ketamine: Low Dose Intravenous Ketamine in Treatment Resistant Depression Patients

• Sponsor: The University of Texas Health Science Center, Houston (Other)
• Overall Status: Completed
• CT.gov ID: NCT02935595
• Collaborator: (none)
• Enrollment: 9
• Location: 1
• Arm: 1
• Actual Duration (Months): 10.1
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The primary goal of the project is to study the effect of Ketamine on cortical neurophysiological function in TRD patients. The proposal employs robust and non-invasive neurophysiological techniques TMS and EEG to investigate the cortical excitability and oscillatory activity in patients with treatment resistant depression.

Condition or Disease	Intervention/Treatment	Phase
Treatment Resistant Depression	Drug: Ketamine	Phase 2

Detailed Description

The primary goal of the project is to study the effect of Ketamine on cortical neurophysiological function in Treatment Resistant Depression(TRD) patients. There are three key preclinical findings regarding Ketamine antidepressant effects that motivate the current study: a) low dose Ketamine causes early increase in glutamate neurotransmission; b) Ketamine initiates synaptic plasticity; c) ketamine infusion leads to rapid improvement in depression symptoms. The proposal essentially employs robust and non-invasive neurophysiological techniques, Auditory Steady State Response(ASSR)-gamma oscillatory response and Transcranial Magnetic Stimulation(TMS) cortical excitability to investigate the above findings in patients with treatment resistant depression.

Study:

Ketamine Infusion:

We will employ an open-label study in which the infusion session, the enrolled TRD patients will receive low dose Ketamine (0.5 mg/kg) over 40 minutes.

Cortical Excitability:

TMS stimulation will be applied to the corresponding region of the contralateral primary motor cortex to determine motor threshold and to examine the motor cortical excitability measures after Ketamine. The optimal coil position will be determined by moving the TMS coil in 1-cm increments over the motor cortical area while delivering single or paired magnetic pulses and by observing maximal contraction of the contralateral abductor pollicis brevis (APB). Electromyography readings will be obtained from the APB muscle. TMS stimulation will then be applied to Left DLPFC or Left Brodmann Area 6 to investigate cortical excitability changes after ketamine. Electroencephalography(EEG) recordings will be concurrent with TMS procedure.

ASSR/EEG paradigm:

Participants may engage in the auditory steady state response task where click trains of 500-ms duration will be presented binaurally at 65 ± 5 decibel(dB). The click train repetition frequencies will be 40 Hz and presented in the context of an auditory oddball paradigm to ensure participant attention to the stimuli. This task will be done while participants undergo EEG recordings.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open-labelOpen-label
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Systematic Investigation of Neurophysiological Correlates of Low Dose Intravenous Ketamine in Treatment Resistant Depression Patients
• Actual Study Start Date: Oct 14, 2016
• Actual Primary Completion Date: Aug 16, 2017
• Actual Study Completion Date: Aug 16, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine Slow infusions of ketamine will take place over a time period of 40 minutes.	Drug: Ketamine; Ketamine Hydrochloride Injection; Other Names: Ketamine Hydrochloride

Outcome Measures

Primary Outcome Measures

1. Cortical Excitability in the Dorsolateral Prefrontal Cortex (DLPFC) as Assessed by Transcranial Magnetic Stimulation-evoked Activity Detected by Electroencephalography (TMS-EEG) [Baseline]

   Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) was performed, and electroencephalography (EEG) recording was performed during TMS stimulation. Data is reported as the local mean field amplitude-area under the curve (LMFA-AUC) from a subset of EEG electrodes around the TMS stimulation site.

2. Cortical Excitability in DLPFC Using TMS-EEG [4 hours]

   Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) was performed, and electroencephalography (EEG) recording was performed during TMS stimulation. Data is reported as the local mean field amplitude-area under the curve (LMFA-AUC) from a subset of EEG electrodes around the TMS stimulation site.

