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| Name | Class |
|---|---|
| National Institute for Health Research, United Kingdom | OTHER_GOV |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Semaglutide | Experimental | Semaglutide pre-filled pen, 0.5mg in 1.5mL, subcutaneous injection |
|
| Placebo | Placebo Comparator | Saline solution 0.9% NaCl, solution for injection 1.5mL, subcutaneous injection syringe |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Semaglutide, 0.5 mg/mL | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 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. | 6-7 days |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6-7 days |
| Emotional impulsivity |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Psychiatry, University of Oxford | Oxford | Oxfordshire | OX3 7JX | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31855395 | Background | Collins L, Costello RA. Glucagon-Like Peptide-1 Receptor Agonists. 2024 Feb 29. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK551568/ | |
| 34003475 | Background | Detka J, Glombik K. Insights into a possible role of glucagon-like peptide-1 receptor agonists in the treatment of depression. Pharmacol Rep. 2021 Aug;73(4):1020-1032. doi: 10.1007/s43440-021-00274-8. Epub 2021 May 18. |
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Anonymised research data without any personal data (e.g., reaction time data) will also be stored on private Open Science Framework (OSF) project components that are accessible only to the research team. We have previously confirmed with the University's Sponsor (formerly CTRG) in December 2019 that OSF can be used in this way to store anonymised data (with no personal data or linking files). Parts of the data might be uploaded to online data repositories or made publicly available on OSF in a completely anonymised fashion, to facilitate open science. Data uploaded in this way will be stored on OSF indefinitely.
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| ID | Term |
|---|---|
| C000591245 | semaglutide |
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|
| Placebo, 0.9% NaCl 1.5mL | Other | 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. |
|
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.
| 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. | 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. | 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) | Across 6-7 days |
| 28386912 | Background | O'Neil PM, Aroda VR, Astrup A, Kushner R, Lau DCW, Wadden TA, Brett J, Cancino AP, Wilding JPH; Satiety and Clinical Adiposity - Liraglutide Evidence in individuals with and without diabetes (SCALE) study groups. Neuropsychiatric safety with liraglutide 3.0 mg for weight management: Results from randomized controlled phase 2 and 3a trials. Diabetes Obes Metab. 2017 Nov;19(11):1529-1536. doi: 10.1111/dom.12963. Epub 2017 Jul 21. |
| 31153593 | Background | Pozzi M, Mazhar F, Peeters GGAM, Vantaggiato C, Nobile M, Clementi E, Radice S, Carnovale C. A systematic review of the antidepressant effects of glucagon-like peptide 1 (GLP-1) functional agonists: Further link between metabolism and psychopathology: Special Section on "Translational and Neuroscience Studies in Affective Disorders". Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders. J Affect Disord. 2019 Oct 1;257:S0165-0327(19)30593-2. doi: 10.1016/j.jad.2019.05.044. Epub 2019 May 28. |
| 27721184 | Background | Mansur RB, Ahmed J, Cha DS, Woldeyohannes HO, Subramaniapillai M, Lovshin J, Lee JG, Lee JH, Brietzke E, Reininghaus EZ, Sim K, Vinberg M, Rasgon N, Hajek T, McIntyre RS. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: A pilot, open-label study. J Affect Disord. 2017 Jan 1;207:114-120. doi: 10.1016/j.jad.2016.09.056. Epub 2016 Oct 1. |
| 26137918 | Background | Moulton CD, Pickup JC, Amiel SA, Winkley K, Ismail K. Investigating incretin-based therapies as a novel treatment for depression in type 2 diabetes: Findings from the South London Diabetes (SOUL-D) Study. Prim Care Diabetes. 2016 Apr;10(2):156-9. doi: 10.1016/j.pcd.2015.06.003. Epub 2015 Jun 29. |
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| 28153641 | Background | Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017 May;4(5):409-418. doi: 10.1016/S2215-0366(17)30015-9. Epub 2017 Jan 31. |
| 31938879 | Background | Godlewska BR, Harmer CJ. Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment. Psychopharmacology (Berl). 2021 May;238(5):1265-1278. doi: 10.1007/s00213-019-05448-0. Epub 2020 Jan 15. |
| 30695707 | Background | Hamer JA, Testani D, Mansur RB, Lee Y, Subramaniapillai M, McIntyre RS. Brain insulin resistance: A treatment target for cognitive impairment and anhedonia in depression. Exp Neurol. 2019 May;315:1-8. doi: 10.1016/j.expneurol.2019.01.016. Epub 2019 Jan 26. |
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| Background | Colwell, M. J., Murphy, S., & Harmer, C. J. (2022). Emotional Go/No-Go Task (Oxford) (Psychopy). Zenodo. https://doi.org/10.5281/zenodo.6207865 |
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