GEMS: Glutamate Emotion Memory Study

Sponsor

University of Oxford (Other)

Overall Status

Recruiting

CT.gov ID

NCT05809609

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Clinical depression often includes a pessimistic view of things which have happened in the past and an impairment in the ability to experience pleasure or looking 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 the investigators are interested in understanding how ketamine can affect how people with depression remember past negative and positive memories and how they experience reward.

The investigators are conducting a study in depressed participants who did not improve with the standard antidepressant treatment to expand our understanding on how ketamine can influence memory, the way people understand emotions and learn from rewards and punishments. Study participants will undergo medical and psychiatric health screening, drug administration (ketamine or saline), questionnaires and computer tasks before and after the administration of the study drug, and an MRI scan after administration of the drug. 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. This project will help us understand how NMDA antagonists may work in depression.

Condition or Disease	Intervention/Treatment	Phase
Treatment Resistant Depression Depression Major Depressive Disorder	Drug: Ketamine Hydrochloride Other: No intervention (placebo)	N/A

Detailed Description

Questions regarding the exact molecular mechanisms of ketamine and its effects on the brain circuitry and networks for the treatment of clinical depression remain largely unanswered. Thus, in the present study the investigators aim to elucidate the effect of ketamine on 1) reconsolidation of autobiographical memories, 2) connectivity of brain circuits involved in autobiographical memories, 3) measures of emotional processing, reward processing and emotional memory in patients suffering from treatment resistant depression. The ultimate goal of this project is to elucidate the antidepressant mechanisms of action of ketamine to facilitate the development of rapid acting antidepressants targeting the glutamatergic system.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants will be assigned to receive ketamine or placebo. Ketamine is not being administered for treatment purposes, the purpose is to understand the mechanisms underpinning its effects.Participants will be assigned to receive ketamine or placebo. Ketamine is not being administered for treatment purposes, the purpose is to understand the mechanisms underpinning its effects.

Masking:

Double (Participant, Investigator)

Masking Description:

All members of the study team will be blinded to the condition a participant is allocated to with the exception of the team member responsible for administering the drug/placebo.

Primary Purpose:

Basic Science

Official 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?

Actual Study Start Date :

Jul 1, 2022

Anticipated Primary Completion Date :

Sep 30, 2023

Anticipated Study Completion Date :

Sep 30, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ketamine Participants in this arm will receive a single intravenous injection, antidepressant dose of Ketamine hydrochloride (0.5mg/kg)	Drug: Ketamine Hydrochloride Ketamine is a high trapping NMDA receptor antagonist which has rapid and reliable antidepressant effects in patients with major depressive disorder (MDD) who fail to respond to at least two antidepressant trials of adequate dose and duration.
Placebo Comparator: Placebo Participants in this arm will receive a single intravenous injection of an inactive placebo (0.9% sodium chloride)	Other: No intervention (placebo) Placebo injection (0.9% sodium chloride)

Arm

Intervention/Treatment

Experimental: Ketamine

Participants in this arm will receive a single intravenous injection, antidepressant dose of Ketamine hydrochloride (0.5mg/kg)

Drug: Ketamine Hydrochloride

Ketamine is a high trapping NMDA receptor antagonist which has rapid and reliable antidepressant effects in patients with major depressive disorder (MDD) who fail to respond to at least two antidepressant trials of adequate dose and duration.

Placebo Comparator: Placebo

Participants in this arm will receive a single intravenous injection of an inactive placebo (0.9% sodium chloride)

Other: No intervention (placebo)

Placebo injection (0.9% sodium chloride)

Outcome Measures

Primary Outcome Measures

Change in magnitude of negative and positive valence adjectives in the autobiographical memory task using a self-reported questionnaire. [-1 and 1 days after ketamine/placebo treatment]
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 calculating the difference in ratings of negative and positive adjectives using a self-reported questionnaire from baseline to after treatment
Brain activation as 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. [1 days after ketamine/placebo treatment]
To investigate the effects of ketamine on: - on brain circuit associated with autobiographical memories