3. Cortical Excitability in DLPFC Using TMS-EEG [24 hours]

   Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) was performed, and electroencephalography (EEG) recording was performed during TMS stimulation. Data is reported as the local mean field amplitude-area under the curve (LMFA-AUC) from a subset of EEG electrodes around the TMS stimulation site.

4. Cortical Excitability in DLPFC Using TMS-EEG [7 days]

Secondary Outcome Measures

1. Severity of Depressive Symptoms as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) [Baseline]

   Total MADRS score ranges from 0 to 60, and a higher score indicates more severe depression, as follows: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression

2. Severity of Depressive Symptoms as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) [4 hours]

   Total MADRS score ranges from 0 to 60, and a higher score indicates more severe depression, as follows: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression

3. Severity of Depressive Symptoms as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) [24 hours]

   Total MADRS score ranges from 0 to 60, and a higher score indicates more severe depression, as follows: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression

4. Safety as Indicated by Number of Adverse Events [24 hours]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Be between 18-60 years of age

• Meet criteria for Treatment Resistant Depression (defined as two or more unsuccessful trials of antidepressants at an adequate dose for at least 4 weeks)

Exclusion Criteria:

• Diagnosed with intellectual disability, eg. Mental retardation, neurodegenerative diseases, eg. Early onset neurocognitive disturbances such as frontotemporal dementia or behavioral disorders, eg. adult onset Attention Deficit Hyperactivity Disorder,

• Diagnosed with Bipolar Disorder (BD),

• Diagnosed with personality disorders,

• Previously or currently diagnosed with psychosis (schizoaffective disorder -SAD) or schizophrenia - SCZ),

• Current major medical problems that affect brain anatomy, neurochemistry, or function, e.g., obstructive sleep apnea requiring Continuous Positive Airway Pressure (CPAP), liver insufficiency, kidney insufficiency, cardiovascular problems, systemic infections, cancer, auto-immune diseases, and any brain disorder (seizure disorder, stroke, dementia, degenerative neurologic diseases); history of any brain diseases, including seizures, stroke, meningitis, encephalitis, dementia, degenerative brain diseases, and head injury with loss of consciousness for any period of time,

• Diagnosed specifically with a cardiovascular disorders such as Hypertension, Arrhythmias, Chronic Heart Failure, Myocardial Infarction (MI) or suffering from Chronic Obstructive Pulmonary Disease (COPD) or asthma. Cardiac clearance prior to enrolling in the study and medical records from physician will be required per patient's Primary Care Physician.

• Patients with increased risk of laryngospasm, active upper respiratory infections, respiratory depression, increased intracranial pressure, thyroid disease, or porphyria,

• Current substance abuse or dependence. Only patients who achieved stable, full remission for at least 6 months will be included

• Pregnancy or Breast feeding. All female in reproductive age will undergo pregnancy tests. Female participants will be required to provide evidence of use of contraceptives during the course of the study,

• Unable to understand the design and requirements of the study.

• Unable to sign the informed consent for any reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Harris County Psychiatric Center	Houston	Texas	United States	77021

Sponsors and Collaborators

• The University of Texas Health Science Center, Houston

Investigators

• Principal Investigator: Sudhakar Selvaraj, MBBS, DPhil, University of Texas

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 2, 2017

More Information

Publications

None provided.

• Responsible Party: Sudhakar Selvaraj, MBBS., DPhil (Oxon)., MRCPsych, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT02935595
• Other Study ID Numbers: HSC-MS-16-0705
• First Posted: Oct 17, 2016
• Last Update Posted: Jan 13, 2022
• Last Verified: Jan 1, 2022

• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Ketamine

Study Results

Participant Flow

Pre-assignment Detail	3 subjects signed consent and were screened, but met exclusion criteria and were thus excluded from the study before starting. 1 subject withdrew consent after screening and did not start the study.

