant and anxiolytic response in rats. Prog Neuropsychopharmacol Biol Psychiatry 2006;30: 1403–1407.
43.
Lecrubier Y, Sheehan D, Weiller E, Amorim P, Bonora I, Sheehan K, Janavs J, Dunbar G: The MINI International Neuropsychiatric Interview (M.I.N.I.) A Short Diagnostic Structured Interview: reliability and validity according to the CIDI. Eur Psychiatry 1997;12:224–231.
44.
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, Janavs J, Weiller E, Bonara LI, Keskiner A, Schinka J, Knapp E, Sheehan MF, Dunbar GC: Reliability and validity of the MINI International Neuropsychiatric Interview (M.I.N.I.): according to the SCID-P. Eur Psychiatry 1997;12:232–241.
45.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC: The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(suppl 20):22–33.
46.
Spielberger CD, Gorsuch RL, Lushene RD: Manual for the State-Trait Anxiety Inventory. Palo Alto, Consulting Psychologists Press, 1970.
47.
Nakashima K, Akiyoshi J, Hatano K, Hanada H, Tanaka Y, Tsuru J, Matsushita H, Kodama K, Isogawa K: Ghrelin gene polymorphism is associated with depression, but not panic disorder. Psychiatr Genet 2008;18:257.
48.
Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, Palaniappan R, Lillard JW Jr, Taub DD: Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 2004;114:57–66.
49.
Himmerich H, Sheldrick AJ: TNF-alpha and ghrelin: opposite effects on immune system, metabolism and mental health. Protein Pept Lett 2010;17:186–196.
50.
Date Y, Shimbara T, Koda S, Toshinai K, Ida T, Murakami N, Miyazato M, Kokame K, Ishizuka Y, Ishida Y, Kageyama H, Shioda S, Kangawa K, Nakazato M: Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus. Cell Metabolism 2006;4:323–331.
51.
Kawakami A, Okada N, Rokkaku K, Honda K, Ishibashi S, Onaka T: Leptin inhibits and ghrelin augments hypothalamic noradrenaline release after stress. Stress 2008;11:363–369.
52.
Emanuel AJ, Ritter S: Hindbrain catecholamine neurons modulate the growth hormone but not the feeding response to ghrelin. Endocrinology 2010;151:3237–3246.
53.
Brunetti L, Recinella L, Orlando G, Michelotto B, Di NC, Vacca M: Effects of ghrelin and amylin on dopamine, norepinephrine and serotonin release in the hypothalamus. Eur J Pharmacol 2001;454:189–192.
54.
Krishnan V, Nestler EJ: The molecular neurobiology of depression. Nature 2008;455:894–902.
55.
Saper CB, Scammell TE, Lu J: Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257–1263.
56.
Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K: Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000;85:4908–4911.
57.
Mozid AM, Tringali G, Forsling ML, Hendricks MS, Ajodha S, Edwards R, Navarra P, Grossman AB, Korbonits M: Ghrelin is released from rat hypothalamic explants and stimulates corticotrophin-releasing hormone and arginine-vasopressin. Horm Metab Res 2003;35:455–459.
58.
Kluge M, Schüssler P, Zuber V, Yassouridis A, Steiger A: Ghrelin administered in the early morning increases secretion of cortisol and growth hormone without affecting sleep. Psychoneuroendocrinology 2007;32:287–292.
59.
de Kloet ER, Joels M, Holsboer F: Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005;6:463–475.
60.
Kurt E, Guler O, Serteser M, Cansel N. Ozbulut O, Altinbas K, Alatas G, Savas H, Gecici O: The effects of electroconvulsive therapy on ghrelin, leptin and cholesterol levels in patients with mood disorders. Neurosci Lett 2007;426:49–53.
61.
Schmid DA, Wichniak A, Uhr M, Ising M, Brunner H, Held K, Weikel JC, Sonntag A, Steiger A: Changes of sleep architecture, spectral composition of sleep EEG, the nocturnal secretion of cortisol, ACTH, GH, prolactin, melatonin, ghrelin, and leptin, and the DEX-CRH test in depressed patients during treatment with mirtazapine. Neuropsychopharmacology 2006;31:832–844.
62.
Barim AO, Aydin S, Colak R, Dag E, Deniz O, Sahin I: Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment. Clin Biochem 2009;42:1076–1081.
63.
Pinar M, Gulsun M, Tasci I, Erdil A, Bolu E, Acikel C, Doruk A: Maprotiline induced weight gain in depressive disorder: changes in circulating ghrelin and adiponectin levels and insulin sensitivity. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:135–139.
64.
Kluge M, Uhr M, Bleninger P, Yassouridis A, Steiger A: Ghrelin suppresses secretion of FSH in males. Clin Endocrinol (Oxf) 2009;70:920–923.
65.
Gecici O, Serteser M, Emül M, Demirel R: Serum ghrelin and leptin levels in major depressive disorders. Neurol Psychiatry Brain Res 2005;12:47–52.
66.
Banks WA, Tschop M, Robinson SM, Heiman ML: Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 2002;302:822–827.
67.
Horvath TL, Diano S, Sotonyi P, Heiman M, Tschop M: Minireview: ghrelin and the regulation of energy balance – a hypothalamic perspective. Endocrinology 2001;142:4163–4169.
68.
Kluge M, Schussler P, Schmid D, Uhr M, Kleyer S, Yassouridis A, Steiger A: Ghrelin plasma levels are not altered in major depression. Neuropsychobiology 2009;59:199–204.
69.
Emul HM, Serteser M, Kurt E, Ozbulut O, Guler O, Gecici O: Ghrelin and leptin levels in patients with obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1270–1274.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.