A Phase 2 interventional study of Ketamine and Normal Saline in Depressive Disorder, Treatment-Resistant and Treatment Resistant Depression (TRD), sponsored by Mayo Clinic. Recruiting at 1 site in United States. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2025-10-14.
Sponsored by Mayo Clinic · Phase 2, Interventional, and Treatment
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.
461 studies on the registry are indexed under Depressive Disorder, Treatment-Resistant; 148 are open to participants now.
This study's planned enrollment of 30 is below the median of 53 across 388 interventional studies indexed under Depressive Disorder, Treatment-Resistant.
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Subjects will receive IV racemic ketamine at a dose of 0.5 mg per kg of the participant's actual body weight, with a maximum dose of 50 mg for individuals weighing over 100 kg.
Drug: Ketamine
Subjects will receive an IV infusion of normal saline over a duration of 40 minutes
Drug: Normal Saline
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
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
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
Correlation between the percent change in serum 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 scores 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 serum Gamma-Aminobutyric Acid (GABA) and Glutamate (Glu) levels during a 40-minute IV infusion of ketamine or normal saline (0.9% sodium chloride) using Liquid Chromatography-Mass Spectrometry (LCMS) and the change in MADRS scores (from baseline to 24 hours).
Time frame: Baseline to the end of 40-minute infusion for serum GABA and Glu. Baseline to 24 hours post-infusion for MADRS
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
Plan to share: Yes — The study results will be uploaded to the website after the completion of the study. All related research findings will be published or submitted to the NIH.
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