Semaglutide and Cognition in Healthy Volunteers

Cognitive Change Clinical Trial

— OxSENSE  

Official title:

Effects of Single-dose Semaglutide on Cognition and Energy in Healthy Volunteers

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06363487
• Other study ID #: R87970/RE001
• Status: Not yet recruiting
• Phase: N/A
• Start date: April 8, 2024
• Est. completion date: June 8, 2024

Study information

• Verified date: April 2024
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 60
• Est. completion date: June 8, 2024
• Est. primary completion date: April 8, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 21 Years to 55 Years

Eligibility

Inclusion Criteria:

• Male or female
• Aged from 21 to 55 years
• Body Mass Index (BMI) from 18 to 30 (because our main outcomes involve cognitive and energy measures, this decision regarding the BMI range has been taken with the purpose of including a more homogeneous sample of healthy participants in terms of baseline cognitive and energy levels)
• Sufficiently fluent English to understand and complete the tasks
• Participant is willing and able to give informed consent for participation in the research
• Not currently taking any regular medications (except the contraceptive pill)

Exclusion Criteria:

• Currently on any regular prescribed medications (except the contraceptive pill), unless unlikely to compromise safety or affect data quality in the opinion of the medical supervisor according to clinical judgement
• History of, or current significant psychiatric illness in the opinion of the medical supervisor according to clinical judgement
• Current alcohol or substance misuse disorder (<6 months)
• Current moderate or severe dyslexia
• History of, or current significant medical illness in the opinion of the medical supervisor according to clinical judgement
• History of, or current pancreatitis
• History of, or current severe congestive heart failure, end-stage renal disease, hepatic disease
• History of, or current significant neurological condition (e.g., epilepsy)
• History of, or current significant thyroid disorder
• History (including family history) of, or current multiple endocrine neoplasia syndrome type-2 (MEN 2) or medullary thyroid carcinoma (MTC)
• Known type-1 or type-2 diabetes mellitus
• Known hypersensitivity to the study drug (i.e., semaglutide)
• Pregnant, breast feeding, or person of child-bearing potential not using appropriate contraceptive measures including hormonal contraception, intrauterine device, bilateral tubal occlusion, vasectomised partner, condom, absolute sexual abstinence - periodic sexual abstinence, withdrawal, and spermicides-only are not acceptable methods of contraception
• Participation in a study that uses the same or similar computer tasks (O-ETB, see below) as those used in the present study
• Participation in a study that involves the use of a medication within the last 3 months

Related Conditions & MeSH terms

• Cognitive Change

Intervention

Drug:
• Semaglutide, 0.5 mg/mL
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.

Other:
• Placebo, 0.9% NaCl 1.5mL
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.

Locations

Country	Name	City	State
United Kingdom	Department of Psychiatry, University of Oxford	Oxford	Oxfordshire

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	NIHR Oxford Health Biomedical Research Centre

Country where clinical trial is conducted

United Kingdom, 

References & Publications (17)

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Bonnelle V, Veromann KR, Burnett Heyes S, Lo Sterzo E, Manohar S, Husain M. Characterization of reward and effort mechanisms in apathy. J Physiol Paris. 2015 Feb-Jun;109(1-3):16-26. doi: 10.1016/j.jphysparis.2014.04.002. Epub 2014 Apr 18. — View Citation

Collins L, Costello RA. Glucagon-Like Peptide-1 Receptor Agonists. 2023 Jan 13. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK551568/ — View Citation

Colwell, M. J., Murphy, S., & Harmer, C. J. (2022). Emotional Go/No-Go Task (Oxford) (Psychopy). Zenodo. https://doi.org/10.5281/zenodo.6207865

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. — View Citation

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. — View Citation

Halahakoon DC, Kaltenboeck A, Martens M, Geddes JG, Harmer CJ, Cowen P, Browning M. Pramipexole Enhances Reward Learning by Preserving Value Estimates. Biol Psychiatry. 2024 Feb 1;95(3):286-296. doi: 10.1016/j.biopsych.2023.05.023. Epub 2023 Jun 15. — View Citation

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. — View Citation

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. — View Citation

Harmer CJ, O'Sullivan U, Favaron E, Massey-Chase R, Ayres R, Reinecke A, Goodwin GM, Cowen PJ. Effect of acute antidepressant administration on negative affective bias in depressed patients. Am J Psychiatry. 2009 Oct;166(10):1178-84. doi: 10.1176/appi.ajp.2009.09020149. Epub 2009 Sep 15. — View Citation

Harmer CJ, Shelley NC, Cowen PJ, Goodwin GM. Increased positive versus negative affective perception and memory in healthy volunteers following selective serotonin and norepinephrine reuptake inhibition. Am J Psychiatry. 2004 Jul;161(7):1256-63. doi: 10.1176/appi.ajp.161.7.1256. — View Citation

KIRCHNER WK. Age differences in short-term retention of rapidly changing information. J Exp Psychol. 1958 Apr;55(4):352-8. doi: 10.1037/h0043688. No abstract available. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature. 2006 Aug 31;442(7106):1042-5. doi: 10.1038/nature05051. Epub 2006 Aug 23. — View Citation

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. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Secondary	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
Secondary	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.	6-7 days
Secondary	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
Secondary	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
Secondary	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