Accepted Manuscript Title: Neurobiology of eating disorders - an overview Authors: Anand Mishra MBBS Junior resident Psychiatry Manu Anand MBBS Junior resident Psychiatry Shreekantiah Umesh MD, DPM Senior resident Psychiatry PII: DOI: Reference:

S1876-2018(16)30036-3 http://dx.doi.org/doi:10.1016/j.ajp.2016.10.009 AJP 971

To appear in: Received date: Revised date: Accepted date:

29-1-2016 3-9-2016 9-10-2016

Please cite this article as: Mishra, Anand, Anand, Manu, Umesh, Shreekantiah, Neurobiology of eating disorders - an overview.Asian Journal of Psychiatry http://dx.doi.org/10.1016/j.ajp.2016.10.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Article title: neurobiology of eating disorders - an overview Article reference: AJP_2016_33 Authors list with affiliations 1. Anand Mishra*, MBBS Junior resident Psychiatry Central Institute of Psychiatry Ranchi, Jharkhand, India 2. Manu Anand, MBBS Junior resident Psychiatry Central Institute of Psychiatry Ranchi, Jharkhand, India 3. Shreekantiah Umesh, MD, DPM Senior resident Psychiatry K.S. Mani Centre for Cognitive Neurosciences Central Institute of Psychiatry Ranchi, Jharkhand, India *First author and corresponding author [email protected]

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Neurobiology of eating disorders and its overlap with other psychiatric illnesses is reviewed. Various articles on neurobiology of eating disorders were reviewed using the keywords like “Eating Disorder”, “Anorexia Nervosa”, “Binge Eating Disorder”, “Neurobiology”, on PUBMED and Google Scholar, and eligible studies were identified. Evidences support presence of neurobiological abnormalities in eating disorders. Further research in neurobiology of eating disorders would guide in developing more effective treatment modalities for this group of disorders.

NEUROBIOLOGY OF EATING DISORDERS INTRODUCTION Eating disorders (ED) are serious illnesses that usually involve eating way too little or way too much, and can seriously jeopardize one‟s health. At one time, rarely mentioned and poorly understood, today ED are one of the most researched and discussed illness throughout the world. We know now that ED are mental disorders that have identifiable causes, clear symptomatology, predictable outcomes, affect people regardless of gender ethnicity or age, and respond to treatment(Kramer & Kittleson, 2005). They most commonly occur among late adolescent and young adult women(Giordano, 2007). These may be chronic, relapsing and are often associated with psychiatric comorbidity and medical sequelae. Among the ED, anorexia nervosa (AN) and bulimia nervosa (BN) are the most common, but DSM 5 also recognized other clinically significant eating disturbances like binge-eating disorder (BED), pica, Avoidant/Restrictive food intake disorder (ARFID), rumination disorder and other specified eating or feeding disorders (OSFED) in its formal diagnostic category after merging feeding and eating disorders in a single chapter(American Psychiatric Association, 2013). Despite of the immense amount of research the pathophysiology of ED is still poorly understood. Though mostly attributed to psychosocial factors, there is growing agreement on the fact that neurobiological vulnerabilities contribute to the pathogenesis of ED(Treasure & Campbell, 1994). Recent studies have shown that genetic factors account for approximately 50-80% of the risk of developing eating disorders(Bulik et al., 2006) and contribute to neurobiological factors underlying ED(Kaye & Strober, 2009). The ED display a unique and complex appetitive symptomatology which is not shared by other psychiatric disorders which suggests that they possibly reflect some aberration in the appetitive pathways(Kaye et al., 2011). In addition, many individuals with ED tend to express behaviors like inhibition/disinhibition, anxiety, depression, obsessionality, body image distortion, perfectionism and anhedonia in concert because they are likely to be encoded in limbic and cognitive circuits known to regulate neurological processes related to appetite, emotionality, and cognitive control(Kaye et al., 2011). Studies on cortico-limbic neural processes in obesity(Berthoud, 2006), brain mechanisms in appetite(Rolls, 2006), gustatory processing(Small, 2006) suggest that individuals can overeat even when satiated and with replete energy stores. It has also been suggested that ED and addiction share overlapping neurobiology(Volkow et al., 2012). However, contrasting symptoms such as underconsumption of food despite of emaciation and decreased rates of substance abuse in AN(Calero‐Elvira et al., 2009; Gadalla & Piran, 2007) highlights the possible existence of differences in neural processes of obesity and addiction. Although the development of a neurobiological model of ED is still in a nascent stage, there are enough evidences to warrant an understanding of the neurobiology as an important approach for further improvement in treatment of ED.

