Ghrelin in psychiatric disorders – A review

Psychoneuroendocrinology (2015) 52, 176—194

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INVITED REVIEW

Ghrelin in psychiatric disorders — A review Dirk Alexander Wittekind ∗, Michael Kluge Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany Received 29 July 2014; received in revised form 13 November 2014; accepted 13 November 2014

KEYWORDS Ghrelin; Psychiatry; Addiction; Alzheimer; Depression; Eating disorder

Summary Ghrelin is a 28-amino-acid peptide hormone, first described in 1999 and broadly expressed in the organism. As the only known orexigenic hormone secreted in the periphery, it increases hunger and appetite, promoting food intake. Ghrelin has also been shown to be involved in various physiological processes being regulated in the central nervous system such as sleep, mood, memory and reward. Accordingly, it has been implicated in a series of psychiatric disorders, making it subject of increasing investigation, with knowledge rapidly accumulating. This review aims at providing a concise yet comprehensive overview of the role of ghrelin in psychiatric disorders. Ghrelin was consistently shown to exert neuroprotective and memoryenhancing effects and alleviated psychopathology in animal models of dementia. Few human studies show a disruption of the ghrelin system in dementia. It was also shown to play a crucial role in the pathophysiology of addictive disorders, promoting drug reward, enhancing drug seeking behavior and increasing craving in both animals and humans. Ghrelin’s exact role in depression and anxiety is still being debated, as it was shown to both promote and alleviate depressive and anxiety-behavior in animal studies, with an overweight of evidence suggesting antidepressant effects. Not surprisingly, the ghrelin system is also implicated in eating disorders, however its exact role remains to be elucidated. Its widespread involvement has made the ghrelin system a promising target for future therapies, with encouraging findings in recent literature. © 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

∗

Introduction............................................................................................................ Methods................................................................................................................ Ghrelin in neurodegenerative diseases/Alzheimer’s disease ............................................................ Ghrelin in addictive disorders .......................................................................................... Ghrelin in schizophrenia ...............................................................................................

Corresponding author at: Semmelweisstrasse 10, 04103 Leipzig, Germany. Tel.: +49 341 25031. E-mail address: [email protected] (D.A. Wittekind).

http://dx.doi.org/10.1016/j.psyneuen.2014.11.013 0306-4530/© 2014 Elsevier Ltd. All rights reserved.

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Ghrelin in psychiatric disorders

6.

7.

8. 9.

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Ghrelin in stress, mood-and anxiety disorders .......................................................................... 6.1. Ghrelin in stress regulation...................................................................................... 6.2. Ghrelin in anxiety disorders ..................................................................................... 6.3. Ghrelin in obsessive compulsive disorder (OCD) ................................................................. 6.4. Ghrelin in depression............................................................................................ Ghrelin in eating disorders ............................................................................................. 7.1. Ghrelin in anorexia nervosa (AN) ................................................................................ 7.2. Ghrelin in bulimia nervosa (BN) ................................................................................. 7.3. Ghrelin in binge eating disorder (BED)........................................................................... Ghrelin in insomnia .................................................................................................... Conclusion and outlook................................................................................................. Role of the funding source ............................................................................................. Conflict of interest ..................................................................................................... Appendix A. Supplementary data..................................................................................... References .............................................................................................................

1. Introduction Ghrelin is a 28-amino-acid peptide hormone, which was first described in 1999 (Kojima et al., 1999). It is primarily synthesized by gastric neuroendocrine cells but has also been identified in a variety of other organs including bowels, kidney, thyroid, lung, lymphatic tissue, placenta, hypothalamus, and pituitary (Gnanapavan et al., 2002). The ghrelin molecule is processed from preproghrelin, a 117 amino acid peptide, which is transcribed from a complex gene on chromosome 3 in the human genome (Kanamoto et al., 2004). In the processing of preproghrelin to ghrelin, other peptides are produced, most importantly obestatin (Zhang et al., 2005). While obestatin has been reported to decrease pancreatic secretion, to enhance memory and to suppress thirst, its real physiological relevance remains elusive (Trovato et al., 2014). The genes encoding both ghrelin and its receptor are almost identical among vertebrates, being conserved in the evolution, suggesting the high relevance of the ghrelin system to the organism (Gahete et al., 2014). Ghrelin was identified as an endogenous ligand for the Growth-Hormone (GH)-Secretagogue-Receptor 1a (GHSR1a), which had been previously discovered (Howard et al., 1996). Consequently, ghrelin triggers the release of GH and was therefore named accordingly (Acronym for Growth Hormone Release Inducing) (Kojima et al., 1999; Takaya et al., 2000). In addition, ghrelin stimulates the hypothalamic—pituitary—adrenal axis (HPA)-axis: In the hypothalamus, it was shown to increase both gene expression of corticotropin releasing hormone (CRH) (Cabral et al., 2012) and release of CRH (Mozid et al., 2003). In addition, ghrelin increases serum levels of ACTH and cortisol in rodents (Wren et al., 2000) and man (Kluge et al., 2007b). Furthermore, ghrelin suppresses secretion of hormones of the hypothalamic—pituitary—gonadal (HPG) axis, namely follicle-stimulating hormone (FSH) (Kluge et al., 2009b, 2012) and luteinizing hormone (LH)(Kluge et al., 2007a). Ghrelin was also repeatedly shown to affect the hypothalamus—pituitary—thyroid (HPT) axis in humans causing an increase of thyroxine but a decrease of thyroid stimulating hormone (TSH) (Kluge et al., 2010b, 2013). Moreover, ghrelin is active in the gastroenteric tract, where it is

