A Multimodal Neuroimaging Study of Brain Activation Patterns Under Ketamine

Study Overview
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Brief Summary
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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.

Official Title
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Brain Activation Patterns Under Emotional and Neurochemic Stimulation With Ketamine: A Multimodal Neuroimaging Study

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Ketamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine<br>i.v. infusion of 0.25 mg/kg S-ketamine over 40 min | Drug: Ketamine<br>* i.v. infusion of 0.25 mg/kg S-ketamine over 40 min<br>|
| Placebo Comparator: Placebo<br>i.v. infusion of NaCl over 40 min | Drug: Placebo<br>* i.v. infusion of NaCl over 40 min<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in functional reactivity to emotional stimuli | fMRI BOLD | Change from baseline to 24h-post infusion | 
| Change in glutamate concentrations in prefrontal cortex | 1H-MRS | Change from baseline to 24h-post infusion | 
| Change in resting-state functional connectivity | rsfMRI | Change from baseline to 24h-post infusion |