NEUROBIOLOGY OF APPETITE Executive function Impulse control Decision-making Prefrontal cortex

Motor planning Motor cortex

Acb CORE

Memory Context Novelty

Acb SHELL

Dorsal thalamus

Amygdala BLA

Pallidum

MD Thalamus “Taste” Thalamus PV Thalamus

CEA

Hypothalamus LH

Multimodal sensory input Emotional processing Reward learning

PVN DMH

Arcuate Midbrain dopamine cells

PB Primary ascending gustatory pathways

Voluntary somatic motor output Reward/motor integration and association

Habit learning

Dorsal striatum

Hippocampus

NTS

Reward, unpredicted events

VMH

Locomotor, digestive, defensive, reproductive behaviours (behavioural control columns)

Autonomic/ visceral output Motor pattern generators

Gustatory visceral input Fig. 1. Brain regions involved in feeding behaviour. Acb, nucleus accumbens; BLA, basolateral amygdala; CEA, central nucleus of the amygdala; DMH, dorsomedial hypothalamus; LH, lateral hypothalamus; MD, mediodorsal thalamic nucleus; NTS, nucleus of the solitary tract; PB, parabrachial nucleus; PV, paraventricular; PVN, paraventricular nucleus of the hypothalamus; VMH, ventromedial nucleus of the hypothalamus(Kelley et al., 2005). “Reprinted from Physiology & behavior, 86(5), Kelley, A. E., Baldo, B. A., Pratt, W. E., & Will, M. J., Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward, 773-795, Copyright (2005), with permission from Elsevier [OR APPLICABLE SOCIETY COPYRIGHT OWNER].”

The sensation of hunger (physiological drive) is associated with a craving for food and several other physiological effects, which cause the person to seek an adequate food supply. While appetite (psychological drive) is a desire for food, often of a particular type, and is useful in helping the individual to choose the quality of food he eats. If the quest for food is successful, the feeling of satiety occurs(Hall, 2010). Both metabolic and non-metabolic factors are involved in the initiation and maintenance of eating behavior. Particularly in humans, non-metabolic factors like cues, reward, cognitive and emotional factors play a major role. The brain regions regulating appetite may be considered as either homeostatic or hedonic(Gibson et al., 2010). If one has not

eaten for long, homeostatic processes would induce hunger perception and if one is not hungry but presented with food stimuli like smell or sight, then hunger perception is elicited concomitantly with bodily responses like salivation. They can be „intrinsic‟ or „extrinsic‟ factors as homeostatic induced hunger mainly arises from processes within the individual, while food preferences and associated rewards are learnt from prior experiences(Arana et al., 2003). Hypothalamus(Arora, 2006) and brainstem as part of the homeostatic system regulate food intake based on caloric need and energy balance(Berthoud & Morrison, 2008; Nisbett, 1972). They integrate inputs from cortical regions involving reward value of food(Kampe et al., 2009; Schwartz, 2006) indicating that „hedonic‟ hunger may be neurally mediated(Berridge, 2009; Haase et al., 2009; Hinton et al., 2004). The neural mechanisms in the hedonic network may override homeostatic signals and contribute to ED. Homeostatic regulation: The lateral nuclei of the hypothalamus perform the role of feeding center by initiating the motor drives to search for food. The ventromedial nuclei of the hypothalamus perform the role of satiety center. Other regions like paraventricular, dorsomedial and arcuate nuclei of hypothalamus also affect the regulation of food intake in important ways. The arcuate nuclei are the sites in the hypothalamus where several hormones released from the gastrointestinal tract and adipose tissue converge to regulate food intake, as well as energy expenditure. The hypothalamus receives neural signals from the gastrointestinal tract that provide sensory information about the filling of stomach; chemical signals signaling satiety from nutrients in the blood; signals from gastrointestinal hormones; hormonal signals from adipose tissue; and signals from the cerebral cortex (taste, smell and sight of the food) that influence feeding behavior. The receptors for various neurotransmitters that modulate feeding behavior are highly expressed in the hypothalamic feeding and satiety centers. These neurotransmitters are broadly categorized as (1) orexigenic substances that stimulate feeding (example – Neuropeptide Y (NPY), Agouti-related protein (AGRP), Melatonin concentrating hormone (MCH), Orexin A & B, Endorphins, Galanin (Gal), glutamate & GABA, Ghrelin, Cortisol, endocannabinoids etc.) or (2) anorexigenic substances that inhibit feeding (Example – α-MSH, leptin, serotonin, CRH, norepinephrine, insulin, glucagon-like peptide (GLP), cholecystokinine (CCK), cocaine and amphetamine regulated transcript (CART), peptide YY (PYY)). Gastrointestinal Filling, CCK, PYY, GLP, Ghrelin and various “oral factors” (chewing, salivation, swallowing and tasting) are operative in short term regulation of food intake. While neuropsychological studies of functions in specific areas of brain support the glucostatic, aminostatic and lipostatic theories in long term regulation of food intake. Also interaction within the hypothalamus between the temperature regulating and food intake regulating system has its effect on the homeostatic regulation of food intake. Leptin, a hormone secreted by adipocytes, stimulates actions at multiple sites in hypothalamus that help in decreasing fat storage, which also includes decreased production of orexigenics and increased production of anorexigenics in the hypothalamus.

