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 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). To test this hypothesis, the investigators have designed a now two-site, open-label study of 18-55-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 current substance use disorder (except nicotine or caffeine). 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 one subanesthetic dose (0.5mg/kg x 40 minute) ketamine infusion. The ketamine infusion will occur 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 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 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.

Objective:

Glutamate-based medications including the glutamate modulator ketamine result in rapid, robust and sustained (typically up to one week) antidepressant effects in randomized controlled trials in treatment-refractory unipolar and bipolar depression. Previous work by the investigators' 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 when administered a subanesthetic dose of ketamine. Based on the prior post hoc results, the investigators seek to prospectively demonstrate that a family history of an alcohol use disorder predicts a more robust antidepressant response to ketamine.

Study Population:

18-55 year old TRD without psychotic features patients in a current major depressive episode of at least moderate severity will be recruited and enrolled in this study. All subjects must not have a current substance use disorder (except nicotine or caffeine). All subjects must be psychotropic medication-free for at least two weeks prior to the ketamine infusion. The targeted number of completers is 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 an alcohol user disorder on the Family Interview for Genetics Studies (FIGS) and Family Tree Questionnaire (FTQ)] and 25 FHN negative subjects.

Design:

This study is currently a single 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 includes a subanesthetic/antidepressant dose ketamine infusion during 7T-MRI.

Outcome Measures:

The primary hypothesis/outcome measure will be 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 glutamate alterations during intravenous ketamine infusions and rs-fMRI as a function of family history status.

INCLUSION CRITERIA:

1. 18 to 55 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. Diagnostic and Statistical Manual-4th Edition-Text Revision (DSM-IV-TR)) diagnosis of major depressive disorder (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 substance use disorder (except for caffeine or nicotine dependence).
4. Pregnant or nursing women or women of childbearing 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 greater than or equal to 4.
18. A current NIMH employee/staff or their immediate family member (N.B. former exclusion criteria likely to be no longer relevant at the University of Iowa Health Care).
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.