Can a low dose of ketamine change how people with treatment-resistant depression remember their lives, deal with emotions, and make decisions?
| ISRCTN | ISRCTN68107842 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN68107842 |
| ClinicalTrials.gov (NCT) | Nil known |
| Clinical Trials Information System (CTIS) | Nil known |
| Integrated Research Application System (IRAS) | 302265 |
| Protocol serial number | IRAS 302265 |
| Sponsor | University of Oxford |
| Funders | Medical Research Council, Wellcome Trust, Janssen Pharmaceuticals |
- Submission date
- 20/04/2023
- Registration date
- 05/05/2023
- Last edited
- 12/09/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Mental and Behavioural Disorders
Plain English summary of protocol
Background and study aims
Clinical depression often involves a pessimistic view of things which have happened in the past and an impairment in the ability to experience pleasure or look forward to things. A licensed drug called ketamine affects the levels of glutamate, a chemical messenger in the brain, and has been used as a treatment, particularly for depression which hasn’t got better with other types of medication. Glutamate plays a role in learning and memory so we are interested in understanding how ketamine can affect how people with depression remember past negative and positive memories. This project will help us understand what is the role of glutamate in depression and will expand our understanding of how ketamine can influence memory, the way people understand emotions and learn from rewards and punishments, and motivation.
Who can participate?
Adults with depression who have not improved with the standard antidepressant treatment
What does the study involve?
Study participants will undergo medical and psychiatric health screening, questionnaires and computer tasks before and after the administration of the study drug (a single infusion of ketamine or a dummy saline placebo), and an MRI scan a day after administration of the drug/placebo. MRI is a type of brain scan that allows us to see how the brain responds during, for example, memories of things which have happened in the past.
What are the possible benefits and risks of participating?
The study will not be of direct benefit to you, but it is hoped that the information obtained will help improve the treatment of depression. Possible risks from taking part involve answering questionnaires and completing memory and computer-based tasks, undergoing an MRI scan and receiving ketamine/placebo. These risks will be discussed with the participants prior to their enrollment in the study. To minimise any harm or risks, participants will be carefully supervised and we will ensure that any risks are minimised by conducting a detailed medical and psychiatric screening and having 24-hour on-call availability for participants in the study.
Where is the study run from?
The Department of Psychiatry, University of Oxford (UK)
When is the study starting and how long it is expected to run?
October 2017 to January 2025
Who is funding the study?
Medical Research Council (UK)
Janssen Pharmaceutical (USA)
Wellcome Trust (UK)
Who is the main contact?
Professor Catherine Harmer (Principal Investigator), catherine.harmer@psych.ox.ac.uk (UK)
Contact information
Principal investigator
Warneford Hospital
Warneford Lane
Oxford
OX3 7JX
United Kingdom
 ORCID ID |
0000-0002-1609-8335 |
|---|---|
| Phone | +44(0)1865 223 961 |
| catherine.harmer@psych.ox.ac.uk |
Scientific
Warneford Hospital
Warneford Lane
Oxford
OX3 7JX
United Kingdom
| ORCID ID |
0000-0002-7937-8596 |
|---|---|
| Phone | +44(0)1865 618303 |
| sara.costi@psych.ox.ac.uk |
Public
Warneford Hospital
Warneford Lane
Oxford
OX3 7JX
United Kingdom
| ORCID ID |
0000-0003-2800-1235 |
|---|---|
| Phone | +44 (0)7847673197 |
| chloe.wigg@psych.ox.ac.uk |
Scientific
Warneford Hospital
Warneford Lane
Oxford
OX3 7JX
United Kingdom
| ORCID ID |
0000-0001-8995-2099 |
|---|---|
| Phone | +44 (0)1865 618313 |
| susannah.murphy@psych.ox.ac.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Randomized parallel-arm placebo-controlled experimental medicine study |
| Secondary study design | Randomised controlled trial |
| Study type | Participant information sheet |
| Scientific title | Does modulation of glutamate transmission in the brain using a sub-anaesthetic dose of ketamine affect autobiographical memory, emotional processing and decision-making in treatment-resistant depression? - The Glutamate Emotion Memory Study (GEMS) |
| Study acronym | GEMS |
| Study objectives | Primary: To investigate the effects of ketamine on negative emotional bias associated with autobiographical memory and the effects of ketamine on brain circuit associated with autobiographical memories Secondary: To investigate the effects of ketamine on positive and non-emotional memories, on measures of emotional processing and emotional memory, on information processing and decision-making and on motivation and anhedonia |
| Ethics approval(s) | Approved 14/01/2022, South Central - Oxford C Research Ethics Committee (Health Research Authority (Bristol), Ground Floor, Temple Quay House, 2 The Square, BS1 6PN, UK; +44 (0)207 104 8241; oxfordc.rec@hra.nhs.uk), ref: 22/SC/0001 |
| Health condition(s) or problem(s) studied | Major depressive disorder |
