Eating Disorders Clinical Trial
Official title:
Neuronal Correlates of Catecholamine Depletion in Patients With Bulimia Nervosa Off Medication and Healthy Controls
Bulimia nervosa is a severe psychiatric disorder characterized by recurrent binge eating
episodes followed by inappropriate compensatory behavior to prevent weight gain such as
self-induced vomiting. With this project, the investigators want to investigate the role of
the neurotransmitter dopamine in bulimia nervosa. Dopamine is reported to have an important
influence on the neural reward system and is involved in the processing of gains and losses.
The reward system is functionally connected to the individual perception of rewards in the
environment. A previous study revealed that under catecholamine depletion including dopamine
depletion women suffering from bulimia nervosa in their past reported mild bulimic symptoms
and their reward processing became dysfunctional: their ability to use rewarding stimuli for
task solving was diminished.
The aim of this study is to investigate the role of reduced dopamine availability in the
development or maintaining of bulimia nervosa and in the dysfunctional processing of
rewarding stimuli and negative visual information. Therefore, the investigators hypothesize
that catecholamine depletion achieved by oral administration of alpha-methyl-paratyrosine
(AMPT) will induce mild bulimic symptoms in females suffering from bulimia nervosa in their
past. In addition, they will reveal dysfunctions in reward and emotional processing under
catecholamine depletion. Using functional magnetic resonance imaging, the investigators
propose that a reduced activation of the nucleus accumbens, a neural structure of the reward
system, will be the neural correlate of this dysfunctional reward processing. Furthermore,
the amygdala, a neural structure that is involved in emotional processing, will show a higher
activation under catecholamine depletion. Genetic factors additionally have an influence on
the dopaminergic system. Therefore, the investigators hypothesize that genetic factors, for
example the COMT val-158-met polymorphism may have an effect on the behavioral and neural
response to catecholamine depletion. In sum, this investigation may help to understand which
changes in reward and emotional processing may lead to a reoccurrence of bulimic symptoms.
In future, the findings of this study may help to develop individual pharmacological and
psychotherapeutical interventions to enhance the outcome of treatment.
Background
The Monoamine Deficiency Hypothesis is one of the most solid theories of the neurobiology of
mood, anxiety disorder, and addiction. There is increasing evidence that monoamine deficiency
also plays an important role in bulimia nervosa. Many indications revealed a disturbance of
the catecholamine system in bulimia nervosa. In symptomatic bulimic patients, the
concentration of norepinephrine and dopamine in cerebrospinal fluid and peripheral blood was
lower than in healthy controls. The neurotransmitter dopamine is thought to be importantly
involved in the processing of rewarding stimuli.
One instructive paradigm for investigating the relationship between catecholaminergic
function and psychiatric disorders has involved the behavioral response to catecholamine
depletion achieved by oral administration of alpha-methyl-paratyrosine (AMPT). This
medication is a tyrosine hydroxylase inhibitor and, therefore, it reduces availability of
catecholamines in the brain by depleting central norepinephrine and dopamine stores. A
relatively large interindividual variation in the response to catecholamine depletion has
been consistently observed. Genetic factors may conceivably contribute to this variation. The
COMT val-158-met polymorphism was found to play a critical role for the activity of the
enzyme catechol-O-methyltransferase (COMT) that metabolizes catecholamines after they have
been released into the synaptic cleft. The enzyme activity in individuals homozygous for the
val-158 allele is about 40% higher than in homozygotes of the met-158 allele. A high activity
of this enzyme is thought to be associated with a higher reduction of catecholamines,
particularly of dopamine in the prefrontal cortex.
In a previous study Gregor Hasler and colleagues were the first to use catecholamine
depletion to evaluate the roles played by norepinephrine and dopamine in the pathophysiology
of bulimia nervosa. The results of this study revealed that under catecholamine depletion
remitted bulimic participants showed dysfunctions in motivated behavior in a reward task. In
addition this study provided preliminary evidence that COMT val-158-met polymorphism explains
some of the variance in the behavioral response to catecholamine depletion. However, in
eating disorders, the pathway leading from genetic polymorphism to neural activity to
neuropsychological abnormalities to risk of eating disorders remains to be determined.
With this new study the investigators want to investigate the neural substrate of the induced
bulimia-associated neuropsychological abnormalities with functional magnetic resonance
imaging (fMRI). An additional goal is to examine the effect of the COMT val-158-met
polymorphism on neural activity.
In the following the investigators will present their central hypotheses:
1. Remitted bulimic participants will reveal impairments in motivated behavior and abnormal
neural activation in a reward task following catecholamine depletion.
2. Remitted bulimic participants will show increased amygdala activation during encoding of
negative pictures under catecholamine depletion.
3. Participants with homozygous val-158 alleles of the COMT val-158-met polymorphism will
show an increased activation in the ventral striatum during a reward task.
4. Participants with at least one met-158 allele of the COMT val-158-met polymorphism will
show higher amygdala activation during the encoding of negative emotional visual
information.
Objective
This study will further elucidate the etiology and pathophysiology of bulimia nervosa at
various levels, ranging from the role of a specific genetic factor to the activity of
specific neural networks to neuropsychological abnormalities and clinical symptoms. It may
provide important insights into a specific pathogenetic pathway of bulimia nervosa related to
the catecholaminergic in particular to the dopaminergic neurotransmitter system. Since a
range of drugs targeting this neurotransmitter system are available, this study may directly
inform the development of novel therapeutic strategies tailored to individual patients.
Methods
Remitted bulimic and healthy control participants will be enrolled into a double-blind,
placebo-controlled cross-over catecholamine/sham depletion study.
The initial assessment comprises physical examinations, a structured psychiatric interview,
clinical ratings and neuropsychological testing.
Catecholamine depletion will be induced by administration of AMPT over 24 hours. Sham
depletion includes diphenhydramine at the first medication intake time point because AMPT
mostly induce mild sedation.
Based on previous reports, the investigators expect maximal depletion 30 hours after the
first dose AMPT. Blood samples will be taken at that time to measure serum prolactin levels
as a proxy of catecholamine synthesis. Behavioral experiments (tasks assessing reward and
emotional processing) will be conducted in a MR-scanner. The participants will complete
various self-report ratings before the first, during and after medication intake.
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