Non Homeostatic Regulation:

Fig. 2. Brain network for appetitive behavior. PFC, prefrontal cortex; OFC, orbitofrontal cortex; VTA, ventral tegmental area; DA, dopamine(Dagher, 2009). Reprinted by permission from Macmillan Publishers Ltd: [INTERNATIONAL JOURNAL OF OBESITY] (Dagher, A. (2009). The neurobiology of appetite: hunger as addiction.International journal of obesity, 33, S30-S33.), copyright (2009).

In humans the meal can be started even in the absence of any depletion signal, purely as an executive cortical decision. Decastro and Plunkett (2002) showed that food intake level change depending on external environment (palatability, dietary restraints, social facilitation etc.).

Four heavily interconnected structures, the amygdala/hippocampus, orbitofrontal cortex (OFC), insula, and striatum are the main elements in the control of appetitive behavior(Dagher, 2009). Especially fMRI studies have shown that anterior insula is most probably the primary gustatory cortex and a portion of the orbitofrontal cortex being the secondary gustatory cortex as both seem to respond to taste(Francis et al., 1999; O'Doherty et al., 2001). In addition to integrating the homeostatic information, as a group these structures are involved in learning, liking and wanting component of reward in respect of food by allocating attention, effort, and motivation for it(Berridge & Robinson, 2003). They all generally respond to food cues which are conditioned stimuli predictive of reward. The cognitive control of appetite is mediated by the modulatory control of prefrontal cortex over the appetitive regions. Based on neuroanatomical observations and findings(Mogenson et al., 1980; Otake & Nakamura, 2000; Usuda et al., 1998; Zahm, 2000) and various receptor studies in nucleus accumbens(Basso & Kelley, 1999; Maldonado-Irizarry et al., 1995; Stratford & Kelley, 1997, 1999; Will et al.,

2003; Zhang et al.,1998 & 2003; Zhang & Kelley, 1997 & 2000; Zheng et al., 2003), Berthoud et al (2008)(Berthoud & Morrison, 2008) suggested a role for accumbens-hypothalamic pathways for the cognitive and emotional brain to override homeostatic regulation.

Fig. 3. Schematic diagram depicting possible interactions between “cognitive” and “emotional” brain with the “metabolic” brain(Berthoud, 2006). "Copyright (2006) Wiley. Used with permission from (Berthoud, Homeostatic and Non-homeostatic Pathways Involved in the Control of Food Intake and Energy Balance, Obesity, The Obesity Society."

