- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT05870501
Synaptic Imaging and Network Activity in Treatment Resistant Depression (SIGNATURE)
Synaptic Imaging and Brain Network Activity Following Ketamine in Treatment Resistant Depression
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
A double-blind active-placebo crossover design will be used to study a single group of people with TRD to assess the effects of ketamine on brain networks activity versus an active placebo (midazolam). Participants will receive three separate IV infusions of ketamine (0.5mg/kg) followed by three separate IV infusions of an active placebo (midazolam (0.045mg/kg)), or 3 IV infusions of midazolam followed by 3 IV infusions of ketamine. Treatment order will be randomized in a crossover design.
The study will consist of 11 visits including a screening visit, baseline assessments, and two main infusion periods each involving 3 separate IV infusions and a post infusion assessment visit 24 hrs after the third infusion. Ketamine or midazolam will be administered at each of the infusion periods in a crossover design.
Assessment visits will include MRI, EEG and cognitive and clinical assessments.
Up to 50 subjects will be enrolled to ensure that evaluable data is obtained from 45 subjects. The primary comparison will be within-subject between active treatment and placebo.
Study Type
Enrollment (Anticipated)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Peter Hawkins, PhD
- Phone Number: 02032283058
- Email: Ketamine-Signature@kcl.ac.uk
Study Locations
-
-
-
London, United Kingdom, SE5 8AF
- Recruiting
- The Institute of Psychiatry, Psychology & Neuroscience, King's College London
-
Contact:
- Peter Hawkins, PhD
- Phone Number: 02032283058
- Email: Ketamine-Signature@kcl.ac.uk
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Be male or female, aged between 18 and 55 years of age inclusive.
- Have a diagnosis of MDD, Bipolar 1 or Bipolar 2 depression and fulfil criteria for TRD depression. TRD patients are defined as having inadequately responded to at least two courses of antidepressants, given in a therapeutic dose and duration (Fekadu et al., 2018).
- Have moderate to severe depression symptoms as demonstrated by a MADRS score greater than 20.
- Be physically healthy, defined as having no clinically relevant abnormalities identified by a detailed medical history and full examination including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests
- Have a good command of the English language.
- Have no or very little knowledge of the Chinese language.
- Provide a personally signed and dated informed consent document indicating that the participant has been informed of and agrees to comply with all aspects of the study.
- Be willing and able to comply with scheduled visits, dosing plan, laboratory trials and any other necessary procedures.
Exclusion Criteria:
- Have a current diagnosed psychiatric disorder, except MDD, Bipolar 1 and Bipolar 2 disorders and comorbid generalised anxiety disorder (GAD), social anxiety and/or social phobia.
- Have a current or previously diagnosed psychotic disorder: Schizophrenia, Schizoaffective Disorder, Delusional disorder, Schizophreniform disorder, Schizotypal (personality) disorder, or Brief psychotic disorder.
- Have previously failed Ketamine as an antidepressant treatment given at a therapeutic dose.
- Have previously experienced an adverse response to ketamine and/or midazolam.
- Have scored 70 or lower in the WASI at the screening visit.
- Have one or more immediate family members with a current or previously diagnosed psychotic disorder.
- Have a medically significant condition which renders them unsuitable for the study (e.g., diabetes, severe cardiovascular disease, severe respiratory disease (e.g. COPD), hepatic or renal failure etc.).
- Be pregnant or breastfeeding, if female.
- Have any MR contra-indications (e.g., metal implants, pacemakers, claustrophobia etc.) which would render them unsuitable for the study.
- Currently consume alcohol in excess of 28 units a week or more than 6 cups of caffeinated drinks per day.
- Smoke more than 5 cigarette per day
- Have taken illicit drugs 7 days prior to admission or current use of drugs of abuse including amphetamines, MDMA, cannabis and opioids Have taken any other medication during the course of the study that has not been discussed. This should be documented by the investigators. (As an exception, 1g paracetamol/24 hours may be taken up to 24 hours prior to any visit).
