Depression - Major Depressive DisorderFenDepNCT07651293
Using Fenfluramine to Test the Serotonin Deficiency Theory of Depression
A study testing Fenfluramine Hydrochloride and [11C]Cimbi-36 in people with Depression - Major Depressive Disorder, run by Imperial College Healthcare NHS Trust at 1 site in United Kingdom.
Trial 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… Read more about this study
- Who is it for?
- Ages 21 years and olderHealthy volunteers can take part
- Conditions the study is for
- Depression - Major Depressive Disorder
- What is being tested?
- Fenfluramine Hydrochloride and [11C]Cimbi-36
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 46 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 1 Jul 2026to Dec 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
- Healthy as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, and laboratory tests.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United Kingdom1 site
entre for Psychedelics Research, Division of Psychiatry Imperial College London, Level 2, Commonwealth Building, Hammersmith Campus, Du Cane Road, London
London, W120NN
About this study
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.
Read more
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.
Read the detailed description
Major depressive disorder (MDD) is a leading cause of disability worldwide and is associated with substantial personal, social, and economic burden. Despite the availability of antidepressant medications, fewer than half of patients achieve an adequate response to first-line treatments, and many fail to reach full remission, highlighting the need for a clearer understanding of the underlying neurobiology to guide more effective and personalised interventions. The most established biological theory of depression is the serotonin deficiency hypothesis, which proposes that in a proportion of patients, depression arises from impaired brain serotonin neurotransmission, particularly within cortical and limbic regions involved in mood regulation. While the efficacy of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic agents is consistent with this hypothesis, most supporting data have been indirect, and prior imaging and peripheral biomarker studies have not provided a definitive, mechanistic test in living humans.
Recent advances in positron emission tomography (PET) have made it possible to measure endogenous serotonin release capacity in the human brain. The agonist radiotracer [11C]Cimbi-36 binds to the active state of the serotonin 2A receptor (5-HT2A), which is densely expressed in frontal and other cortical regions implicated in mood and affect regulation. Because agonist tracers are more sensitive than antagonist tracers to competition from endogenous neurotransmitters, increases in synaptic serotonin can be inferred from reductions in [11C]Cimbi-36 binding following a pharmacological challenge that releases serotonin. Using this methodology with a d-amphetamine challenge, prior work in healthy volunteers established that acute monoamine release reduces [11C]Cimbi-36 binding in the frontal cortex and other cortical areas. In a subsequent case-control PET study, patients undergoing a major depressive episode were found to have significantly reduced serotonin release capacity, defined as the percentage reduction in [11C]Cimbi-36 binding after d-amphetamine compared to placebo, providing the first direct in vivo evidence of impaired serotonin release in depression.
However, d-amphetamine releases dopamine and noradrenaline in addition to serotonin, so it remains unclear whether the observed deficit in release capacity is specific to the serotonin system or reflects broader monoaminergic dysfunction. Dl-fenfluramine is a more selective serotonin-releasing agent that has previously been used as a single-dose challenge in neuroendocrine and neurobiological studies of mood and anxiety disorders. Fenfluramine increases presynaptic serotonin release and leads to downstream effects such as prolactin elevation and changes in thermoregulation, which can be blocked by 5-HT2A receptor antagonists, indicating that its functional effects depend on serotonin acting at postsynaptic 5-HT receptors rather than direct agonist activity at 5-HT2A itself. Preclinical PET and microdialysis work has shown that fenfluramine produces robust serotonin release and larger reductions in [11C]Cimbi-36 binding than d-amphetamine, suggesting that a fenfluramine challenge may offer a more sensitive and specific assay of cortical serotonin release capacity.
The FenDep study is a case-control, observational brain imaging study designed to use dl-fenfluramine and [11C]Cimbi-36 PET to test the serotonin deficiency hypothesis of depression and to explore whether baseline serotonin release capacity predicts subsequent SSRI treatment response. The study will enrol approximately 26 adults with moderate to severe MDD and 20 healthy control (HC) participants.
Following an initial pre-screening telephone contact, potentially eligible individuals will be screened for mental and physical health. Screening also includes completion of a battery of psychometric instruments assessing depression, anxiety, stress, rumination, anhedonia, well-being, personality traits, and connectedness.
