A Phase 1 interventional study of Ketamine and Midazolam in Major Depressive Episode, Unipolar Depression and Bipolar Depression, sponsored by St Patrick's Hospital, Ireland. Completed at 1 site in Ireland. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-01-18.
Sponsored by St Patrick's Hospital, Ireland · Phase 1, Interventional, and Other
Randomised, controlled, parallel-group, pilot clinical trial of ketamine vs. midazolam as an adjunctive therapy for depression. The main purpose of the pilot study is to assess trial processes to help inform a future definitive trial.
Pragmatic, randomised, controlled, parallel-group, pilot trial. Trial participants will be patients admitted to St Patrick's University Hospital for treatment of a depressive episode. The investigators aim to recruit up to 20 participants who will be eligible for this study and randomly allocate 10 patients to each group. The participants will undergo usual inpatient care as prescribed by their treating team for the index acute depressive episode. Both participants and assessors will be blind to treatment allocation. Consented participants will be randomly allocated in a 1:1 ratio to a four week course of either once-weekly ketamine or midazolam infusions. Block randomisation will be independently performed. Physical, psychotomimetic and cognitive outcomes will be monitored before, during and after infusions. Blood samples will be taken at four time-points in the first infusion session and before the final infusion for neuroplasticity biomarker studies. Both groups will continue treatment as usual. Participates will also be followed up over a three month period.
Exclusion Criteria:
Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist.
Drug: Ketamine
Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist.
Drug: Midazolam
A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.
Also known as: Ketalar
A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Also known as: Hypnovel
The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24)
The HRSD assesses severity of depressive symptoms and is commonly used to measure depression severity. It was initially a 17-item format with the optional addition of 4 items making up the 21-item version. In addition to the original 21 items, the 24-item HRSD includes items on helplessness, hopelessness and worthlessness; its score range is 0-77, with higher scores reflecting greater burden of depressive symptoms. Response to antidepressant treatment is defined as achieving ≥60% decrease from baseline HRSD-24 and score ≤16. Remission criteria are ≥60% decrease in HRSD from baseline and score ≤10. Criteria for relapse are ≥10 point increase in HRSD-24 compared to responder baseline score plus HRSD ≥16; in addition, increase in the HRSD should be maintained one week later. Participants will have a baseline (T0) HRSD-24 score. This will be repeated 1 week after each of 4 once-weekly infusions (T1-4) and follow-up measures after another 5 (T9) and 11 (T15) weeks, week 15 is reported.
Time frame: 15 weeks
The Quick Inventory of Depressive Symptoms, Self-report Version (QIDS-SR16)
The QIDS-SR16 is a validated self-report measure of depressive symptoms. This consists of 16 questions rated 0-3. Its score range is 0-48, with higher scores reflecting greater burden of depressive symptoms. Participants will have a baseline (T0) QIDS-SR16 score. This will be repeated one week after each of four once-weekly infusions (T1-4) and follow-up measures after another five (T9) and 11 (T15) weeks. Week 15 scores are reported.
