Mini-review
Role of brain-derived neurotrophic factor in eating disorders:
1. Introduction........................................................... 500
factor; BITE, Bulimic Investigatory Test, Edinburgh; BN, bulimia nervosa; CCK,
n Depression Rating Scale; 5-HT, 5-hydroxytryptamine; NPY, neuropeptide-Y;
Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 499–504
www.elsevier.com/locate/pnpbpAbbreviations: AN, anorexia nervosa; BDNF, brain-derived neurotrophic
cholecystokinin; CRH, corticosterone-releasing hormone; HDRS, Hamilto2. Animal studies ......................................................... 500
3. Human studies ......................................................... 501
3.1. Human serum ...................................................... 501
3.2. Genetic studies ..................................................... 501
3.3. Personality traits..................................................... 502
4. Concluding remarks ...................................................... 503
Acknowledgement .......................................................... 503
References .............................................................. 503Recent findings and its pathophysiological implications
Kenji Hashimoto
T
, Hiroki Koizumi, Michiko Nakazato, Eiji Shimizu, Masaomi Iyo
Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan
Accepted 28 January 2005
Available online 9 March 2005
Abstract
Eating disorders, which include anorexia nervosa (AN) and bulimia nervosa (BN), are disorders characterized by abnormal patterns of
weight regulation and eating behaviors, and by disturbances in attitudes and perceptions toward weight and body shape. Brain-derived
neurotrophic factor (BDNF) plays a critical role in regulating neural survival, development, function, and plasticity in the brain. Recent
findings using heterozygous BDNF (F) knock-out (reduced BDNF levels) mice have provided evidence that BDNF plays a role in regulating
eating behaviors. Recently, we found that serum levels of BDNF in patients with eating disorders are significantly decreased compared with
normal controls. In addition, an association between the BDNF gene polymorphism and eating disorders has been demonstrated. We
reviewed the role of BDNF in the pathophysiology of eating disorders and the BDNF gene as a susceptibility gene for eating disorders.
Considering the low levels of BDNF in patients with eating disorders, using drugs that increase the BDNF levels and/or BDNF gene therapy
are possible novel therapeutic approaches. Providing confirmation that the BDNF gene is the true susceptibility gene for eating disorders
could lead to rapid therapeutic progress in treating these disorders. In addition, a more complete understanding of the signal transduction
pathway via the p75 neurotrophin receptor (p75
NTR
) and TrkB receptors would provide new perspectives for treating eating disorders.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Anorexia nervosa; Brain-derived neurotrophic factor (BDNF); Bulimia nervosa; Eating disorders; Polymorphism
Contents0278-5846/$ - s
doi:10.1016/j.pn
p75
NTR
, p75 ne
T Correspondi
E-mail addrurotrophin receptor; PPY, peptide-YY; PET, positron emission tomography; tPA, tissue plasminogen activator.ee front matter D 2005 Elsevier Inc. All rights reserved.
pbp.2005.01.007
ng author. Tel.: +81 43 226 2147; fax: +81 43 226 2150.
ess: hashimoto@faculty.chiba-u.jp (K. Hashimoto).

Diagnostic and Statistical Manual of Mental Disorders,
Fourth Ed. (DSM-IV; American Psychiatric Association;
elucidate the role of BDNF in weight regulation, Rios et al.
Diagnostic criteria for anorexia nervosa (AN)
A. Refusal to maintain body weight at or above a minimally normal weight
for age and height (e.g., weight loss leading to maintenance of body
weight less than 85% of that expected; or failure to make expected
weight gain during period of growth, leading to body weight less than
85% of that expected).
B. Intense fear of gaining weight or becoming fat, even though
underweight.
C. Disturbance in the way in which one’s body weight or shape is
experienced, undue influence of body weight or shape on self-evaluation,
or denial of the seriousness of the current low body weight.
D. In postmenarcheal females, amenorrhea, i.e., the absence of at least three
consecutive menstrual cycles. (A woman is considered to have
amenorrhea if her periods occur only following hormone, e.g., estrogen,
administration.)
Specify type
Restricting type: during the current episode of anorexia nervosa, the
person has not regularly engaged in binge-eating or purging behavior
(i.e., self-induced vomiting or the misuse of laxatives, diuretics,
or enemas)
Binge-eating/purging type: during the current episode of anorexia
nervosa, the person has regularly engaged in binge-eating or purging
behavior (i.e., self-induced vomiting or the misuse of laxatives, diuretics,
or enemas)
Diagnostic criteria for bulimia nervosa (BN)
A. Recurrent episodes of binge eating. An episode of binge eating
is characterized by both of the following:
1. Eating, in a discrete period of time (e.g., within any 2-h period),
an amount of food that is definitely larger than most people would eat
during a similar period of time and under similar circumstances
2. A sense of lack of control over eating during the episode (e.g., a
feeling that one cannot stop eating or control what or how much one
is eating)
B. Recurrent inappropriate compensatory behavior in order to prevent
weight gain, such as self-induced vomiting; misuse of laxatives,
diuretics, enemas, or other medications; fasting; or excessive exercise.
