Ketamine Alcohol (in Treatment-Resistant Depression)
Status:
Recruiting
Trial end date:
2021-09-01
Target enrollment:
Participant gender:
Summary
A single subanesthetic dose infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist
ketamine has rapid and robust antidepressant effects in patients with treatment-refractory
major depressive disorder (TRD). A family history of an alcohol use disorder (Family History
Positive, FHP) is one of the strongest identified predictors of an improved antidepressant
response to ketamine. Like ketamine, alcohol is a functional NMDA receptor antagonist. FHP is
associated with differential response to both alcohol, e.g. decreased body sway and plasma
cortisol, and ketamine, e.g. blunted psychotomimetic side effects. One of the primary
mechanistic hypotheses for ketamine's antidepressant action is the acute intrasynaptic
release of glutamate from major output neurons, e.g. cortical pyramidal cells. Preliminary
clinical studies have demonstrated this acute glutamate "surge" in response to subanesthetic
dose ketamine. Based on these findings, the investigators hypothesize that ketamine's
enhanced antidepressant efficacy in FHP TRD subjects is, at least in part, attributable to
increased glutamate release relative to TRD subjects without a family history of alcohol use
disorder (Family History Negative, FHN). The investigators also hypothesize that alcohol
similarly augments glutamate release in this bio- logically-enriched subgroup, which may be a
more objective biomarker than family history status. To test these hypotheses, the
investigators have designed a now two-site, open-label study of 21-65 year old medically and
neurologically healthy, currently moderately-to-severely depressed TRD patients. In total,
the investigators plan to recruit 25 FHP and 25 FHN TRD subjects. All subjects must not have
a lifetime substance use disorder (except nicotine or caffeine), no lifetime history of an
alcohol use disorder and socially drink. The experimental portion consists of two phases. The
preliminary first phase is a medication taper (if needed) and psychotropic medication-free
period. The experimental second phase comprises two pharmacokinetically-defined basal-bolus
alcohol and one subanesthetic dose (0.5mg/kg x 40 minute) ketamine infusions. The first
alcohol infusion will establish the pharmacokinetic profile for a subsequent alcohol infusion
occurring during 7T-magnetic resonance imaging (MRI), both resting-state functional MRI
(rs-fMRI) and magnetic resonance spectroscopy (MRS) to detect glutamate in the ventromedial
prefrontal cortex/ventral anterior cingulate cortex (vmPFC/vACC). The ketamine infusion will
also occur during 7T-MRI. The primary outcome measure is group mean change in
Montgomery-Åsberg Depression Rating Scale (MADRS) score from pre-ketamine infusion (baseline)
to one week post-infusion, where the investigators observed ketamine's greatest
antidepressant effect in FHP TRD. Additional outcome measures are vmPFC/vACC glutamate change
in response to ketamine and alcohol challenge based on family history status. In summary,
this study will provide key mechanistic information on ketamine's improved antidepressant
efficacy in a biologically-enriched subgroup. This will contribute to the systematic
development of more efficacious, personalized treatments for major depression in an effort to
reduce its enormous public health burden.
Phase:
Phase 2
Details
Lead Sponsor:
Mark Niciu National Institute of Mental Health (NIMH)