The aim of the project is to establish a multimodal imaging approach for the investigation of the neural mechanisms underlying neuroreceptor regulation, glutamatergic metabolism and brain function that are of particular relevance for major depressive disorder (MDD) and that can be translated into clinical applications.

There is growing evidence for imbalance with regard to glutamatergic neurotransmission in stress-related affective disorders. Further support for the hypothesis that dysfunctional glutamatergic signaling underlies major depressive disorder, and indeed that its reversal constitutes a potential efficacious mechanism of action, is provided by the evidence that pharmacological compounds active at the N-methyl-D-aspartate (NMDA) ionotropic glutamate receptor such as ketamine exert rapid antidepressant effects. As a tool compound ketamine enables the safe investigation of the brain region-specific effects of NMDA receptor antagonism in terms of glutamatergic neurotransmission, brain function and the association of these neural changes with emotional state, thereby allowing for increased understanding of the therapeutic mechanism of action.

The possibility to simultaneously study brain perfusion (arterial spin labeling), functional brain activity (fMRI) and connectivity (resting state fMRI), neurometabolism (proton magnetic resonance spectroscopy) and metabotropic glutamate receptor densities (positron emission tomography) will unravel their functional interplay in the mechanisms underlying the regulation of mood and cognition. Combining those imaging modalities with treatment interventions in healthy subjects and depressed patients, this project aims at providing insight into the neuropharmacological effects of ketamine and its antidepressant properties.

Inclusion Criteria:

• treatment resistant depressive episode
• no restrictions regarding antidepressant medication

Exclusion Criteria:

• lifetime antidepressant treatment with ketamine
• lifetime recreational use of ketamine
• cardiovascular diseases such as hypertonia, cardiac insufficiency or myocardial infarct in the past six months
• insufficiently treated anemia
• hyper- or hypothyroidism
• lifetime increased intracranial pressure or glaucoma
• chronic physical diseases
• hepatorenal dysfunction
• any relevant psychiatric or neurological comorbidity, in particular dementia, epileptic seizures (lifetime), schizophrenia (lifetime), psychosis (lifetime), or post-traumatic stress disorder (current).
• acute suicidality
• substance abuse disorders
• recent heart or head surgery
• metallic body implants
• agoraphobia
• pregnancy
• left handedness