Neuronal Correlates of Catecholamine Depletion in Patients With Bulimia Nervosa Off Medication and Healthy Controls
试验速览
- 阶段
- 不适用
- 状态
- 暂停
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Number of participants with side effects
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Diagnostic
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •age: 18-60
- •caucasian ethnicity
- •right handedness
- •normal or corrected to normal vision and hearing performance
- •remitted bulimic participants: have met the DSM IV criteria for bulimia nervosa in the past
- •remitted bulimic participants: have been asymptomatic for at least1 month
- •signed written informed consent
- •Exclusion Criteria
- •healthy volunteers: any lifetime psychiatric diagnosis
- •healthy volunteers: any lifetime psychiatric diagnosis in first-degree relatives
- •no or impaired understanding of the tasks or the risks of the study
- •medical or neurological illnesses likely to affect physiology or anatomy
- •suicidal ideation or suicide attempts within the last 8 weeks
- •current use of psychotropic drugs
- •history of drug including alcohol and nicotine (not more than 10 cigarettes per day) abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria) longer than 2 years
- •pyloroduodenal obstruction (gastrointestinal stenosis)
- •current pregnancy
- •current breast feeding
- •cardiac pacemaker
- •heart or brain surgery
- •metallic implants and alien objects in the body
- •tattoos on head, neck or shoulders as well as permanent make-up
- •claustrophobia
排除标准
- 未提供
研究组 & 干预措施
AMPT
Experimental:
alpha-methyl-paratyrosine (AMPT, trade name: Demser), body-weight adjusted dosage (40 mg/kg body weight, maximum 4000mg) at 4 time points over 24 hours
干预措施: AMPT/ Demser (Drug)
Diphenhydramine & placebo
Diphenhydramine (25mg, trade name in Switzerland: Benocten) at the first medication intake time point, placebo at the second to fourth intake time point (medication intake over 24 hours)
干预措施: Diphenhydramine (Drug)
Diphenhydramine & placebo
Diphenhydramine (25mg, trade name in Switzerland: Benocten) at the first medication intake time point, placebo at the second to fourth intake time point (medication intake over 24 hours)
干预措施: Placebo (Drug)
结局指标
主要结局
Number of participants with side effects
时间窗: 1 year
次要结局
- Performance differences in behavioral tasks after catecholamine depletion(4 years)
- Differences in neural activation assessed during functional magnetic resonance imaging (fMRI) and in performance in behavioral tasks in the different conditions between the different genotypes(4 years)
- Differences in neural activation assessed during functional magnetic resonance imaging (fMRI) in the different conditions(4 years)