Using Fenfluramine to Test the Serotonin Deficiency Theory of Depression

NCT07651293 | Not Yet Recruiting

• 2 other identifiers: 354525APP28983
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

Clinical depression is a common and disabling condition characterised by persistent low mood and loss of interest that interferes with daily functioning. Serotonin is a key brain neurotransmitter involved in mood regulation, and a leading theory proposes that depression is associated with impaired serotonin function (the serotonin deficiency hypothesis), which underpins the use of selective serotonin reuptake inhibitors (SSRIs) as first-line antidepressant treatments. However, the strength and specificity of the link between serotonin dysfunction and depressive symptoms in humans remains uncertain and requires direct evidence in living human brains. Positron Emission Tomography (PET) allows in vivo quantification of neurotransmitter receptor systems using a radioactive tracer that binds to specific brain targets. The serotonin 2A receptor (5-HT2A) agonist tracer \[11C\]Cimbi-36 enables measurement of the active-state 5-HT2A receptor, which is highly expressed in cortical regions implicated in mood regulation. When combined with a pharmacological challenge that acutely increases serotonin levels, changes in \[11C\]Cimbi-36 binding can be used to estimate serotonin release capacity across different brain regions. Previous work using an amphetamine challenge with \[11C\]Cimbi-36 has shown reduced serotonin release capacity in the frontal cortex of patients with depression compared with healthy controls, providing preliminary support for the serotonin deficiency hypothesis. However, amphetamine releases multiple neurotransmitters in addition to serotonin, limiting the ability to attribute these effects specifically to serotonergic dysfunction. Dl-fenfluramine is a more selective serotonin-releasing agent and therefore offers a targeted approach to probe serotonin release in the human brain. This case-control observational study will compare serotonin release capacity between unmedicated adults with Major Depressive Disorder (MDD) and healthy control participants using dl-fenfluramine challenge combined with \[11C\]Cimbi-36 PET imaging. The primary objective is to test whether individuals with MDD show reduced fenfluramine-induced serotonin release, indexed by changes in \[11C\]Cimbi-36 binding, relative to healthy controls. Secondary objectives include exploring how multimodal imaging, blood biomarkers, and behavioural measures relate to serotonin release capacity and depressive symptom severity. Following completion of imaging, participants with MDD who will start SSRI treatment as part of their usual clinical care will be followed for 8 weeks with remote assessments. The study will examine whether baseline measures of serotonin release capacity predict subsequent clinical response to SSRIs, defined primarily by change in clinician-rated depression scores over the treatment period. Together, these data aim to provide a more precise test of the serotonin deficiency hypothesis of depression and to identify potential biomarkers of SSRI treatment response in MDD.

Conditions

Depression - Major Depressive Disorder

Keywords

Major Depressive Disorder; Serotonin; PET; Fenfluramine; [11C]Cimbi-36; SSRI; Serotonin Deficiency Theory of Depression

Outcome Measures

Primary Outcomes (1)

• Change in cortical [11C]Cimbi-36 non-displaceable binding potential (BPND) after dl-fenfluramine versus placebo (serotonin release capacity)

  Serotonin release capacity (SRC) will be quantified as the percentage change in \[11C\]Cimbi-36 non-displaceable binding potential (BPND) in cortical regions (frontal, occipital, parietal, temporal, limbic) between the placebo Positron emission tomography (PET) scan and the dl-fenfluramine PET scan within each participant. The primary region of interest is the frontal cortex. BPND will be derived from 90-minute dynamic \[11C\]Cimbi-36 PET data using arterial input and multilinear analysis-1 (MA1), with cerebellum as the reference region. SRC will then be compared between the Major Depressive Disorder (MDD) and healthy control groups as the primary mechanistic endpoint.

  Approximately 3.5 hours after dl-fenfluramine or placebo dosing on each of the two imaging visits (within 14 days)

Secondary Outcomes (22)

• Dl-fenfluramine plasma concentration after single 60 mg oral dose

  Baseline, 3.5 hours, and 5 hours after dosing on each of the two imaging visits (dl-fenfluramine and placebo)

• Prolactin levels after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)

  Baseline, 3.5 hours, and 5 hours after dosing on each of the two imaging visits (dl-fenfluramine and placebo)

• Depression scores in Major Depressive Disorder (MDD) patients

  Baseline, Scan Visit 1, Scan Visit 2, SSRI treatment start, 2 weeks after SSRI treatment, and 8 weeks after SSRI treatment

• Functional magnetic resonance imaging (fMRI) measures of emotional face reactivity after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)

  During the MRI session on each of the two imaging visits (approximately 5 hours after dosing)

• Arterial spin labelling (ASL) cerebral blood flow after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)

  During the MRI session on each of the two imaging visits (approximately 5 hours after dosing)

Other Outcomes (10)

