Using Fenfluramine to Test the Serotonin Deficiency Theory of Depression

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.

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.

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.

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.

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.

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

At the screening/baseline visit, all participants complete the Spielberger State-Trait Anxiety Inventory - Trait subscale (STAI Form Y-2), a 20-item self-report measure of stable, dispositional anxiety. Total scores range from 20 to 80, where higher scores indicate greater trait anxiety. This baseline score will be used to characterise the psychological profile of each group and examined in relation to PET-derived serotonin release capacity, other biological measures, and subsequent SSRI treatment response in the MDD group.

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

At the screening/baseline visit, all participants complete the Snaith-Hamilton Pleasure Scale (SHAPS), a 14-item self-report measure of hedonic tone (the capacity to experience pleasure). Each item is rated on a 4-point Likert scale (0 = strongly disagree to 3 = strongly agree), with positively worded items reverse-coded, giving total scores ranging from 0 to 42, where higher scores indicate greater anhedonia (reduced ability to experience pleasure). This baseline score will be used to characterise the psychological profile of each group and examined in relation to Positron emission tomography (PET) scan-derived serotonin release capacity, other biological measures, and subsequent Selective Serotonin Reuptake Inhibitors (SSRIs) treatment response in the Major Depressive Disorder (MDD) group.

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

At the screening/baseline visit, all participants complete the Ruminative Responses Scale (RRS), a 22-item self-report measure of the tendency to ruminate in response to low mood. Total scores range from 22 to 88, where higher scores indicate greater ruminative responding. This baseline score will be used to characterise the psychological profile of each group and examined in relation to Positron emission tomography (PET) scan-derived serotonin release capacity, other biological measures, and subsequent Selective Serotonin Reuptake Inhibitors treatment response in the Major Depressive Disorder (MDD) group.

Baseline mental wellbeing - Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) total score

At the screening/baseline visit, all participants complete the Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS), a 14-item self-report measure of mental wellbeing covering positive affect and functioning over the past two weeks. Total scores range from 14 to 70, where higher scores indicate greater mental well-being. This baseline score will be used to characterise the psychological profile of each group and examined in relation to Positron emission tomography (PET) scan-derived serotonin release capacity, other biological measures, and subsequent Selective Serotonin Reuptake Inhibitors treatment response in the Major Depressive Disorder (MDD) group.