181 181 181 182 182 183 183 183 184 184 184 185 185 185 185

involved in the regulation of glucose homeostasis, insulin and glucagon (Dezaki, 2013). Ghrelin, which is released in a pulsatile manner (Natalucci et al., 2005) exists in an acylated (AG) and des-acylated form (DAG) (Kojima et al., 1999). The posttranslational acylation is performed by the Ghrelin-Oacyl-transferase (GOAT), which is expressed in most tissues and was only identified in 2008 (Gutierrez et al., 2008; Yang et al., 2008). In contrast to DAG, AG binds to the GHSR-1a and the majority of functions is mediated by this variant (Kojima and Kangawa, 2010). DAG represents the majority of circulating ghrelin and was initially considered to be inactive. However, more recent evidence indicates that DAG also exerts actions and might be a functional inhibitor of AG (Delhanty et al., 2014). AG also exerts a multitude of other biological actions: As the only peripheral orexigenic (appetite-stimulating) hormone it is crucially involved in the regulation of energy homeostasis, appetite (Tschöp et al., 2000; Wren et al., 2000; Nakazato et al., 2001) and blood gluose (McFarlane et al., 2014). Ghrelin causes an increase of food intake (Tschöp et al., 2000; Wren et al., 2001) at least in part by stimulating hypothalamic neurons containing the orexigenic peptides neuropeptide Y (NPY) and agouti-related protein (Kamegai et al., 2001). Ghrelin levels rise in states of hunger and when anticipating food intake and drop afterwards (Cummings et al., 2001). Ghrelin has been shown to be an important player in the regulation of many central nervous system (CNS) functions like sleep (Kluge et al., 2008), cognition (Andrews, 2011), mood (Chuang and Zigman, 2010) and reward (Jerlhag et al., 2009). Data considering to what extent ghrelin is expressed in the CNS is inconsistent (Furness et al., 2011). Ghrelin is actively transported across the blood—brainbarrier in a satiable mechanism (Banks et al., 2002; Banks, 2008) and can passively diffuse through fenestrated capillaries in the hypothalamus (Schaeffer et al., 2013). Ghrelin has been repeatedly shown to exert discrete central and peripheral actions and some evidence suggests that central and peripheral ghrelin signaling are at least partially distinct from each other. For example, when ghrelin transport into the CNS was blocked in mice, this did not alter

178 alcohol-induced reward and alcohol intake, while administration of a ghrelin antagonist did (Jerlhag et al., 2014a). Furthermore, a study evaluating central and peripheral secretion patterns in sheep found that ghrelin levels in the CNS were up to 1000-fold lower in the CNS than in plasma and that central ghrelin levels were markedly pulsatile, with more peaks than in central ghrelin levels. In addition, when 1 mg of acylated ghrelin was injected, plasma levels rose more than ten-fold, while cerebrospinal fluid (CSF)-ghrelin levels only doubled 40—50 min after the injection (Grouselle et al., 2008). This suggests that the communication between central and peripheral ghrelin system is slow and not very pronounced. In line with ghrelin’s effects in the CNS, there is more and more evidence for an important role of ghrelin in psychiatric disorders. Especially for addictive disorders an involvement of ghrelin has been repeatedly shown (Jerlhag et al., 2006, 2007; Vengeliene, 2013) and ghrelin’s role in mood and anxiety disorders (Steiger et al., 2011), neurodegenerative diseases (Frago et al., 2002; Gahete et al., 2011) and eating disorders (Otto et al., 2001; Atalayer et al., 2013) is being increasingly elucidated. Several reviews have recently been published on ghrelin in addictive disorders (Andrews, 2011; Dickson et al., 2011; Leggio et al., 2011; Vengeliene, 2013; Panagopoulos and Ralevski, 2014), neurodegenerative diseases (Andrews, 2011; Gahete et al., 2011; Dos Santos et al., 2013), mood disorders (Chuang and Zigman, 2010; Andrews, 2011; Schellekens et al., 2012) and eating disorders (Atalayer et al., 2013; Méquinion et al., 2013; Monteleone and Maj, 2013). However, there is no review so far summarizing the role of ghrelin in psychiatric disorders. Currently, evidence is accumulating very fast and it is becoming increasingly difficult to keep an overview. This review therefore aims to provide a comprehensive but concise overview of the role of ghrelin in psychiatric disorders.

2. Methods Selection of the disorders included in this review was done on the basis of the International Statistical Classification of Diseases and Related Health Problems (ICD-10; World Health Organization, 1993). For every psychiatric disorder summarized in the F-chapter of the ICD-10, a thorough literature research was performed on MEDLINE to identify studies investigating the ghrelin system in this disorder. Search terms are provided in the appendix (online). Furthermore, reference lists of recent original works and reviews were searched. All psychiatric disorders for which data on ghrelin was available were included. For these disorders, all studies investigating ghrelin in humans were included. Animal- and in vitro-studies were included if they investigated ghrelin in an animal model of a psychiatric disorder or a clinical effect of ghrelin.

3. Ghrelin in neurodegenerative diseases/Alzheimer’s disease Soon after its discovery in 1999, a neuroprotective effect of ghrelin was first postulated (Frago et al., 2002). Since then, a large body of evidence has accumulated which not only confirms this observation but also strongly suggests

D.A. Wittekind, M. Kluge a role of ghrelin in neurogenesis, neural plasticity, learning, memory and neurodegenerative diseases, most notably Alzheimer’s disease (AD) (Carlini et al., 2002, 2004; Diano et al., 2006; Chung et al., 2008; Atcha et al., 2009; Moon et al., 2011; Bayliss and Andrews, 2013; Martins et al., 2013; Walker et al., 2014). Ghrelin receptors are widely expressed throughout the CNS, especially in the hypothalamus, pituitary gland, hippocampus, ventral tegmental area (VTA) and the amygdala (Diano et al., 2006; Zigman et al., 2006; Andrews, 2011; Landgren et al., 2011; Cruz et al., 2013; Gahete et al., 2014). The findings of the majority of studies are unanimous, suggesting a memory-enhancing and neurogenetic effect as specified below. It was shown repeatedly that ghrelin exerts its cognitive effects especially in the hippocampus, a structure crucially involved in memory formation and learning. For example, ghrelin was able to enter the hippocampus via the blood—brain barrier and to promote here dendritic spine synapse formation as well as long-term potentiation in mice (Diano et al., 2006). Furthermore, various research groups showed that ghrelin can induce hippocampal neurogenesis using both in vitro and in vivo experiments (Chen et al., 2011; Davis et al., 2011; Li et al., 2013; Stoyanova et al., 2013; Zhao et al., 2014). A recent study showed that GHSR1a-knock-out (KO) mice exhibit reduced cell proliferation and survival in the dentate gyrus of the hippocampus following chronic stress when compared to wild-type mice (Walker et al., 2014). The relevance of these findings is supported by the observation that ghrelin was consistently shown to enhance memory performance and spatial learning in rodents (Diano et al., 2006; Atcha et al., 2009; Chen et al., 2011; Davis et al., 2011; Gahete et al., 2011) except for one study reporting a memory impairing effect (Zhao et al., 2014). Studies in humans are scarce and yielded contradictory results. Ghrelin serum levels were found to be both positively correlated with verbal learning (Bellar et al., 2013) and negatively correlated with verbal learning and other cognitive domains (Spitznagel et al., 2010). In addition, a placebo controlled cross over study testing ghrelin’s effect on overnight consolidation of motor learning did not detect significant differences between ghrelin and placebo condition (Dresler et al., 2010). Clearly, more methodically consistent studies are needed to further elucidate the relationship between serum ghrelin levels and memory performance in humans. The studies discussed so far in this chapter refer to ghrelin’s effects in cognitively able rodents and human subjects. The studies discussed hereafter show that there is also evidence from animal and in vitro models of AD that ghrelin may also have neuroprotective, i.e. preventive, and beneficial effects in this disease. In an AD mouse model induced by intrahippocampal injection of amyloid-␤(Aß)-oligomers, peripherally administered AG was shown to ameliorate cognitive dysfunction and neurodegeneration in the hippocampus (Moon et al., 2011). In this study, AG was able to reduce microgliosis, thus preventing an inflammatory response in the CNS. Intriguingly, cognitive dysfunction was even restored after ghrelin injection. In line with these findings, ghrelin reduced toxicity of Aß-oligomers by decreasing production of superoxides and modulating mitochondrial metabolism in cultured