- Have consumed alcohol or caffeine within 12h and/or nicotine 4h hours prior to the screening visit, study day 1, 2 and 3 and each infusion visit until discharged at the end of each of those visits.
- Have consumed grapefruit juice or Seville oranges-containing products 24 hours prior to admission.
- Have used any prescribed medication in the 3 weeks prior to enrolment or non-prescription medication (other than paracetamol) in the previous 7 days, excluding medication prescribed for bipolar I and II and MDD.
- Have a significant history of drugs of abuse (including benzodiazepines) or positive drugs of abuse test.
- Have received another new chemical entity in the 1 month before dosing or taken part in another research study using drugs within 1 month before dosing.
- Have an acute illness within 2 weeks before the start of study.
- Have any clinically significant abnormalities in clinical chemistry (including liver function tests), haematology or urinalysis results.
- Have self-reported HIV, hepatitis B or hepatitis C
- Have a definite or suspected personal or family history of intolerance or hypersensitivity to drugs and/or their excipients, judged to be clinically relevant by the investigator.
- Have a history or presence of gastrointestinal, hepatic or renal disease or other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
- Have uncontrolled hypertension, or supine systolic BP outside of the range of 90 to 140 mmHg and a supine diastolic BP outside the range of 40 to 90 mmHg, after a period of acclimatisation.
- Have a decrease in systolic BP of > 25 mmHg or a decrease in diastolic BP of > 15 mmHg when going from resting in bed to standing position, with or without symptoms such as dizziness or light- headedness. (For determination of orthostatic hypotension, lying and standing BP will be recorded after the subject has rested for 10 minutes and has had resting BP recorded followed by measurements 5 minutes after standing)
- Have had treatment in the previous 3 months with any drug known to have a well-defined potential for hepatotoxicity (e.g., halothane).
- Have a risk of suicide according to the investigator's clinical judgment (eg, per C-SSRS positive answer on question 5 within 6 months or has made a suicide attempt within 6 months prior to screening visit).
- Have started a course of hormone replacement therapy within 8 weeks prior to the screening visit.
- Be a subject who, in the opinion of the investigator, should not participate in the study for reasons of safety.
- Have a score of more than 20 on the YMRS at study day 1 and at each subsequent assessment
- Be a subject who, in the opinion of the investigator, has a significant history of mixed episodes.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Ketamine followed by midazolam
Ketamine 0.5mg/kg (three IV infusions) followed by midazolam 0.045mg/kg (three IV infusions)
|
0.5mg/kg IV infusion
0.045mg/kg IV infusion
|
Experimental: Midazolam followed by ketamine
Midazolam 0.045mg/kg (three IV infusions) follower by ketamine 0.5mg/kg (three IV infusions)
|
0.5mg/kg IV infusion
0.045mg/kg IV infusion
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To investigate the effects of ketamine on brain resting state functional magnetic resonance imaging (fMRI) connectivity in patients with depression compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
Change in resting state connectivity measured with fMRI
|
Baseline and 24 hours post third IV infusion
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To investigate the effects of ketamine on fMRI task-based activity during an emotional processing task compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
Changes in task related fMRI activity using an emotional processing task (Region of Interest (ROIs): Anterior cingulate cortex (ACC), medial frontal cortex; whole brain analysis)
|
Baseline and 24 hours post third IV infusion
|
To investigate the effects of ketamine on fMRI task-based activity during a reward-processing task compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
Changes in task related fMRI activity using a reward processing task.
(Regions of interest (ROIs): striatal, thalamic and prefrontal regions; whole brain analysis)
|
Baseline and 24 hours post third IV infusion
|
To investigate the effects of ketamine on prolactin levels
Time Frame: Baseline and 40 minutes post third IV infusion
|
Blood samples analysed for prolactin levels at baseline, pre third infusion and post third infusion of ketamine and placebo
|
Baseline and 40 minutes post third IV infusion
|
To investigate the effects of ketamine on anhedonic symptoms (as measured by SHAPS) compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
The Snaith-Hamilton Pleasure Scale (SHAPS) is a self report scale of hedonic experience and is assessed at baseline and 24 hrs post infusion of ketamine and placebo.