Time frame: 15 weeks
The Clinician-Administered Dissociative States Scale (CADSS)
The CADSS measures dissociative symptoms. It will be administered before, during and after infusions in order to capture the range of possible subjective side effects of either agent. This consists of 23 questions and scores for each question range from 0-4. The maximum score is 92 with higher scores indicating more dissociative symptoms. Participants will have the CADSS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
Time frame: 4 weeks
The Brief Psychiatric Rating Scale (BPRS)
The BPRS measures psychotomimetic effects. The investigators will use the positive symptoms subscale of the Brief Psychiatric Rating Scale. The 4-item positive symptoms subscale measures suspiciousness, hallucinations, unusual thought content, and conceptual disorganisation. Each question is scored between 0-7. The maximum score in this 4-item questionnaire is 28. Higher scores indicate more severe psychotic symptoms. Participants will have the BPRS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
Time frame: 4 weeks
Young Mania Rating Scale (YMRS; Mood Item)
Investigators will use the mood item of them YMRS to assess for psychotomimetic effects. This item is rated 0-4. The higher scores reflect elevated mood. Participants will have the YMRS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
Time frame: 4 weeks
The Patient-Rated Inventory of Side Effects (PRISE)
The PRISE will be used to document other general adverse events by patients before, during and after infusions. This is a patient self-report used to qualify side effects by identifying and evaluating the tolerability of each symptom. It is a 9 item assessment of the side effects in the following symptom domains; Gastrointestinal, Heart, Skin, Nervous System, Eyes/Ears, Genital/Urinary, Sleep, Sexual Functioning, and Other. Each domain has multiple symptoms which can be endorsed. For each domain the patient rates whether or not the symptoms are tolerable or distressing. Data below represent the number of participants from which there was an endorsement of each listed event. Participants will have the PRISE performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
Time frame: 4 weeks
The Montreal Cognitive Assessment (MoCA)
The MOCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. It is scored out of a maximum of 30. The higher scores indicate better cognition. The MOCA will be performed at baseline, one day after infusions 1 and 4 and 12 weeks after the final infusion.
Time frame: 15 weeks
Potential participants were those who were admitted to St Patrick's University Hospital, Dublin, for treatment of a major depressive episode (either unipolar or bipolar depression) between 06.09.17 and 12.06.18.
| Milestone | Ketamine | Midazolam |
|---|---|---|
| Started | 13 | 12 |
| Completed | 8 | 8 |
| Not completed | 5 | 4 |
The HRSD assesses severity of depressive symptoms and is commonly used to measure depression severity. It was initially a 17-item format with the optional addition of 4 items making up the 21-item version. In addition to the original 21 items, the 24-item HRSD includes items on helplessness, hopelessness and worthlessness; its score range is 0-77, with higher scores reflecting greater burden of depressive symptoms. Response to antidepressant treatment is defined as achieving ≥60% decrease from baseline HRSD-24 and score ≤16. Remission criteria are ≥60% decrease in HRSD from baseline and score ≤10. Criteria for relapse are ≥10 point increase in HRSD-24 compared to responder baseline score plus HRSD ≥16; in addition, increase in the HRSD should be maintained one week later. Participants will have a baseline (T0) HRSD-24 score. This will be repeated 1 week after each of 4 once-weekly infusions (T1-4) and follow-up measures after another 5 (T9) and 11 (T15) weeks, week 15 is reported.
| score on a scale | Ketamine | Midazolam |
|---|---|---|
| The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24) | 11.2 (6.2 to 16.2) | 16.6 (7.8 to 25.3) |
The QIDS-SR16 is a validated self-report measure of depressive symptoms. This consists of 16 questions rated 0-3. Its score range is 0-48, with higher scores reflecting greater burden of depressive symptoms. Participants will have a baseline (T0) QIDS-SR16 score. This will be repeated one week after each of four once-weekly infusions (T1-4) and follow-up measures after another five (T9) and 11 (T15) weeks. Week 15 scores are reported.
