Investigating the Neuropsychological Effects of 5-HT2a Antagonism

NCT07022366 | Recruiting

• 1 other identifier: R95550/RE001
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

Serotonin is an important chemical in the brain that helps control mood, sleep, and appetite. Most antidepressant medications work by affecting serotonin to help improve symptoms. A serotonin receptor is like a "lock" on the surface of brain cells, and serotonin acts like a "key" that fits into these locks. When serotonin binds to the receptor, it sends a signal that helps control different functions in the brain, like mood and behavior. There are different types of serotonin receptors, and each one affects different parts of the brain. Pimavanserin is a medication licensed in the United States of America for the treatment of patients with Parkinson's Disease. It has a very specific effect on one type of serotonin receptor (the serotonin 2a receptor). In this study, the investigators will use pimavanserin to understand more about this serotonin receptor, which may help develop new treatments for depression in the future. More specifically, the study will focus on how pimavanserin impacts cognitive functions such as memory, how we process emotional information and how we make decisions, and will compare these effects to a placebo (a treatment that doesn't have active ingredients).

Conditions

Healthy

Keywords

serotonin 2a; pimavanserin

Outcome Measures

Primary Outcomes (1)

• Sensitivity to loss and reward

  Choice behaviour on the Probabilistic Reversal Learning Task (PRL)

  6-8 hours post-intervention

Secondary Outcomes (5)

• Emotional memory

  6-8 hours post-intervention

• Facial expression recognition

  6-8 hours post-intervention

• Behavioural response inhibition

  6-8 hours post-intervention

• Cognitive Flexibility

  6-8 hours post-intervention

• Sleep

  Night following pimavanserin administration

Study Arms (2)

Pimavanserin

EXPERIMENTAL

Single dose of pimavanserin (10mg)

Drug: Pimavanserin 10mg

Placebo

PLACEBO COMPARATOR

Single dose of matched placebo

Drug: Placebo

Interventions

Pimavanserin 10mg DRUG

Single dose of pimavanserin (10mg)

Pimavanserin

Placebo DRUG

Sucrose tablet

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Willing and able to give informed consent for participation in the research
• Aged 18-45 years
• Good vision and hearing
• Body mass index (BMI) within the range of 18-35kg/m2 (This is to ensure an appropriate pharmacokinetic profile for pimavanserin is achieved by all participants)
• Sufficiently fluent in English to understand tasks
• Willing to avoid drinking any alcohol the day before the research visit

You may not qualify if:

• Currently receiving or seeking treatment for any mental health condition
• Any past or current history of severe and/or serious psychiatric disorder, including but not limited to schizophrenia, psychosis, bipolar affective disorder, severe major depressive disorder, obsessive compulsive disorder (covered in SCID-5 assessment in screening procedures)
• ADHD requiring treatment with stimulant or other centrally-acting drugs
• Regular alcohol consumption of more than 21 units per week
• A head injury causing concussion or unconsciousness in the past 6 months
• Pregnancy / intention to become pregnant during the study or breastfeeding
• Any use of recreational drugs in the last three months
• Participation in any other drug study in the last three months
• Participation in any other study with the same tasks in the last year
• History of cardiac disease or cardiac arrhythmias
• Prolonged QTc interval on baseline ECG
• Current usage of other drugs known to prolong QT interval including Class 1A or 3 antiarrhythmics, e.g. certain antibiotics (getifloxacin, moxifloxacin)
• Current use of drugs that inhibit CYP3A4 (eg Clarithromycin. Diltiazem. Erythromycin. Fluconazole). Participants will be asked to avoid grapefruit juice in the week before the study.
• Current use of psychoactive medication that in the opinion of the Chief Investigator may interfere with the study measures
• History of, or current medical condition(s) which, in the opinion of the Investigator may interfere with the safety of the participant or the scientific integrity of the study, including epilepsy/seizures, brain injury, severe hepatic or renal disease, severe gastro-intestinal problems, Central Nervous System (CNS) tumours, severe neurological problems (e.g. Parkinson's disease; blackouts requiring hospitalisation);