The scale ranges from 14-56, with a higher score indicating higher levels of anhedonia
|
Baseline and 24 hours post third IV infusion
|
To investigate the effects of ketamine on depression symptoms (as measured by MADRS) compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
The Montgomery-Asberg Depression Rating Scale is a interview based scale of depression symptoms and is assessed at baseline of each session and 24 hrs post infusion of ketamine and placebo.
The scale ranges from 0-60, with a higher score indicating an higher severity of depression symptoms.
|
Baseline and 24 hours post third IV infusion
|
To investigate the effects of ketamine on depression symptoms (as measured by QIDS) compared to placebo
Time Frame: Baseline, pre infusion and 24 hours post third IV infusion
|
The Quick Inventory of Depressive Symptomatology-Self Report (QIDS) is a self report scale of depression symptoms and is assessed at baseline, pre infusion and 24 hrs post third infusion of ketamine and placebo The scale ranges from 0-42, with a higher score indicating an higher severity of depression symptoms.
|
Baseline, pre infusion and 24 hours post third IV infusion
|
To investigate the effects of ketamine on the M3VAS compared to placebo
Time Frame: Baseline, pre infusion and 24 hours post third IV infusion
|
The Maudsley 3-item Visual Analogue Scale (M3VAS) is a self report visual analogue scale (VAS) of three main domains of depression symptoms (mood, pleasure and suicidality) and is assessed at baseline, pre infusion and 24 hrs post third infusion of ketamine and placebo.
The VAS ranges from 0-100 on each domain, with a higher score indicating an higher severity of that domain.
|
Baseline, pre infusion and 24 hours post third IV infusion
|
To investigate the effects of ketamine on brain perfusion (ASL) compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
Arterial spin labelling (ASL) is a measure of blood flow or perfusion in the brain.
Measures are taken at baseline and 24 hours post third infusion of ketamine and placebo
|
Baseline and 24 hours post third IV infusion
|
To investigate the blood plasma concentration (μg/mL) of ketamine following the third IV infusion
Time Frame: 40 minutes, 120 minutes, 200 minutes and 24 hours post third IV infusion
|
Blood samples will be taken to measure the blood concentration of ketamine at specific time points post infusion
|
40 minutes, 120 minutes, 200 minutes and 24 hours post third IV infusion
|
To investigate the blood plasma concentration (μg/mL) of hydroxynorketamine following the third IV infusion
Time Frame: 40 minutes, 120 minutes, 200 minutes and 24 hours post third IV infusion
|
Blood samples will be taken to measure the blood concentration of hydroxynorketamine (a metabolite of ketamine) at specific time points post infusion
|
40 minutes, 120 minutes, 200 minutes and 24 hours post third IV infusion
|
To investigate the blood plasma concentration (μg/mL) of norketamine following the third IV infusion
Time Frame: 40 minutes, 120 minutes, 200 minutes and 24 hours post third IV infusion
|
Blood samples will be taken to measure the blood concentration of norketamine (a metabolite of ketamine) at specific time points post infusion
|
40 minutes, 120 minutes, 200 minutes and 24 hours post third IV infusion
|
To investigate the effects of ketamine on a short battery of cognitive tasks compared to placebo
Time Frame: Baseline 24 hours post third IV infusion
|
The Cognition is a self administered web-based battery of cognitive tasks that will be conducted at baseline, and 24 hours post third infusion of ketamine and placebo
|
Baseline 24 hours post third IV infusion
|
To investigate the effects of ketamine on blood biomarkers related to synaptogenesis compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
Blood samples taken at baseline and 24 hours post third infusion of ketamine and placebo will be analysed for markers of synaptic plasticity (Brain derived neurotrophic factor (BDNF))
|
Baseline and 24 hours post third IV infusion
|
To investigate the effects of ketamine on the power of frequency bands (alpha, theta, gamma) in resting EEG
Time Frame: Baseline and 24 hours post third IV infusion
|
Electroencephalogram (EEG) is an brain imaging technique that allows the recording of brain electrical activity and will be conducted at baseline, and 24 hours post third infusion of ketamine and placebo
|
Baseline and 24 hours post third IV infusion
|
To investigate the effects of ketamine on structural connectivity (DTI) compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
Diffusion tensor imaging (DTI) is a measure of brain tissue microstructure.