Eligible participants then attend two imaging visits, separated by approximately 14 days. The study uses a single-blind, balanced-order design in which each participant receives dl-fenfluramine (60 mg oral liquid) on one imaging day and a placebo on the other, with the order counterbalanced across participants. Dosing occurs approximately 3.5 hours before the PET scan to coincide with peak plasma levels of dl-fenfluramine. PET imaging is performed with intravenous administration of up to 300 MBq of [11C]Cimbi-36, followed by 90 minutes of dynamic data acquisition and arterial blood sampling via a radial arterial cannula to allow kinetic modelling of radiotracer uptake and metabolism. A venous cannula is used for tracer injection and additional venous sampling. The primary region of interest is the frontal cortex, with the cerebellum serving as a reference region for calculation of non-displaceable binding potential (BPND) using the multilinear analysis-1 (MA1) model. Serotonin release capacity (SRC) is operationalised as the relative reduction in [11C]Cimbi-36 BPND after dl-fenfluramine compared with placebo.
Alongside PET, a comprehensive multimodal imaging, including Magnetic Resonance Imaging (MRI) and electroencephalography (EEG), and a behavioural task battery is collected during the imaging visits. Visit procedures also include repeated measurements of blood pressure and heart rate, pharmacokinetic assessment of dl-fenfluramine and prolactin, and subjective drug effect ratings.
After completing both imaging visits, MDD participants return to their usual clinical care. In case participants initiate SSRI treatment as part of standard practice, the study team conducts three remote follow-up assessments by video call over an 8-week observational period. At these contacts, clinician-rated and self-report depression scales and other relevant questionnaires are administered. The primary clinical outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score after 8 weeks of SSRI treatment, with response defined as a 50% or greater reduction from baseline, enabling investigation of whether baseline serotonin release capacity and related imaging/biomarker measures predict antidepressant response.
The primary objective of FenDep is to compare fenfluramine-induced serotonin release capacity in cortical regions between unmedicated adults with MDD and healthy controls using [11C]Cimbi-36 PET. By combining a selective serotonin releaser with a validated PET methodology for measuring serotonin release, multimodal imaging, behavioural tasks, blood-based biomarkers, and prospective SSRI treatment follow-up, FenDep aims to deliver a rigorous test of the serotonin deficiency hypothesis in MDD and to identify mechanistically informed biomarkers that could support future stratified treatment approaches.
- Conditions
- Depression - Major Depressive Disorder
- Being tested
- Fenfluramine Hydrochloride, [11C]Cimbi-36, Placebo
- Keywords
- Major Depressive Disorder, Serotonin, PET, Fenfluramine, [11C]Cimbi-36, SSRI, Serotonin Deficiency Theory of Depression
- Medical subject headings
- Depressive Disorder, Major
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Fenfluramine HydrochlorideDrug
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.
[11C]Cimbi-36Radiation
[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).
PlaceboDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Fenfluramine Hydrochloride; Radiation: [11C]Cimbi-36; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Plasma concentrations of dl-fenfluramine will be measured from venous blood samples obtained on the dl-fenfluramine imaging day at approximately 0, 3.5, and 5 hours after dosing. For each visit, dl-fenfluramine plasma concentration will be summarised (e.g. as average or change from baseline across post-dose time points) and compared between dl-fenfluramine and placebo within subjects, and between Major Depressive Disorder (MDD) and healthy control groups, and related to Positron emission tomography (PET) scan-derived serotonin release capacity.
Measured: 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)
Plasma prolactin concentrations will be measured from venous blood samples taken on both imaging days (dl-fenfluramine and placebo) approximately 0, 3.5, and 5 hours after dosing. For each visit, prolactin response will be summarised (e.g. as average or change from baseline across post-dose time points) and compared between dl-fenfluramine and placebo within subjects, and between Major Depressive Disorder (MDD) and healthy control groups, and related to Positron emission tomography (PET) scan-derived serotonin release capacity.
