Intravenous Ketamine for Treatment-Resistant Depression

Phase 2RecruitingNCT06668571

Mayo Clinic30 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Depressive Disorder, Treatment-Resistant Treatment Resistant Depression (TRD)

Interventions

KetamineDRUG

The subjects will receive 1:1 single IV racemic ketamine (dosed @0.5 mg/kg actual body weight) (n=15) 40-min infusion in an MRI scanner, followed by an optional open-label ketamine infusion (available to everyone) 1-7 days after the initial treatment

Normal SalineDRUG

The subjects will receive 1:1 single IV normal saline/placebo (n=15) 40-min infusion in an MRI scanner, followed by an optional open-label ketamine infusion (available to everyone) 1-7 days after the initial treatment

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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 (\> 1 year) remission * History of traumatic brain injury that resulted in loss of consciousness with brain bleeding * 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 3 months * Hepatic insufficiency (2.5 X ULN for AST or ALT) within 3 months 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 * Poorly controlled hypertension.

Locations (1)

Mayo Clinic in Rochester

Rochester, Minnesota, United States

RECRUITING

Outcomes

Primary Outcomes

Peak (% change from baseline) Anterior Cingulate Cortex metabolites (Gamma-Aminobutyric Acid and Glutamate)

To measure peak (% change from baseline) Anterior Cingulate Cortex (ACC) Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels during a 40-minute IV ketamine or normal saline (0.9% sodium chloride) infusion utilizing fMRS (functional Magnetic Resonance Spectroscopy)

Time frame: Baseline to the end of 40-minute infusion

Change in peripheral Gamma-Aminobutyric Acid and Glutamate levels

Change in peripheral Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels measured utilizing liquid chromatography-mass spectrometry (LCMS) at baseline and the end of 40-minute infusion

Time frame: Baseline to the end of 40-minute infusion

Change in the Montgomery Asberg Depression Rating Scale

Montgomery Asberg Depression Rating Scale (MADRS) is a 10-item clinician rating of depressive symptoms used in the previous ketamine research studies. Higher scores represent higher levels of depression.

Time frame: Baseline to 24-hours post-infusion

Correlation between the percent change in central (anterior cingulate cortex) Gamma-Aminobutyric Acid and Glutamate levels and the change in depression severity measured using the Montgomery-Åsberg Depression Rating Scale

Outcome measure: Changes in the total Montgomery-Asberg Depression Rating Scale (MADRS) scale from baseline (pre-infusion) to 24 hours post-infusion. MADRS will be compared by randomized arm as a continuous variable as well as defined by remission status (MADRS≤9). The total MADRS score can range from 0 to 60, with higher scores indicating a worse outcome. We aim to evaluate the correlation between the percent change in anterior cingulate cortex (ACC) Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels (from baseline to peak) during a 40-minute IV infusion of ketamine or normal saline (0.9% sodium chloride) using functional magnetic resonance spectroscopy (fMRS) and the change in MADRS scores (from baseline to 24 hours).

Time frame: Baseline to the end of 40-minute infusion for GABA and Glu. Baseline to 24 hours post-infusion for MADRS

Central Contacts

Nicole Reinicke

CONTACT

507-422-1835 reinicke.nicole@mayo.edu

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Secondary Outcomes

Change in McIntyre And Rosenblat Rapid Response Scale

The McIntyre and Rosenblat Rapid Response Scale (MARRRS) is a validated self-report instrument designed to assess rapid treatment response in the context of rapid-acting antidepressant drugs (RAADs), such as ketamine. The scale comprises 14 items and has shown promising psychometric properties, including high internal consistency and significant convergent validity. Each item is scored on a 4-point ordinal scale, where 0 indicates the absence of symptoms and 3 signifies the highest severity of symptoms. The total score ranges from 0 to 42, with higher scores indicating a more severe state of depression.

Time frame: Baseline to up to 24 hours post-infusion

Change in Quick Inventory of Depressive Symptomatology (Self-Report)

The Quick Inventory of Depressive Symptomatology (QIDS-SR-16) is a depression scale that assesses the symptom domains of major depressive disorder, with scores ranging from 0 to 27. Higher scores indicate more severe depressive symptoms. The individual items evaluate key aspects such as sadness, anhedonia (the loss of pleasure), and sleep disturbances, which may manifest as insomnia or hypersomnia. Additionally, the scale addresses changes in appetite or weight and includes assessments of psychomotor agitation or retardation. It also measures fatigue or loss of energy, feelings of worthlessness or excessive guilt, and difficulties in concentration. Furthermore, the scale incorporates items related to suicidal ideation, offering a comprehensive overview of both the emotional and physical symptoms experienced by individuals with depression.

