Intravenous Ketamine for Treatment-Resistant Depression

The purpose of this study is to to evaluate the relationships between peak (% change from baseline) central GABA and Glu levels during a 40-min IV ketamine or normal saline infusion utilizing fMRS, and change in peripheral GABA and Glu levels from baseline to 24-hr postinfusion utilizing LCMS, with baseline to 24-hr post-infusion change in depression (MADRS) in 30 TRD adults.

This will be a randomized, double-blind, placebo-controlled, parallel-group study where adult subjects with treatment refractory major depressive disorder (MDD) will receive 1:1 single IV racemic ketamine (n=15) or normal saline (placebo) (n=15) infusion in an MRI scanner, followed by an optional open-label ketamine infusion. In this innovative comparative study utilizing novel dynamic sliding-window fMRS and liquid chromatography-mass spectrometry (LCMS), we will investigate the dynamic relationship between GABA and Glu levels measured centrally and peripherally, respectively, with change in depression symptoms utilizing the Montgomery Asberg Depression Rating Scale (MADRS).12 Given preclinical models of reduced ACs and glutamatergic function in depression, we will also include an exploratory analysis of ACs metabolomic markers associated with ketamine treatment response.

Eligibility Criteria:
Inclusion Criteria:

* Ability to provide informed consent
* Meets diagnostic criteria for major depressive disorder without psychotic features per the SCID DSM-IV-TR
* PHQ-9 total score ≥ 15 at screening
* Treatment-resistant depression, as defined by failure of at least two previous antidepressant treatments within the current depressive episode. Failed antidepressant treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks, trial of transcranial magnetic stimulation (TMS) or an acute series of at least 6 administrations of electroconvulsive therapy (ECT)
* Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria

Exclusion Criteria:

* Inability to speak English
* Inability to provide consent or have a legal guardian
* Patients with a BMI \> 40 kg/m2.
* Personality disorder being the primary diagnosis
* Diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, or active psychotic symptoms
* Active post-traumatic stress disorder symptoms based on clinical assessment
* Ongoing prescription of \> 2 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment
* Medications known to affect glutamate (i.e., Riluzole, Carbamazepine) or GABA (zaleplon, zolpidem, zopiclone, Valproate, Gabapentin, Pregabalin, tiagabine, and vigabatrin) are prohibited within two weeks prior to administration of study drug and at least 24 hours after last dose of study drug
* Monoamine Oxidase Inhibitors (MAOIs) are prohibited two weeks prior to administration of study drug
* Opioid antagonists (naltrexone, naloxone, nalmefene, methylnaltrexone, buprenorphine and naloxone combination) are prohibited within two weeks prior to administration of study drug and at least 24 hours after last dose of study drug
* CYP3A4 inducers carbamazepine and modafinil are prohibited within two weeks prior to administration of study drug and at least 24 hours after last dose of study drug.
* Currently undergoing TMS, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression
* ECT in the past 6 months
* Any active or unstable medical condition judged by the study psychiatrist as conferring too great a level of medical risk to allow inclusion in the study
* A history of bleeding in the brain
* Arteriovenous malformation or a history of aneurysm
* Use of methamphetamine, cocaine, or cannabis. Abuse of stimulant (s) within the prior 12 months
* Any current substance use disorder (excluding nicotine and caffeine). Note: Persons will be allowed to enroll in this study if their substance use is in complete (not partial) and sustained (\&gt; 1 year) remission
* History of traumatic brain injury that resulted in loss of consciousness
* History of tonic-clonic (grand mal) seizures
* Developmental delay, intellectual disability, or intellectual disorder
* Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months
* Minor or Major Neurocognitive disorder
* Received ketamine treatment for depression within the prior 2 months
* History of either poor antidepressive response to or poor tolerability of ketamine (any route of administration) when previously administered
* History of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic for 6 months
* Hepatic insufficiency (2.5 X ULN for AST or ALT) within 1 year of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver
* Gastroesophageal reflux disease that is poorly managed
* A diagnosis of Complex Regional Pain Syndrome (CRPS)
* Pregnancy, or nursing
* History of claustrophobia with active symptoms that would interfere with the MRI
* Any contraindication to MRI safety questionnaire