Ghrelin in psychiatric disorders hippocampal neurons (Martins et al., 2013). Other recent in vitro studies also described cell-protective properties (Martins et al., 2013; Gomes et al., 2014). Ghrelin and ghrelin agonists respectively were also shown twice to be effective in another mouse model of dementia where hippocampal neurogenesis is impaired (Dhurandhar et al., 2013; Moon et al., 2014). One research group showed that peripherally administered ghrelin could reactivate hippocampal neurogenesis (Moon et al., 2014). In the other study, long-term administration of an orally administered ghrelin agonist improved performance in the water-maze test compared to controls and reduced levels of Aß-plaques, microgliosis and inflammation in the CNS (Dhurandhar et al., 2013). In the latter, mice were fed ad libitum, thus suggesting that ghrelin also has neuroprotective effects in the absence of caloric restriction (Dhurandhar et al., 2013). Recent evidence has shed some light on the wide variety of molecular mechanisms by which ghrelin mediates its neuroprotective and antiapoptotic properties. For example, mitochondrial metabolism has been shown to be favorably influenced by ghrelin (Andrews et al., 2009; Bayliss and Andrews, 2013). This is of importance, as mitochondrial dysfunction has been implicated in the pathogenesis of dementia (Ghavami et al., 2014). In addition, several studies indicate an involvement of the phosphatidylinositol3-kinase (PI3K) (Chung et al., 2008; Chen et al., 2011; Ribeiro et al., 2014). Other mechanisms probably involved include the modulation of neurotrophic factors (Ma et al., 2011) and extracellular signal regulated kinase (ERK 1/2) (Chung et al., 2008; Chen et al., 2011; Ma et al., 2011). For more detailed information please see the relevant reviews (Andrews, 2011; Frago et al., 2011). In line with results from animal studies, Gahete and colleagues showed in a post mortem study that expression of ghrelin mRNA is reduced in three different regions of the temporal gyrus in human subjects previously suffering from AD as compared to unaffected control subjects (Gahete et al., 2010). The temporal lobe is well known to play a pivotal role in memory and is one of the most affected regions in AD (Braak and Braak, 1991; Gahete et al., 2010, 2011). Moreover, also GOAT, newly discovered splice variants of ghrelin (In1-ghrelin) and GHSR1a were all significantly reduced in AD. Interestingly, a splice variant of GHSR1a, GHRS1b, which is known to be a strong inhibitor of GHRS1a (Leung et al., 2007), was increased in patients with AD. These results suggest an involvement of the ghrelin system in human AD. Whether a disruption of the ghrelin system is causally involved in human Alzheimer’s disease cannot, however, be answered at this stage, due to the lack of interventional studies. In a cross-sectional study, fasting ghrelin serum concentrations in 14 patients with AD and 14 healthy controls, matched for body mass index (BMI) and age, did not significantly differ (Proto et al., 2006). Cross sectional design and small study size make results hard to interpret, though. Also, as discussed in Section 1, serum levels do not necessarily reflect correctly the situation in the brain. Ghrelin levels in CSF, however, have so far not been assessed in patients suffering from dementia. Results of a genetic study investigating the connection of 5 single nucleotide polymorphisms (SNP) of the ghrelin gene with risk of AD found only a very weak association. One SNP, Leu90Gln, of the ghrelin gene showed a marginal association with age of disease onset, no

179 association was found between the SNPs and risk for the disease (Shibata et al., 2011). Thus, more research is needed before definite conclusions can be drawn about the causal involvement of ghrelin in human AD. A series of recent and very promising interventional studies in in vitro and animal models of dementia (Moon et al., 2011, 2014; Dhurandhar et al., 2013; Martins et al., 2013; Gomes et al., 2014) point to a protective and preventive effect of ghrelin in dementia. Again, this does not answer the question, whether a disturbance in the ghrelin system is causally involved in the pathogenesis of dementia. However, the results of these reports justify and should give rise to further studies investigating both ghrelin’s role in human AD and also ghrelin’s or ghrelin agonists’ potential as a new therapeutic approach for AD.

4. Ghrelin in addictive disorders Of all psychiatric disorders, ghrelin’s role in addiction is most thoroughly researched. It is known that the orexigenic hormone ghrelin, released in times of energy deficiency, enhances the motivation for food intake. There is considerable evidence that ghrelin is required for mediating the incentive and rewarding effect of palatable food in both animals and humans (Jerlhag et al., 2007; Malik et al., 2008; Egecioglu et al., 2010; Perello et al., 2010; Chuang et al., 2011). This might represent a physiological mechanism to increase the incentive to consume palatable food in times of famish to ensure energy homeostasis (Lockie and Andrews, 2013). This hypothesis is supported by the phenomenon of stress eating and the observation that ghrelin mediates stress-induced food-reward in mice (Chuang et al., 2011). Also, a strong overlap of neurobiological mechanisms regulating food and drug reward has been repeatedly hypothesized (Thiele et al., 2004; Morganstern et al., 2011; Jerlhag et al., 2014b) and results from animal and human studies involving ghrelin in food and drug reward, presented in the following, seem to lend further support to this hypothesis. For example, GHSR-1a-KO mice did not show an increase of dopamine release in the nucleus accumbens (NAc), a crucial element of the brain’s reward system, usually observed with palatable food (Egecioglu et al., 2010). Furthermore, central and systemic administration of ghrelin caused a dopamine release in the nucleus accumbens in rodents (Abizaid et al., 2006; Jerlhag et al., 2006, 2007, 2012; Jerlhag, 2008; Quarta et al., 2009). Dopamine release in the NAc leads to a hedonic feeling of reward and is necessary for the development of addiction (Jerlhag et al., 2006; Ross and Peselow, 2009). Comparably in humans, ghrelin injection was associated with stronger activation of structures of the reward system (amygdala, orbitofrontal cortex, anterior insula, striatum, VTA) than placebo injection in an f-MRI study investigating neural response to pictures of food (Malik et al., 2008). The activation was positively correlated with self-rated hunger ratings. Interestingly, ghrelin also increased response in brain areas involved in attention and memory and improved recall of food pictures (Malik et al., 2008). Furthermore, GABAergic transmission, repeatedly shown to be involved in alcohol intake (Hyytiä and Koob, 1995;

