REVIEW ARTICLE CNS Drugs 2001; 15 (2): 119-136

1172-7047/01/0002-0119/$22.00/0

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Aetiopathogenesis and
Pathophysiology of Bulimia Nervosa
Biological Bases and Implications for Treatment
Francesca Brambilla
Dipartimento di Scienze Neuropsichiche, Istituto Scientifico Ospedale S. Raffaele, Milan, Italy

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
1. Evidence for a Biological Cause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
1.1 Factors Influencing Biochemical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
1.1.1 Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
1.1.2 Instability of Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
1.1.3 External and Internal Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
2. Genetic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
3. Alterations in Neurotransmitter Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
3.1 Noradrenergic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
3.2 Dopaminergic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
3.3 Serotonergic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
4. Alterations in Neurohormonal Peptide Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
4.1 Hunger-Stimulating Neurohormonal Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
4.2 Hunger-Inhibiting Neurohormonal Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
4.3 Satiety-Stimulating Neurohormonal Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
4.4 Neurohormonal Peptides not Related to Eating . . . . . . . . . . . . . . . . . . . . . . . . . . 127
4.5 Peripheral Hormones Influencing Eating Behaviour . . . . . . . . . . . . . . . . . . . . . . . . 127
5. Implications for Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
5.1 Psychodynamic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
5.2 Psychopharmacological Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Abstract Bulimia nervosa is an eating disorder characterised by recurrent episodes of

binge eating and associated efforts to purge the ingested calories through self-
induced vomiting, laxative or diuretic abuse, fasting or intensive exercise. The
aetiopathogenesis and pathophysiology of the disorder are currently unclear. Bio-
logical bases have been proposed repeatedly, based on several lines of evidence:
hunger, satiety and food choice are regulated by neurotransmitters and neuro-
peptides, and impairment of eating habits may be related to alterations in the
secretion of these chemicals; genetic studies suggest that these neurotransmitter
systems are dysfunctional in individuals with bulimia nervosa; and the frequent
comorbidity of bulimia nervosa with major depressive and obsessive-compulsive
disorders, conditions in which multiple alterations of brain biochemical functions
have been demonstrated.
120 Brambilla

Data in the literature suggest that levels of noradrenaline (norepinephrine) and

serotonin (5-hydroxytryptamine; 5-HT) are lower in individuals with bulimia
nervosa than in healthy controls. Levels of dopamine are similar to, or lower than,
those in controls. After remission of the disorder, noradrenergic function returns
to that seen in controls, whereas dopaminergic and serotonergic function rebound
to levels higher than in controls. Among the neuropeptides, alterations in the
levels of neuropeptide Y, peptide YY, β-endorphin, corticotrophin-releasing hor-
mone, somatostatin, cholecystokinin and vasopressin have been found in the
symptomatic phase of bulimia nervosa, with a return to levels seen in controls
after remission.
Pharmacological treatment of bulimia nervosa that is directed at correction of
the neurochemical alterations observed is difficult because of the complexity of
the impairments. However, such treatment is necessary and should be continued
long after symptomatic remission to ensure reinstitution of cerebral biochemical
homeostasis.

1. Evidence for a Biological Cause
The complex combination of psychopathologi-
cal and physical symptoms in bulimia nervosa
(BN) has favoured a proliferation of aetiopath-
ogenetic hypotheses, mostly linked to the model
adopted to describe and interpret the disorder. Fac-
tors that have been suggested to be the aetiopath-
ogenetic basis for BN, or at least to be mandatory
cofactors in its development, include:
• psychodynamic, sociocultural, sociofamilial and
behavioural factors
• previously inappropriate feeding habits of the
patients and/or their relatives
• risk factors, including a history of anorexia ner-
vosa (AN)
• comorbidity factors, such as the presence of ma-
jor affective disorder (MDD), anxiety disorders,
personality disorders, or drug and alcohol abuse.
These suggestions are supported by detailed
studies using complex methodologies, and by sub-
stantial case reports. While each factor has its mer-
its, any one is insufficient to define the cause and
course of bulimia nervosa.
A biological aetiopathogenetic hypothesis of
BN has been advanced in the hope of finding, as
with many other psychiatric disorders, a link be-
tween impairment of secretion of specific neuro-
transmitters, neuropeptides, neurohormones or pe-
ripheral hormones, and the development, course,
response to therapy and prognosis of BN. Once
substantiated, such a hypothesis would enable spe-
cific pharmacological treatments for the disorder
to be proposed.
Possible biochemical causes of BN are sug-
gested primarily by 3 observations. Firstly, neuro-
transmitters, neuropeptides, neurohormones and
peripheral hormones modulate eating behaviour in
terms of perception of hunger, satiety, taste and
food choice.[1,2] Even though BN cannot be sim-
plistically defined as an impairment of the modu-
lation of these eating parameters in the context of
body needs, it is well known that these processes
are impaired in individuals with the disorder. Such
individuals show increased hunger, decreased sati-
ety and increased preference for fattening foods
(lipids, carbohydrates).[3-11] It has been suggested
that these impairments are only secondary to the
quantitative and qualitative nutritional alterations
which characterise the disorder.[12] However, a pri-
mary deficit in hypothalamic or suprahypothala-
mic biological mechanisms which regulate these
perceptions and related behaviours cannot be ex-
cluded from involvement in the modulation of the
symptoms of BN.