Measured: 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
In patients with Major Depressive Disorder (MDD), depressive symptom severity will be assessed with the clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS), a 10-item scale with total scores ranging from 0 to 60, where higher scores indicate more severe depression. MADRS will be administered at each study visit in MDD participants. For those patients initiating Selective Serotonin Reuptake Inhibitor (SSRI) treatment after the imaging visits as part of their standard clinical care, the MADRS will also be assessed at treatment initiation, 2 weeks, and 8 weeks after treatment. Change in MADRS scores (absolute change and percentage reduction from baseline) will be used to define clinical response and remission, and these outcomes will be related to baseline positron emission tomography (PET)-derived serotonin release capacity and other biomarkers.
Measured: 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)
On both imaging days (dl-fenfluramine and placebo), participants complete a Functional magnetic resonance imaging (fMRI) emotional face-reactivity task during which brain responses to emotional facial expressions (e.g. neutral, positive, and negative valenced) are measured. Task-evoked Blood-Oxygen-Level-Dependent (BOLD) signal, particularly in regions such as the amygdala and frontal cortex, will be compared between dl-fenfluramine and placebo within subjects, between Major Depressive Disorder (MDD) and healthy control groups, and examined for associations with Positron emission tomography (PET) scan-derived serotonin release capacity and clinical measures.
Measured: 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)
On both imaging days (dl-fenfluramine and placebo), participants undergo arterial spin labelling (ASL) to quantify regional cerebral blood flow at rest. ASL-derived cerebral blood flow values in predefined regions of interest (e.g. frontal cortex and limbic areas) will be compared between dl-fenfluramine and placebo within subjects, between Major Depressive Disorder (MDD) and healthy control groups, and examined for relationships with Positron emission tomography (PET) scan-derived serotonin release capacity and clinical/behavioural measures.
Measured: During the MRI session on each of the two imaging visits (approximately 5 hours after dosing)
Neuromelanin-sensitive Magnetic Resonance Imaging (MRI) measures of striatal dopamine signal after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
On both imaging days (dl-fenfluramine and placebo), participants undergo a neuromelanin-sensitive Magnetic Resonance Imaging (MRI) sequence to quantify signal intensity in striatal regions as an indirect marker related to dopaminergic innervation. Neuromelanin-weighted signal in predefined striatal regions of interest will be compared between dl-fenfluramine and placebo within subjects, between Major Depressive Disorder (MDD) and healthy control groups, and explored in relation to Positron emission tomography (PET) scan-derived serotonin release capacity and clinical/behavioural measures.
Measured: During the MRI session on each of the two imaging visits (approximately 5 hours after dosing)
Magnetic resonance spectroscopy (MRS) measures of glutamate and Gamma-Aminobutyric acid (GABA) in anterior cingulate cortex after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
On both imaging days (dl-fenfluramine and placebo), single-voxel proton Magnetic resonance spectroscopy (MRS) is acquired in the anterior cingulate cortex to quantify metabolites including glutamate and Gamma-Aminobutyric acid (GABA). Metabolite concentrations (e.g. glutamate, GABA and related ratios) will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD)and healthy control groups, and examined for associations with Positron emission tomography (PET) scan-derived serotonin release capacity and clinical/behavioural measures.
Measured: During the MRI session on each of the two imaging visits (approximately 5 hours after dosing)
Electroencephalography (EEG) measures after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
On both imaging days (dl-fenfluramine and placebo), Electroencephalography (EEG) is recorded to characterise resting-state and task-related electrophysiological activity (including linear and non-linear measures) in healthy controls and Major Depressive Disorder (MDD) participants. EEG metrics will be compared between dl-fenfluramine and placebo within subjects, between MDD and healthy control groups, and explored in relation to Positron emission tomography (PET) scan-derived serotonin release capacity and other imaging, behavioural, and clinical measures.
Measured: During EEG sessions conducted on each of the two imaging visits (approximately 2 hours after dosing)
Behavioural measures of reinforcement learning after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
On both imaging days (dl-fenfluramine and placebo), participants will complete the Probabilistic Instrumental Learning Task (PILT), a computerised reinforcement-learning task. The outcome measure will be the proportion of optimal choices on loss trials (choosing the symbol associated with the lower probability of monetary loss), expressed as a percentage from 0 to 100, where higher values indicate better performance (more optimal choices). This measure will be compared between dl-fenfluramine and placebo within subjects, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to positron emission tomography (PET)-derived serotonin release capacity and clinical measures.
