Using Fenfluramine to Test the Serotonin Deficiency Theory of Depression

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

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.

Sponsors & Collaborators

• University of Oxford

  collaborator OTHER

• Imperial College Healthcare NHS Trust

  lead OTHER

Principal Investigators

• David Nutt, Professor · Centre for Psychedelic Research, Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, UK

• Phillip Cowen, Professor · Department of Psychiatry, University of Oxford

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

21 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2026-07-01

Primary Completion

2028-07-31

Completion

2028-12-31

Countries

• United Kingdom

Study Locations