180 McBride and Li, 1998; Cruz et al., 2013), was increased after local ghrelin application in rats (Cruz et al., 2013). Importantly, ghrelin’s effects on dopamine release were shown to be mediated by GHSR-1a. If GHSR-1a was antagonized, the effects described above were not observed (Abizaid et al., 2006; Jerlhag et al., 2011, 2012). Antagonism of the N-methyl-D-aspartate receptor (NMDA receptor) also blunted ghrelin-induced dopamine release in the ventral tegmental area, another key structure in the brain’s reward system, suggesting an involvement of the glutamatergic system (Jerlhag et al., 2011). This is of relevance, as this system is known to be involved in the manifestation of addictive disorders (Ross and Peselow, 2009) and is hypothesized to have indications in depressive disorders (Pilc et al., 2013). There is another relevant aspect how ghrelin affects the development of addiction, namely its role in conditioned learning. Ghrelin reinforces behavior, mediating and facilitating the learning effects that are involved in addictive behavior (Egecioglu et al., 2010; Wellman et al., 2012). Accordingly, findings from a variety of animal studies indicate that ghrelin is crucially involved in the pathogenesis of addiction: Ghrelin receptor antagonism reduced operant self-administration of alcohol and high alcohol consumption in rats (Kaur and Ryabinin, 2010; Landgren et al., 2012). In a more recent study, ghrelin KO-mice displayed significantly less voluntary alcohol consumption than wild type mice (Bahi et al., 2013). Ghrelin antagonism in wild type mice reduced alcohol consumption and locomotor activity (Bahi et al., 2013). Furthermore, ghrelin antagonism reduced alcohol consumption in rats after 2, 5 and 10 months of voluntary alcohol consumption and reduced alcohol deprivation effects as well as rebound drinking (Suchankova et al., 2013). Similar results were obtained when testing the effects of the psychostimulant cocaine. Rats showed enhanced locomotor activity and conditioned place preference after systemic administration of ghrelin and cocaine compared to cocaine alone. Central infusion of ghrelin led to an enhanced self-administration of heroin and enhanced heroin-seeking behavior (Maric et al., 2012) and increased dopaminergic transmission caused by nicotine (Palotai et al., 2013). In humans, fasting ghrelin serum levels in early abstinent alcohol dependent patients were elevated compared to healthy controls. The amount of alcohol consumed before abstinence was inversely correlated, while the duration of abstinence was positively correlated with ghrelin serum levels after abstinence (Kim et al., 2005). Alcohol was also consistently shown to lower ghrelin serum levels, both after acute administration and in chronic use (Calissendorff et al., 2005, 2006; Kraus et al., 2005; Zimmermann et al., 2007; Badaoui et al., 2008). In support of this, other studies also show that ghrelin levels are suppressed before drinking cessation and increase rapidly after the beginning of abstinence (Kraus et al., 2005; Koopmann et al., 2012; Leggio et al., 2012). Accordingly, it was repeatedly reported that ghrelin serum levels were positively associated with alcohol craving in abstinent patients (Addolorato et al., 2006; Koopmann et al., 2012; Leggio et al., 2012). Moreover, a very recent study showed that ghrelin increases alcohol craving. In this double-blind, placebo-controlled study, intravenous administration of ghrelin increased alcohol craving in

D.A. Wittekind, M. Kluge alcohol-dependent heavy drinkers in a dose-dependent manner. This effect was not observed for the desire to drink juice or consume food (Leggio et al., 2014). A possible involvement of ghrelin in human nicotine addiction has also been shown in two recent studies. The first found that high ghrelin levels in the first 24—48 h after smoking cessation were associated with increased craving and risk of smoking relapse after 4 weeks (al’Absi et al., 2014). The second reported that intrauterine exposure to cigarette smoke was associated with increased ghrelin levels in adulthood, highlighting the strong interaction of the ghrelin system with addictive substances (Paslakis et al., 2014a). There is also some support for a role of ghrelin in addiction from genetic studies: One SNP of the GHSR-1a gene was associated with high alcohol consumption (Landgren et al., 2008). In another population, the frequency of the more early-onset, heredity-driven type 2 alcohol dependence, reporting of strong withdrawal symptoms and of parental alcohol dependence were positively associated with polymorphisms of the ghrelin gene (Landgren et al., 2010). In summary, ample evidence shows an involvement of ghrelin in the regulation of both food and drug reward. Results from interventional studies (Kaur and Ryabinin, 2010; Landgren et al., 2012; Suchankova et al., 2013; Leggio et al., 2014) and experiments with GHSR-1a-KO-mice (Bahi et al., 2013) indicate that ghrelin plays a causal, pro-addictive role in the pathogenesis of addictive disorders. Accordingly, ghrelin antagonism at the GHSR-1a was associated with a decrease of alcohol consumption in a series of animal experiments (Kaur and Ryabinin, 2010; Landgren et al., 2012; Suchankova et al., 2013). Thus, the ghrelin system appears to be a promising target for the development of new drugs for treatment of addiction in humans.

5. Ghrelin in schizophrenia Since schizophrenia is associated with a high level of psychological stress (Lodge and Grace, 2011), alterations in the ghrelin system seem probable. Indeed, two studies comparing ghrelin levels in schizophrenic patients and healthy controls showed that ghrelin levels were significantly higher in schizophrenic patients (Birkás Kováts et al., 2005; Palik et al., 2005), with one study finding reduced serum ghrelin levels (Togo et al., 2004). More studies exist assessing the influence of antipsychotic medication on ghrelin levels. Here, results are divergent. While some studies suggest an increase of ghrelin in response to treatment with atypical antipsychotics (AAP) (Esen-Danaci et al., 2008; Murashita et al., 2005; Palik et al., 2005; Sentissi et al., 2009), others found no difference (Himmerich et al., 2005; Theisen et al., 2005) or a decrease in ghrelin levels (Togo et al., 2004; Hosojima et al., 2006; Kim et al., 2008; Tanaka et al., 2008; Wysoki´ nski et al., 2014). Interestingly, those studies that assessed a long-term administration of antipsychotics found an increase of ghrelin in patients who experienced a weight gain (Jin et al., 2008), possibly suggesting a disruption of the negative feedback mechanism of ghrelin secretion. However, data is too inconsistent to draw definite conclusions.

