Asian Journal of Psychiatry 25 (2017) 91–100

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Asian Journal of Psychiatry

journal homepage: www.elsevier.com/locate/ajp

Review article

Neurobiology of eating disorders - an overview

Anand Mishra, MBBS, Junior resident Psychiatrya,* ,
Manu Anand, MBBS, Junior resident Psychiatrya ,
Shreekantiah Umesh, MD, DPM, Senior resident Psychiatryb
a
Central Institute of Psychiatry, Ranchi, Jharkhand, India
b
K.S. Mani Centre for Cognitive Neurosciences, Central Institute of Psychiatry, Ranchi, Jharkhand, India

A R T I C L E I N F O

Article history:
Received 29 January 2016
Received in revised form 3 September 2016
Accepted 9 October 2016
Available online xxx

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
2. Neurobiology of appetite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
2.1. Homeostatic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
2.2. Non homeostatic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
3. Neurobiology of ED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.1. Genetic evidences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.2. Neuropsychological evidences . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.3. Interoceptive awareness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3.4. Obsessisonality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
3.5. Neuroimaging evidences . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4. Neurotransmitters and neuropeptides . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.1. Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.2. Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
4.3. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
5. Clinical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
6. The research domain criteria (RDoC) framework for research in ED . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

1. Introduction that have identifiable causes, clear symptomatology, predictable

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
* Corresponding author.
E-mail address: anandmishraxxxxxxx@gmail.com (A. Mishra).
outcomes, affect people regardless of gender ethnicity or age, and
respond to treatment (Kramer and 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),

http://dx.doi.org/10.1016/j.ajp.2016.10.009
1876-2018/ã 2016 Elsevier B.V. All rights reserved.
92 A. Mishra et al. / Asian Journal of PsychiatryAJP 25 (2017) 91–100

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 contrib-
ute to the pathogenesis of ED (Treasure and 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 and 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, obses-
sionality, 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
and 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.
2. Neurobiology of appetite
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

