Reward-specific Changes of the Chemical Messenger Dopamine in the Brain of Healthy and Depressed People

Major depressive disorder was shown to be associated with pathological alterations within neurotransmitter systems of the brain. Based on earlier study results, it is assumed that the neurotransmitter dopamine is relevant for several symptoms of depression, e.g., loss of interest or pleasure and lack of motivation. Thus, it is assumed that the synthesis of dopamine in the brain of depressed individuals could be impaired. The specific effect of common antidepressants on the human reward system in depression has not yet been sufficiently investigated. In particular, it is unclear whether depressed patients exhibit reward-specific changes of dopamine synthesis, and whether or not these changes can be differentially affected by diverse types of antidepressants. Neurotransmitter systems can be visualized in the brain using positron emission tomography (PET). Additionally, brain structure and function can be studied using magnetic resonance imaging (MRI). For the visualization of dopamine synthesis in the brain, the radioligand \[18F\]FDOPA can be used in PET measurements. To assess task-relevant changes of diverse radioligands and thus specific metabolic processes in the brain during specific tasks, a recently developed PET-approach can be used which has already been successfully applied in a pilot study with healthy volunteers. In the present project, 60 depressed subjects and 30 healthy controls will undergo PET/MR-imaging twice. Depressed subjects will be assigned to 1 of 2 treatment groups. 30 depressive subjects will receive bupropion, the other 30 patients will be treated with escitalopram. After a treatment period of 6 weeks, the 2nd PET measurement will be performed in all participants, aiming to detect potential reward-specific changes of dopamine synthesis. The investigators hypothesize that reward-specific changes of dopamine synthesis will be lower in depressed subjects than in healthy controls, that reward-specific changes of dopamine synthesis will be significantly higher in the bupropion group than in the escitalopram group, and that the changes of dopamine synthesis will be associated with functional changes in the brain (measured by simultaneous functional MRI scans). This will be the first study comparing the effects of escitalopram and bupropion on task-specific dopamine synthesis and thus on the human reward system. The study is expected to yield new insights for individual treatment concepts in the therapy of depression.


Eligibility Criteria:
Inclusion Criteria:

* Male and female subjects aged between 18-65 years of age
* Depressive patients: DSM-IV diagnosis of MDD following SCID I, HDRS29, MADRS and BDI-II
* Satisfactory general health as determined by past medical history, physical examination, vital signs at screening
* Vital signs measured after 3 minutes resting in the supine position must be within the following ranges: oral body temperature between 35.0-37.5 °C, systolic blood pressure 90-140 mmHg, diastolic blood pressure 50-90 mm Hg, pulse rate 40-100 bpm
* Subjects must weigh 50-100 kg to participate in this study with a BMI within 19-26.
* Sufficient visual and auditory performance for neuropsychological testing
* Written informed consent will be obtained prior to the start of any study procedures. Therefore, willingness and competence to sign the informed consent form is needed.
* Potential patients must be able to communicate well with the investigator and comply with the requirements of the study
* Only participants who are legally authorized to give informed consent will be included in the present study.

Exclusion Criteria:

* Depressed patients: Presence of any severe / unstable neurological, somatic or psychiatric comorbidity
* Healthy controls: Any psychiatric disease or any severe / unstable neurological or somatic disease
* Presence of psychotic symptoms
* Acute suicidality
* Any contraindication for magnetic resonance or PET imaging
* Presence of any metallic implant in the head
* History of clinically significant drug allergy; history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to one of the study drugs or multiple study drugs (known hypersensitivity to bupropion, escitalopram)
* Other clinically significant abnormality on physical, neurological, or laboratory examination or on electrocardiogram (ECG) that, in the opinion of the investigator precludes the patient from the study
* Ingestion of antidepressants or other psychotropic agents within the last 6 months Previous escitalopram- or bupropion intake
* Antidepressive trials wit DBS, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) or Ketamine
* Current smoking, substance abuse including alcohol, drugs of abuse, or any medication in a manner which is indicative of substance-related disorders (e.g. substance dependency) according to DSM-IV
* Failure to comply with the study protocol or follow the instructions of the investigators
* Positive urine pregnancy test
* Known pregnancy or lactation
* MRI scan that shows evidence of stroke, infarct, or other space occupying lesion or structural abnormality
* History of any other drug or alcohol abuse or misuse
* Participation in any clinical investigation within 12 weeks prior to dosing
* Evidence from an Allen test of incomplete communication between the radial and ulnar artery, in either hand
* Significant radiation exposure (\>5 mSv) in the frame of participation in trials within the past 10 years