Ghrelin in psychiatric disorders

6. Ghrelin in stress, mood-and anxiety disorders 6.1. Ghrelin in stress regulation Various findings of animal and human studies indicate a crucial involvement of ghrelin in the regulation of stress response. Neural pathways regulating stress overlap largely with those regulating mood, fear and anxiety. Structures commonly involved include the amygdala, the hippocampus, the subgenual anterior cingulate cortex, the paraventricular thalamic nucleus and hypothalamic structures, like the paraventricular hypothalamic nucleus (Hsu et al., 2014). Consequently, a modulation of neural pathways regulating stress is very likely to influence mood and behavior. This strong overlap has been explained by an evolutionary selection of neurobiological pathways which ensured survival by regulating the response to environmental threats through initiating behavioral changes, such as fear, mood and feeding behavior (Bowers et al., 2012; Schellekens et al., 2012). In support of this, administration of ghrelin consistently causes an increase of the hormones of the HPA axis (stress axis) as specified in the introduction. Several reports suggest that manipulation of the HPA axis is associated with changed ghrelin levels (Davis et al., 2004; Bruder et al., 2005; Yakabi et al., 2011; Kageyama et al., 2012; Khan et al., 2014) but effects were not concordant. The interaction of the ghrelin and HPA-system was subject of a recent study. Meyer and colleagues showed that enhanced fear learning and an increase of circulating ghrelin in response to stress were possible also after adrenalectomy, indicating a stress response independent from the HPA axis. In a series of elegant experiments with rats, they showed that increased GHSR-1a-receptor activity was sufficient and necessary for enhanced fear. For example, systemic infusion of a ghrelin receptor agonist enhanced fear memory but did not increase CRF or corticosterone. However, ghrelin’s effects were dependent on growth hormone (GH) in the amygdala. These findings let the authors suggest ‘‘that ghrelin mediates a novel branch of the stress response’’ (Meyer et al., 2013). Existing data robustly show a rise of serum ghrelin after exposure to psychological stress in both rodents (Kristenssson et al., 2006; Lutter et al., 2008; Ochi et al., 2008) and humans (Rouach et al., 2007; Raspopow et al., 2010; Monteleone et al., 2012), except for one study, which found no increase (Zimmermann et al., 2007). In line with that, women reporting many interpersonal stressors had higher serum ghrelin levels than those reporting few interpersonal stressors (Jaremka et al., 2014). Furthermore, ghrelin modulated the physiological response to mental stress in humans by decreasing blood pressure and up-regulating muscle sympathetic nervous system activity, suggesting a physiological role of ghrelin in stress response (Lambert et al., 2011).

6.2. Ghrelin in anxiety disorders Ghrelin’s exact role in anxiety is strongly debated (Chuang et al., 2011; Meyer et al., 2013). While an involvement appears very likely, there is no consensus on whether ghrelin alleviates or aggravates anxiety and anxiety-like behavior.

181 The most widely noted paper supporting anxiolytic effects for ghrelin is the study by Lutter et al. (2008). Higher ghrelin serum levels, induced by subcutaneous ghrelin injections and caloric restriction, led to anxiolytic-like effects in the ‘elevated plus maze’. While anxiolytic-like effects were seen in all models in wild-type mice, no such effects were noted in GHSR-1a-KO mice. The authors concluded that ghrelin is able to counteract anxiety-like behavior occurring in times of elevated stress (Lutter et al., 2008). Anxiolytic effects were also observed in another study after ghrelin infusion into the amygdala. Interestingly, feeding in the time between ghrelin infusion and anxiety testing abolished these anxiolytic effects (Alvarez-Crespo et al., 2012). This finding let authors hypothesize that the rise of ghrelin due to hunger leads to ‘‘a feeding response, but if no food is available, it could be advantageous for survival if emotional (anxietylike) behaviors that would otherwise limit the animal from finding food are suppressed’’ (Alvarez-Crespo et al., 2012). In other words, ghrelin, in times of stress and hunger, might modify behavior in a way that helps the animal find food. In a third study, an anxiolytic effect of ghrelin after exposure to acute stress, with ghrelin-knock-out mice showing more anxiety-like behavior, was found. Of note, in unstressed conditions, these mice showed less anxiety-like behavior than their wild-type littermates suggesting an anxiogenic effect. The authors postulated a dual effect of ghrelin with a mildly anxiogenic effect under normal conditions and an anxiolytic effect in acute stress (Spencer et al., 2012). In line with the latter finding, several studies in unstressed rodents (Asakawa et al., 2001; Carlini et al., 2002, 2004; Hansson et al., 2011; Currie et al., 2012, 2014) support an anxiogenic effect of ghrelin. Yet, ghrelin was also found to be associated with increased anxiety-like behavior and enhanced fear memory after chronic stress. However, a trend toward impairment of fear memory, suggesting an anxiolytic effect, was observed after acute stress in this study (Meyer et al., 2013). Thus, ghrelin might exert anxiolytic effects in acute stress while promoting anxiogenic behavior in unstressed and chronically stressed conditions. The conflicting results concerning ghrelin’s role in anxiety are not easily mitigated. The presumption that ghrelin exerts a dual effect, i.e. both anxiogenic and anxiolytic depending on the conditions (Spencer et al., 2012; Meyer et al., 2013) can reconcile some but not all conflicting findings. Therefore, methodological aspects like the way of administration might be of importance, taking into account that peripheral and central ghrelin is probably at least partly separated as discussed in the introduction. In fact, studies showing an anxiolytic effect administered ghrelin peripherally (Lutter et al., 2008; Spencer et al., 2012), while those studies showing an anxiogenic effect injected ghrelin centrally (Carlini et al., 2002, 2004; Currie et al., 2012, 2014; Meyer et al., 2013). Comparably, ghrelin’s effects on sleep depend on the way of administration with a sleep impairing effect after central administration (Szentirmai et al., 2006) and a sleep-improving effect after peripheral administration (Kluge et al., 2010a). Furthermore, there is some evidence that ghrelin exerts different effects depending on the site of administration in the CNS (Carlini et al., 2004; Cone et al., 2014). Dosage, study design and timing of administration and behavioral tests might be other factors leading to contradictory results (Chuang and Zigman, 2010).

182 There are just three studies in humans investigating ghrelin’s potential role in anxiety disorders. The first reported higher ghrelin serum levels in non-responders with panic disorder than in responders and healthy controls (Ishitobi et al., 2012). Furthermore, an association between panic disorder and a polymorphism of the ghrelin gene was reported (Hansson et al., 2013) but not ascertained by an earlier study (Nakashima et al., 2008).

6.3. Ghrelin in obsessive compulsive disorder (OCD) Ghrelin in OCD was studied only once so far. In this study, ghrelin plasma levels of patients with OCD, patients with OCD and major depressive disorder (MDD) and healthy controls were compared. No differences were found between groups and ghrelin was not associated with severity of illness in both OCD and MDD (Emül et al., 2007).

