Intravenous Ketamine Effects on Functional Neuroanatomy

The purpose of this study is to investigate the neuroanatomical effects of ketamine treatment on patients with treatment-resistant depression. The investigators will compare the neuroimaging of patients several days before and after injection in order to assess the more durable changes induced by ketamine. In addition, changes in perfusion will be analyzed, in addition to changes in neurovascular coupling, and functional connectivity that are correlated with psychiatric measures.

Study Overview

• Status: Withdrawn
• Conditions: Depression
• Intervention / Treatment: Drug: Ketamine

Detailed Description

The present study is designed as a prospective data analysis of patient response to the use of ketamine to treat treatment-resistant depression. For Phase I trail, 10 patients of any gender with an age range of 18 to 70 who have undergone the outlined procedure will be recruited for inclusion. Patients will be examined by the principle investigator. All patients must be diagnosed with persistent treatment-resistant depression and prescribed ketamine. Patients will be accepted regardless of if the depression coincided with anxiety and/or pain. Patient status will be assessed using the Beck Depression Inventory, Beck Anxiety Inventory, and Brief Pain Inventory. Patients must have a Beck Depression Inventory score of 10 or above. These scores will be used as baseline data. Patients will be offered the option of participating in the study and provided informed consent for neuroimaging before and after the ketamine treatment.

A week before the scheduled ketamine treatment, the patients will have fMRI scans, including structural T1, Arterial Spin Labeling, and Resting BOLD. The scans take around 30 minutes at no charge to the patients. The ketamine will be injected per the doctor's orders to achieve a dissociative state; dosages varies between 75mg - 1000mg depending on every individual's unique treatment plan. The same scans will be taken two days after treatment.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Santa Monica, California, United States, 90403
      • Neurological Associates of West Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• In order for a subject to be considered for this study, the patient must have been diagnosed with treatment-resistant depression, meaning the patient failed three medications and has been suffering from moderate treatment-resistant depression for over 6 months, indicated by a Beck Depression Inventory score of 10 or above. The patient must have been prescribed ketamine as part of their treatment plan, completely independent of any research. The patient must be willing to comply with the study protocol.

Exclusion Criteria:

• In order for a subject to be considered for this study, he/she may not have any of the following:

  • Advanced stages of any terminal illness or any active cancer that requires chemotherapy
  • Hepatic impairment
  • Significant cytopenia
  • Cardiovascular, cerebrovascular, and peripheral vascular arterial thrombosis
  • Women who are pregnant, may become pregnant, or are breastfeeding
  • Any counter indications to ketamine
  • Subjects unable to give informed consent or in vulnerable categories, such as prisoners

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Ketamine; The present study is designed as a prospective data analysis of patient response to the use of ketamine to treat treatment-resistant depression. For Phase I trail, 10 patients of any gender with an age range of 18 to 70 who have undergone the outlined procedure will be recruited for inclusion. A week before the scheduled ketamine treatment, the patients will have fMRI scans, including structural T1, Arterial Spin Labeling, and Resting BOLD. The scans take around 30 minutes at no charge to the patients. The ketamine will be injected per the doctor's orders to achieve a dissociative state; dosage will vary (see below) depending on every individual's unique treatment plan. The same scans will be taken two days after treatment.