• Baseline trait anxiety - Spielberger State-Trait Anxiety Inventory, Trait subscale (STAI-T) total score

  Screening/baseline visit prior to any imaging or pharmacological intervention

• Baseline anhedonia - Snaith-Hamilton Pleasure Scale (SHAPS) total score

  Screening/baseline visit prior to any imaging or pharmacological intervention

• Baseline depressive rumination - Ruminative Responses Scale (RRS) total score

  Screening/baseline visit prior to any imaging or pharmacological intervention

Study Arms (2)

Major Depressive Disorder (MDD) Arm

EXPERIMENTAL

This arm includes adults with a current moderate to severe Major Depressive Disorder episode, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition, and currently unmedicated for at least 8 weeks. Participants attend one screening visit and two imaging visits (approx. 14 days apart). At each imaging visit, they undergo \[11C\]Cimbi-36 brain scans, pharmacokinetic, behavioural, and psychometric assessment. On one imaging day, they receive a single oral dose of dl-fenfluramine 60 mg, and on the other they receive placebo, with order balanced and allocation randomised across participants. Dosing occurs approximately 3.5 hours before \[11C\]Cimbi-36 to capture peak pharmacodynamic effects. After completion of both imaging visits, participants in this arm commencing Selective Serotonin Reuptake Inhibitor treatment under their treating clinician are monitored over an 8-week observational period with remote clinical assessments of depressive symptomatology.

Drug: Fenfluramine Hydrochloride; Radiation: [11C]Cimbi-36; Drug: Placebo

Healthy Control (HC) Arm

ACTIVE COMPARATOR

This arm includes adults who are physically and psychiatrically healthy, as determined by medical history, physical examination, and screening investigations, and who have no current or past Axis I psychiatric disorder. Participants attend one screening visit and two imaging visits (approx.14 days apart). At each imaging visit, they undergo \[11C\]Cimbi-36 brain scan, pharmacokinetic blood sampling, behavioural tasks, and psychometric assessment. On one imaging day, they receive a single oral dose of dl-fenfluramine 60 mg, and on the other, they receive a placebo, with orders balanced and allocation randomised across participants. Dosing occurs approximately 3.5 hours before \[11C\]Cimbi-36 to capture peak pharmacodynamic effects. Unlike the patients' arm, healthy control participants do not receive antidepressant treatment or longitudinal clinical follow-up, but provide the reference comparison group for dl-fenfluramine-induced changes in \[11C\]Cimbi-36 scan.

Drug: Fenfluramine Hydrochloride; Radiation: [11C]Cimbi-36; Drug: Placebo

Interventions

Fenfluramine Hydrochloride DRUG

Single oral dose of 60 mg dl-fenfluramine oral solution, administered once on one of the two imaging days, approximately 3.5 hours before \[11C\]Cimbi-36 brain scan to coincide with peak pharmacodynamic effects. Dl-fenfluramine is a selective serotonin-releasing agent (licensed in the United Kingdom for Dravet syndrome) used here as an acute pharmacological challenge to probe cortical serotonin release capacity, with associated venous sampling for plasma levels and prolactin as pharmacodynamic markers.

Healthy Control (HC) Arm; Major Depressive Disorder (MDD) Arm

[11C]Cimbi-36 RADIATION

\[11C\]Cimbi-36 is a carbon-11-labelled serotonin 2A receptor (5-HT2A) agonist Positron emission tomography (PET) radiotracer that preferentially binds to the active state of cortical 5-HT2A receptors and is sensitive to displacement by endogenous serotonin. In this study, up to 300 MBq is administered intravenously on each of two PET sessions (one after dl-fenfluramine and one after placebo).

Healthy Control (HC) Arm; Major Depressive Disorder (MDD) Arm

Placebo DRUG

Placebo consists of an oral solution of orange juice matched in volume, appearance, and taste to the dl-fenfluramine preparation but containing no active drug. It is administered once on one of the two imaging days, approximately 3.5 hours before the \[11C\]Cimbi-36 brain scan, with allocation randomised and order balanced across participants to maintain single-blind conditions.

Healthy Control (HC) Arm; Major Depressive Disorder (MDD) Arm

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Aged 21 years and over.
• Able to lie comfortably on their back for scanning.
• Participants must agree to use one of the contraception methods listed in Appendix 1.
• Capable of providing written informed consent and willing to comply with the requirements and restrictions listed in the consent form.
• Able to read, comprehend, and record information written in English.
• Able to access the internet through their own electronic device.
• Major depressive episode diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) as moderate to severe.
• Scoring above 20 on the Montgomery-Åsberg Depression Rating Scale (MADRS).
• Have never taken antidepressants, or are currently unmedicated for at least 8 weeks before signing the informed consent form.
• Not classified as treatment-resistant.
• Ongoing relationship with a general practitioner (GP) or other healthcare professional.
• \- Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, and laboratory tests.