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]”.
 A. Mishra et al. / Asian Journal of PsychiatryAJP 25 (2017) 91–100
the homeostatic system regulate food intake based on caloric need
and energy balance (Berthoud and 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 (Fig. 1).
2.1. 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 gastro-
intestinal 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 –
a-MSH, leptin, serotonin, CRH, norepinephrine, insulin, gluca-
gon-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 opera-
tive in short term regulation of food intake. While neuropsycho-
logical 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 hypothala-
mus 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 orexi-
genics and increased production of anorexigenics in the hypothal-
amus.
2.2. Non homeostatic regulation
In humans the meal can be started even in the absence of any
depletion signal, purely as an executive cortical decision. de Castro
and Plunkett, 2002 showed that food intake level change
depending on external environment (palatability, dietary
restraints, social facilitation etc.) (Fig. 2).
Four heavily interconnected structures, the amygdala/hippo-
campus, 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.,
93
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).
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 and 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 (Mogen-
son et al., 1980; Otake and Nakamura, 2000; Usuda et al., 1998;
Zahm, 2000) and various receptor studies in nucleus accumbens
(Basso and Kelley, 1999; Maldonado-Irizarry et al., 1995; Stratford
and Kelley, 1997, 1999; Will et al., 2003; Zhang et al., 1998, 2003;
Zhang and Kelley, 1997, 2000; Zheng et al., 2003) and (Berthoud
and Morrison, 2008) suggested a role for accumbens-hypothalamic
pathways for the cognitive and emotional brain to override
homeostatic regulation (Fig. 3).
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
and Alexander, 1998; Nonogaki et al., 1998). Also 5-HT1A and 5-
HT1 B 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 and Imperato, 1988; Wise and 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 and Baldwin, 1990; Meister,
2007; Parker and Bloom, 2012; Stanley et al., 1993, 1996; Stratford
and 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
94 A. Mishra et al. / Asian Journal of PsychiatryAJP 25 (2017) 91–100
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.".
expenditure, reducing body weight, along with increased expres-
sion 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 and Seroogy, 1999), as shown in
animal studies.
High levels of endocannabinoids (anandamide and 2-arach-
idonoylglycerol (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 and Kirkham, 2002) and thus hinting at a
potential interactive role of endogenous opioids in the reward
aspect of feeding behavior.
3. 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 neurobiologi-
cal 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).
3.1. Genetic evidences
Several studies have implicate genes involved in the serotoner-
gic & 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 and
Remschmidt, 1995; Kaye et al., 1990, 1998a, 1998b; 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).
3.2. Neuropsychological evidences
In a first of its kind study in which healthy men from military
services military service were starved, Keys et al. found neuro-
psychological 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 et al., 2012a, 2012b, 2012c). 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).
3.3. 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
 A. Mishra et al. / Asian Journal of PsychiatryAJP 25 (2017) 91–100
for the integrity of the internal body state and connects to systems
responsible for attention, planning and action, through dorsolat-
eral striatal pathways (Chikama et al., 1997; Craig, 2002; Paulus
and 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.
3.4. Obsessisonality
Research has found the possibility of phenomenological and
functional overlap between ED and obsessive – compulsive
disorder (OCD) (Altman and Shankman, 2009; Murphy et al.,
2004) which has led to the suggestion of a shared etiopathogenesis
between the two disorders (Bellodi et al., 2001; 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 and
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).
3.5. 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 and
Treasure, 2005). Parietal cortex studies (Delvenne et al., 1997;
McGlynn and 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; Titova et al., 2013; Uher
et al., 2003, 2004). 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 fronto-striatal circuitry
involvement similar to autism as seen in excessive appetitive and
emotional restraint in both (Fonville et al., 2014; Martinez et al.,
2014; Pepin and 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 and Kim, 1996).
4. Neurotransmitters and neuropeptides
4.1. Serotonin
5-HT abnormalities can lead to appetite dysregulation (Blun-
dell, 1984; Leibowitz and Shor-Posner, 1986). There are studies
suggesting presence of monoamine dysfunction both in ill and
95
recovering ED (Brewerton et al., 1990; Engel et al., 2005; Jimerson
et al., 1997; Kaye and Strober, 2009; Walsh and Devlin, 1998). There
are evidences (Anderson et al., 1990; Biggio et al., 1974; Fernstrom
and Wurtman, 1971, 1972; Gibbons et al., 1979; Messing et al., 1976;
Young and Gauthier, 1981) showing that plasma tryptophan levels
are lowered by a restricted diet, leading to decreased 5-HT
production (Goodwin et al., 1987a, 1987b), 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 and Manke, 1994).
CSF 5-HIAA levels are significantly reduced in AN while normal in B
(Jimerson et al., 1992; Kaye et al., 1984, 1988). Various studies have
shown dysregulated binding potentials in 5-HT1A, 5-HT1B and 5-
HT2A receptors in ED (Bailer et al., 2007a, 2007b; 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 et al.,
2007b, 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 and Deutch,
1996; Freedman et al., 2000).
4.2. 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 and 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).
4.3. 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 and Maj, 2013).
Similarly increased endocannabinoids (specifically ananda-
mide) 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 and Maj, 2013).
Lastly several peripheral neuropeptides such as leptin(Bara-
nowska 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 and
Kaye, 2003). This leads to dysfunctional DA activation and
disturbances in normal appetite (Chattopadhyaya et al., 2007).
96 A. Mishra et al. / Asian Journal of PsychiatryAJP 25 (2017) 91–100
5. 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 and Esposito, 1998; De Vry and 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 et al., 2007a, 2007b). 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 and Devlin, 1995). From their clinical experi-
ence, 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, 1991; Walsh et al., 2006).
6. 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 and 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 et al., 2012c; Wildes and
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 (Caglar-Nazali 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 under-
standing of ED.
7. 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 and Barraclough, 1998) among all psychiatry illnesses,
the neurobiological aspect of ED definitely warrants further
research. The current treatment modalities from pharmacother-
apy 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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