Several neurotransmitters are involved in the normal feeding behavior(Kalra et al., 1999). Serotonin has a hypophagic effect probably mediated by postsynaptic 5-HT2C receptors(Leibowitz & Alexander, 1998; Nonogaki et al., 1998). Also 5-HT1A and 5-HT1B receptors are considered to have opposing effects on feeding behavior. Dopamine, via its action in the nucleus accumbens, seems to be associated with the reinforcement effect in feeding (food cues)(Di Chiara & Imperato, 1988; Wise & Rompré, 1989). Its release in hypothalamus seems to be associated with the duration of meal consumption, thus associated with meal size(Meguid et al., 2000). There are evidences supporting a stimulatory role of GABA and glutamate in several species(Ebenezer & Baldwin, 1990; Meister, 2007; Parker & Bloom, 2012; Stanley et al., 1993 & 1996; Stratford & Kelley, 1997; Van Den Pol, 2003). Brain noradrenaline alteration can increase or decrease eating(Wellman, 2000). Several studies show that acetylcholine receptor ligand nicotine reduces appetite and alters feeding patterns(Grunberg et al., 1986; Jo et al., 2005; Levin et al., 1987; Miyata et al., 1999). Brain derived Neurotropic Factor (BDNF) has also been shown to influence both the homeostatic and hedonic mechanisms of appetite. Its role in decreasing food intake, increasing energy expenditure, reducing body weight, along with increased expression in brain centers for appetite has been demonstrated in animals(Nakagawa et al., 2000; Tsuchida et al., 2001). It is also highly expressed in the central reward pathways which hints at a role in modulation of the positive hedonic eating with respect to palatable food(Cordeira et al., 2010; Numan & Seroogy, 1999), as shown in animal studies.

High levels of endocannabinoids (anandamide and 2-arachidonoylglycerol (2-AG)) and cannabinoid receptors have also been demonstrated in the limbic systems of food deprived animals(Kirkham et al., 2002). The endocannabinoids affect feeding behavior and the reward processing associated with it. Following short term food deprivation, they regulate the actions of orexigenic and anorexigeic substances and by their effect on the mesolimbic dopaminergic pathway, increase the level of motivation to search and consume more rewarding food items(Cota et al., 2003). The cannabinoid induced wanting and liking for food has been shown to be mediated by increased dopaminergic activity in the nucleus accumbens(Solinas et al., 2006), which can be reduced by opioid antagonists(Williams & Kirkham, 2002) and thus hinting at a potential interactive role of endogenous opioids in the reward aspect of feeding behavior.

NEUROBIOLOGY OF ED: Despite of the obstacles like the confounding effect of malnourishment, difficulty in premorbid identification of probable patients, tendency to cross between subtypes and lack of consensus on definition for recovery(Kaye et al., 2011), studies in neuropsychology, neuroimaging and receptor functions have contributed to a growing body of knowledge on the neurobiological aspect of ED. Hence a constantly strengthening consensus is there about the neurobiological vulnerabilities making substantial contribution to the pathogenesis of ED(Hausswolff‐Juhlin et al., 2015). Genetic evidences: Several studies have implicate genes involved in the serotonergic & dopaminergic system along with those involved in weight regulation as the possible candidates in the neurobiology of ED(Frey et al., 2000; Hebebrand et al., 1997; Hebebrand & Remschmidt, 1995; Kaye, 1990 & 1998; Koronyo-Hamaoui et al., 2002). Although genome wide linkage studies have been equivocal, still variations in the 5-HT2A receptor gene(Gorwood et al., 2003) and the Val66Met variant in BDNF(Ribases et al., 2003) have good evidence(Scherag et al., 2010). Neuropsychological evidences: In a first of its kind study in which healthy men from military services military service were starved, Keys et al found neuropsychological changes similar to ED(Keys et al., 1950). Studies have also shown that patients with AN have specific thinking styles with characteristics of seeing things in detail, perfectionism, difficulties in „set shifting‟ and weak „central coherence‟ (having difficulty in seeing the larger picture due to focusing on minute details)(Gillberg et al., 1996; Keys et al., 1950; Tchanturia et al., 2005). Difficulties in emotional processing and altered reward sensitivity are also seen(Oldershaw et al., 2012). Though these symptoms disappear with refeeding in many, they do persist in some post recovery and are also seen in non suffering first degree relatives (Holliday et al., 2014; Rose et al., 2012). Superior working memory performance in ED helps in practicing strategies to avoid food cues which are considered irrelevant or unwanted by the individual(Brooks, O‟Daly, Uher, Schiöth, et al., 2012). Inadequate self perception and ruminations about body weight and shape suggest of a possible