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Period Title: Overall Study
STARTED	5
COMPLETED	4
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Overall Participants	5
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.20 (10.38)
Sex: Female, Male (Count of Participants)
Female	3 60%
Male	2 40%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	4 80%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	Cortical Excitability in the Dorsolateral Prefrontal Cortex (DLPFC) as Assessed by Transcranial Magnetic Stimulation-evoked Activity Detected by Electroencephalography (TMS-EEG)
Description	Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) was performed, and electroencephalography (EEG) recording was performed during TMS stimulation. Data is reported as the local mean field amplitude-area under the curve (LMFA-AUC) from a subset of EEG electrodes around the TMS stimulation site.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Data was not collected for one participant.

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Measure Participants	4
Mean (Standard Deviation) [microvolt * milliseconds (µV * ms)]	446.08 (209.13)

2. Primary Outcome

Title	Cortical Excitability in DLPFC Using TMS-EEG
Description	Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) was performed, and electroencephalography (EEG) recording was performed during TMS stimulation. Data is reported as the local mean field amplitude-area under the curve (LMFA-AUC) from a subset of EEG electrodes around the TMS stimulation site.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

Data was not collected for 1 participant.

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Measure Participants	4
Mean (Standard Deviation) [microvolt * milliseconds (µV * ms)]	319.71 (206.04)

3. Primary Outcome

Title	Cortical Excitability in DLPFC Using TMS-EEG
Description	Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (DLPFC) was performed, and electroencephalography (EEG) recording was performed during TMS stimulation. Data is reported as the local mean field amplitude-area under the curve (LMFA-AUC) from a subset of EEG electrodes around the TMS stimulation site.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Data was not collected for 1 participant.

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Measure Participants	4
Mean (Standard Deviation) [microvolt * milliseconds (µV * ms)]	330.30 (222.45)

4. Primary Outcome

Title	Cortical Excitability in DLPFC Using TMS-EEG
Time Frame	7 days

Outcome Measure Data

Analysis Population Description

Data was not collected from any participant at 7 days.

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Measure Participants	0

5. Secondary Outcome

Title	Severity of Depressive Symptoms as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS)
Description	Total MADRS score ranges from 0 to 60, and a higher score indicates more severe depression, as follows: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Data was not collected for one participant.

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Measure Participants	4
Mean (Standard Deviation) [units on a scale]	24.50 (7.09)

6. Secondary Outcome

Title	Severity of Depressive Symptoms as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS)
Description	Total MADRS score ranges from 0 to 60, and a higher score indicates more severe depression, as follows: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

Data was not collected for one participant.

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Measure Participants	4
Mean (Standard Deviation) [units on a scale]	22.5 (9.73)

7. Secondary Outcome

Title	Severity of Depressive Symptoms as Assessed by the Montgomery-Asberg Depression Rating Scale (MADRS)
Description	Total MADRS score ranges from 0 to 60, and a higher score indicates more severe depression, as follows: 0 to 6 - normal/symptom absent 7 to 19 - mild depression 20 to 34 - moderate depression >34 - severe depression
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Data was not collected for one participant.

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Measure Participants	4
Mean (Standard Deviation) [units on a scale]	16.25 (7.66)

8. Secondary Outcome

Title	Safety as Indicated by Number of Adverse Events
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
Measure Participants	5
Number [adverse events]	1

Adverse Events

Time Frame	24 hours
Arm/Group Title	Ketamine
Arm/Group Description	Slow infusions of ketamine will take place over a time period of 40 minutes. Ketamine: Ketamine Hydrochloride Injection
All Cause Mortality
	Ketamine
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Serious Adverse Events
	Ketamine
	Affected / at Risk (%)	# Events
Total	0/5 (0%)
Other (Not Including Serious) Adverse Events
	Ketamine
	Affected / at Risk (%)	# Events
Total	1/5 (20%)
Psychiatric disorders
Depersonalization	1/5 (20%)	1

Limitations/Caveats

[Not Specified]

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.