The second important point in support of the
biological aetiopathogenesis of BN is the fact that
although the more conspicuous and overtly striking
symptoms of the disorder are those directly related

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (2)
Aetiopathogenesis-Pathophysiology of Bulimia Nervosa
to impairment of eating habits (including bingeing
alternating with severe dieting; choice of particu-
larly fattening foods; and vomiting), it is obvious
that these are only peripheral to the real core of the
disorder. Increased impulsivity, compulsivity, ob-
sessionality, aggressiveness, sensation seeking,
phobias, depressed mood, anxiety disorders [par-
ticularly obsessive-compulsive disorder (OCD)
and panic disorder] and personality disorders in
various combinations characterise BN, or at least
are present as comorbidities. It is worth keeping in
mind that it has been suggested that OCD repre-
sents the core of a spectrum of which eating disor-
ders, and therefore BN, could be a part.[13-17] Since
each of these psychiatric pathologies has been link-
ed to specific impairments in brain biochemistry,
the same impairment could also be involved in the
development of BN.
The third indication that organic factors might
be the cause of BN is an indirect one. It stems from
the observation that psychotropic drugs, both tricyc-
lic antidepressants (TCAs) and selective serotonin
(5-hydroxytryptamine; 5-HT) reuptake inhibitors
(SSRI), greatly improve bulimic symptomatol-
ogy. This suggests that alterations in the secretion
of neurotransmitters that can be manipulated by the
above-mentioned drugs are involved in the devel-
opment of BN.
1.1 Factors Influencing Biochemical Findings
1.1.1 Malnutrition
Before reviewing the data on the possible bio-
logical bases of BN, it must be mentioned that stud-
ies of this disorder, and to a greater extent interpre-
tation of their results, have always been hampered
by the effect that malnutrition and its well known
biological consequences have on brain biochemi-
cal function. This may possibly obscure the aetio-
pathogenetic meaning of alterations in cerebral
function. BN – unlike AN – is not characterised by
starvation and cachexia; however, it is associated
with purging procedures, alternating periods of
starvation and bingeing, and a lack of macro- and
micronutrients due to incorrect food selection. This
has led to the suggestion that the impairments in
© Adis International Limited. All rights reserved.
121
brain biochemistry described in BN are not a pri-
mary alteration responsible for aetiopathogenesis
of the disorder, but are secondary to malnutrition.
Some of these changes are similar to those obser-
ved in starvation and in AN, and they disappear
after nutritional recovery from the disorder.[18]
Some observations, however, suggest that not
all the brain biochemical impairments observed in
BN are malnutrition-dependent. Firstly, some of
the neurotransmitter, neuropeptide and neuro-
hormone alterations observed during the symp-
tomatic phases of the disorder are different from
those reported in simple malnutrition, both quanti-
tatively and qualitatively. Secondly, some of the
impairments observed during the symptomatic
phases are present with the same characteristics af-
ter recovery from the disorder (when malnutrition
has totally regressed) or at least involve the same
neurotransmitters, neuropeptides and neurohor-
mones. These two observations suggest that the
biochemical alterations observed in the symptom-
atic phases of the disorder are not always nutrition-
dependent, and that some of them might be linked
to the bulimic psychopathology.
1.1.2 Instability of Clinical Features
Another factor that can interfere with the inter-
pretation of the biochemical impairments seen in
BN is the fact that the clinical characteristics of the
disorder are not always stable. Often, the appearance
of BN is preceded by short or long phases of AN,
or at least by severe dieting imposed by the desire
to reduce genuine excess weight or full-blown obe-
sity. Also, BN and AN [sometimes of the restricted
(AN-R) and sometimes of the bingeing-purging
(AN-BP) type] can alternate, each being an impor-
tant factor for the reappearance or perpetuation of
the other. Finally, BN can result in binge eating
disorder or simple obesity.
This flowing back and forth from one syndrome
to another is very common and has even led to the
suggestion that eating disorders are a continuum from
AN-R to AN-BP to BN to binge eating disorder and
possibly to obesity, each disorder sharing with the
others some common psychopathological aspects
and being discordant for others. It is possible that
CNS Drugs 2001; 15 (2)
122
they all have common biological bases, but certain-
ly each shows biochemical differences.
1.1.3 External and Internal Factors
External and internal factors, apart from those
related to nutrition, can also influence brain bio-
chemical function. These include:
• life events
• previous organic diseases
• previous psychopharmacological therapies
• previous or current use/abuse of alcohol and drugs
• comorbidities with other psychopathologies.
All these factors may interfere with the modula-
tion of secretion of neurotransmitters, neuropeptides,
neurohormones and peripheral hormones, and make
interpretation of the meaning of possible biochem-
ical impairments extremely difficult.
Even with all these drawbacks, some of the data
obtained so far are very intriguing and suggest that
there is a biological basis to BN. These findings
should be taken into consideration when establish-
ing therapeutic approaches centred on the aetiopatho-
genetic core of the disorder.
2. Genetic Factors
Genetic factors have been proposed to be the basis
of BN. Familial studies, defining the presence of a
liability to the proband illness and suggesting the
presence of a genetic component accounting for
this liability, have produced conflicting data. No
secondary cases in first degree relatives of those
with BN were observed in one study,[19] while in
others 1.7 to 9.6% of first degree relatives were
found to be affected by BN or by subthreshold eat-
ing disorders.[20-22] Twin studies have demonstra-
ted that concordance rates for BN are higher in mono-
zygotic (22%) than in dizygotic (8.7%) twins.[23-25]
These two observations suggest that a genetic com-
ponent may play a role in the development of the
disorder.
Very few studies have looked for gene alter-
ations that may possibly be responsible for the de-
velopment of eating disorders, and those that have
mostly relate to AN. In BN, studies of genotype
counts and allele frequencies for polymorphism of
catechol-O-methyltransferase (COMT), one of the
© Adis International Limited. All rights reserved.