Measures are taken at baseline and 24 hours post third infusion of ketamine and placebo
|
Baseline and 24 hours post third IV infusion
|
To investigate the effects of ketamine on visual and auditory based ERPs compared to placebo
Time Frame: Baseline and 24 hours post third IV infusion
|
Event related potentials (ERPs) are an EEG measure related to brain electrical activity that can be produced by visual and auditory stimuli
|
Baseline and 24 hours post third IV infusion
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To investigate the effects of ketamine on the cerebral metabolic rate of oxygen utilization (CMRO2) as a measure of brain tissue metabolism using fMRI
Time Frame: 24 hours post third IV infusion
|
The cerebral metabolic rate of oxygen can be assessed using specialised fMRI pulse sequences
|
24 hours post third IV infusion
|
Baseline measures of common genetic markers (SNPs) for genetic disease risk load
Time Frame: Baseline measure
|
Blood samples taken at baseline will be used for DNA analysis
|
Baseline measure
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Mitul Mehta, PhD, King's College London
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Behavioral Symptoms
- Mental Disorders
- Pathologic Processes
- Nervous System Diseases
- Neurologic Manifestations
- Neurobehavioral Manifestations
- Bipolar and Related Disorders
- Depression
- Depressive Disorder
- Disease
- Anhedonia
- Bipolar Disorder
- Mood Disorders
- Depressive Disorder, Major
- Depressive Disorder, Treatment-Resistant
- 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
- Tranquilizing Agents
- Psychotropic Drugs
- Hypnotics and Sedatives
- Adjuvants, Anesthesia
- Anti-Anxiety Agents
- GABA Modulators
- GABA Agents
- Ketamine
- Midazolam
Other Study ID Numbers
- 297200
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Depressive Disorder
-
York UniversityCentre for Addiction and Mental HealthSuspendedDisorder, Major DepressiveCanada
-
Shalvata Mental Health CenterUnknownMAjor Depressive DisorderIsrael
-
Wyeth is now a wholly owned subsidiary of PfizerCompletedDepressive Disorder, Major Depressive DisorderUnited States
-
Samsung Medical CenterUnknownMajor Depressive Disorder, Anxiety DisorderKorea, Republic of
-
Seasons Biotechnology (Taizhou) Co., Ltd.CompletedMajor Depressive Disorder (MDD)India
-
Repurposed Therapeutics, Inc.Unknown
-
GlaxoSmithKlineCompletedMajor Depressive Disorder (MDD)United States
-
Seasons Biotechnology (Taizhou) Co., Ltd.CompletedMajor Depressive Disorder (MDDIndia
-
Gangnam Severance HospitalCompletedMajor Depressive Disorder(MDD)Korea, Republic of
-
University College, LondonCompletedUnipolar Major Depressive DisorderUnited Kingdom
Clinical Trials on Ketamine
-
Grace Lim, MD, MSNational Institute of Mental Health (NIMH)RecruitingPain, Postoperative | Depression, PostpartumUnited States
-
Ullevaal University HospitalUniversity of OsloCompleted
-
Assistance Publique - Hôpitaux de ParisCompletedArthroplasty, Replacement, HipFrance
-
Assiut UniversityCompletedKetamine Causing Adverse Effects in Therapeutic UseEgypt
-
Lawson Health Research InstituteUnknownBone Fractures | Dislocations
-
Eye & ENT Hospital of Fudan UniversityCompletedPain, Procedural | Emotions | Separation AnxietyChina
-
The University of Texas Health Science Center,...TerminatedPost Partum DepressionUnited States
-
Lotus Clinical Research, LLCiX Biopharma Ltd.Completed
-
Antonios LikourezosCompleted