Low Dose Intravenous Ketamine in Treatment Resistant Depression Patients (ketamine)

• ClinicalTrials.gov Identifier: NCT02935595
• Recruitment Status: Completed
• First Posted: October 17, 2016
• Results First Posted: August 31, 2020
• Last Update Posted: January 13, 2022
• Sponsor: The University of Texas Health Science Center, Houston
• Information provided by (Responsible Party): Sudhakar Selvaraj, The University of Texas Health Science Center, Houston

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 (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open-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: October 14, 2016
• Actual Primary Completion Date: August 16, 2017
• Actual Study Completion Date: August 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 Name: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 7 days ]

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

United States, Texas

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)

Documents provided by Sudhakar Selvaraj, The University of Texas Health Science Center, Houston:

Study Protocol and Statistical Analysis Plan  [PDF] August 2, 2017

More Information

• 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: October 17, 2016
• Results First Posted: August 31, 2020
• Last Update Posted: January 13, 2022
• Last Verified: January 2022

Additional relevant MeSH terms:

Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Behavioral Symptoms; Mood Disorders; Mental Disorders; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action