6.4. Ghrelin in depression There is still some debate on ghrelin’s role in depression. However, the majority of studies indicate an antidepressant effect while only two studies point to a depressogenic effect. In a pioneering publication, Lutter and colleagues reported that mice with elevated ghrelin levels, either due to calorie restriction or subcutaneous injection, showed significantly less depressive-like symptoms in the forced swim test. In addition, in chronic social defeat stress (CSDS), a rodent model of chronic stress with aspects of major depression where social avoidance is caused by periods of struggle with a dominant animal, GHRS-1a-KO mice showed significantly more social avoidance than wild-type mice (Lutter et al., 2008). These findings were recently backed up: Again, GHSR-1a-KO mice showed significantly more depressive-like behavior in response to CSDS than their CSDS-exposed wild type littermates and elevated ghrelin levels induced by caloric restriction failed to exert anti-depressive effects in GHSR-1a-KO mice (Walker et al., 2014). In addition, systemic treatment with a neuroprotective compound enhancing hippocampal neurogenesis led to potent antidepressant effects in these mice. The authors thus speculated that ghrelin’s antidepressant properties are mediated by its proneurogenic properties (Walker et al., 2014). This study not only provides a possible mechanism by which ghrelin exerts its antidepressant effects but also links ghrelin’s role in depression to its role in neurodegenerative disorders. Furthermore, a reduction of depressive-like behavior in CSDS in GHSR-1a-KO mice following ghrelin-induced activation of specific catecholaminergic neurons expressing GHSR-1a was reported (Chuang et al., 2011). While the latter studies point to a more longer-term antidepressant effect of ghrelin, also acutely administered ghrelin was shown to reverse depressive-like behavior in mice after olfactory bulbectomy, a further rodent model for depression (Carlini et al., 2012). The same group showed that such a reduction of depressive-like behavior was associated with reduced gene expression and plasma levels of arginine vasopressin (AVP), suggesting that the antidepressant effect could be mediated at least in part via AVP (Poretti et al., 2014). Finally, ghrelin was shown to increase noradrenergic (Date

D.A. Wittekind, M. Kluge et al., 2006; Kawakami et al., 2008; Emanuel and Ritter, 2010; Carlini et al., 2012) as well as serotonergic transmission (Ogaya et al., 2011; Hansson et al., 2014). Thus, an increase of both serotonergic and noradrenergic transmission would support an antidepressant effect of ghrelin according to the monoamine hypothesis of depression, still a common model of depression (Krishnan and Nestler, 2008). In contrast, two studies suggest depressogenic properties of ghrelin (Kanehisa et al., 2006; Hansson et al., 2011). In the first, long-term administration of ghrelin over 4 weeks in rats was associated with both a decrease in serotonergic transmission in the dorsal raphe nuclei and pro-depression effects (Hansson et al., 2011). In the other study, administration of ghrelin anti-sense DNA into the lateral ventricle of rats induced antidepressant-like effects (Kanehisa et al., 2006). Against this research approach could be argued since it is unclear whether ghrelin is produced in the brain in relevant amounts at all (Furness et al., 2011). Unfortunately, the authors did not measure ghrelin concentration following their treatment, missing the opportunity to corroborate their research approach and to provide a clearer indication that the observed effects are related to the ghrelin system (Kanehisa et al., 2006). Data for ghrelin and depression in humans is limited and not consistent. Compared to healthy subjects, ghrelin plasma or serum levels in patients with MDD were found to be lower (Barim et al., 2009), higher (Gecici et al., 2005; Kurt et al., 2007; Ozsoy et al., 2014), and comparable, respectively (Schanze et al., 2008; Kluge et al., 2009a; Matsuo et al., 2012). One study reported higher levels in therapyrefractory patients but not in treatment responders (Ishitobi et al., 2012). A recent study found no difference in basal ghrelin levels between patients and healthy controls but a significantly blunted response to a standard glucose load in patients with MDD. The authors concluded that a functional test might be more suitable to detect differences between diagnostic groups than cross sectional blood assessments (Paslakis et al., 2014b). In fact, all of the above quoted studies determined ghrelin cross sectionally, either just once or once before and once after treatment, usually after an overnight fast (Barim et al., 2009; Ozsoy et al., 2014; Schanze et al., 2008). Only one study provided nocturnal ghrelin plasma patterns derived from 32 points in time (Kluge et al., 2009a). Since ghrelin levels depend on BMI and nutritional status (before or after food intake), varying findings can be partly explained by heterogeneous methodology and study limitations. For example, BMI in patients was significantly lower (Barim et al., 2009) and higher (Schanze et al., 2008) respectively, and some of the patients were treated with antidepressants (Schanze et al., 2008; Matsuo et al., 2012). Several studies observed a decrease of ghrelin during antidepressant treatment which accompanied both psychopathological improvement and in some studies weight gain (Schmid et al., 2006; Ozsoy et al., 2014), although one study found an increase (Pinar et al., 2008). Also electroconvulsive therapy (ECT) was shown to reduce ghrelin serum levels to a level comparable to those of healthy controls (Kurt et al., 2007). In addition, an association between ghrelin gene polymorphisms and depression was found (Nakashima et al., 2008). To our knowledge, there is only one intervention study in patients with MDD. In this study, we found a

Ghrelin in psychiatric disorders marginally significant antidepressant effect in men after acute administration of ghrelin (4 × 50 ␮g; Kluge et al., 2011). A mood-enhancing effect had been previously also observed in some healthy subjects after a single, comparatively high dose of ghrelin (100 ␮g) (Schmid et al., 2005). In agreement with an mood-improving effect are also findings that depressive symptoms in healthy subjects caused by catecholamine depletion were associated with a decrease of ghrelin plasma levels (Homan et al., 2013). In conclusion, increasing evidence suggests that ghrelin has antidepressant effects while there are few studies indicating the opposite. Antidepressant effects were observed following both rather longer-term and short-term exposure to ghrelin. There is no clear picture yet by which mechanism such effects might be mainly mediated. Proneurogenic effects (Walker et al., 2014), the reduction of the stress hormone AVP (Poretti et al., 2014) and the activation of catecholaminergic neurons (Chuang et al., 2011) have been identified as possible mechanisms contributing to ghrelin’s presumed antidepressant effect. Furthermore, as discussed earlier, ghrelin alleviates mitochondrial dysfunction (Andrews et al., 2009; Bayliss and Andrews, 2013). This might also have implications in depression since mitochondrial dysfunction has been suggested as a possible pathogenetic mechanism in MDD (Gardner and Boles, 2011). Overall, the promising evidence from animal and initial human studies warrants and should give rise to the conduction of methodically robust human studies in the future.

