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NCT07651293

Using Fenfluramine to Test the Serotonin Deficiency Theory of Depression

Sponsor: Imperial College Healthcare NHS Trust

View on ClinicalTrials.gov

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.

Key Details

Gender

All

Age Range

21 Years - Any

Study Type

INTERVENTIONAL

Enrollment

Start Date

2026-07-01

Completion Date

2028-12

Last Updated

2026-06-16

Healthy Volunteers

Yes

Conditions

Depression - Major Depressive Disorder

Interventions

DRUG

Fenfluramine Hydrochloride

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.

RADIATION

[11C]Cimbi-36

\[11C\]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).

DRUG

Placebo

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.

Inclusion Criteria for All Participants: * 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. Inclusion Criteria for Participants with Major Depressive Disorder (MDD): * 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. Inclusion Criteria for Healthy Controls: \- Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, and laboratory tests. Exclusion Criteria for All Participants: * 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. Exclusion Criterion for MDD Participants: \- History of suicide attempts requiring hospitalisation. Exclusion Criteria for Healthy Controls: * 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.

Locations (1)

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

London, United Kingdom