Time frame: Baseline to up to 24 hours post-infusion

Changes in short chain acylcarnitine levels

Changes in short-chain acylcarnitine (AC) levels-early change (baseline to 40 minutes) and late change (100 minutes to 24 hours)-among patients who received a 40-minute IV infusion of either ketamine or normal saline (0.9% sodium chloride).

Time frame: Baseline to up to 24 hours post-infusion.

Changes in short-chain acylcarnitine levels and ketamine-related remission

To evaluate the relationship between changes in short-chain AC levels-early change (baseline to 40 minutes) and late change (100 minutes to 24 hours)-among remitters and non-remitters (MADRS \< 10) at 24 hours.

Time frame: Baseline to up to 24 hours post-infusion.

Changes in mTOR (mechanistic Target of Rapamycin)

To investigate the changes in mTOR from baseline to the end of infusion with IV ketamine compared to normal saline. To investigate the correlation between anhedonia phenotypes (baseline) and the percent change in mTOR from baseline. Anhedonia phenotypes will be assessed using the MADRS and the SHAPS.

Time frame: Baseline to the end of 40-minute infusion

Change in the Snaith-Hamilton Pleasure Scale

The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale that measures anhedonia, the inability to experience pleasure. The items cover the domains of: social interaction, food and drink, sensory experience, and interest/pastimes. A score of 2 or less constitutes a "normal" score, while an "abnormal" score is defined as 3 or more. A higher total score indicates greater levels of anhedonia.

Time frame: Baseline to up to 24 hours post-infusion

Changes in neurocognitive functioning

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)is a brief, standardized, individually administered battery to measure cognitive change in immediate memory, visuospatial/constructional orientation, language (naming, fluency), attention, and delayed memory. The 12 subtests that comprise the RBANS require approximately 30 minutes to administer.

Time frame: Baseline to 24 hours post-infusion

Change in Beck Scale for Suicidal Ideation

The Beck Scale for Suicidal Ideation consists of 19 items which can be used to evaluate a patient's suicidal intentions. It can also be used to monitor a patient's response to interventions over time. Each of the 19 items is rated on a 0-3 point scale (range 0-38, with higher scores indicating greater suicidal ideations or risk), and includes specific items that assess wish to live, wish to die, desire to make an active suicide attempt, passive suicidal desire, duration of suicidal ideations, frequency of suicidal ideations, and subjective level of control over suicidal actions.

Time frame: Baseline to up to 24 hours post-infusion

Changes in Dimensional Anhedonia Rating Scale

The Dimensional Anhedonia Rating Scale (DARS) measures anhedonia, including facets of desire, motivation, effort, and consummatory pleasure. The scale has demonstrated high internal consistency, reliability, and validity across studies. It has shown superiority in distinguishing MDD subgroups. The DARS total score ranges from 0 to 68. A lower DARS score reflects more severe anhedonia, while a higher score indicates lower anhedonia.

Time frame: Baseline to up to 24 hours post-infusion

Change in Clinical Global Impression

The Clinical Global Impression (CGI) is assessed using a 7-point scale. The CGI-Severity (CGI-S) of Illness measures the severity of the patient's condition, ranging from 1 (normal) to 7 (among the most severely ill patients). In addition, the CGI-Improvement (CGI-I) scale evaluates changes in the patient's condition from baseline, which is prior to the ketamine infusion. The CGI-I scale is rated as follows: 1 indicates "very much improved" since the initiation of treatment, 2 signifies "much improved," 3 denotes "minimally improved," 4 represents "no change from baseline," 5 means "minimally worse," 6 indicates "much worse," and 7 reflects "very much worse" since the initiation of treatment.

Time frame: Baseline to up to 24 hours post-infusion

Perceived Stress

The Perceived Stress Scale is a 10-item self-rated tool that measures the frequency of an individual's perception of stress over the last month

Time frame: Baseline to up to 24 hours post-infusion

Resilience

The Brief Resilience Scale (BRS) is a reliable tool for assessing resilience, specifically focused on an individual's ability to bounce back or recover from stress. The BRS ranges from 1 to 5, with higher scores indicating greater resilience-that is, a stronger ability to bounce back from stress.

Time frame: Baseline to 24 hours post-infusion