Brambilla
main enzymes involved in catecholamine produc-
tion, have shown no differences between individu-
als with BN and controls; this seems to exclude the
possibility that a variant of the COMT gene could
confer susceptibility to BN.[26] However, the gene
for the serotonin transporter, which determines the
reuptake of serotonin from the intersynaptic cleft,
seems to be involved in the development of BN. A
functional polymorphism of this gene has recently
been shown, with an insertion allele and a deletion
allele, the latter leading to low transcriptional rates
of the serotonin transporter protein. The deletion
allele is more prevalent in individuals with BN
compared with controls, while the insertion allele
is lacking in those with BN, implying a serotonin
impairment in the development of the disorder.[26]
3. Alterations in
Neurotransmitter Systems
3.1 Noradrenergic System
The noradrenergic system was the first and the
most often investigated neurotransmitter system in
eating disorders. This is perhaps because noradren-
aline (norepinephrine) has been proved to stimu-
late hunger and preferential consumption of carbo-
hydrates in experimental animals and humans.[1,2,27]
In addition, impairments of central noradrenergic
function have been observed in AN, MDD, OCD
and panic disorder, four pathologies often associ-
ated with, or possibly concurring in, the develop-
ment and course of BN.[28-30] Data about central
noradrenergic activity in BN, however, are scarce;
table I summarises the findings of studies that have
assessed noradrenergic function in individuals
with BN.
In the symptomatic phases of BN, CSF levels of
noradrenaline are lower than in healthy controls,
with a return to control levels during the phases of
remission.[31-35] Basal plasma levels of noradrena-
line are similar to those seen in healthy individuals.
The levels of noradrenaline increase to higher than
control values after a meal-test, while the plasma
noradrenaline responses to orthostatic position,
CNS Drugs 2001; 15 (2)
Aetiopathogenesis-Pathophysiology of Bulimia Nervosa 123

ergometric exercises or psychological stress are blunt-
ed compared with those in controls.[35-39]
Studies of peripheral noradrenergic receptor
sensitivity have revealed that the chronotropic re-
sponse to the infusion of the β-adrenergic agonist
isoprenaline (isoproterenol) is greater in individu-
als with BN than in controls, while the function of
β-adrenergic receptors measured in mononuclear
leucocytes is normally maintained.[40-42] The num-
ber and affinity of platelet α2-adrenoceptors are in-
creased, while basal and stimulated adenylate cy-
clase levels in platelets are similar to those seen in
controls.[37,43-44]
Data on central noradrenergic function, as exam-
ined indirectly by measuring basal peripheral secre-
tions of the noradrenaline-dependent hormonal
axis, are conflicting. The basal secretions of the
hypothalamic-pituitary-adrenal (HPA) axis and of
growth hormone, which are stimulated by noradren-
aline, are generally reported to be similar to control
levels or, occasionally, to be increased.[45-48] Basal
secretion of prolactin, which is inhibited by nor-
adrenaline, is reported to be at control levels or de-
creased.[46] This suggests that, in individuals with
BN, secretion of noradrenaline is generally unchanged
or increased compared with that in unaffected in-
dividuals, in the latter case overstimulating the hy-
pothalamic releasing and inhibiting hormones
(RHs, IHs) and the dependent peripheral hormones.
However, the functions of the noradrenaline-stim-
ulated hypothalamic-pituitary-gonadal (HPG) and
hypothalamic-pituitary-thyroid (HPT) axes are
similar to those in healthy individuals or are de-
creased,[49-53] which argues against the hypothesis
of increased central noradrenergic activity in BN.
The functional investigation of hypothalamic nor-
adrenaline secretion, using the α2-adrenergic recep-
tor agonist clonidine and measuring the downstream

Table I. Noradrenergic function in bulimia nervosa (see section 3.1 for references)
Functional parameter Source/test State of parameter compared with healthy individuals
active phase remission
Basal NE levels CSF ↓ ↔
Plasma ↔
NE-stimulatory tests Meal ↑
Orthostatic position ↓
Ergometric exercise ↓
Psychological stress ↓
NE receptors β-Adrenergic in leucocytes ↔
α-Adrenergic in platelets ↑
NE-dependent hormones Plasma HPAa ↔↑ ↔
Plasma growth hormone level ↔↑ ↔
Plasma prolactin level ↔↓ ↔
Plasma HPGb ↔↓ ↔
Plasma HPTc ↔↓ ↔
NE-dependent hormonal testsd HPA ↑↔ ↔
Growth hormone level ↔ ↔
Prolactin level ↔↓ ↔
HPG ↔ ↔
HPT ↔↓ ↔
a Corticotropin-cortisol levels.
b Gonadotropin-gonadal hormone levels.
c Thyrotropin-thyroid hormone levels.
d Tests which stimulate peripheral hormonal secretion by acting on hypothalamic noradrenaline receptors.
HPA = hypothalamic-pituitary-adrenal axis; HPG = hypothalamic-pituitary-gonadal axis; HPT = hypothalamic-pituitary-thyroid axis; NE =
noradrenaline (norepinephrine); ↑ = increased; ↓ = decreased; ↔ = no change.

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (2)
124
increase of growth hormone secretion, has shown
normal responses.[54,55]
Thus, the question of whether central noradren-
ergic function is altered in BN is still unresolved
and open to further investigation.
3.2 Dopaminergic System
Dopamine modulates feeding behaviour by in-
hibiting hunger and reducing protein consump-
tion.[1,2] In addition, central dopaminergic impair-
ments have been reported in patients with AN,
MDD and OCD.[17,56-61] Therefore, the function of
the dopaminergic system in BN has been investi-
gated. Table II summarises the findings of these
studies.