| Intervention | Randomization Participants are randomised using an online randomisation tool (www.sealedenvelope.com) to either placebo or ketamine arms. The randomisation code is drawn up by a researcher not involved in the remaining study visits. Randomisation is stratified for gender and order of conditions on the emotional processing task. The randomisation list containing the participant study ID and the allocation is updated when each new participant enters the randomised phase. The study arms are as follows: Study arm 1: Ketamine hydrochloride 0.5mg/kg diluted in 40mL of sodium chloride 0.9% and administered at a constant rate (60ml/h) over the course of 40 minutes Study arm 2: 40mL of sodium chloride 0.9% administered at a constant rate (60ml/h) over the course of 40 minutes Intervention providers: Intervention preparation, administration and disposal are carried out by two unblinded staff members (dispenser and checker). The dispenser is a medically qualified clinician. The dispensing, administration and disposal are conducted under the supervision of a consultant psychiatrist who is on call and at the hospital site during the entire duration of the infusion. The checker can be another medically qualified clinician or nursing personnel. Participants undergo the infusion of ketamine/placebo at the Clinical Research Facility (CRF), Warneford Hospital, a facility that offers the resources and support needed for the close monitoring of participants during the administration of the study intervention. Mode of delivery: Intravenous administration using an infusion pump over the course of 40 minutes Outcome measures: The primary outcomes include the change in the magnitude of negative and positive valence adjectives in the autobiographical memory task measured using a self-reported questionnaire. To investigate the effects of ketamine on negative emotional bias associated with autobiographical memories in TRD patients. Each negative (guilty/ashamed, depressed/sad, angry/frustrated, upset, anxious/worried, worthless) and positive (grateful, energetic/motivated, hopeful, confident, loved, happy) valence adjectives. will be rated on a scale from 0 to 100. Change in magnitude will be assessed by calculating the difference in ratings of negative and positive adjectives using a self-reported questionnaire from baseline to after treatment [Time Frame: -1 and 1 day after ketamine/placebo treatment] Brain activation is measured by functional magnetic resonance in a network of areas related to autobiographical memories, including the medial prefrontal cortex and associated networks during the autobiographical memory task. To investigate the effects of ketamine on: brain circuit associated with autobiographical memories [Time Frame: 1 day after ketamine/placebo treatment] The secondary outcome measures will investigate the effects of ketamine on: 1. Emotional processing such as emotional recognition the classification of positive and negative descriptor words, recall of positive and negative descriptor words and recognition of positive and negative descriptor words 2. Reward processing 3. Brain circuit associated with reward processing 4. Choice behaviour in win and loss trials 5. Pupil dilation in the context of RL decision-making task 6. Motivation processing |
| Intervention type | Drug |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Ketamine hydrochloride 0.5 mg/kg, sodium chloride 0.9% |
| Primary outcome measure(s) |
1. Change in the magnitude of negative and positive valence adjectives in the autobiographical memory task measured using a self-reported questionnaire on day -1 and 1 day after ketamine/placebo treatment |
| Key secondary outcome measure(s) |
1. Accuracy measured using a computer-based task of facial expression recognition (FERT) on -1 day, and up to 2 hours after ketamine/placebo treatment |
| Completion date | 06/01/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 20 Years |
| Upper age limit | 60 Years |
| Sex | All |
| Target sample size at registration | 60 |
| Key inclusion criteria | 1. Male or female 2. Aged 20-60 years old 3. Willing and able to give informed consent for participation in the study 4. Sufficiently fluent English to understand and complete the tasks 5. Registered with a GP and consents to GP being informed of participation in the study 6. Participants need to meet a number of concurrent clinical criteria: Current criteria for Major Depressive Disorder, in a current major depressive episode, as determined by the SCID-5 7. Inadequate response to at least one and no more than three antidepressant treatments; Currently taking a licensed antidepressant at a therapeutic dose for at least four weeks 8. Pre-menopausal women and male participants engaging in sex with a risk of pregnancy must agree to use a highly effective method of contraception from Screening Visit until 30 days after receiving the study medication treatment 9. Male participants must not donate sperm until 30 days after receiving the study medication 10. Participants taking non-prescription/prescription medication may still be entered into the study, if, in the opinion of the Investigator, the medication received will not interfere with the study procedures or compromise safety 11. Willingness to refrain from driving, cycling, or operating heavy machinery, until the following morning or a restful sleep has occurred, whichever is later 12. Willingness to refrain from drinking alcohol for 3 days before the infusion visit and one day before any of the other visits throughout the study |