association between psychological profile and neurobiology in the pathogenesis of cognitive aberrations in ED(Shafran et al., 2004). Amygdala due to its involvement in anxiety and fear may be associated with the learned fear of food in ED(Costafreda et al., 2013). Interoceptive awareness: Altered interoceptive awareness seems to be a precipitating and reinforcing factor in AN (Bruch, 1962; Fassino et al., 2004; Garner et al., 1983; Kaye et al., 2011). Interoception is the awareness of the physiological condition of the complete body(Craig, 2002). The insula is important in interoceptive monitoring of sensations vital for the integrity of the internal body state and connects to systems responsible for attention, planning and action, through dorsolateral striatal pathways(Chikama et al., 1997; Craig, 2002; Paulus & Stein, 2006). Studies have found altered activity in insula of ill AN patients(Nozoe et al., 1993). Studies have also found elevated pain thresholds in ED(Papežová et al., 2005), which persists post recovery(Stein et al., 2003) and is suggestive of altered interoceptive awareness. Recent fMRI studies(Haase et al., 2009; Vocks et al., 2011; Wagner et al., 2008) focussing on the appetitive circuitry using tastants, also suggest that a dysfunctional interoceptive processing characterized by altered sensitivity and/or setpoint for sensory-interoceptive-reward processes in response to palatable food(Small, 2009) might be a trait characteristic of AN. Obsessisonality: Research has found the possibility of phenomenological and functional overlap between ED and obsessive–compulsive disorder (OCD)(Altman & Shankman, 2009; Murphy et al., 2004) which has led to the suggestion of a shared etiopathogenesis between the two disorders(Bellodi et al., 2014; Robbins et al., 2012). Many studies have shown dysfunctional limbic and cognitive neural networks both in ED(Uher et al., 2003) and OCD(Insel, 1992; Saxena, 2003). Elevated levels of impulsivity is seen in both ED(Boisseau et al., 2009 & 2012) and OCD(Lochner & Stein, 2006; Morein-Zamir et al., 2010). Behavioral and cognitive inhibition impairment similar to OCD has also been seen in ED(Galimberti et al., 2012; Murphy et al., 2004). Neuroimaging evidences: In general all neuroimaging show cerebral atrophy and enlarged ventricles in patients with AN(Titova et al., 2013) and to a lesser extent in BN(Krieg et al., 1989). Presence of enlarged ventricles despite normal weight in ED suggests there possibility as a predisposing disturbance in the development of an ED(Kiriike et al., 1990).Studies in brain lesions have found diagnostic EDs to be associated with right frontal and temporal lobe damage(Uher & Treasure, 2005). Parietal cortex studies(Delvenne et al., 1997; McGlynn & Schacter, 1989; Nozoe et al., 1995) suggest parietal dysfunction(Delvenne et al., 1997) and its effect on body image distortion in ED. Dorsolateral prefrontal cortex is implicated as an indicator of cognitive control in AN while as vulnerabilities in cognitive control in BN(Brooks et al., 2011; Brooks, O‟Daly, Uher, Friederich, et al., 2012; Titova et al., 2013; Uher et al., 2003 & 2014). The basal ganglia, the striatum in particular, (dorsal with excessive inhibition of appetite and ventral involving parietal cortex, with dysfunctional sense of self and body image of distortion), is associated with abnormal responses to food and altered motivation in those with ED(Hausswolff‐Juhlin et al., 2015). fMRI studies on