| score on a scale | Ketamine | Midazolam |
|---|---|---|
| The Quick Inventory of Depressive Symptoms, Self-report Version (QIDS-SR16) | 9.1 (5.6 to 12.6) | 11.4 (4.9 to 18.0) |
The CADSS measures dissociative symptoms. It will be administered before, during and after infusions in order to capture the range of possible subjective side effects of either agent. This consists of 23 questions and scores for each question range from 0-4. The maximum score is 92 with higher scores indicating more dissociative symptoms. Participants will have the CADSS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
| score on a scale | Ketamine | Midazolam |
|---|---|---|
| The Clinician-Administered Dissociative States Scale (CADSS) | 5.3 ± 7.2 | 2.5 ± 3.5 |
The BPRS measures psychotomimetic effects. The investigators will use the positive symptoms subscale of the Brief Psychiatric Rating Scale. The 4-item positive symptoms subscale measures suspiciousness, hallucinations, unusual thought content, and conceptual disorganisation. Each question is scored between 0-7. The maximum score in this 4-item questionnaire is 28. Higher scores indicate more severe psychotic symptoms. Participants will have the BPRS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
| score on a scale | Ketamine | Midazolam |
|---|---|---|
| The Brief Psychiatric Rating Scale (BPRS) | 4.1 ± 0.4 | 4.0 ± 0 |
Investigators will use the mood item of them YMRS to assess for psychotomimetic effects. This item is rated 0-4. The higher scores reflect elevated mood. Participants will have the YMRS performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
| score on a scale | Ketamine | Midazolam |
|---|---|---|
| Young Mania Rating Scale (YMRS; Mood Item) | 0.1 ± 0.4 | 0.1 ± 0.4 |
The PRISE will be used to document other general adverse events by patients before, during and after infusions. This is a patient self-report used to qualify side effects by identifying and evaluating the tolerability of each symptom. It is a 9 item assessment of the side effects in the following symptom domains; Gastrointestinal, Heart, Skin, Nervous System, Eyes/Ears, Genital/Urinary, Sleep, Sexual Functioning, and Other. Each domain has multiple symptoms which can be endorsed. For each domain the patient rates whether or not the symptoms are tolerable or distressing. Data below represent the number of participants from which there was an endorsement of each listed event. Participants will have the PRISE performed before, during (+30mins) and after (+60mins) each of the four once-weekly infusions.
| participants | Ketamine | Midazolam |
|---|---|---|
| dry mouth | 1 | 1 |
| diarrhoea | 0 | 0 |
| Constipation | 0 | 0 |
| Nausea / vomiting | 0 | 0 |
| Palpitation | 0 | 0 |
| Chest pain | 0 | 0 |
| Rash | 0 | 0 |
| Headache | 0 | 0 |
| Tremors | 0 | 0 |
| Poor coordination | 1 | 0 |
| Dizziness | 2 | 0 |
| Blurred vision | 0 | 0 |
| Difficulty urinating | 0 | 0 |
| Difficulty sleeping | 0 | 0 |
| Sleeping too much | 0 | 1 |
| Anxiety | 2 | 0 |
| Poor concentration | 0 | 1 |
| Restlessness | 2 | 0 |
| Fatigue | 3 | 1 |
The MOCA was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, conceptual thinking, calculations, and orientation. It is scored out of a maximum of 30. The higher scores indicate better cognition. The MOCA will be performed at baseline, one day after infusions 1 and 4 and 12 weeks after the final infusion.
| score on a scale | Ketamine | Midazolam |
|---|---|---|
| The Montreal Cognitive Assessment (MoCA) | 26.4 ± 3.1 | 28.5 ± 1.4 |
Collected over Adverse event information was collected over the entire study time frame, 10 months (September 2017 - June 2018). For each participant, data was collected over a period of 15 weeks which included 3 weeks of intervention and 12 weeks of follow up assessments.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Ketamine | 0/13 (0%) | 0/13 (0%) | 0/13 (0%) |
| Midazolam | 0/12 (0%) | 0/12 (0%) | 0/12 (0%) |
| Age, Continuous(years) | Ketamine | Midazolam | Total |
|---|---|---|---|
| Mean | 48.9 ± 13.1 | 52.3 ± 12.5 | 50.5 ± 12.6 |
| Sex: Female, Male(Participants) | Ketamine | Midazolam | Total |
|---|---|---|---|
| Female | 8 | 5 | 13 |
| Male | 5 | 7 | 12 |
| Race (NIH/OMB)(Participants) | Ketamine | Midazolam | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 13 | 12 | 25 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24)(units on a scale) | Ketamine | Midazolam | Total |
|---|---|---|---|
| Mean | 28.4 ± 4.3 | 27.4 ± 4.3 | 27.7 ± 3.9 |
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St Patrick's Hospital, Ireland