Data obtained during the symptomatic phases of
BN are contradictory. CSF levels of homovanillic
acid (HVA), the main metabolite of dopamine, were
found to be similar to those in healthy individuals,[33]
or reduced in patients with very frequent episodes
of bingeing and vomiting compared with those who
did not binge daily.[31] Plasma HVA levels were re-
duced[62] or increased[63,64] compared with healthy
individuals and may remain increased after short term
abstinence from bingeing-purging.[63,64]
Data from the studies of basal secretion of the
dopamine-dependent peripheral hormones support
the hypothesis of possibly increased dopaminergic
activity. In some individuals with BN, basal values of
growth hormone (dopamine-stimulated) are increa-
sed and those of the prolactin (dopamine-inhibited)
are decreased.[46,47] Functional investigations us-
ing growth hormone response to the dopamine agon-
ist apomorphine show results similar to those found
Table II. Dopaminergic function in bulimia nervosa (see section 3.2 for references)
Functional parameter Source/test
Basal HVA level CSF
Plasma
DA-dependent hormones Plasma growth hormone level
Plasma prolactin level
DA-dependent hormonal tests Growth hormone level
Prolactin level
DA = dopamine; HVA = homovanillic acid; ↑ = increased; ↓ = decreased; ↔ = no change.
© Adis International Limited. All rights reserved.
Brambilla
in healthy individuals,[61] suggesting that central
dopaminergic function is not impaired in BN.
Thus, the question of dopaminergic activity in BN
is not resolved.
3.3 Serotonergic System
The function of the serotonergic system in eat-
ing disorders has been extensively investigated. In
experimental animals and in humans, serotonin
stimulates satiety and inhibits the consumption of
carbohydrates and lipids.[1,2,65] Serotonin also mod-
ulates mood, anxiety, obsessionality, compulsivity
and aggressiveness, and its secretion and function
have been found to be impaired in AN, MDD, panic
disorder and OCD, disorders that are often com-
orbid with BN.[66-73] Table III summarises the find-
ings of studies that have investigated serotonergic
function in patients with BN.
During the symptomatic phases of BN, global
turnover of serotonin and CSF levels of 5-
hydroxyindoleacetic acid (5-HIAA), the main me-
tabolite of serotonin, are similar to those[33] or re-
duced compared with those[17,74-79] in healthy
individuals; during recovery CSF 5-HIAA levels
are higher than those in controls.[77] Platelet levels
and uptake of serotonin are similar to those in
healthy individuals.[80,81] Plasma levels of trypto-
phan, the precursor amino acid of serotonin, are
unchanged or low, with a return to levels seen in
healthy individuals after recovery. The tryptophan/
large neutral amino acid ratio is reduced in patients
who do not develop satiety after episodes of binge-
ing and vomiting, and unchanged in those who do,
compared with healthy individuals.[82-85]
State of parameter compared with healthy individuals
active phase remission
↔↓
↑↓ ↑
↔↑ ↔
↓ ↔
↑ ↔
↓ ↔
CNS Drugs 2001; 15 (2)
Aetiopathogenesis-Pathophysiology of Bulimia Nervosa
Table III. Serotonergic function in bulimia nervosa (see section 3.3 for references)
Functional parameter Source/test
Serotonin level CSF
5-HIAA level CSF
Platelets
Tryptophan level Plasma
LNA/Tr Plasma
Receptors Imipramine binding
Serotonin-dependent hormones Prolactin level
HPAa
Serotonin-dependent hormonal tests Prolactin level
Cortisol level
a Corticotropin-cortisol level.
HPA = hypothalamic-pituitary-adrenal axis; LNA/Tr = large neutral amino acid/tryptophan ratio; 5-HIAA = 5-hydroxyindoleacetic acid; ↑ =
increased; ↓ = decreased; ↔ = no change.
The sensitivity of serotonin receptors in plate-
lets has been investigated by studying imipramine
binding. Receptor sensitivity was found to be re-
duced in patients with BN.[86] Serotonin reuptake or
platelet aggregation are increased[87-89] or similar
to controls.[90,91]
Studies of the function of serotonin-dependent
peripheral hormones show that serotonin-stimulated
basal prolactin levels are unchanged or decreas-
ed,[46] while serotonin-inhibited corticotropin-re-
leasing hormone (CRH) secretion is unchanged or
increased,[45] both tentatively pointing to reduced
serotonergic function in BN compared with that in
unaffected individuals. Prolactin stimulation tests
using serotonin receptor agonists (L-tryptophan, m-
chlorophenylpiperazine, D-L and D-fenflurmanine)
reveal reduced activity of the system.[75,92-95] The re-
duction in secretion of serotonin or the reduction in
postsynaptic receptor function seem to correlate with
the frequency of the bingeing-vomiting episodes.[76,79]
These data, particularly the observation that dif-
ferent response measures of serotonergic function
(including biological and clinical ones) are unchang-
ed, increased or decreased in the same individual
compared with healthy individuals, suggest that sero-
tonergic function in BN is dysregulated, possibly
with reduced secretion of the amine and reduced
sensitivity of postsynaptic serotonin receptors.[79]
© Adis International Limited. All rights reserved.
125
State of parameter compared with healthy individuals
active phase remission
↓↔
↔ ↑
↔↑
↔↓ ↔
↓
↓
↔↓ ↔
↔↑ ↔
↓ ↔
↓ ↔
4. Alterations in Neurohormonal
Peptide Secretion
The well known influence of neurohormonal
peptides on eating behaviour in experimental ani-
mals and humans has led to the search for possible
impairments of their secretory patterns in eating
disorders. Data for BN are still scarce and their
aetiopathogenetic meaning is difficult to interpret;
however, they indicate some interesting research
pathways for the future. Tables IV and V summa-
rise the findings from studies that have assessed the
function of neuropeptide systems in individuals
with BN.
4.1 Hunger-Stimulating
Neurohormonal Peptides
Among the hunger-stimulating neurohormonal
peptides, a central role is played by endogenous
opioids, which also stimulate preferential carbo-
hydrate consumption.[2] This observation has led
to the suggestion that endogenous opioids might be
involved in the development of BN. In addition,
impairments of endogenous opioid secretion have
been observed in AN, MDD and panic disorder.[96-98]
CSF levels of β-endorphin, a centrally and peri-
pherally secreted endogenous opioid, are lower in
individuals with BN than in unaffected individuals.
CSF levels of dynorphin, possibly the most potent
hunger-stimulating opioid, are unchanged.[99,100]
CNS Drugs 2001; 15 (2)
126 Brambilla

Table IV. Neuropeptide levels in bulimia nervosa (for references see phases, bingeing induces increases in PYY levels
sections 4.1 to 4.3) to those that are higher than those in controls.[112]
Neuropeptide Source/test Level compared with Neurotensin, gastrin and galanin are stimulators
healthy individuals
active phase remission
of hunger and of preferential lipid selection.[109]
β-Endorphin CSF ↓ ↔ CSF and plasma levels of these neuropeptides are
Plasma ↑↔↓ similar to those in healthy individuals at basal con-
PBMC ↔ ↔ ditions and after a meal test during the symptom-
Dynorphin CSF ↔ atic phases of BN.[113,114]
NPY CSF ↔ ↔
Plasma ↔
4.2 Hunger-Inhibiting
PYY CSF ↔ ↑↔
Neurohormonal Peptides
Plasma ↑↔
Neurotensin CSF ↔
The main neurohormonal inhibitors of hunger
Galanin CSF ↔
Gastrin CSF ↔
are CRH and somatostatin.[115] Impairments in these
Somatostatin CSF ↔ ↑ neuropeptides are seen in AN, MDD and anxiety
CCK-8 CSF ↓ disorders.[116,117]
PBMC ↓ ↓ There are no data regarding CSF levels of CRH
Plasma: test meal ↓ in BN; however, indirect observations using the
CCK-8 = cholecystokinin-8; NPY = neuropeptide Y; PBMC = pe- CRH stimulation test suggest that CRH secretion
ripheral blood mononuclear cells; PYY = = peptide YY; ↑ = in-
creased; ↓ = decreased; ↔ = no change. might be either unchanged or increased compared
with unaffected individuals.[45,118] CSF levels of
somatostatin are similar to control levels during the
Plasma levels of β-endorphin have been reported symptomatic phases of BN and increase to higher
to be unchanged,[101] increased[102,103] or decreas- than usual values after recovery.[111,117]
ed.[104-106] β-Endorphin levels in peripheral blood
mononuclear cells (PBMCs), a compartment which 4.3 Satiety-Stimulating
mirrors the secretion and receptor modulation of Neurohormonal Peptides
central neurons, are similar to those seen in healthy
Cholecystokinin (CCK), produced both cen-
individuals.[107]
trally and peripherally, is considered to be a phys-
Neuropeptide Y (NPY) and peptide YY (PYY)
iological stimulator of satiety and an inhibitor of
are considered to be among the most important stim-
lipid consumption.[115] Impairments in CCK secre-
ulators of hunger and of preferential carbohydrate tion have been reported in panic disorder and in
intake.[108] Impairments of NPY secretion have AN.[119,120]
been reported in AN, MDD and anxiety disor-
ders.[109-111] CSF levels of NPY and PYY are sim-
ilar in BN during the symptomatic phases of the Table V. Peripheral hormones influencing eating behaviour in
bulimia nervosa (see section 4.5 for references)
disorder to those in unaffected individuals. NPY lev-
Hormone Test Level compared with healthy
els are also unchanged after remission from the dis- individuals
order, while PYY levels increase to markedly high active phase remission
values during the phases of abstinence from binge- Leptin Basal ↔↓
Meal test ↓
ing and vomiting, to return to control levels after
Estrogens Basal ↔↓ ↔
recovery.[110-112] Plasma levels of the two neuro- Cortisol Basal ↔↑ ↔
peptides are unchanged compared with controls Insulin Basal ↔ ↔
during both the symptomatic and the remission Prolactin Basal ↑↔↓ ↔
phases of BN. However, during the symptomatic ↑ = increased; ↓ = decreased; ↔ = no change.

© Adis International Limited. All rights reserved. CNS Drugs 2001; 15 (2)
Aetiopathogenesis-Pathophysiology of Bulimia Nervosa
CSF levels of CCK are reduced in BN.[121,122]
The alteration does not seem to correlate either
with body mass index values or with the frequency
and severity of bingeing and vomiting episodes.
Instead, it correlates with anxiety, hostility, aggres-
siveness and impairment of interpersonal sensitiv-
ity manifested by the patients.[122]
The level of CCK in PBMCs is reduced during
the symptomatic phase of the disorder, and also
during a phase of initial recovery.[107] The plasma
basal values and secretory response of CCK to a
meal test are normal or blunted.[123-126] Intravenous
CCK-8 administration was reported to suppress a
single binge in several patients with BN.[123]
4.4 Neurohormonal Peptides not Related
to Eating
Vasopressin influences the regulation of drink-
ing and modulates hydrosaline metabolism, which
are both altered in BN.[127] Vasopressin also affects
the regulation of cognitive processes, particularly
learning and memory.[128] Alterations in the secre-
tion of vasopressin have been observed in AN,
MDD and anxiety disorders.[129,130]
CSF levels of vasopressin are high in BN, while
plasma levels after an osmotic stimulus or after the
administration of metoclopramide or during insu-
lin-induced hypoglycaemia are lower than those
seen in unaffected controls.[131,132]
4.5 Peripheral Hormones Influencing
Eating Behaviour
Peripherally secreted hormones may influence
eating behaviour by acting directly on CNS path-
ways which are responsible for food consumption,
or by modulating the secretion of neurotransmit-
ters, neuropeptides and neurohormones which are
known regulators of eating behaviour. They reach
the CNS by crossing the blood-brain barrier, by
passing through areas where there is no blood-brain
barrier (median eminence) or where the barrier is
less compact (circumventricular organs), or by
binding to transport systems in the blood-brain bar-
rier.
