Brain scan study to finally test if low serotonin causes depression

Copied word for word from the study's registry entry, so the wording is the study team's rather than ours.

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.