You may not qualify if:

• Presence of a general medical or psychiatric condition (excluding MDD in the relevant population), as revealed by a physical and psychiatric examination, which, in the opinion of the Principal Investigator (PI), would impair the safety of the participant or the scientific integrity of the study.
• Ongoing treatment with medication that, in the opinion of the investigator, would compromise participant safety or the scientific integrity of the study, including but not limited to compounds known to interact with the serotonin 2A (5-HT2A) receptor or to have a significant effect on the synthesis and/or release of serotonin (5-HT).
• Use of illicit compounds in the 3 months before consent, including but not limited to classic psychedelics, stimulants, 3,4-methylenedioxymethamphetamine (MDMA), and cannabis.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• The participant is mentally or legally incapacitated.
• Contraindications to blood sampling and/or arterial cannulation, including but not limited to peripheral vascular disease or Raynaud's phenomenon.
• Contraindications to the administration of dl-fenfluramine include medications that have a significant effect on the synthesis and/or release of 5-HT.
• Abnormal Allen's test and/or prolonged Prothrombin Time (PT), due to the arterial cannulation required for the positron emission tomography (PET) scans.
• Participation in another research study involving ionising radiation exceeding 10 mSv within the last year.
• Contraindications to magnetic resonance imaging (MRI) scans include, but are not limited to, pacemakers, recent metallic implants, foreign bodies in the eye, or other contraindications identified by a standard pre-MRI questionnaire.
• Claustrophobia or any other condition that would render the participant incapable of undergoing MRI/PET scanning.
• Pregnancy or breastfeeding.
• \- History of suicide attempts requiring hospitalisation.
• History of an Axis I psychiatric diagnosis.
• History of a neurological or general medical illness that, in the opinion of the investigator, would compromise participant safety or the scientific integrity of the study.

Sponsors & Collaborators

• Imperial College Healthcare NHS Trust: lead
• University of Oxford: collaborator

Study Sites (1)

entre for Psychedelics Research, Division of Psychiatry Imperial College London, Level 2, Commonwealth Building, Hammersmith Campus, Du Cane Road, London

London, W120NN, United Kingdom

Location

Related Publications (3)

• Colwell MJ, Tagomori H, Shang F, Cheng HI, Wigg CE, Browning M, Cowen PJ, Murphy SE, Harmer CJ. Direct serotonin release in humans shapes aversive learning and inhibition. Nat Commun. 2024 Aug 9;15(1):6617. doi: 10.1038/s41467-024-50394-x.

  PMID: 39122687 BACKGROUND

• Agnorelli C, Garling HD, Paterson LM, Erritzoe D, Knudsen GM. Recent advances in PET measures of brain 5-HT release. J Cereb Blood Flow Metab. 2026 Mar 19:271678X261427944. doi: 10.1177/0271678X261427944. Online ahead of print.

  PMID: 41854028 BACKGROUND

• Erritzoe D, Godlewska BR, Rizzo G, Searle GE, Agnorelli C, Lewis Y, Ashok AH, Colasanti A, Boura I, Farrell C, Parfitt H, Howes O, Passchier J, Gunn RN, Politis M, Nutt DJ, Cowen PJ, Knudsen GM, Rabiner EA. Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge. Biol Psychiatry. 2023 Jun 15;93(12):1089-1098. doi: 10.1016/j.biopsych.2022.10.012. Epub 2022 Oct 29.

  PMID: 36635177 BACKGROUND

Related Links

• Related Info

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Fenfluramine; Cimbi-36

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals

Study Officials

• David Nutt, Professor

  Centre for Psychedelic Research, Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, UK

  PRINCIPAL INVESTIGATOR

• Phillip Cowen, Professor

  Department of Psychiatry, University of Oxford

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David Erritzoe, MD., PhD.

CONTACT

+447503289090; d.erritzoe@imperial.ac.uk

Claudio Agnorelli, PhD

CONTACT

07341723258; c.agnorelli21@imperial.ac.uk

Study Design

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

Model Details: This is a single-centre, case-control, interventional brain-imaging study with two parallel groups (Major Depressive Disorder and healthy controls) and a within-subject, single-blind, cross-over drug challenge design

Study Record Dates

• First Submitted: June 2, 2026
• First Posted: June 16, 2026
• Study Start: July 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): December 1, 2028
• Last Updated: June 16, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: IPD will be available following publication of primary results (anticipated within 12 months of study completion) and will remain accessible for a minimum of 10 years after the end of data collection
• Access Criteria: Pseudonymised IPD will be available to researchers for non-commercial research purposes upon submission of a data sharing request to the Chief Investigator. Access is granted under a Data Sharing Agreement requiring review by the sponsor.

Locations

GB (1)