This open-label trial (n=60) tests the hypothesis that ketamine (35mg/70kg) infusion will be especially effective in those who have a family history of alcohol abuse (Family History Positive, FHP).
The trial will test this by administrating ketamine and also alcohol and measuring (f)MRI data in the participants (of which half have an FHP).
Some more data from the trail description about the design and outcome measures:
“This study is a two-site, open-label protocol in psychotropic medication-free depressed subjects. This protocol consists of two phases. Phase I consists of a medication taper (if needed) and at least two week drug-free period. Phase II has three subphases: Subphase IIA (alcohol clamp infusion #1 with neurophysiological assessments), Subphase IIB (alcohol clamp infusion #2 during 7T-MRI) and Subphase IIC (subanesthetic/antidepressant dose ketamine infusion during 7T-MRI).”
“The primary hypothesis/outcome measure will be the mean change in MADRS total score from the pre-ketamine infusion (baseline) to 7 days post-infusion between the FHP and FHN groups. Other exploratory measures include neurophysiological responses to intravenous alcohol, glutamate) alterations during intravenous alcohol infusion and ketamine infusions, and rs-fMRI as a function of family history status.“
Trial DetailsA 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.
NCT Number NCT02122562
Measures UsedMontgomery-Asberg Depression Rating Scale
A ten-item diagnostic questionnaire used to measure the severity of depressive symptoms in patients with mood disorders.
Beck Depression Inventory
The Beck Depression Inventory (BDI) contains 21 self-report items, completed using a multiple-choice format. Scores range from 0-63 with higher scores associated with more severe depression.
Columbia-Suicide Severity Rating Scale
The Columbia-Suicide Severity Rating Scale (CSSRS) is a suicidal ideation and behaviour rating scale created by researchers at Columbia University, University of Pennsylvania, University of Pittsburgh and New York University to evaluate suicide risk
Clinical-Administered Dissociative Symptoms Scale
The Clinical-Administered Dissociative Symptoms Scale (CADSS) is a scale used to measure dissociative states such as those induced by ketamine.
Clinical Global Impression - Improvement Scale
The Clinical Global Impression - Improvement Scale (CGI-I) is a standardized assessment scale for determining the effects of mental health treatment among psychiatric patients.
Hamilton Depression Rating Scale
The Hamilton Depression Rating Scale (HDRS) is a multiple item questionnaire used to provide an indication of depression, and as a guide to evaluating recovery. The scale consists of 17 items which each item being scoring on a 3 or 5 point scale. The higher the score, the more likely a person is depressed.