© Adis International Limited. All rights reserved.
127
Leptin, the peripheral product of the ob gene in
adipose tissue, is a relatively recently discovered
hormone. It seems to play a key role in the regula-
tion of feeding behaviour and bodyweight by act-
ing centrally as a satiety factor[133] and peripherally
by regulating energy expenditure.[134] Moreover,
leptin is involved in the control of multiple neuro-
endocrine functions which are impaired in eating
disorders, including the HPA, HPT and HPG axes
and secretion of growth hormone and insulin.[135]
Because of its effects on eating behaviour, energy
expenditure, fat deposition and the endocrine axes,
which are all altered in eating disorders, central
and peripheral levels of leptin have been measured.
In AN, peripheral levels of leptin are de-
creased.[136-142] Data on leptin levels in BN are rel-
atively scarce and their meaning is unclear. Most
of the published studies have explored morning
plasma levels in women with the disorder, without
comparison with controls,[139,140] or in patients at
different stages of nutritional and behavioural
treatment,[141] or after recovery from the disorder.[142]
The results from these analyses suggest that serum
leptin levels in individuals with BN are similar to
those of unaffected individuals and are negatively
correlated with the body mass index.[138,142]
More recently,[143,144] basal leptin levels in un-
treated women with BN were found to be signif-
icantly lower than in healthy women and to posi-
tively correlate with bodyweight. Moreover, leptin
secretion did not respond normally to a fasting-re-
feeding stimulus. In fact, levels of the hormone
decreased only minimally during fasting and in-
creased minimally during refeeding.[143] It was sug-
gested that in individuals with BN leptin maintains
its function as a sensor of bodyweight changes, but
it loses its role of signalling acute changes in en-
ergy balance.
Among peripheral hormones, glucocorticoids,
insulin and prolactin are hunger stimulators.[145-148]
Glucocorticoids at low levels stimulate feeding
and promote fat and protein storage, while in high
levels they reduce protein storage. Glucocorticoid
levels are mostly higher than in controls in individ-
uals with BN, with a return to control levels after
CNS Drugs 2001; 15 (2)
128
recovery.[149] Insulin levels are generally similar to
those seen in unaffected individuals.[150] Data on the
secretion of prolactin are contradictory, with un-
changed, reduced or increased levels reported.[151-153]
In experimental animals, estrogens are inhibi-
tors of hunger and food consumption.[154] In gen-
eral, estrogen secretion is preserved in BN or re-
duced only in subgroups of patients with more
marked nutritional impairments than the general
bulimic population.[152,155]
The significance of changes in glucocorticoid,
insulin, prolactin and estrogen levels on the course
of BN is difficult to interpret. Apart from their in-
fluence on hunger, satiety and food choice, periph-
eral hormones may modulate central neurotrans-
mitter secretion and receptor function, particularly
noradrenergic, dopaminergic and serotonergic func-
tion. Thus, although the hormonal impairments have
been considered to be related to the state of malnu-
trition of the patients, they may influence the course
of the disorder and its prognosis.
5. Implications for Treatment
The data reviewed in sections 3 and 4 on the
central and peripheral biological impairments that
occur in BN which have possible aetiopathogenetic
significance suggest some implications for treatment.
5.1 Psychodynamic Therapy
Since alterations in brain biochemistry occur in
BN, it appears appropriate to suggest that treatment
should be based on pharmacotherapy. This therapy
should aim to correct the alterations in the secretion
of neurotransmitters, neuropeptides, neurohormones,
peripheral hormones and related receptors and sec-
ond messengers which are present during the
course of the disorder.
However, pharmacotherapy is not necessarily
mandatory. Psychodynamic therapies have been
shown to be effective in the treatment of BN.[15] It
is not known how these treatments induce improve-
ment of or recovery from the disorder, or which are
the central pathways involved in the process. The
fact that most, although not all, of the central and
peripheral biological alterations observed during
© Adis International Limited. All rights reserved.
Brambilla
the symptomatic phase of BN disappear after suc-
cessful psychodynamic therapy seems to suggest
that psychodynamic interventions might modulate
the biological systems whose impairments are pos-
sibly involved in the development, course and
prognosis of eating disorders. However, the biolog-
ical improvements observed after successful psy-
chotherapeutic treatments might be only secondary
to the reinstatement of normal eating behaviour
and nutrition and not related to primary correction
of a pathological biochemistry of the disorder, of
which only the alterations persisting after the ap-
parent recovery of BN would be an expression.
This is a field worthy of further long term control-
led studies in large populations.
5.2 Psychopharmacological Therapy
Effective psychopharmacological therapy of
BN relies, at present, on the use of antidepressant
drugs, including both TCAs and SSRIs. Double-
blind and placebo-controlled studies support the
use in BN of the SSRIs fluoxetine and fluvoxamine
and of various TCAs that influence serotonin re-
uptake and secretion[156-160] in terms of both short
term and long-lasting improvement of, or recovery
from, the disorder. These treatments are also useful
for controlling the comorbidities (including MDD,
OCD, panic disorder, post-traumatic stress disor-
der and phobias) and personality alterations (ag-
gressiveness, impulsiveness, proneness to drug and
alcohol addiction) that frequently occur in BN, all
of which have been proved to be linked to sero-
tonergic dysfunction and to respond to the admin-
istration of serotonin-stimulating drugs.