Measured: During behavioural testing on each of the two imaging visits (approximately 6 hours after dosing)
Behavioural measures of affective interference after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
On both imaging days (dl-fenfluramine and placebo), participants will complete the Affective Interference Go/No-Go task, which measures response inhibition during exposure to emotional face distractors. The outcome measure will be the proportion of correct no-go responses (trials on which participants correctly withhold a response when a no-go signal is presented), expressed as a percentage from 0 to 100, where higher values indicate better inhibitory control. This measure will be compared between dl-fenfluramine and placebo within subjects, between participants with Major Depressive Disorder (MDD) and healthy controls, and examined in relation to positron emission tomography (PET)-derived serotonin release capacity and clinical measures.
Measured: During behavioural testing on each of the two imaging visits (approximately 6 hours after dosing)
Subjective depression scores in Major Depressive Disorder (MDD) patients
In patients with Major Depressive Disorder (MDD), depressive symptom severity will be assessed with the the Beck Depression Inventory-II (BDI-II), a 21-item self-report scale assessing the presence and severity of depressive symptoms over the past two weeks. Total scores range from 0 to 63, where higher scores indicate more severe depression. BDI-II will be administered at each study visit in MDD participants. For those patients initiating Selective Serotonin Reuptake Inhibitor (SSRI) treatment after the imaging visits as part of their standard clinical care, the BDI-II will also be assessed at treatment initiation, 2 weeks, and 8 weeks after treatment. Change in BDI-II scores (absolute change and percentage reduction from baseline) will be used to define clinical response and remission, and these outcomes will be related to baseline positron emission tomography (PET)-derived serotonin release capacity and other biomarkers.
Measured: Baseline, Scan Visit 1, Scan Visit 2, SSRI treatment start, 2 weeks after SSRI treatment, and 8 weeks after SSRI treatment
Subjective drug effect - Visual Analogue Scale (VAS): Any drug effect
On both imaging days (dl-fenfluramine and placebo), participants rated their subjective experience using a Visual Analogue Scale (VAS), a 100 mm line on which the distance from the left endpoint determines the score. For this item, scores range from 0 ("not at all") to 100 ("extremely"), where higher scores indicate a stronger perceived drug effect. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Good drug effect
n both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from 0 ("not at all") to 100 ("extremely"), where higher scores indicate a stronger perceived good/positive drug effect. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Bad drug effect
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from 0 ("not at all") to 100 ("extremely"), where higher scores indicate a stronger perceived bad/negative drug effect. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Drug liking
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from 0 ("not at all") to 100 ("extremely"), where higher scores indicate greater liking of the drug effect. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Drug high
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from 0 ("not at all") to 100 ("extremely"), where higher scores indicate a greater sense of drug-induced high. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Stimulated
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from 0 ("not at all") to 100 ("extremely"), where higher scores indicate greater perceived stimulation. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Talkative
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from -50 ("not at all") to +50 ("extremely"), with 0 representing the participant's normal state, where higher scores indicate greater than normal talkativeness and lower scores indicate less than normal talkativeness. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Open
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from -50 ("not at all") to +50 ("extremely"), with 0 representing the participant's normal state, where higher scores indicate greater than normal feelings of openness and lower scores indicate less than normal openness. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Concentration
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from -50 ("not at all") to +50 ("extremely"), with 0 representing the participant's normal state, where higher scores indicate greater than normal concentration and lower scores indicate reduced concentration relative to normal. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Sense of time
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from -50 ("not at all") to +50 ("extremely"), with 0 representing the participant's normal state, where higher scores indicate a greater than normal sense of time passing and lower scores indicate a reduced sense of time relative to normal. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Speed of thinking
On both imaging days (dl-fenfluramine and placebo), participants rate their subjective experience using a Visual Analogue Scale (VAS). For this item, scores range from -50 ("slowed") to +50 ("racing"), with 0 representing the participant's normal state, where positive scores indicate faster than normal thinking and negative scores indicate slower than normal thinking. Ratings are obtained at approximately 3 hours after dosing and will be compared between dl-fenfluramine and placebo within participants, between Major Depressive Disorder (MDD) and healthy control groups, and examined in relation to dl-fenfluramine plasma levels, prolactin response, and positron emission tomography (PET)-derived serotonin release capacity.
