KARMA-dep: Ketamine as an Adjunctive Therapy for Major Depression

• Sponsor: St Patrick's Hospital, Ireland (Other)
• Overall Status: Completed
• CT.gov ID: NCT03256162
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 2
• Actual Duration (Months): 12.5
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Episode; Unipolar Depression; Bipolar Depression	Drug: Ketamine; Drug: Midazolam	Phase 1

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Ketamine as an Adjunctive Therapy for Major Depression - a Randomised Controlled Pilot Trial: The KARMA-Dep Trial
• Actual Study Start Date: Sep 7, 2017
• Actual Primary Completion Date: Sep 21, 2018
• Actual Study Completion Date: Sep 21, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist.	Drug: Ketamine; A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.; Other Names: Ketalar
Active Comparator: Midazolam 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 midazolam will be administered in four infusions, each one week apart.; Other Names: Hypnovel

Outcome Measures

Primary Outcome Measures

1. The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24) [15 weeks]

   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.

Secondary Outcome Measures

1. The Quick Inventory of Depressive Symptoms, Self-report Version (QIDS-SR16) [15 weeks]

   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.

2. The Clinician-Administered Dissociative States Scale (CADSS) [4 weeks]

   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.

3. The Brief Psychiatric Rating Scale (BPRS) [4 weeks]

   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.

4. Young Mania Rating Scale (YMRS; Mood Item) [4 weeks]

   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.

5. The Patient-Rated Inventory of Side Effects (PRISE) [4 weeks]

   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.

6. The Montreal Cognitive Assessment (MoCA) [15 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• ≥18 years old

• Hamilton Rating Scale for Depression-24 item version (HRSD-24) score of ≥21

• Voluntary admission for treatment of an acute depressive episode

• Meet Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-V) criteria for a major depressive disorder (MDD) and bipolar affective disorder (current episode depression)

Exclusion Criteria:

• Current involuntary admission

• Medical condition rendering unfit for ketamine/midazolam

• Active suicidal intention

• Dementia

• History of Axis 1 diagnosis other than major depression

• Electroconvulsive Therapy (ECT) administered within the last two months

• Alcohol/substance dependence in previous six-months

• Pregnancy or inability to confirm use of adequate contraception during the trial

• Breastfeeding women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St Patrick's University Hospital	Dublin		Ireland	D8

Sponsors and Collaborators

• St Patrick's Hospital, Ireland

Investigators

• Principal Investigator: Declan M McLoughlin, PhD, St Patrick's Mental Health Services and Trinity College Dublin

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 13, 2017

More Information

Additional Information:

• Research Team Website

Publications

None provided.

• Responsible Party: Prof Declan McLoughlin, Professor, St Patrick's Hospital, Ireland
• ClinicalTrials.gov Identifier: NCT03256162
• Other Study ID Numbers: 01/17; 2016-004764-18
• First Posted: Aug 21, 2017
• Last Update Posted: Jan 18, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Prof Declan McLoughlin, Professor, St Patrick's Hospital, Ireland: ketamine; glutamate
• Additional relevant MeSH terms: Depression; Depressive Disorder; Bipolar Disorder; Midazolam; Ketamine

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	Treatment-as-usual, by the participants' treating teams, continued throughout the entire trial.

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Period Title: Overall Study
STARTED	13	12
COMPLETED	8	8
NOT COMPLETED	5	4

Baseline Characteristics

Arm/Group Title	Ketamine	Midazolam	Total
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.	Total of all reporting groups
Overall Participants	13	12	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.9 (13.1)	52.3 (12.5)	50.5 (12.6)
Sex: Female, Male (Count of Participants)
Female	8 61.5%	5 41.7%	13 52%
Male	5 38.5%	7 58.3%	12 48%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	13 100%	12 100%	25 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	28.4 (4.3)	27.4 (4.3)	27.7 (3.9)

Outcome Measures

1. Primary Outcome

Title	The Hamilton Rating Scale for Depression-24 Item Version (HRSD-24)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Measure Participants	8	8
Mean (95% Confidence Interval) [score on a scale]	11.2	16.6

2. Secondary Outcome

Title	The Quick Inventory of Depressive Symptoms, Self-report Version (QIDS-SR16)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Measure Participants	8	8
Mean (95% Confidence Interval) [score on a scale]	9.1	11.4

3. Secondary Outcome

Title	The Clinician-Administered Dissociative States Scale (CADSS)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Measure Participants	8	8
Mean (Standard Deviation) [score on a scale]	5.3 (7.2)	2.5 (3.5)

4. Secondary Outcome

Title	The Brief Psychiatric Rating Scale (BPRS)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Measure Participants	8	8
Mean (Standard Deviation) [score on a scale]	4.1 (0.4)	4.0 (0)

5. Secondary Outcome

Title	Young Mania Rating Scale (YMRS; Mood Item)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Measure Participants	8	8
Mean (Standard Deviation) [score on a scale]	0.1 (0.4)	0.1 (0.4)

6. Secondary Outcome

Title	The Patient-Rated Inventory of Side Effects (PRISE)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Measure Participants	8	8
dry mouth	1 7.7%	1 8.3%
diarrhoea	0 0%	0 0%
Constipation	0 0%	0 0%
Nausea / vomiting	0 0%	0 0%
Palpitation	0 0%	0 0%
Chest pain	0 0%	0 0%
Rash	0 0%	0 0%
Headache	0 0%	0 0%
Tremors	0 0%	0 0%
Poor coordination	1 7.7%	0 0%
Dizziness	2 15.4%	0 0%
Blurred vision	0 0%	0 0%
Difficulty urinating	0 0%	0 0%
Difficulty sleeping	0 0%	0 0%
Sleeping too much	0 0%	1 8.3%
Anxiety	2 15.4%	0 0%
Poor concentration	0 0%	1 8.3%
Restlessness	2 15.4%	0 0%
Fatigue	3 23.1%	1 8.3%

7. Secondary Outcome

Title	The Montreal Cognitive Assessment (MoCA)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine	Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.	Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
Measure Participants	8	8
Mean (Standard Deviation) [score on a scale]	26.4 (3.1)	28.5 (1.4)

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	Tolerability of the trial agents was assessed at multiple points before, during and after treatment sessions using various assessments including the CADSS, BPRS, PRISE and YMRS. These have been used in other clinical trials which have used ketamine as a treatment for depressive disorders. We also carried out physical health assessments during the infusion clinics (e.g. vital signs).
Arm/Group Title	Ketamine		Midazolam
Arm/Group Description	Participants will receive four once-weekly infusions of ketamine at 0.05mg/kg. All infusions will be administered by a consultant anaesthetist. Ketamine: A sub-anaesthetic dose of ketamine will be administered in four infusions, each one week apart.		Participants will receive four once-weekly infusions of midazolam at 0.045mg/kg. All infusions will be administered by a consultant anaesthetist. Midazolam: A sub-anaesthetic dose of midazolam will be administered in four infusions, each one week apart.
All Cause Mortality
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/12 (0%)
Serious Adverse Events
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine		Midazolam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/12 (0%)

Limitations/Caveats

As this is a pilot trial, participant numbers are low.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.