| Key exclusion criteria | 1. History of /or current DSM.5 bipolar disorder, schizophrenia or emotionally unstable personality disorder [co-morbid anxiety disorders (including agoraphobia, generalized anxiety disorder, social anxiety disorder and panic disorder) and Posttraumatic Stress Disorder (PTSD) are allowed] 2. Participants who fulfill current criteria for other comorbid disorders may still be entered into the study, if, in the opinion of the Investigator, the psychiatric diagnosis will not compromise safety or affect data quality 3. Diagnosis of a major cognitive disorder or evidence of cognitive impairment 4. Clinically significant risk of suicide 5. Participants undergoing or who have undergone electroconvulsive therapy for the treatment of the current episode of depression 6. Substance or alcohol use disorder over the past 6 months 7. Regular alcohol consumption of more than 21 units a week or excessive alcohol consumption up to three days before any of the in-person study visits or inability to abstain from alcohol for more than 3 days 8. Moderate cigarette use (> 10 cigarettes per day) 9. History of, or current general medical conditions that in the opinion of the Investigator may interfere with the safety of the participant or the scientific integrity of the study 10. Current pregnancy (as determined by urine pregnancy test), breastfeeding, planning a pregnancy, or unwillingness to practice birth control during the study 11. Clinically significant abnormalities of laboratory tests, physical examination, or ECG. A participant with a clinical abnormality or parameters outside the reference range for the population being studied may be included only if the Investigator considers that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures 12. Current or history of heart rhythm disorders 13. Clinically significant untreated hypertension 14. Any contraindication to MRI including claustrophobia, any trauma or surgery which may have left magnetic material in the body, magnetic implants or pacemakers, and inability to lie still for 1 hour or more 15. Previous participation in a study using the same, or similar, emotional processing tasks in the last three months 16. Previous lifetime use of ketamine or phencyclidine 17. Participants with planned medical treatment within the study period that might interfere with the study procedures 18. Participant who is unlikely to comply with the clinical study protocol or is unsuitable for any other reason, in the opinion of the Investigator. |
| Date of first enrolment | 20/04/2022 |
| Date of final enrolment | 30/12/2024 |
Locations
Countries of recruitment
- United Kingdom
- England
Study participating centres
Warneford Hospital
Warneford Lane
Oxford
OX3 7JX
United Kingdom
Warneford Lane
Oxford
OX3 7JX
United Kingdom
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan summary | Available on request |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from Prof Catherine Harmer, catherine.harmer@psych.ox.ac.uk. Data which has been fully de-identified may be shared with other academic and commercial organisations in the future, including those outside of the EU, to allow for large meta-analyses or international collaborations. Participants will be informed of this. All research data will be archived on the Department of Psychiatry network drive and the other University of Oxford servers for 10 years, after which it will be securely destroyed. All paper CRFs, ICFs and TMFs will be archived in the University storage facility with a date for destruction. Consent is required and obtained from study participants as part of the informed consent form. The study staff will ensure that the participants’ anonymity is maintained. The participants will be identified only by a participant ID number on all study documents and any electronic database, with the exception of the consent and contact forms (which will be stored securely in a locked filing cabinet in the Neuroscience Building, Department of Psychiatry, University of Oxford) and the prescription and randomisation forms which will be stored securely in a locked cabinet at the Clinical Research Facility (CRF), Oxfordhealth Foundation Trust. All documents will be stored securely and will be only accessible to study staff and authorised personnel. The study will comply with the UK General Data Protection Regulation (UK GDPR) and Data Protection Act 2018, which require data to be anonymized as soon as it is practical to do so. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
Editorial Notes
12/09/2024: The following changes were made:
1. The recruitment end date was changed from 30/09/2024 to 30/12/2024.
2. The intention to publish date was changed from 30/09/2024 to 30/12/2025.
3. The study overall end date was changed from 30/03/2024 to 06/01/2025.
20/02/2024: The recruitment end date was changed from 28/02/2024 to 30/09/2024.
03/10/2023: The recruitment end date was changed from 30/09/2023 to 28/02/2024.
09/05/2023: Internal review.
04/05/2023: Trial's existence confirmed by the HRA and Health and Care Research Wales (HCRW) (UK).