Measured: Approximately 3 hours after dosing on each of the two imaging visits
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2026
- Study start1 Jul 2026 (estimated)
- Primary completionJul 2028 (estimated)
- Study completionDec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Depression - Major Depressive DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- 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
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 46 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Imperial College Healthcare NHS Trust
- Sponsor type
- University, hospital or other
- Collaborators
- University of Oxford
- Responsible party
- Sponsor
- Investigators
- David Nutt, Professor, Principal investigator, Centre for Psychedelic Research, Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, UKPhillip Cowen, Professor, Principal investigator, Department of Psychiatry, University of Oxford
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07651293
- Sponsor's protocol ID
- 354525
- Other IDs
- APP28983
- Acronym
- FenDep
- Status last verified
- Jun 2026
- First submitted
- 2 Jun 2026
- Last updated
- 16 Jun 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The main study outcomes (primary and secondary) will be reported in peer-reviewed, open-access publications after study completion and once the main analyses have been concluded. Results will be presented in aggregate and, where appropriate, in pseudo-anonymised form that does not allow identification of individual participants. No personally identifiable information (e.g. names, dates of birth, contact details, National Health System numbers) will be shared with other researchers or collaborators outside the sponsor sites. At present, there is no confirmed plan to share de-identified individual participant-level datasets beyond the immediate study team. Any future IPD sharing would require additional approvals and agreements.
Publications
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.
PubMed 39122687Agnorelli 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.
PubMed 41854028Erritzoe 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.
PubMed 36635177
Study at a glance
From the registry record, last updated by the sponsor on 16 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Using Fenfluramine to Test the Serotonin Deficiency Theory of Depression
- ClinicalTrials.gov ID
- NCT07651293
- Acronym / sponsor ID
- FenDep / 354525
- Conditions
- Depression - Major Depressive Disorder
- Keywords
- Major Depressive Disorder, Serotonin, PET, Fenfluramine, [11C]Cimbi-36, SSRI, Serotonin Deficiency Theory of Depression
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 46 participants (estimated)
- Lead sponsor
- Imperial College Healthcare NHS TrustUniversity, hospital or other
- Collaborators
- University of Oxford
- Study start
- 1 Jul 2026 (estimated)
- Primary completion
- Jul 2028 (estimated)
- Study completion
- Dec 2028 (estimated)
- First posted
- 16 Jun 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Major depressive disorder (MDD) is a leading cause of disability worldwide and is associated with substantial personal, social, and economic burden. Despite the availability of antidepressant medications, fewer than half of patients achieve an adequate response to first-line treatments, and many fail to reach full remission, highlighting the need for a clearer understanding of the underlying neurobiology to guide more effective and personalised interventions. The most established biological theory of depression is the serotonin deficiency hypothesis, which proposes that in a proportion of patients, depression arises from impaired brain serotonin neurotransmission, particularly within cortical and limbic regions involved in mood regulation. While the efficacy of selective serotonin reuptake inhibitors (SSRIs) and other serotonergic agents is consistent with this hypothesis, most supporting data have been indirect, and prior imaging and peripheral biomarker studies have not provided a definitive, mechanistic test in living humans.
Recent advances in positron emission tomography (PET) have made it possible to measure endogenous serotonin release capacity in the human brain. The agonist radiotracer [11C]Cimbi-36 binds to the active state of the serotonin 2A receptor (5-HT2A), which is densely expressed in frontal and other cortical regions implicated in mood and affect regulation. Because agonist tracers are more sensitive than antagonist tracers to competition from endogenous neurotransmitters, increases in synaptic serotonin can be inferred from reductions in [11C]Cimbi-36 binding following a pharmacological challenge that releases serotonin. Using this methodology with a d-amphetamine challenge, prior work in healthy volunteers established that acute monoamine release reduces [11C]Cimbi-36 binding in the frontal cortex and other cortical areas. In a subsequent case-control PET study, patients undergoing a major depressive episode were found to have significantly reduced serotonin release capacity, defined as the percentage reduction in [11C]Cimbi-36 binding after d-amphetamine compared to placebo, providing the first direct in vivo evidence of impaired serotonin release in depression.