Drug: Ketamine; The ketamine will be injected per the doctor's orders to achieve a dissociative state; dosage varies between 75mg - 1000mg depending on every individual's unique treatment plan.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
fMRI T1 baseline	T1-data was collected as a sagittal MPRAGE sequence. T1 images are corrected for field biasing and then skull stripped and linearly registered to standard MNI space. Each patients' T1 image is segmented into 100 cortical and 15 subcortical areas using the Harvard-Oxford Cortical and Subcortical structural atlas. Mean volume is computed for each of these regions for each patient, which can be used for quantitative comparison.	Images to be acquired 7 days prior to Ketamine intervention
fMRI T1 post-intervention comparison	T1-data was collected as a sagittal MPRAGE sequence. T1 images are corrected for field biasing and then skull stripped and linearly registered to standard MNI space. Each patients' T1 image is segmented into 100 cortical and 15 subcortical areas using the Harvard-Oxford Cortical and Subcortical structural atlas. Mean volume is computed for each of these regions for each patient, which can be used for quantitative comparison.	Images to be acquired at 2 days post-treatment
Arterial Spin Labeling (fMRI) baseline	Pulsed Arterial Spin Labeling is collected as an echo planar sequence. ASL data is superimposed over the acquired T1-weighted brain image demonstrating a map of cerebral perfusion. Quantification to CBF values (milliliters of blood per 100g of tissue per minute) is implemented and voxel-based comparisons showing perfusion values relative to the acquired data range are used for quantification.	Images to be acquired 7 days prior to Ketamine intervention
Arterial Spin Labeling (fMRI) post-intervention comparison	Pulsed Arterial Spin Labeling is collected as an echo planar sequence. ASL data is superimposed over the acquired T1-weighted brain image demonstrating a map of cerebral perfusion. Quantification to CBF values (milliliters of blood per 100g of tissue per minute) is implemented and voxel-based comparisons showing perfusion values relative to the acquired data range are used for quantification.	Images to be acquired at 2 days post-treatment
fMRI Resting Bold baseline	The signal change measured in BOLD imaging comes from the brain oversupplying the region of activation with oxygen, leading to a focal decrease in deoxygenated hemoglobin. Processed BOLD imaging allows for visualization of hemodynamic response (HR) and neurovascular coupling (NVC) based on signal variability and distribution. These elements can be quantified and used for comparison.	Images to be acquired 7 days prior to Ketamine intervention
fMRI Resting Bold post-intervention comparison	The signal change measured in BOLD imaging comes from the brain oversupplying the region of activation with oxygen, leading to a focal decrease in deoxygenated hemoglobin. Processed BOLD imaging allows for visualization of hemodynamic response (HR) and neurovascular coupling (NVC) based on signal variability and distribution. These elements can be quantified and used for comparison.	Images to be acquired at 2 days post-treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beck Depression Inventory	The BDI-II is a 21-question multiple-choice self-report inventory. Each question involves four possible responses, ranging in intensity from "0" (this item does not apply) to "3" (this item applies severely). The test is scored as the sum of all of the response values; this number is used to determine the severity of depressive symptoms. A score of 0 to 3 is possible for each question with a maximum total score of 63 points. The standard cutoff scores are as follows: 0-13 total points = minimal depression; 14-19 total points = mild depression; 20-28 total points = moderate depression; and 29-63 total points = severe depression. A reduction in the total score by at least 30% is considered to be clinically significant.	7 days prior to treatment
Beck Depression Inventory	The BDI-II is a 21-question multiple-choice self-report inventory. Each question involves four possible responses, ranging in intensity from "0" (this item does not apply) to "3" (this item applies severely). The test is scored as the sum of all of the response values; this number is used to determine the severity of depressive symptoms. A score of 0 to 3 is possible for each question with a maximum total score of 63 points. The standard cutoff scores are as follows: 0-13 total points = minimal depression; 14-19 total points = mild depression; 20-28 total points = moderate depression; and 29-63 total points = severe depression. A reduction in the total score by at least 30% is considered to be clinically significant.	Day of treatment
Beck Depression Inventory	The BDI-II is a 21-question multiple-choice self-report inventory. Each question involves four possible responses, ranging in intensity from "0" (this item does not apply) to "3" (this item applies severely). The test is scored as the sum of all of the response values; this number is used to determine the severity of depressive symptoms. A score of 0 to 3 is possible for each question with a maximum total score of 63 points. The standard cutoff scores are as follows: 0-13 total points = minimal depression; 14-19 total points = mild depression; 20-28 total points = moderate depression; and 29-63 total points = severe depression. A reduction in the total score by at least 30% is considered to be clinically significant.	2 days after treatment
Beck Anxiety Inventory	The BAI is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety symptoms. Each of the 21 items asks whether the patient has experienced various anxiety symptoms in the last two weeks, and if so, how severely. Each question/answer is scored on a scale value of "0" (not at all) to "3" (severely). Higher total scores indicate more severe anxiety symptoms. The maximum total score possible is 63 points. The standard cutoff scores are: 0-7 = minimal anxiety; 8-15 = mild anxiety; 16-25 = moderate anxiety; 26-63 = severe anxiety. A reduction in score by at least 30% is considered clinically meaningful.	7 days prior to treatment
Beck Anxiety Inventory	The BAI is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety symptoms. Each of the 21 items asks whether the patient has experienced various anxiety symptoms in the last two weeks, and if so, how severely. Each question/answer is scored on a scale value of "0" (not at all) to "3" (severely). Higher total scores indicate more severe anxiety symptoms. The maximum total score possible is 63 points. The standard cutoff scores are: 0-7 = minimal anxiety; 8-15 = mild anxiety; 16-25 = moderate anxiety; 26-63 = severe anxiety. A reduction in score by at least 30% is considered clinically meaningful.	Day of treatment
Beck Anxiety Inventory	The BAI is a 21-question multiple-choice self-report inventory that is used for measuring the severity of anxiety symptoms. Each of the 21 items asks whether the patient has experienced various anxiety symptoms in the last two weeks, and if so, how severely. Each question/answer is scored on a scale value of "0" (not at all) to "3" (severely). Higher total scores indicate more severe anxiety symptoms. The maximum total score possible is 63 points. The standard cutoff scores are: 0-7 = minimal anxiety; 8-15 = mild anxiety; 16-25 = moderate anxiety; 26-63 = severe anxiety. A reduction in score by at least 30% is considered clinically meaningful.	2 days after treatment
Brief Pain Inventory	Self-report measure containing a composite pain score and functional interference score. The pain subscale contains 4 questions, each with answers ranging from 0 'no pain' to 10 'pain as bad as you can imagine.' Total possible score for the pain subscale is 40 points. The functional/interference subscale contains 7 questions, with each answer ranging from 0 'does not interfere' to 10 'completely interferes.' The maximum possible score for the interference subscale is 70 points. The total overall composite BPI score is out of 100 maximum points. A clinical improvement is considered a decrease in BPI overall composite score by at least 30% from baseline.	7 days prior to treatment
Brief Pain Inventory	Self-report measure containing a composite pain score and functional interference score. The pain subscale contains 4 questions, each with answers ranging from 0 'no pain' to 10 'pain as bad as you can imagine.' Total possible score for the pain subscale is 40 points. The functional/interference subscale contains 7 questions, with each answer ranging from 0 'does not interfere' to 10 'completely interferes.' The maximum possible score for the interference subscale is 70 points. The total overall composite BPI score is out of 100 maximum points. A clinical improvement is considered a decrease in BPI overall composite score by at least 30% from baseline.	Day of Treatment
Brief Pain Inventory	Self-report measure containing a composite pain score and functional interference score. The pain subscale contains 4 questions, each with answers ranging from 0 'no pain' to 10 'pain as bad as you can imagine.' Total possible score for the pain subscale is 40 points. The functional/interference subscale contains 7 questions, with each answer ranging from 0 'does not interfere' to 10 'completely interferes.' The maximum possible score for the interference subscale is 70 points. The total overall composite BPI score is out of 100 maximum points. A clinical improvement is considered a decrease in BPI overall composite score by at least 30% from baseline.	2 days post-treatment