C. The binge eating and inappropriate compensatory behaviors both occur,
on average, at least twice a week for 3 months.
D. Self-evaluation is unduly influenced by body shape and weight.
E. The disturbance does not occur exclusively during episodes of
anorexia nervosa.
Specify type
Purging type: during the current episode of bulimia nervosa, the person
has regularly engaged in self-induced vomiting or the misuse of
laxatives, diuretics, or enemas
Non-purging type: during the current episode of bulimia nervosa,
the personas used other inappropriate compensatory behaviors, such
as fasting or excessive exercise, but has not regularly engaged in
self-induced vomiting or the misuse of laxatives, diuretics, or enemas
! Purging Type: during the current episode of bulimia nervosa, the person
has regularly engaged in self-induced vomiting or the misuse of
laxatives, diuretics, or enemas
! Non-purging Type: during the current episode of bulimia nervosa,
the person has used other inappropriate compensatory behaviors, such
as fasting or excessive exercise, but has not regularly engaged in
self-induced vomiting or the misuse of laxatives, diuretics, or enemas
From American Psychiatric Association (1994) Diagnostic and Statistical
Manual of Mental Disorders (Fourth Ed.), American Psychiatric Press.
rmacTable 1). The etiology of eating disorders is presumed to be
complex, and to be influenced by multiple developmental,
social, and biological processes (Becker et al., 1999; Kaye et
al., 2000; Fairburn and Harrison, 2003; Walsh and Devlin,
1998; Klein and Walsh, 2004).
Brain-derived neurotrophic factor (BDNF) is recognized
as a critical regulator in the survival, differentiation, and
outgrowth of select peripheral and central neurons during
development and in adulthood, and is also implicated in the
synaptic plasticity of such brain functions as learning and
memory (Snider, 1994; Thoenen, 2000; Schinder and Poo,
2000; Huang and Reichardt, 2001; Malcangio and Less-
mann, 2003; Mattson, 2002; Mattson et al., 2003, 2004; Lu,
2003a). Several lines of evidence suggest that BDNF plays
an important role in the pathophysiology of psychiatric
diseases, including mood disorders, and in the mechanism
of action of therapeutic agents (Duman et al., 1997; Duman,
2002; Tamminga et al., 2002; Manji et al., 2003; Nestler et
al., 2002; Coyle and Duman, 2003; Green and Craddock,
2003; Angelucci et al., 2004; Hashimoto et al., 2004).
2. Animal studies
There is also evidence supporting the critical role of
BDNF in regulating eating behaviors in animals. For
example, heterozygous BDNF (F) knock-out mice (e.g.,
approximately 50% levels of BDNF of wild-type mice)
show enhanced inter-male aggressiveness and hyperphagia
accompanied by significant weight gain in early adulthood,
and these behavioral abnormalities have been correlated
with 5-hydroxytryptamine (5-HT) dysfunction in the brain,
since these behavioral abnormalities were ameliorated by
chronic administration of the selective 5-HT re-uptake
inhibitor fluoxetine (Lyons et al., 1999). Furthermore,
heterozygous BDNF (F) knock-out mice exhibit abnormal-
ities in eating behavior or locomotor activity, and infusion of1. Introduction
People suffering from eating disorders exhibit serious
disturbances in eating behavior, such as extreme and
unhealthy reduction of their food intake or severe over-
eating, as well as feelings of distress about, or extreme
concern over, their body shape or weight. Eating disorders
frequently develop during adolescence or early adulthood,
but some studies have reported their onset during childhood
or later in adulthood. Eating disorders affect some 1–3% of
women in the United States (Becker et al., 1999; Kaye et al.,
2000; Walsh and Devlin, 1998; Fairburn and Harrison,
2003; Klein and Walsh, 2004; Polivy and Herman, 2002).
The major types of eating disorders are anorexia nervosa
(AN) and bulimia nervosa (BN) that are diagnosed by the
K. Hashimoto et al. / Progress in Neuro-Psychopha500the BDNF protein can transiently reverse abnormal eating
behaviors (Lyons et al., 1999; Kernie et al., 2000). To helpTable 1
Diagnosis of eating disorders
ology & Biological Psychiatry 29 (2005) 499–504(2001) have generated conditional mutants in which BDNF
has been eliminated from the brain after birth through the