However, d-amphetamine releases dopamine and noradrenaline in addition to serotonin, so it remains unclear whether the observed deficit in release capacity is specific to the serotonin system or reflects broader monoaminergic dysfunction. Dl-fenfluramine is a more selective serotonin-releasing agent that has previously been used as a single-dose challenge in neuroendocrine and neurobiological studies of mood and anxiety disorders. Fenfluramine increases presynaptic serotonin release and leads to downstream effects such as prolactin elevation and changes in thermoregulation, which can be blocked by 5-HT2A receptor antagonists, indicating that its functional effects depend on serotonin acting at postsynaptic 5-HT receptors rather than direct agonist activity at 5-HT2A itself. Preclinical PET and microdialysis work has shown that fenfluramine produces robust serotonin release and larger reductions in [11C]Cimbi-36 binding than d-amphetamine, suggesting that a fenfluramine challenge may offer a more sensitive and specific assay of cortical serotonin release capacity.
The FenDep study is a case-control, observational brain imaging study designed to use dl-fenfluramine and [11C]Cimbi-36 PET to test the serotonin deficiency hypothesis of depression and to explore whether baseline serotonin release capacity predicts subsequent SSRI treatment response. The study will enrol approximately 26 adults with moderate to severe MDD and 20 healthy control (HC) participants.
Following an initial pre-screening telephone contact, potentially eligible individuals will be screened for mental and physical health. Screening also includes completion of a battery of psychometric instruments assessing depression, anxiety, stress, rumination, anhedonia, well-being, personality traits, and connectedness.
Eligible participants then attend two imaging visits, separated by approximately 14 days. The study uses a single-blind, balanced-order design in which each participant receives dl-fenfluramine (60 mg oral liquid) on one imaging day and a placebo on the other, with the order counterbalanced across participants. Dosing occurs approximately 3.5 hours before the PET scan to coincide with peak plasma levels of dl-fenfluramine. PET imaging is performed with intravenous administration of up to 300 MBq of [11C]Cimbi-36, followed by 90 minutes of dynamic data acquisition and arterial blood sampling via a radial arterial cannula to allow kinetic modelling of radiotracer uptake and metabolism. A venous cannula is used for tracer injection and additional venous sampling. The primary region of interest is the frontal cortex, with the cerebellum serving as a reference region for calculation of non-displaceable binding potential (BPND) using the multilinear analysis-1 (MA1) model. Serotonin release capacity (SRC) is operationalised as the relative reduction in [11C]Cimbi-36 BPND after dl-fenfluramine compared with placebo.
Alongside PET, a comprehensive multimodal imaging, including Magnetic Resonance Imaging (MRI) and electroencephalography (EEG), and a behavioural task battery is collected during the imaging visits. Visit procedures also include repeated measurements of blood pressure and heart rate, pharmacokinetic assessment of dl-fenfluramine and prolactin, and subjective drug effect ratings.
After completing both imaging visits, MDD participants return to their usual clinical care. In case participants initiate SSRI treatment as part of standard practice, the study team conducts three remote follow-up assessments by video call over an 8-week observational period. At these contacts, clinician-rated and self-report depression scales and other relevant questionnaires are administered. The primary clinical outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score after 8 weeks of SSRI treatment, with response defined as a 50% or greater reduction from baseline, enabling investigation of whether baseline serotonin release capacity and related imaging/biomarker measures predict antidepressant response.
The primary objective of FenDep is to compare fenfluramine-induced serotonin release capacity in cortical regions between unmedicated adults with MDD and healthy controls using [11C]Cimbi-36 PET. By combining a selective serotonin releaser with a validated PET methodology for measuring serotonin release, multimodal imaging, behavioural tasks, blood-based biomarkers, and prospective SSRI treatment follow-up, FenDep aims to deliver a rigorous test of the serotonin deficiency hypothesis in MDD and to identify mechanistically informed biomarkers that could support future stratified treatment approaches.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
- Model description
- 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
| Arm | Type | Receives |
|---|---|---|
| Major Depressive Disorder (MDD) Arm | Experimental | Drug: Fenfluramine Hydrochloride, Radiation: [11C]Cimbi-36, Drug: PlaceboThis 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. |
| Healthy Control (HC) Arm | Active comparator | Drug: Fenfluramine Hydrochloride, Radiation: [11C]Cimbi-36, Drug: PlaceboThis 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. |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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.