restrictive AN have shown hyper-reactivity of amygdala(Pietrini et al., 2011). AN has frontostriatal circuitry involvement similar to autism as seen in excessive appetitive and emotional restraint in both(Fonville et al., 2014; Martinez et al., 2014; Pepin & Stagnitti, 2012). Changes similar to anxiety disorder in the frontal and temporal cortex have been seen in ED(Gordon et al., 2001; Nozoe et al., 1993; Schulte-Rüther et al., 2012; Zald & Kim, 1996). Neurotransmitters and neuropeptides: Serotonin - 5-HT abnormalities can lead to appetite dysregulation(Blundell, 1984; Leibowitz & Shor-Posner, 1986). There are studies suggesting presence of monoamine dysfunction both in ill and recovering ED(Brewerton et al., 1990; Engel et al., 2005; Jimerson et al., 1997; Kaye & Strober, 2009; Walsh & Devlin, 1998). There are evidences(Anderson et al., 1990; Biggio et al., 1974; Fernstrom & Wurtman, 1971, 1972; Gibbons et al., 1979; Messing et al., 1976; Young & Gauthier, 1981) showing that plasma tryptophan levels are lowered by a restricted diet, leading to decreased 5-HT production(Goodwin, Fairburn, et al., 1987; Goodwin, Fraser, et al., 1987), which downregulates 5-HT transporter density(Huether et al., 1997) along with supersensitivity of postsynaptic receptors. Data showing reduced plasma tryptophan in emaciated AN(Schweiger et al., 1986) has led to the idea that dietary restraint has anxiety reducing character in AN(Kaye et al., 2003; Strober, 1995; Vitousek & Manke, 1994). CSF 5-HIAA levels are significantly reduced in AN while normal in BN(Jimerson et al., 1992; W. H. Kaye et al., 1984, 1988 & 1998). Various studies have shown dysregulated binding potentials in 5-HT1A, 5-HT1B and 5HT2A receptors in ED(Bailer, Frank, Henry, Price, Meltzer, Becker, et al., 2007; Frank et al., 2002; Tammela et al., 2003). Harm avoidance and 5-HT2A binding in lateral and medial OFC, cingulate cortex and parietal cortex show correlation in patients with AN(Bailer, Frank, Henry, Price, Meltzer, Mathis, et al., 2007; Bailer et al., 2005), who in general score high on harm avoidance and low on novelty seeking and reward dependence(Klump et al., 2004). Studies also suggest a possibility of mesial temporal (amygdala)-cingulate 5HT1A/2A imbalance as a common trait in AN subgroups in relation to behavioral inhibition, anticipatory anxiety or integration of mood and cognition(Charney & Deutch, 1996; Freedman et al., 2000). Dopamine - Dopaminergic dysfunction in fronto-striatal circuit can be responsible for the failure to form hedonic association with rewarding stimuli in ED(Frank et al., 2005; Steinglass & Walsh, 2006; Wagner et al., 2007). In AN reduced CSF DA metabolites(Kaye et al., 1984) which persists post recovery(Kaye et al., 1999), altered frequency of functional polymorphism of D2 receptor genes(Bergen et al., 2005) and increased D2/D3 receptor binding in anteroventral striatum(Frank et al., 2005). In BN the dopamine receptors are reduced and dopamine release is decreased in the striatum(Broft et al., 2012). Surprisingly people with BED have increased dopamine release in the striatum(Wang et al., 2011). Overall in people with ED it seems there is an imbalance in the antagonistically acting 5-HT and DA neurocircuitry(Daw et al., 2002; Duvvuri et al., 2009). Others – A recent meta-analysis of several studies has shown that BDNF levels are reduced in individuals with AN or BN(Brandys et al., 2011) which could be an adaptive way of improving food consumption in persistent starvation(Monteleone & Maj, 2013).

Similarly increased endocannabinoids (specifically anandamide) have been seen in AN and BED patients, but not in BN(Monteleone et al., 2005). Also CB1 receptor markers are seen in higher amount in the bloods of AN and BN patients(Frieling et al., 2009) which can been correlated with their increased number in the insula in these patients as shown in a PET study(Gérard et al., 2011). Thus the dysregulation of the endocannabinoid system may also reflect an adaptive response to improve hunger and food intake(Monteleone & Maj, 2013). Lastly several peripheral neuropeptides such as leptin(Baranowska et al., 2008), ghrelin(Monteleone et al., 2003; Otto et al., 2001; Palmiter, 2007; Tanaka et al., 2002), CCK(Philipp et al., 1991), PYY(Prince et al., 2009), oxyntomodulin(Cohen et al., 2003) etc. are also found dysregulated in people with AN and BN(Bailer & Kaye, 2003). This leads to dysfunctional DA activation and disturbances in normal appetite(Chattopadhyaya et al., 2007).