Secondary Outcome Measures

Accuracy on a computer-based task of facial expression recognition (FERT) [-1 day, and up to 2 hours after ketamine/placebo treatment]
To investigate the effects of ketamine on: - emotional processing such as emotional recognition.
Reaction time on a computer-based task of facial expression recognition (FERT) [-1 day, and up to 2 hours after ketamine/placebo treatment]
To investigate the effects of ketamine on: - emotional processing such as emotional recognition.
Accuracy to classify positive and negative descriptor words using the Emotional Categorisation Task (ECAT) [Up to 2 hours after ketamine/placebo treatment]
To investigate the effects of ketamine on: - emotional processing such as classification of positive and negative descriptor words
Reaction time to classify positive and negative descriptor words using the Emotional Categorisation Task (ECAT) [Up to 2 hours after ketamine/placebo treatment]
To investigate the effects of ketamine on: - emotional processing such as classification of positive and negative descriptor words
Number of positive and negative words correctly recalled (hits) and number of words incorrectly recalled (false alarms) using the Emotional Recall Task (EREC) [Up to 2 hours after ketamine/placebo treatment]
To investigate the effects of ketamine on: - emotional processing such as recall of positive and negative descriptor words
Accuracy to correctly (hits) and incorrectly (false alarms) recognise positive and negative words using the Emotional Recognition Memory Task (EMEM) [Up to 2 hours after ketamine/placebo treatment]
To investigate the effects of ketamine on: - emotional processing such as recognition of positive and negative descriptor words
Reaction time to correctly (hits) and incorrectly (false alarms) recognise positive and negative words using the Emotional Recognition Memory Task (EMEM) [Up to 2 hours after ketamine/placebo treatment]
To investigate the effects of ketamine on: - emotional processing such as recognition of positive and negative descriptor words
Change in response choice during gain and loss using the Probabilistic Instrumental Learning Tasks (PILT) [1 day after ketamine/placebo treatment]
To investigate the effects of ketamine on: - reward processing
Brain activation as measured by functional magnetic resonance imaging during the Probabilistic Instrumental Learning Tasks (PILT) in reward-related brain areas, including the ventral striatum and associated networks [1 days after ketamine/placebo treatment]
To investigate the effects of ketamine on: - on brain circuit associated with reward processing
Explore performance on information processing and monetary win/loss reinforcement learning (RL) decision-making tasks. [1 days after ketamine/placebo treatment]
To investigate the effects of ketamine on: - choice behaviour on win and loss trials
Explore performance on information processing and monetary win/loss reinforcement learning (RL) decision-making tasks using pupillometry [1 days after ketamine/placebo treatment]
To investigate the effects of ketamine on: - pupil dilation in context of RL decision making task
Change in choice behaviour (effort and/or reward sensitivity) on accepted offers between session one and two using the Apples Gathering Task (AGT). [Up to 2 hours after ketamine/placebo treatment and 7 days after ketamine/placebo treatment]
To investigate the effects of ketamine on: - motivation processing

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Willing and able to give informed consent for participation in the study
Sufficiently fluent English to understand and complete the tasks
Registered with a GP and consents to GP being informed of participation in the study

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.
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.
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.

Acceptable methods of contraception include:

Condoms
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal or transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation oral, injectable or implantable
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
Vasectomy (or vasectomised partner)
Sexual abstinence. [Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), and spermicides only are not acceptable methods of contraception.]
Male participants must not donate sperm until 30 days after receiving the study medication.
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
Willingness to refrain from driving, cycling, or operating heavy machinery, until the following morning or a restful sleep has occurred, whichever is later.
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.

Exclusion Criteria:

The participant may not enter the study if ANY of the following apply:
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]
Participants who fulfil 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
Diagnosis of a major cognitive disorder or evidence of cognitive impairment
Clinically significant risk of suicide
Participants undergoing or who have undergone electroconvulsive therapy for the treatment of the current episode of depression
Substance or alcohol use disorder over the past 6 months
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
Moderate cigarette use (> 10 cigarettes per day)
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
Current pregnancy (as determined by urine pregnancy test), breastfeeding, planning a pregnancy, or unwillingness to practice birth control during the course of the study
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
Current or past history of heart rhythm disorders
Clinically significant untreated hypertension
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
Previous participation in a study using the same, or similar, emotional processing tasks in the last three months
Previous lifetime use of ketamine or phencyclidine
Participant with planned medical treatment within the study period that might interfere with the study procedures
Participant who is unlikely to comply with the clinical study protocol or is unsuitable for any other reason, in the opinion of the Investigator.