Key exclusion criteria (15 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Fenfluramine HydrochlorideSingle 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. | Drug | Healthy Control (HC) Arm, Major Depressive Disorder (MDD) Arm |
| [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). | Radiation | Healthy Control (HC) Arm, Major Depressive Disorder (MDD) Arm |
| PlaceboPlacebo 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. | Drug | Healthy Control (HC) Arm, Major Depressive Disorder (MDD) Arm |
Primary outcome
Change in cortical [11C]Cimbi-36 non-displaceable binding potential (BPND) after dl-fenfluramine versus placebo (serotonin release capacity)
Time frame: Approximately 3.5 hours after dl-fenfluramine or placebo dosing on each of the two imaging visits (within 14 days)
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.
22 secondary outcomes
Dl-fenfluramine plasma concentration after single 60 mg oral dose
Time frame: 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)
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: During the MRI session on each of the two imaging visits (approximately 5 hours after dosing)
Neuromelanin-sensitive Magnetic Resonance Imaging (MRI) measures of striatal dopamine signal after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
Time frame: During the MRI session on each of the two imaging visits (approximately 5 hours after dosing)
Magnetic resonance spectroscopy (MRS) measures of glutamate and Gamma-Aminobutyric acid (GABA) in anterior cingulate cortex after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
Time frame: During the MRI session on each of the two imaging visits (approximately 5 hours after dosing)
Electroencephalography (EEG) measures after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
Time frame: During EEG sessions conducted on each of the two imaging visits (approximately 2 hours after dosing)
Behavioural measures of reinforcement learning after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
Time frame: During behavioural testing on each of the two imaging visits (approximately 6 hours after dosing)
Behavioural measures of affective interference after dl-fenfluramine and placebo in healthy controls and patients with Major Depressive Disorder (MDD)
Time frame: During behavioural testing on each of the two imaging visits (approximately 6 hours after dosing)
Subjective depression scores in Major Depressive Disorder (MDD) patients
Time frame: Baseline, Scan Visit 1, Scan Visit 2, SSRI treatment start, 2 weeks after SSRI treatment, and 8 weeks after SSRI treatment
Subjective drug effect - Visual Analogue Scale (VAS): Any drug effect
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Good drug effect
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Bad drug effect
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Drug liking
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Drug high
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Stimulated
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Talkative
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Open
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Concentration
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Sense of time
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Subjective drug effect - Visual Analogue Scale (VAS): Speed of thinking
Time frame: Approximately 3 hours after dosing on each of the two imaging visits
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Jun 2026.
- Background: PubMed 39122687Colwell 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.
- Background: PubMed 41854028Agnorelli 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.
- Background: PubMed 36635177Erritzoe 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.
- Related InfoLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. The main study outcomes (primary and secondary) will be reported in peer-reviewed, open-access publications after study completion and once the main analyses have been concluded. Results will be presented in aggregate and, where appropriate, in pseudo-anonymised form that does not allow identification of individual participants. No personally identifiable information (e.g. names, dates of birth, contact details, National Health System numbers) will be shared with other researchers or collaborators outside the sponsor sites. At present, there is no confirmed plan to share de-identified individual participant-level datasets beyond the immediate study team. Any future IPD sharing would require additional approvals and agreements.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
David Nutt, Professor principal investigator
Centre for Psychedelic Research, Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, UK
Phillip Cowen, Professor principal investigator
Department of Psychiatry, University of Oxford
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Fenfluramine Hydrochloride and [11C]Cimbi-36 in people with Depression - Major Depressive Disorder, run by Imperial College Healthcare NHS Trust at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 16 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact David Erritzoe, MD., PhD. (+447503289090, d.erritzoe@imperial.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in cortical [11C]Cimbi-36 non-displaceable binding potential (BPND) after dl-fenfluramine versus placebo (serotonin release capacity) (time frame: Approximately 3.5 hours after dl-fenfluramine or placebo dosing on each of the two imaging visits (within 14 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07651293, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Jun 2026.