CLINICAL PERSPECTIVE: Early intervention appears to be the most effective treatment for those with EDs(Fisher et al., 2010). 5-HT2A receptor due to its response to SSRI is of interest in ED as it is associated with modulation of appetite and mood(Bailer et al., 2004; Bonhomme & Esposito, 1998; De Vry & Schreiber, 2000; Simansky, 1995; Stockmeier, 1997). For AN in adults, there is no consistent evidence to date for an effective treatment of choice(Hausswolff‐Juhlin et al., 2015). AN do not respond well to Selective Serotonin Reuptake Inhibitors (SSRIs)(Walsh et al., 2006) because there is dysfunction in 5-HT neurocircuitry leading to reduced 5-HT release at the synapse while SSRI rely on 5-HT release(Duvvuri et al., 2009). Also increased 5-HT1A receptor activity in AN accounts for poor response to medications(Bailer, Frank, Henry, Price, Meltzer, Mathis, et al., 2007). A WFSBP task force on ED found grade B evidence for use of olanzapine, grade C evidence for quetiapine and risperidone and no conclusive evidence for antidepressants(Aigner et al., 2011) in AN as characterized by weight gain. In BN treatment there is grade A evidence for fluoxetine in high dosage, and also for topiramate and TCA, as characterized by reduced episodes of binge eating(Mitchell et al., 2003). Though relapse during treatment is quite common(Walsh & Devlin, 1995). From their clinical experience, Kaye et al. suggested better response to SSRI in RAN compared to BAN and poor response in some BN even to high dosage of SSRI(Kaye et al., 2001; Kaye et al., 1991; Walsh et al., 2006).

The Research Domain Criteria (RDoC) framework for research in ED: The RDoC in its bid to make psychiatry more precise, tries to incorporate research in terms of various units of analysis (genes, molecules, cells, circuits, physiology, behavior, and self-reports) into the identified dimensions of behavior (negative valence system, positive valence system, cognitive systems, systems for social processes and arousal & regulatory systems)(Insel et al., 2010) for established psychiatric illnesses. In contrast to the categorical approach, it provides a unique way to investigate the association between neural processes, etiology and outcome in individuals with ED(Wildes & Marcus, 2015). Also considering the diagnostic instability, high rate of comorbidity and a predominance of “other specified feeding or eating disorder” diagnosis,

a utilization of a broader inclusion and exclusion criteria improves the validity of studies in the RDoC approach(Sanislow et al., 2010). The interest in the dimensional approach in classifying eating disorders is increasing steadily(Brooks, Rask-Andersen, et al., 2012; Wildes & Marcus, 2013). Several studies as discussed in preceding sections have provided support for various RDoC dimensions in eating disorders. For example – Hyper-responsiveness in fear circuits to provoking stimuli(Friederich et al., 2013) (negative valence system), dysregulated reward processing(Manwaring et al., 2011; Steinglass et al., 2012) (positive valence), fronto-striatal circuit hypoactivity in eating disorder during performance on tasks involving response inhibition(Balodis et al., 2013; Marsh et al., 2011; Oberndorfer et al., 2011), and impaired attachment and social communication(CaglarNazali et al., 2014) (social processes) etc. A detailed discussion of these studies is beyond the scope of this text and interested readers are advised to refer to relevant studies as mentioned. Overall, an RDoC approach to studies in future can prove beneficial to the advancement of our understanding of ED.

CONCLUSION: The DSM 5 reorganized its classification system for eating disorder with the idea of improving the clinical utility. In addition to introduction of some new and reintroduction of some old diagnostic entities it specifically decided not to consider obesity as a psychiatric diagnosis(Attia et al., 2013). The evidences on the neurobiological studies focussing on the disorders other than AN, BN and to some extent BED, is largely lacking. Still from the available studies it would be safe to conclude that neurobiology has an important role in the pathogenesis of ED. Owing to the inconsistencies across studies our current knowledge at best might be called nascent, but nevertheless considering the associated morbidity and the fact that AN has the highest mortality rate(Arcelus et al., 2011; Harris & Barraclough, 1998) among all psychiatry illnesses, the neurobiological aspect of ED definitely warrants further research. The current treatment modalities from pharmacotherapy to psychotherapy being not very promising, further refinement in the neurobiological model may guide us in a better targeted approach to treatment.

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