Ketamine and fast antidepressant response: A translational neurobiological, imaging, and clinical approach (Suported by the Swiss National Science Foundation)

Major depression during the courses of unipolar (only depressive episodes) and bipolar (depressive and manic/hypomanic episodes) disorders ranks among the top causes of medical disability. One of the main difficulties in treating depression is the week-long delay in onset of therapeutic action of pharmaco- but also psychotherapy.
Results of clinical studies and studies in animals indicate that ketamine, a widely used anaesthetic acting at the N-methyl-D-aspartate (NMDA) receptor, has a rapid antidepressant efficacy. A single sub-anesthetic intravenous dose of ketamine, has been shown to induce a very fast (within hours) and robust antidepressant effect in 3 double-blinded, placebo controlled trials of excellent quality even if involving small numbers of unipolar and bipolar depressed patients. Preliminary results suggest that this rapid effect involves mechanisms of brain plasticity, especially at dendritic spine synapses of neurons in the frontal cortex.
This translational project aims at documenting the clinical efficacy and a better understanding of the neurobiological mechanisms of the action of ketamine. Uni- and bipolar depressed patients will be injected unique or repeated small doses of ketamine and the immediate and prolonged effect on brain function at the metabolic and cognitive level will be documented using functional magnetic resonance imaging. The quality and quantity of brain plasticity in different regions of the animal brain will also be studied after ketamine administration, at the cellular and the whole brain level using fluorescence microscopy and functional neuroimaging techniques.
Our clinical studies will eventually allow a better integration of ketamine administration in a clinical treatment schedule if the rapid and substantial clinical effect can be demonstrated. This could lead to a new treatment approach of depression, since current antidepressant all target monoamine neurotransmitter systems (serotonin, noradernaline, dopamine), wheas ketamine interferes with glutamatergic neurotransmission. The preclinical studies will allow answering fundamental questions pertaining to the structural-neuronal changes induced by ketamine, including the kinetics of the formation of spines, their relation to changes in local brain metabolism, the brain regions where the spines are formed, and, very importantly, the implication of the serotonergic system in their formation.

PSYCHE (Personalised monitoring SYstems for Care in mental Health, supported by the European Union, SPECIFIC PROGRAMME: FP7) project develops a personal, cost-effective, multi-parametric monitoring system based on textile platforms and portable sensing devices for the long term and short term acquisition of data from selected class of patients affected by mood disorders. PSYCHE is focusing on mental diseases management, in particular it is targeting bipolar patients. The project will use a novel approach based on the paradigm that a 24 hours monitoring in a natural setting, through a naturalistic approach will provide parameters, indexes and trends; that will be used to assess mood status, to support patients, to predict and anticipate treatment response at its earlier phases, to prevent relapse and to alert physicians in case of critical events.