The Neurophysiological Effects of Intravenous Alcohol as Potential Biomarkers of Ketamine's Rapid Antidepressant Effects in Major Depressive Disorder

Objective:

Glutamate-based medications including the N-methyl-D-aspartate (NMDA) receptor antagonist
ketamine result in rapid, robust and sustained (up to one week) antidepressant effects in
randomized controlled trials in treatment-refractory unipolar and bipolar depression.
Previous work by our group has demonstrated that a family history of alcohol dependence
predicts a more robust antidepressant response to ketamine in both treatment-resistant
unipolar and bipolar depression.

Recently-detoxified alcoholics and affected first-degree relatives display blunted
psychotomimetic, cognitive and other neuropsychiatric effects with a subanesthetic dose of
ketamine. Also, a family history of alcoholism alone predicts differential response to
intravenous alcohol. Based on our prior post hoc results, we seek to prospectively
demonstrate that a family history of alcohol dependence predicts a more robust antidepressant
response to ketamine. We will also explore potential biomarkers of ketamine s antidepressant
effects in treatment-refractory depressed patients at risk of alcohol dependence (using
physiological and neurochemical responses to alcohol).

Study Population:

21-65 year old treatment-resistant major depressive disorder without psychotic features
patients in a current major depressive episode of at least moderate severity will be
recruited and enrolled in this protocol. All subjects must also be free of a lifetime
substance use disorder diagnosis with the exception of a nicotine or caffeine use disorder)
and will be psychotropic medication-free for at least two weeks prior to the first alcohol
infusion. Our targeted number of completers will be 50 depressed subjects (60 signing consent
to account for attrition): 25 FHP subjects [as defined by either one first degree relative or
two second-degree relatives with alcohol dependence on the Family Interview for Genetics
Studies (FIGS) and Family Tree Questionnaire (FTQ)] and 25 FHN negative subjects.

Design:

This study is a single-site, open-label protocol in psychotropic medication-free depressed
subjects admitted to the Clinical Research Center s Mood and Anxiety Disorder Inpatient
Research Unit (7-SE). This protocol consists of two phases (Phase I and Phase II). The first
phase consists of the medication taper and drug-free period. The second phase will have three
subphases: Subphase IIA ( alcohol clamp infusion #1 with neurophysiological assessments), IIB
( alcohol clamp infusion #2 during 7 Tesla-Magnetic Resonance Spectroscopy/Imaging
(7T-MRS/I)) and IIC (subanesthetic/antidepressant dose ketamine infusion during 7T-MRS/I).

Outcome Measure:

The primary hypothesis/outcome measure will be change in mean Montgomery-Asberg Depression
Rating Scale (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 infusion, brain neurochemical alterations
during intravenous alcohol infusion, brain neurochemical alterations during intravenous
ketamine infusion and resting state (task-free) functional magnetic resonance imaging as a
function of family history of an alcohol use disorder.

- INCLUSION CRITERIA:

1. 21 to 65 years of age.

2. A level of understanding sufficient to agree to all required tests and
examinations, sign an informed consent document and verify understanding by a
score greater than or equal to 90% on the consent quiz.

3. DSM-IV-TR diagnosis of MDD, single-episode (296.30) or recurrent (296.20) without
psychotic features based on clinical assessment and confirmed by a Structured
Clinical Interview for the DSM-IV- Patient Version (SCID-P). Subjects must be
experiencing a current major depressive episode of at least 2 weeks duration.

4. Past failure of greater than or equal to one standard antidepressant trial based
on the Antidepressant Treatment History Form (ATHF).

5. MADRS score greater than or equal to 20 at baseline and the day of ketamine
infusion.

EXCLUSION CRITERIA:

1. Inadequate knowledge of family mental and substance use history, e.g. adoption.

2. Current psychotic features or prior diagnosis of a DSM-IV-TR psychotic spectrum
disorder, e.g. schizophrenia, schizoaffective disorder, bipolar I disorder with
psychotic features, MDD with psychotic features, or bipolar disorder, e.g. bipolar I
disorder without psychotic features, bipolar II disorder and bipolar disorder not
otherwise specified (NOS).

3. Current/active DSM-IV-TR drug or alcohol use disorder (except for caffeine or nicotine
dependence), currently seeking help for alcohol problems, abstinent with a history of
an alcohol use disorder, non-drinkers (no alcohol in the past year), or a history of
alcohol-induced flushing reactions.

4. Pregnant or nursing women or women of child bearing potential not using at least one
medically accepted means of contraception (to include oral, injectable, or implant
birth control, condom or diaphragm with spermicide, intrauterine devices (IUD), tubal
ligation, abstinence or partner with vasectomy).

5. Serious, unstable medical conditions/problems including hepatic, renal,
gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic,
immunologic, or hematologic disease, e.g. uncontrolled asthma, uncontrolled
hyper/hypothyroidism or active cancer.

6. Presence of any medical illness likely to alter brain morphology and/or physiology
(e.g., hypertension, diabetes) even if controlled by medications.

7. Clinically significant abnormal laboratory tests.

8. Subjects with one or more seizures without clear and resolved etiology and head injury
with loss of consciousness for > 5 minutes or requiring hospitalization.

9. Treatment with psychiatric medications, e.g. selective serotonin reuptake inhibitors,
serotonin norepinephrine reuptake inhibitors, benzodiazepines and antipsychotics, at
least two weeks of study phase II.

10. Treatment with fluoxetine within 5 weeks of study phase II.

11. Treatment with device-based treatment for depression, e.g. electroconvulsive therapy
(ECT), transcranial magnetic stimulation (TMS) and vagal nerve stimulation (VNS),
within 4 weeks of study phase II.

12. Lifetime history of deep brain stimulation.

13. Treatment with any disallowed concomitant medications.

14. Positive HIV test

15. Presence of ferromagnetic implants, e.g, heart pacemaker or aneurysm clip, or other
contraindications to magnetic resonance imaging (MRI), e.g. claustrophobia or hearing
loss.

16. Clinically-significant anatomical brain abnormalities detected on routine brain MRI.

17. Subjects who, in the investigator s judgment, pose a current serious suicidal or
homicidal risk, or who have a MADRS item 10 score of >4.

18. A current NIMH employee/staff or their immediate family member.

19. Currently engaged in an evidence-based structured psychotherapy for mood and/or
anxiety disorders, e.g. cognitive-behavioral therapy (CBT) or interpersonal
psychotherapy (IPT).

Additionally, the Investigators may exclude or terminate any patient for clinical reasons.