7. Ghrelin in eating disorders It appears obvious that the function of the ghrelin system is disturbed in eating disorders. As outlined above, ghrelin is a key hormone in the regulation of energy homeostasis, enhancing appetite and food intake and modulating brain activity in areas that control appetitive behavior (Malik et al., 2008). Consequently, many studies examine changes in the ghrelin system in eating disorders, besides anorexia nervosa (AN) and bulimia nervosa (BN) also binge eating disorder (BED) which was approved for inclusion in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013) as its own category of eating disorder recently.

183 (Tolle et al., 2003). Furthermore, also the preoccupation with food, common to many patients with AN, could possibly increase ghrelin levels to some degree since pictures of food have been found to increase ghrelin levels (Schüssler et al., 2012) The ghrelin system in AN seems to react similarly to food intake as in healthy controls. The majority of studies show a similar percental decline after a meal as in normal weight subjects (Stock et al., 2005; Nakahara et al., 2007; Sedlᡠcková et al., 2011). This is further supported by the observation that under therapy, ghrelin levels tend to drop toward normal levels and that the magnitude of the drop is negatively correlated to weight gained, suggesting that alterations in ghrelin levels in AN are a consequence, rather than a cause, of the disease (Otto et al., 2001, 2005; SorianoGuillén et al., 2004; Tanaka et al., 2004; Janas-Kozik et al., 2007; Monteleone and Maj, 2013). Furthermore, all these studies reported higher levels of ghrelin in patients with AN than healthy subjects before as well as after the meal. This is most likely due to an adaption to chronic food restriction, aiming at promoting increased food intake even after a meal (Stock et al., 2005; Nakahara et al., 2007; Sedlᡠcková et al., 2011). However, one study found that after a meal, ghrelin levels significantly fell in the control group but did not fall in the AN group (Nedvídková et al., 2003). Two ghrelin intervention studies in AN have been performed to date. 5 female patients with restricting-type AN responded to open treatment with ghrelin for 14 days with increased sensation of hunger and increased energy intake, suggesting that they still respond to ghrelin signaling and that alterations in the ghrelin system are probably not due to a loss of function of this system (Hotta et al., 2009). However, another study did not find an effect on appetite after short-term (300 min) ghrelin administration (Miljic et al., 2006). Genetic studies showed no or only a weak association of the ghrelin gene with AN. In a family trio analysis of 114 patients with AN and their parents, a transmission disequilibrium was observed for one ghrelin-gene SNP (Leu72Met) in AN (Dardennes et al., 2007). However, the majority of studies did not find any association between this gene variant and AN (Ando et al., 2006; Cellini et al., 2006; Monteleone et al., 2006; Pinheiro et al., 2010; Kindler et al., 2011). In addition, an association of a GOAT polymorphism with AN was reported (Müller et al., 2011).

7.1. Ghrelin in anorexia nervosa (AN) 7.2. Ghrelin in bulimia nervosa (BN) Increased plasma and serum levels of ghrelin in AN compared to healthy controls have been consistently reported (Otto et al., 2001; Nedvídková et al., 2003; Tanaka et al., 2003; Misra et al., 2004; Soriano-Guillén et al., 2004; Stock et al., 2005; Nakahara et al., 2007; Monteleone et al., 2008; Germain et al., 2010; Sedlᡠcková et al., 2011). This is most likely due to ghrelin levels depending on the body’s energy stores (Tschöp et al., 2001; Soriano-Guillén et al., 2004) as well as on acute nutritional status (Cummings et al., 2001). Furthermore, cognitive restrained eating, i.e. deliberately eating less than desired, increases serum ghrelin levels (Schur et al., 2008). Accordingly, when compared to constitutionally thin women, AN patients had similar BMIs but less body fat and showed higher ghrelin serum concentrations

Results for fasting ghrelin levels in patients with BN varied between studies. While 2 research groups reported higher fasting ghrelin plasma levels in BN than in healthy controls (Tanaka et al., 2002; Kojima et al., 2005), others did not find differences (Monteleone et al., 2003, 2005b, 2008; Tanaka et al., 2004). Methodological differences such as type of assay (RIA, ELISA) or using plasma or serum might at least in part explain those different findings (Espelund et al., 2003; Atalayer et al., 2013). While findings on fasting ghrelin levels in BN were inconsistent, there is some other evidence that excessive food intake in BN might be promoted by enhanced ghrelin levels (Monteleone et al., 2010): In a sham feeding study where a meal is first presented

184 and smelled and then food is chewed but not swallowed, patients with BN showed a significantly stronger increase of ghrelin levels in the cephalic phase of food digestion (after food presentation) than healthy controls. Moreover, this increase was positively correlated with the frequency of binge-purging in patients with BN (Monteleone et al., 2010). In addition, another consistent finding indicates a disturbance of the ghrelin system in BN: the ghrelin drop following food ingestion was significantly blunted in BN when compared to controls (Monteleone et al., 2003, 2005b; Kojima et al., 2005; Ando, 2013). In agreement with the reduced decline of the orexigenic hormone ghrelin, the natural satiety response following binge-eating episodes occurring in BN, is lacking (Monteleone et al., 2005b). As with AN, studies investigating associations of the ghrelin gene with BN show mixed results with one study finding an association between BN and the Leu72Met allele of the ghrelin gene (Ando et al., 2006), while others found no such association (Cellini et al., 2006; Monteleone et al., 2006; Kindler et al., 2011).

D.A. Wittekind, M. Kluge

Figure 1 stress.

Model of ghrelin’s proposed effects in hunger and

of ghrelin as compared to healthy subjects, possibly facilitating binge eating. Similar observations have been made for BED, where a blunted decline of ghrelin was also found. For all three disorders, genetic data are scarce with only few suggesting a possible involvement.