Sponsors & Collaborators

• University of Oxford: lead

Study Sites (1)

Department of Psychiatry, University of Oxford

Oxford, United Kingdom

RECRUITING

Related Publications (6)

• Vargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, Cameron LP, Patel SD, Hennessey JJ, Saeger HN, McCorvy JD, Gray JA, Tian L, Olson DE. Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors. Science. 2023 Feb 17;379(6633):700-706. doi: 10.1126/science.adf0435. Epub 2023 Feb 16.

  PMID: 36795823 BACKGROUND

• Nordstrom AL, Mansson M, Jovanovic H, Karlsson P, Halldin C, Farde L, Vanover KE, Hacksell U, Brann MR, Davis RE, Weiner DM. PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. Int J Neuropsychopharmacol. 2008 Mar;11(2):163-71. doi: 10.1017/S1461145707007869. Epub 2007 Aug 21.

  PMID: 17708779 BACKGROUND

• Luppi AI, Girn M, Rosas FE, Timmermann C, Roseman L, Erritzoe D, Nutt DJ, Stamatakis EA, Spreng RN, Xing L, Huttner WB, Carhart-Harris RL. A role for the serotonin 2A receptor in the expansion and functioning of human transmodal cortex. Brain. 2024 Jan 4;147(1):56-80. doi: 10.1093/brain/awad311.

  PMID: 37703310 BACKGROUND

• Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, Bird C, Blom RE, Brennan C, Brusch D, Burke L, Campbell-Coker K, Carhart-Harris R, Cattell J, Daniel A, DeBattista C, Dunlop BW, Eisen K, Feifel D, Forbes M, Haumann HM, Hellerstein DJ, Hoppe AI, Husain MI, Jelen LA, Kamphuis J, Kawasaki J, Kelly JR, Key RE, Kishon R, Knatz Peck S, Knight G, Koolen MHB, Lean M, Licht RW, Maples-Keller JL, Mars J, Marwood L, McElhiney MC, Miller TL, Mirow A, Mistry S, Mletzko-Crowe T, Modlin LN, Nielsen RE, Nielson EM, Offerhaus SR, O'Keane V, Palenicek T, Printz D, Rademaker MC, van Reemst A, Reinholdt F, Repantis D, Rucker J, Rudow S, Ruffell S, Rush AJ, Schoevers RA, Seynaeve M, Shao S, Soares JC, Somers M, Stansfield SC, Sterling D, Strockis A, Tsai J, Visser L, Wahba M, Williams S, Young AH, Ywema P, Zisook S, Malievskaia E. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med. 2022 Nov 3;387(18):1637-1648. doi: 10.1056/NEJMoa2206443.

  PMID: 36322843 BACKGROUND

• Dirks B, Fava M, Atkinson SD, Joyce M, Thase ME, Howell B, Lin T, Stankovic S. Adjunctive Pimavanserin in Patients with Major Depressive Disorder: Combined Results from Two Randomized, Double-Blind, Placebo-Controlled Phase 3 Studies. Psychopharmacol Bull. 2022 Oct 27;52(4):8-30. doi: 10.64719/pb.4448.

  PMID: 36339271 BACKGROUND

• Bhagwagar Z, Hinz R, Taylor M, Fancy S, Cowen P, Grasby P. Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907. Am J Psychiatry. 2006 Sep;163(9):1580-7. doi: 10.1176/ajp.2006.163.9.1580.

  PMID: 16946184 BACKGROUND

MeSH Terms

Interventions

pimavanserin

Central Study Contacts

Susannah Murphy, PhD

CONTACT

+441865618313; susannah.murphy@psych.ox.ac.uk

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 27, 2025
• First Posted: June 15, 2025
• Study Start: February 10, 2025
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: April 29, 2026

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

GB (1)