SSRIs and TCAs may also affect some of the
biochemical alterations reported in sections 3 and
4. The serotonergic deficiency observed during the
course of the disorder might benefit from the ad-
ministration of SSRIs and of TCAs that are rela-
tively serotonin-selective. These drugs may also
correct the higher than normal serotonergic func-
tion observed after recovery, through modulation
of presynaptic and postsynaptic serotonin receptor
activity (although this phenomenon has not been
sufficiently investigated and proved to be valid in
CNS Drugs 2001; 15 (2)
Aetiopathogenesis-Pathophysiology of Bulimia Nervosa
the treatment of BN). Reinstatement of serotoner-
gic function could entrain a correction of the dopa-
mine hypersecretion observed after recovery from
the disease, as a result of the modulatory effect of
serotonin on dopaminergic function.[161-164]
At present, the significance of the serotonergic,
dopaminergic and somatostatin alterations which
persist after the improvement/recovery of BN is
unknown. It is also not know whether they repre-
sent the basis of the disease and its relapses, the
basis of the behavioural pathologies frequently oc-
curring in BN, or of some of the psychological al-
terations of the disease or its comorbidities. These
aspects need further study, but it seems obvious
that the persistence of alterations in brain biochem-
istry after the improvement of symptoms of the
disease, no matter how they are obtained, need to
be taken into therapeutic consideration if the aim
of a treatment is to fully correct the psychopathol-
ogy of BN, and not only its bingeing-vomiting
symptomatology.
The SSRIs and TCAs may also correct the HPA
hyperactivity that occurs in BN, as proved in ex-
perimental animals and in other psychiatric pathol-
ogies where the HPA system is also hyperfunctio-
nal.[165-168] Since CRH, corticotropin and cortisol
modulate not only eating behaviour but also cog-
nitive, affective and behavioural parameters which
are impaired in BN, the correction of their secre-
tory impairment may be important for the overall
improvement of the eating disorder.
At present, SSRI and TCA pharmacotherapy
has been validated for the treatment of BN. How-
ever, the fact that some biological impairments
persist after significant psychopharmacologically
induced improvement of the disorder and that BN
may relapse long after improvements occur sug-
gest that these drugs are sometimes not sufficient
to correct the biochemical pathologies which may
be the basis of the disorder. In particular, the dopa-
mine hypersecretion observed after recovery, re-
vealed by increased plasma HVA levels,[63,64] is in-
triguing, since the dysfunction has also been
observed in OCD, personality disorders, and some
of the behavioural abnormalities that also charac-
© Adis International Limited. All rights reserved.
129
terise BN. Treatment with antipsychotics, how-
ever, has not proved to be successful in BN and,
possibly, drugs should be used which inhibit exces-
sive dopamine secretion and not antagonise post-
synaptic dopamine receptor function.
The development of drugs to correct the neu-
ropeptide-neurohormonal alterations occurring in
BN should also be considered. These might possi-
bly modulate not only the eating behaviour but also
the other psychopathological aspects of the disor-
der. This is a field that is being actively investi-
gated and certainly worthy of further study.
6. Conclusions
The data on the biological basis of BN that are
reviewed in sections 1 to 4 are too few and often
too contradictory to allow definite conclusions to
be drawn. However, some suggestions may be ad-
vanced.
The genetic studies, although preliminary and
needing confirmation, seem to suggest a pathology
of the serotonergic system in the development of
BN. This hypothesis might be confirmed by the
biochemical data on central serotonergic function
obtained in the symptomatic phase of the disorder
and after its remission.
Central noradrenergic function is reduced in the
symptomatic phase of the disorder. In contrast, pe-
ripheral noradrenergic function is relatively un-
changed, increased or decreased compared with
that in unaffected individuals. The differences be-
tween central and peripheral secretion of noradren-
aline are not surprising, since the metabolic activities
of the two compartments do not always coincide
and since they express different physiological
functions. The contradictory data related on peri-
pheral noradrenergic activity may be due to meth-
odological factors, including patient selection,
phases of the disorder, previous life events and pre-
vious treatments. The fact that all noradrenergic
impairments disappear after remission of the dis-
order suggests that the noradrenergic alterations are
state-dependent, and that, therefore, they are un-
likely to precede the development of the disorder
in a pathogenetic role.
CNS Drugs 2001; 15 (2)
130
Central dopaminergic function has been ob-
served to be unchanged or decreased compared with
healthy individuals and its peripheral expression
unchanged or increased. This dissociation is intri-
guing, especially because peripheral secretion of
the main metabolite, HVA, reflects the central ac-
tivity of the system, of which it has been considered
an accurate mirror.[162] The fact that after remission
of the disorder plasma HVA levels may be higher
than normal hints at the possibility that hyperactiv-
ity of this system could be involved in the patho-
genesis of BN.
Data on central serotonergic function are con-
tradictory, with unchanged or reduced secretion of the
amine reported. However, most studies tend to sup-
port the existence of a deficiency of brain seroton-
ergic function during the symptomatic phase of the
disorder and hyperactivity of the system in the re-
mission phase. This observation, together with the
genetic findings reported above, hint at the hypoth-
esis that serotonergic impairment may be a trait
phenomenon, possibly involved in the pathogene-
sis of BN.
A deficit of secretion of serotonin during the
acute phase of the disease could be responsible for
increased dopamine secretion, as revealed by the
dopamine-dependent basal hormonal secretion,
since serotonin has been reported to inhibit dopa-
minergic function.[161,162] However, serotonin has
also been found to stimulate dopaminergic func-
tion in the striatum, the accumbens and the amyg-
dala.[163,164] This could explain the high plasma
levels of 5-HIAA and HVA observed in the remis-
sion or recovery phases of BN. Which of the two
opposite effects of serotonin may be responsible
for the dopaminergic impairment observed in BN
is difficult to say and is worthy of further investi-
gation.
Serotonin also inhibits noradrenergic function
and therefore increased activity of the system would
be expected. However, the opposite is found in the
symptomatic phase of BN, followed by reduced,
rather than unchanged, noradrenergic function dur-
ing remission.
© Adis International Limited. All rights reserved.
Brambilla
Data on brain neuropeptide levels are also very
scanty. However, two observations are intriguing.