Collaborators and Investigators

• Sponsor: Neurological Associates of West Los Angeles
• Investigators: Principal Investigator: Taylor Kuhn, PhD, The Neurological Associates of West Los Angeles

Publications and helpful links

General Publications

• Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000 Feb 15;47(4):351-4. doi: 10.1016/s0006-3223(99)00230-9.
• Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008 Feb 15;63(4):349-52. doi: 10.1016/j.biopsych.2007.05.028. Epub 2007 Jul 23.
• Deakin JF, Lees J, McKie S, Hallak JE, Williams SR, Dursun SM. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry. 2008 Feb;65(2):154-64. doi: 10.1001/archgenpsychiatry.2007.37.
• Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003 Apr 15;53(8):649-59. doi: 10.1016/s0006-3223(03)00231-2.
• Lepine JP, Briley M. The increasing burden of depression. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):3-7. doi: 10.2147/NDT.S19617. Epub 2011 May 31.
• Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron. 2005 Mar 3;45(5):651-60. doi: 10.1016/j.neuron.2005.02.014.
• U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health. (2019). Major Depression. Retrieved from https://www.nimh.nih.gov/health/statistics/major-depression.shtml
• U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health. (2018). Depression. Retrieved from https://www.nimh.nih.gov/health/topics/depression/index.shtml

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 2, 2020
• Primary Completion (ACTUAL): May 28, 2020
• Study Completion (ACTUAL): May 28, 2020

Study Registration Dates

• First Submitted: December 16, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (ACTUAL): December 20, 2019

Study Record Updates

• Last Update Posted (ACTUAL): June 1, 2020
• Last Update Submitted That Met QC Criteria: May 28, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: treatment-resistant depression; intravenous ketamine
• Additional Relevant MeSH Terms: Behavioral Symptoms; Depression; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: 20190792

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data from this study will not be made publicly available due to ethical and privacy concerns. Anonymized data will be available upon reasonable request from any qualified investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes