Ketamine + Mindfulness for Depression

NOTE: The study's target sample size was revised after beginning the study, based on a revised available budget.

• Intravenous Ketamine (Drug): Single infusion of intravenous racemic ketamine (0.5mg/kg over 40min)
• Brief Mindfulness Exercises (Behavioral): 30min guided training in mindfulness meditation immediately prior to infusion
• Academic Exercises (Behavioral): 30min of mental math and other academic cognitive puzzles completed silently/mentally

Primary outcomes

• Montgomery-Asberg Depression Rating Scale [24hrs post-intervention]: Clinician-rated depression (range: 0-60; higher scores = worse outcome)
• Montgomery-Asberg Depression Rating Scale [5 days post-intervention]: Clinician-rated depression (range: 0-60; higher scores = worse outcome)
• Montgomery-Asberg Depression Rating Scale [12 days post-intervention]: Clinician-rated depression (range: 0-60; higher scores = worse outcome)
• Montgomery-Asberg Depression Rating Scale [21 days post-intervention]: Clinician-rated depression (range: 0-60; higher scores = worse outcome)
• Montgomery-Asberg Depression Rating Scale [30 days post-intervention]: Clinician-rated depression (range: 0-60; higher scores = worse outcome)
• State Mindfulness Scale [80min post-infusion]: Self-reported mindfulness (range 21-105; higher scores = more mindfulness)

Secondary outcomes

• Modified Hamilton Depression Rating Scale [24hrs post-intervention]: Clinician-rated depression (range: 0-52; higher scores = worse outcome)
• Modified Hamilton Depression Rating Scale [5 days post-intervention]: Clinician-rated depression (range: 0-52; higher scores = worse outcome)
• Modified Hamilton Depression Rating Scale [12 days post-intervention]: Clinician-rated depression (range: 0-52; higher scores = worse outcome)
• Modified Hamilton Depression Rating Scale [21 days post-intervention]: Clinician-rated depression (range: 0-52; higher scores = worse outcome)
• Modified Hamilton Depression Rating Scale [30 days post-intervention]: Clinician-rated depression (range: 0-52; higher scores = worse outcome)
• Quick Inventory of Depressive Symptoms [24hrs post-intervention]: Self-reported depression (range: 0-27; higher scores = worse outcome)
• Quick Inventory of Depressive Symptoms [5 days post-intervention]: Self-reported depression (range: 0-27; higher scores = worse outcome)
• Quick Inventory of Depressive Symptoms [12 days post-intervention]: Self-reported depression (range: 0-27; higher scores = worse outcome)
• Quick Inventory of Depressive Symptoms [21 days post-intervention]: Self-reported depression (range: 0-27; higher scores = worse outcome)
• Quick Inventory of Depressive Symptoms [30 days post-intervention]: Self-reported depression (range: 0-27; higher scores = worse outcome)
• Hood Mysticism Scale [40 minutes post-intervention]: clinician-administered to assess mystical experiences (range: -64 to +64; higher scores = greater mystical experience)
• Mindful Attention Awareness Scale [24hrs post-intervention]: self-reported trait mindfulness (range: 1-6; higher scores=greater mindfulness)
• Mindful Attention Awareness Scale [5 days post-intervention]: self-reported trait mindfulness (range: 1-6; higher scores=greater mindfulness)
• Mindful Attention Awareness Scale [12 days post-intervention]: self-reported trait mindfulness (range: 1-6; higher scores=greater mindfulness)
• Mindful Attention Awareness Scale [21 days post-intervention]: self-reported trait mindfulness (range: 1-6; higher scores=greater mindfulness)
• Mindful Attention Awareness Scale [30 days post-intervention]: self-reported trait mindfulness (range: 1-6; higher scores=greater mindfulness)
• Daily Spiritual Experience Scale [5 days post-intervention]: self-reported spiritual experiences (range: 1-6; higher scores=greater spiritual experience)
• Daily Spiritual Experience Scale [12 days post-intervention]: self-reported spiritual experiences (range: 1-6; higher scores=greater spiritual experience)
• Daily Spiritual Experience Scale [21 days post-intervention]: self-reported spiritual experiences (range: 1-6; higher scores=greater spiritual experience)
• Daily Spiritual Experience Scale [30 days post-intervention]: self-reported spiritual experiences (range: 1-6; higher scores=greater spiritual experience)

Other outcomes

• Sustained Attention Response Task (SART) Omission Errors [infusion +24 hours (1 day)]: performance-based measure of mindful attention
• Sustained Attention Response Task (SART) Self-reported Task Focus [infusion +24 hours (1 day)]: self-report rating of being on-task (range: 1-7; higher score=more on-task)
• Awe Experience Scale [infusion +80min]: self-report measure of awe-inspiring experiences (range: 30-210; higher score=greater awe)
• Dual Probe Video Task [infusion +24 hours (1 day)]: attentional bias (proportion score) towards sad film clips (range: 0-1.0; higher score=greater attention bias towards sad films)
• Pain Rating Via Quantitative Sensory Testing [1-hour post-infusion]: Pain rating obtained from Quantitative Sensory Testing by mechanical temporal summation (range: 0-10; higher score=more pain)
• PROMIS Pain Intensity Score [1-hour post-infusion]: PROMIS Pain Intensity Short Form scale T-score (range=0-100; higher score=worse pain)
• PROMIS Pain Interference Score [1-hour post-infusion]: PROMIS Pain Interference Short Form scale T-score (range=0-100; higher score=worse pain)

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

All participants will:

1. be between the ages of 18 and 65 years,
2. score ≥ 14 on the Hamilton Depression Rating Scale (modified Ham-D)
3. possess a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document

Exclusion Criteria:

All participants:

1. Presence of lifetime bipolar, psychotic, or autism spectrum; current problematic substance use (e.g., ongoing moderate-to-severe substance use disorder);
2. Acute suicidality or other psychiatric crises requiring treatment escalation. We will use the Columbia Suicide Severity Rating Scale (CSSRS) as both an initial exclusion criteria (CSSRS "Baseline/Screening" Version for past 1month period) and as grounds for rescue/removal (CSSRS "Since Last Visit" form). The CSSRS will be administered using a paper form by an experienced and thoroughly trained clinical assessor on the study team. Subjects with CSSRS suicide ideation scores scored "yes" on items 4 (active suicidal ideation with some intent to act) and/or 5 (active suicidal ideation with specific plan and intent) will be excluded from the study, and if enrolled, will be exited from the study and referred immediately to the nearest emergency mental health facility for additional thorough assessment and appropriate treatment referral.
3. Changes made to treatment regimen within 4 weeks of baseline assessment.
4. Reading level <6th grade as per patient self-report.
5. Patients who have received ECT in the past 2 months prior to Screening.
6. Current pregnancy or breastfeeding
7. Patients must be reasonable medical candidates for ketamine infusion, as determined by a physician co-investigator. Serious, unstable medical illnesses including respiratory \[obstructive sleep apnea, or history of difficulty with airway management during previous anesthetics\], cardiovascular \[including ischemic heart disease and uncontrolled hypertension\], and neurologic \[including history of severe head injury\] will be exclusions.
8. Clinically significant abnormal findings of laboratory parameters \[including urine toxicology screen for unreported drugs of abuse\], vitals, or ECG.
9. Uncontrolled or poorly controlled hypertension, as determined by a physician co-investigator's review of vitals collected during screening and any other relevant medical history/records.
10. Patients with one or more seizures without a clear and resolved etiology.
11. Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior to Screening.
12. Past intolerance or hypersensitivity to ketamine.
13. Patients taking medications with known activity at the NMDA or AMPA glutamate receptor \[riluzole, amantadine, memantine, topiramate, dextromethorphan, D-cycloserine\], or the mu-opioid receptor \[opiate medications--morphine, oxycodone, heroin, fentanyl)\]. However, lamotrigine will not be a study exclusion given that it has been shown not to impact ketamine's safety profile or its antidepressant efficacy.
14. Patients taking any of the following medications: St John's Wort, theophylline, tramadol, metrizamide.
15. Patients who report meditating with mindfulness techniques >1 hour weekly (on average) for the past 6 months or longer.

Participant flow

Outcome results

• Montgomery-Asberg Depression Rating Scale (Primary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 12.50 +/- 7.94; Intravenous Ketamine + Academic Exercises 13.30 +/- 8.90
• Montgomery-Asberg Depression Rating Scale (Primary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 15.81 +/- 7.84; Intravenous Ketamine + Academic Exercises 14.30 +/- 10.69
• Montgomery-Asberg Depression Rating Scale (Primary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 15.43 +/- 8.42; Intravenous Ketamine + Academic Exercises 17.21 +/- 11.74
• Montgomery-Asberg Depression Rating Scale (Primary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 18.90 +/- 11.71; Intravenous Ketamine + Academic Exercises 17.10 +/- 11.39
• Montgomery-Asberg Depression Rating Scale (Primary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 18.55 +/- 12.02; Intravenous Ketamine + Academic Exercises 20.05 +/- 11.64
• State Mindfulness Scale (Primary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 77.68 +/- 13.74; Intravenous Ketamine + Academic Exercises 83.33 +/- 15.27
• Modified Hamilton Depression Rating Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 10.00 +/- 5.17; Intravenous Ketamine + Academic Exercises 9.55 +/- 5.50
• Modified Hamilton Depression Rating Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 10.95 +/- 5.13; Intravenous Ketamine + Academic Exercises 10.15 +/- 6.60
• Modified Hamilton Depression Rating Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 10.67 +/- 6.30; Intravenous Ketamine + Academic Exercises 11.11 +/- 6.32
• Modified Hamilton Depression Rating Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 12.05 +/- 7.09; Intravenous Ketamine + Academic Exercises 11.30 +/- 6.67
• Modified Hamilton Depression Rating Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 12.69 +/- 7.42; Intravenous Ketamine + Academic Exercises 12.45 +/- 6.90
• Quick Inventory of Depressive Symptoms (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 6.55 +/- 5.08; Intravenous Ketamine + Academic Exercises 6.90 +/- 5.10
• Quick Inventory of Depressive Symptoms (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 8.05 +/- 4.31; Intravenous Ketamine + Academic Exercises 9.90 +/- 7.58
• Quick Inventory of Depressive Symptoms (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 8.80 +/- 4.94; Intravenous Ketamine + Academic Exercises 7.95 +/- 5.70
• Quick Inventory of Depressive Symptoms (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 9.68 +/- 5.18; Intravenous Ketamine + Academic Exercises 8.50 +/- 5.83
• Quick Inventory of Depressive Symptoms (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 9.30 +/- 5.22; Intravenous Ketamine + Academic Exercises 8.47 +/- 4.94
• Hood Mysticism Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises -.05 +/- 5.59; Intravenous Ketamine + Academic Exercises .05 +/- 5.70
• Mindful Attention Awareness Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 3.73 +/- 1.05; Intravenous Ketamine + Academic Exercises 3.80 +/- .92
• Mindful Attention Awareness Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 3.90 +/- .80; Intravenous Ketamine + Academic Exercises 4.15 +/- .96
• Mindful Attention Awareness Scale (Secondary), Mean, score on a scale: Intravenous Ketamine + Mindfulness Exercises 3.90 +/- .92; Intravenous Ketamine + Academic Exercises 4.09 +/- .87
• 13 more outcome measures not shown.

Adverse events

Time frame: 24 hours

Other adverse events by term

Limitations and caveats: Pilot study leading to small numbers of patients in each treatment arm. Descriptive statistics are reported without statistical analysis to directly compare groups, given the small number of patients within each group leading to low statistical power.

• Results publication: Kheirkhah M, McDonald N, Aepfelbacher J, Rengasamy ML, Shivanekar S, Spotts C, Cooper I, Baumeister A, Bell E, Do-Nguyen K, Woody ML, Hossein S, Henter ID, Nugent AC, Hejazi NS, Jamalabadi H, Yavi M, Walter M, Zarate CA Jr, Price RB. Mindfulness, music, visual occlusion in ketamine therapy for depression: do they change outcomes? A qualitative and quantitative analysis of a randomized controlled trial. Front Psychiatry. 2025 Sep 2;16:1642025. doi: 10.3389/fpsyt.2025.1642025. eCollection 2025. PMID 40964432

• Study Protocol and Statistical Analysis Plan (PDF, 2022-06-09)

• Rebecca Price, PhD, Principal investigator, University of Pittsburgh