Establishing Glutamatergic Changes as the Mechanism of Action in the Rapid Antidepressant Effects of Ketamine
University of Pennsylvania
Summary
In the treatment of Major Depressive Disorder (MDD), ketamine can produce rapid but short-lasting improvements in mood. In order to develop a new generation of treatments with rapid and sustained efficacy, a better understanding of the mechanism of action is urgently needed. One candidate mechanism is the modulation of synaptic strength mediated by glutamatergic activity as ketamine has been suggested to increase synaptic strength. Although determining how ketamine impacts the glutamatergic system is essential to isolating its mechanism of action, the invasive nature of most assessment methods has limited our ability to do so in humans. The proposed research aims to determine if changes in glutamatergic activity, reflecting the modulation of synaptic strength, underlie the antidepressant effects of ketamine. In this project, the investigators will utilize a novel measure of glutamate imaging, GluCEST, to assess changes in glutamatergic activity to assess synaptic strength following ketamine administration. Ten individuals (aged 25-65) with a DSM-V diagnosis of MDD will undergo baseline GluCEST imaging prior to and following ketamine infusion. Both clinician-administered and subjective mood measures will be collected. It is predicted that ketamine will improve mood and increase glutamatergic activity and synaptic strength. Results from this project have the potential to identify the modifiable mechanisms by which rapid antidepressants work which could ultimately stimulate the development of novel interventions that work through the modulation of glutamatergic activity.
Description
Consent and Virtual Screening: Participants who meet initial inclusion criteria via phone screen will be invited to the complete a virtual visit that will include additional screening (e.g. Medical history), Structured Clinical Interview for DSMV (SCID) and clinician-administered measures of mood to determine final study eligibility. At the outset of this visit, all participants will receive verbal and written explanation of the general goals and risks of the study and will virtually sign an informed consent. The results of the SCID will be used to characterize the study population and to det…
Eligibility
- Age range
- 25–65 years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: 1. Age between 25 and 65 years; 2. Current depression as assessed on the SCID; 3. Treatment-resistant depression, as defined by failure of at least two previous antidepressant or mood stabilizing treatments within the current depressive episode. Failed antidepressant or mood stabilizing treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks 4. Able to comprehend English, as all questionnaires are in this language 5. Ability to provide informed consent Ability to pass a comprehension assessment test related to effects of ketamine and…
Interventions
- DrugKetamine only
The primary study intervention involves the administration of intravenous ketamine (0.5 mg/kg) over a 40-minute infusion. Ketamine, an NMDA receptor antagonist, has shown rapid antidepressant effects in individuals with treatment-resistant depression.
Location
- University of PennsylvaniaPhiladelphia, Pennsylvania