The first concerns the elevated levels of PYY and
somatostatin that occur during remission, PYY be-
ing a very potent stimulator and somatostatin an
inhibitor of hunger and carbohydrate consumption.
The fact that the levels of the two neuropeptides are
similar to those seen in controls during the symp-
tomatic phase of BN and increase to higher than
control levels in remission suggests that the alter-
ations may be a marker for predisposition to chronic
disease or to its relapse. Which of the two phenom-
ena, hunger stimulation by PYY or inhibition by
somatostatin, might be the prevailing one for the
prognosis of BN is difficult to say, since one can
be the consequence of the other, in a homeostatic
attempt by the brain to maintain control of im-
pulses. Another point worth mentioning is that it
has been reported that NPY is co-secreted with nor-
adrenaline in the CNS, the amine and the neuro-
peptide possibly having reciprocal modulatory ac-
tivity.[169] However, central NPY secretion is
unchanged while noradrenergic activity is de-
creased during the symptomatic phase of the disor-
der. This suggests that the normal relationship be-
tween the amine and the neuropeptide is disrupted.
The second interesting point is the reduced cen-
tral and peripheral secretion of CCK, one of the
most important stimulators of satiety and inhibitors
of lipid consumption. Its deficiency could be an
important factor in the pathogenesis of BN. Unfor-
tunately, available data refer only to the symptom-
atic phase of the disorder and not to remission, leav-
ing open the question of whether the impairment is
a state or a trait one, and whether it may be involved
in the pathogenesis of BN. CCK is co-secreted in
the CNS and in the periphery with dopamine,[169]
the amine and the neuropeptide possibly modulat-
ing the secretion of the other. The fact that CCK
secretion is reduced and dopamine activity might
be increased in parallel suggests that the normal
relationship between dopamine and CCK, like that
of dopamine and serotonin, is well preserved.
Taken together, the data reported in the litera-
ture seem to suggest the existence of a complex
CNS Drugs 2001; 15 (2)
Aetiopathogenesis-Pathophysiology of Bulimia Nervosa
neurotransmitter-neuropeptide pathology in BN,
which could, tentatively, explain the pathogenesis of
the disturbed eating behaviour of individuals with
the disorder. At the same time, this pathology could
be the link with the psychopathologies which are
often comorbid with BN, particularly AN, OCD
and MDD, since most of the biological alterations
observed in BN are found also in these disorders.
This pathology may also be involved in the patho-
genesis of other anxiety disorders (panic disorder,
post-traumatic stress disorder, phobias, generalised
anxiety), personality disorders, drug and alcohol
addiction, and impulsiveness and aggressiveness,
which are part of the core of BN. Unfortunately,
most of the studies in the literature have not con-
sidered this aspect, particularly in regard to neu-
ropeptides-neurohormones, and there are very few
data on the correlations between biological impair-
ments and psychopathological aspects of the disor-
der, apart from those related to bingeing and vom-
iting.
Another point worth consideration regards the
data obtained after remission. The term remission
has been applied sometimes to the short term and
sometimes to the long-lasting abstinence from bul-
imic symptomatology, either spontaneously or
therapeutically obtained. Short term abstinence
might be a more transient phenomenon than long-
lasting abstinence, being therefore prognostically
different. Moreover, remission has always referred
to the symptoms of bingeing and purging, rather
than to the complex psychopathology of the dis-
ease. Thus, it is difficult to define the significance
of the neurobiological aspects of remission. These
should be more carefully investigated.
The alterations in brain biochemistry that are
observed in individuals with BN suggest that treat-
ment with psychotropic drugs is necessary to ob-
tain stable recovery from the disorder. Considering
the extreme complexity of the impairments, it is
difficult to decide which type of pharmacotherapy
would be the most appropriate to obtain a defini-
tive correction of the brain pathology. Drugs acting
on the serotonergic system are already used with
apparently positive results, although not always
© Adis International Limited. All rights reserved.
131
definitive ones. The use of agents which increase
serotonergic function during the symptomatic phase
of BN seems appropriate on the basis of what has
been reported in section 3.3, since they may correct
dysfunction in the serotonergic and dopaminergic
systems in parallel, and this may possibly entrain
changes in the CCK system. However, this type of
therapy should be continued long after remission
of the disease, since serotonergic and dopamin-
ergic alterations during the asymptomatic phases
of the disorder may represent negative risk factors
for its relapse.
This review has considered only the biological
impairments associated with BN from the perspec-
tive of studying its aetiopathogenesis. It is not sug-
gested that these impairments are entirely respon-
sible for the development, course, prognosis and
responses to therapy of the disorder. It is well
known that the pathogenesis of BN is complex and
includes both biological alterations (possibly ge-
netically determined) and environmental aspects,
which interact during the development of the dis-
order. However, the biochemical alterations which
occur during the course of BN, and might possibly
precede it as demonstrated by their presence long
after recovery, may influence the capacity of indivi-
duals with the disorder to cope with the environment,
thus ultimately influencing also the psychodyna-
mic aspects of BN. In fact, correct neurotransmitter-
neuropeptide function is mandatory for modula-
tion of the capacity to adapt to internal or external
stimuli, to confront novelty and positive or nega-
tive life events, to adapt to the environment, and to
establish social interactions. Thus, the neurobio-
logical pattern of an individual might be the basis
not only of the full-blown disorder but also of the
behavioural characteristics which predispose to its
development.
More data are needed to further clarify the bio-
logical basis of BN. These should be obtained from
larger populations and over prolonged periods of
time, including symptomatic and remission phases,
and also episodes of AN and binge eating disorder
alternating with BN. The parallel effects of psy-
chotropic drugs on clinical and biological aspects
CNS Drugs 2001; 15 (2)
132
and investigations using brain imaging and molec-
ular biology studies would also be useful.
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