7.3. Ghrelin in binge eating disorder (BED) Binge eating disorder is characterized by recurring episodes of eating large amounts of food, which are accompanied by a feeling of lack of control, shame, disgust, guilt and embarrassment. These episodes occur even without feelings of hunger and take place at least once a week for three months (American Psychiatric Association, 2013). Basal serum levels of ghrelin were found to be suppressed in binge-eating disorder (Geliebter et al., 2005; Monteleone et al., 2005a; Troisi et al., 2005). This is in line with the finding that ghrelin levels are lower in obese people, most likely due to down-regulation of orexigenic signals (Tschöp et al., 2001; Shiiya et al., 2002; Soriano-Guillén et al., 2004). Only one study did not find differences in serum ghrelin between BED patients and healthy subjects (Munsch et al., 2009). In addition, a smaller decline of ghrelin levels after a meal was found in BED patients compared to healthy controls, similar to observations made in BN patients (Geliebter et al., 2005). Again, the satiety-effect of food might be smaller in patients with BED than controls, promoting excessive food intake, considering that not only absolute ghrelin levels, but also the change in ghrelin levels might mediate satiety (Geliebter et al., 2005). Genetic data for ghrelin in BED is very scarce. There is only one report of a possible association of the Leu72Met polymorphism of the ghrelin gene with BED (Monteleone et al., 2007). In summary, the ghrelin system shows extensive alterations in eating disorders. In AN, ghrelin levels are higher than in normal weight subjects, most likely as a compensatory mechanism for chronic energy deficiency. Also, patients show a similar response to food intake as healthy adults, with a similarly large drop after a meal. When body weight normalizes in AN, so do ghrelin levels, further supporting the hypothesis that elevations of ghrelin are a consequence, rather than a cause, of AN. Ghrelin as a treatment for AN could be a potentially promising approach, but more data has to be generated to assess efficacy and safety. In BN, results concerning serum levels of ghrelin differ. However, robust evidence shows a blunted postprandial decline

8. Ghrelin in insomnia To our knowledge, only one study investigated ghrelin in primary insomnia. Here, nocturnal ghrelin levels in 14 men suffering from insomnia and 24 age and body weight matched controls were measured at three time points (Motivala et al., 2009). The insomnia patients showed significantly lower nocturnal ghrelin levels. This result is in line with the consistent finding that ghrelin improves sleep in men: A deep sleep or non-REM sleep promoting effect was found in young men (Weikel et al., 2003; Kluge et al., 2008), elderly men (Kluge et al., 2010a) and depressed men (Kluge et al., 2011). In contrast, ghrelin did not significantly affect sleep in young (Kluge et al., 2008), elderly (Kluge et al., 2010a) or depressed (Kluge et al., 2011) women. In men, acute sleep deprivation was associated with decreased nocturnal ghrelin plasma levels (Dzaja et al., 2004) further supporting a sleep-promoting effect. In addition, ghrelin plasma levels tended to be higher in the recovery night after sleep deprivation than in the night before sleep deprivation, also pointing to a sleep improving effect (Schüssler et al., 2006). While ghrelin levels were shown to be decreased during insomnia or sleep deprivation, ghrelin plasma levels in the morning after reduced sleep were found to be increased fitting well with the observation that chronic insomnia is associated with obesity (Spiegel et al., 2004; Taheri et al., 2004; Schmid et al., 2008).

9. Conclusion and outlook In this review, we aimed to provide a concise but comprehensive overview of ghrelin’s possible involvement in psychiatric disorders. Ghrelin has implications in major psychiatric disorders, most notably Alzheimer’s disease, addictive disorders as well as anxiety- and depressive disorders. What seems to be surprising at a first glance is the widespread involvement of just one molecule in so

Ghrelin in psychiatric disorders many cerebral systems. An explanation for this might be found in ghrelin‘s possible evolutionary function: Ghrelin is a hormone released in hunger and stress. The existing evidence suggests that it leads to distinct alterations in behavior that might be favorable for survival in these times of increased threat. It is known to augment appetite, intake of energy-dense food (Perello et al., 2010) and hedonic feeding, especially in stress (Chuang et al., 2011). This way, it leads to an increase in the organism’s motivation for food intake, thus ensuring energy homeostasis. In support of this, a recent review suggests that ghrelin, via an interaction with dopamine signaling, alters the motivational state of an organism, increasing incentive to obtain food (Lockie and Andrews, 2013). This would explain ghrelin’s involvement in addictive disorders, especially since food reward and drug reward seem to share common neurobiological pathways (Thiele et al., 2004; Morganstern et al., 2011; Jerlhag et al., 2014b). Beyond that, substantial evidence suggests that ghrelin might act as an intrinsic antidepressant agent, protecting from depressive-like symptoms in response to stress (Lutter et al., 2008; Walker et al., 2014) and consequently promoting behavior which ensures survival. Finally, it has been observed that ghrelin enhances memory consolidation via a multitude of molecular mechanisms (Carlini et al., 2002; Frago et al., 2002; Atcha et al., 2009; Dhurandhar et al., 2013). We hypothesize that this, paralleling findings suggesting memory-enhancing effects of other stress hormones (Joëls et al., 2011), represents an evolutionary evolved mechanism to better remember episodes of elevated hunger and stress (Fig. 1). Another property of ghrelin offering a possible explanation for its widespread involvement is its protective effect on mitochondrial function (Andrews et al., 2009; Bayliss and Andrews, 2013). An alteration in mitochondrial function has indeed been suggested in Alzheimer’s disease, depression and addictive disorders (Gardner and Boles, 2011; Ghavami et al., 2014; Sadakierska-Chudy et al., 2014). To what extent ghrelin is causally involved in the pathogenesis of these disorders is very difficult to judge. Best evidence for a causal involvement exists for addictive disorders as described above. For depressive/anxiety disorders and for Alzheimer’s disease, data is, at the current stage, not sufficient to draw definite conclusions. Further evidence is needed to shed more light on this issue. Promising results from animal studies (Moon et al., 2011, 2014; Landgren et al., 2012; Bahi et al., 2013; Dhurandhar et al., 2013; Martins et al., 2013; Suchankova et al., 2013; Gomes et al., 2014; Walker et al., 2014), show the possible potential of ghrelin or ghrelin antagonism as novel pharmaceutical approaches for a variety of psychiatric disorders. In fact, ghrelin has been used in anorexia nervosa (Hotta et al., 2009) and a number of pilot studies in nonpsychiatric diseases like tumor-cachexia, showing promising effects (Nagaya et al., 2005; Lundholm et al., 2010; Garin et al., 2013). Furthermore, ghrelin was administered to many study participants, so far showing excellent safety with very few and mild adverse events (Garin et al., 2013). However, due to the complexity of the ghrelin system, possible interactions, like weight-gain in ghrelin agonism, have to be taken into consideration. Future research investigating the significance of the ghrelin system in psychiatric disorders should involve animal

185 studies designed to judge its causal involvement. Also, more studies are needed investigating to what extent central and peripheral ghrelin signaling are functionally interacting, as knowledge of this is very important when developing possible new ghrelin-based therapeutic agents. Furthermore, the promising results from animal studies should now give rise to more human studies to verify to what extent results from animal studies can be extrapolated to human disorders. On this scaffold, controlled, randomized studies on the efficacy of ghrelin as a treatment agent in psychiatry should be performed.

Role of the funding source This preparation of this review was not supported by any funding source.

Conflict of interest None of the authors has to disclose a conflict of interest.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/ 10.1016/j.psyneuen.2014.11.013.

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