Semaglutide is a glucagon-like peptide 1 receptor agonist (GLP-1RA). It is a safe medication approved for use in type-2 diabetes mellitus (T2DM) and obesity. Primarily, it works by counteracting insulin-resistance and inducing weight loss. It also acts on several other interconnected neurobiological, immunological (esp. inflammatory), endocrine-metabolic, and gut-brain axis processes that play a role in depressive symptoms. Its effects on cognition and energy are currently unknown. In this study we are using semaglutide as an experimental tool to further investigate these relationships.
Semaglutide is a novel GLP-1RA licensed for T2DM and obesity, which mainly works by offsetting insulin-resistance and stimulating weight loss (1). It also acts on various neurobiological, immunological, endocrine-metabolic, and gut-brain axis processes that play a role in depressive symptoms (2). Preliminary evidence suggests these drugs are safe from a neuropsychiatric perspective (3) and could be beneficial in unipolar (4) and bipolar depression (5) - an outcome possibly mediated by inflammatory pathways (6). The proposed study investigates the effects of semaglutide on cognition and energy, which are currently unknown. Work in our laboratory established that short-term use of conventional antidepressants in healthy volunteers shifts reward sensitivity and emotional cognition (7) - an important neuropsychological mechanism of antidepressant action (8). An experimental medicine trial that assesses the effects of semaglutide on reward sensitivity emotional cognition can validate its potential to be repurposed for treating depressive disorders (9). Moreover, brain insulin resistance, likely lessened by semaglutide, is associated with deficit in impulse-control as well as non-emotional cognitive and energy impairment in people with depression (10). Finally, defining the overall cognitive and energy profile of semaglutide is important for the many people already taking it for its licensed indications (i.e., T2DM, obesity). Therefore, the primary objective of this study is to assess the effect of a single dose of semaglutide 0.5mg subcutaneous injection vs placebo on reward sensitivity tasks in healthy volunteers. Secondary objectives include the investigation of the effects of semaglutide on other cognitive domains (emotional processing, impulsivity, memory) and energy/activity levels. Psychological questionnaires are also measured as relevant covariates.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
TRIPLE
Enrollment
70
Injected subcutaneously (pre-filled pen) in the upper arm (preferred site), in the abdomen, or in the thigh according to participant's preference. The participant will be asked to wear an eye blindfold during the time of the study medication/placebo administration, to avoid compromising blinding. It is not possible to blind the researcher administering the medication/placebo because semaglutide comes in specific pre-filled pens. The person who administers the subcutaneous injection will be suitably trained and experienced, and have been authorised to do so by the Principal Investigator - they will not be involved in other aspects of the study for that participant to avoid compromising blinding.
Injected subcutaneously (subcutaneous injection syringe) in the upper arm (preferred site), in the abdomen, or in the thigh according to participant's preference. The participant will be asked to wear an eye blindfold during the time of the study medication/placebo administration, to avoid compromising blinding. The person who administers the subcutaneous injection will be suitably trained and experienced, and have been authorised to do so by the Principal Investigator - they will not be involved in other aspects of the study for that participant to avoid compromising blinding.
Department of Psychiatry, University of Oxford
Oxford, Oxfordshire, United Kingdom
Reward (learning)
Win/loss and valence on a computer-based task of reward processing (i.e., probabilistic instrumental learning task), comparing those receiving drug vs placebo.
Time frame: 6-7 days
Reward (effort-based)
Win/loss and valence on a computer-based task of reward processing (i.e., apple-gathering task), comparing those receiving drug vs placebo.
Time frame: 6-7 days
Reward (primary)
Valence on a computer-based task of reward processing (i.e., taste strip task), comparing those receiving drug vs placebo.
Time frame: 6-7 days
Emotional processing
Accuracy and reaction times on a computer-based task of emotional processing (i.e., facial expression recognition), comparing those receiving drug vs placebo.
Time frame: 6-7 days
Emotional impulsivity
Accuracy and reaction times on a computer-based task of emotional response inhibition (i.e., affective go/no-go task), comparing those receiving drug vs placebo.
Time frame: 6-7 days
Memory (short- and medium-term) processing
Accuracy and reaction times on a computer-based tasks of (short- and medium-term) memory (auditory-verbal learning task), comparing those receiving drug vs placebo.
Time frame: 6-7 days
Memory (working) processing
Accuracy and reaction times on a computer-based task of working memory (N-back), comparing those receiving drug vs placebo.
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Time frame: 6-7 days
Energy/activity
Ecological momentary assessment (4 times/day) on 7-point Likert energy/activity scale (very tired to very energetic, very inactive to very active)
Time frame: Across 6-7 days