Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Background: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. Methods: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16–30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. Results: Following d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). Conclusions: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Biological Psychiatry |
| Vol/bind | 93 |
| Udgave nummer | 12 |
| Sider (fra-til) | 1089-1098 |
| ISSN | 0006-3223 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This work was supported by an Imanova (now Invicro) IMPETUS pilot PET grant (to DE), from a center grant to Center for Experimental Medicine NeuroPharmacology (http://www.neuropharm.eu) from Innovation Fund Denmark (Grant No. 4108-00004B [to GMK]), and a Medical Research Council Project grant (to OH) and an MRC Programme grant (Grant No. MR/K022202/1 [to PJC]). The study was sponsored by Imanova Ltd. (now Invicro), London, United Kingdom, and the Danish Innovation Fund (NeuroPharm grant) and was approved by the local ethics committees (reference No. 17/EE/0484) and the Administration of Radioactive Substances Advisory Committee (reference No. RPC 630/3764/-37465). All participants provided written informed consent. PET and magnetic resonance scans of the brain were carried out at the Invicro Imaging Centre, Hammersmith Hospital, London, United Kingdom. We thank all the volunteers for their participation as well as the invaluable contributions of the Imanova/Invicro clinical staff for their excellent technical support. We also thank Oxford and King's collaborators for help with recruitment and Dr. Brandon Weiss for valuable statistical input. EAR wishes to acknowledge support and funding by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley, NHS Foundation Trust, and King's College London. DE has within the last 2 years received fees for scientific advisory work from the following (novel psychedelic) companies: Mydecine, Field Trip Health, Entheon, SmallPharma Ltd, Aya Biosciences, Clerkenwell Health, and Mindstate Design Lab; and has received an honorarium fee from each of Compass Pathways and Lundbeck for a talk about psychedelic science. GR, GES, YL, JP, RNG, and EAR are all employees of Invicro, an imaging company that performs contract work for a large range of pharmaceutical and biotech companies (>30 industry partners over the past 2 years). IB has received editor fees from Elsevier. OH is a part-time employee and stock holder of Lundbeck A/s, and has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan, and has a patent for the use of dopaminergic imaging. AHA was funded by National Institute of Health Research Academic Clinical Fellowship and Kings College London scholarship (the funders had no role in this study). PJC is co-applicant on an MRC grant which involves collaboration with Pfizer, and holds a patent on behalf of Oxford University for the use of ebselen in patients with resistant depression. DJN reports speaking honoraria for Lundbeck and Otsuka (both more than 2 years ago). MP is employed by the University of Exeter and has received grant funding for research projects from Michael J Fox Foundation for Parkinson's Research, Invicro, City Electrical Factors, F. Hoffmann-La Roche AG, Glaxo Wellcome R&D Ltd, Piramal Imaging, European Commission, CHDI Foundation, IBA Pharma S.A. Eli Lilly & Company; honoraria for editing a book from Elsevier; and consultancy fee for advisory board from F. Hoffmann-La Roche AG. GMK has received honoraria as a speaker for H Lundbeck and Sage Biogen, and as a consultant for Sanos. BRG, CA, AC, CF, HP report no biomedical financial interests or potential conflicts of interest.
Funding Information:
We thank all the volunteers for their participation as well as the invaluable contributions of the Imanova/Invicro clinical staff for their excellent technical support. We also thank Oxford and King’s collaborators for help with recruitment and Dr. Brandon Weiss for valuable statistical input. EAR wishes to acknowledge support and funding by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley, NHS Foundation Trust, and King’s College London.
Funding Information:
This work was supported by an Imanova (now Invicro) IMPETUS pilot PET grant (to DE), from a center grant to Center for Experimental Medicine NeuroPharmacology ( http://www.neuropharm.eu ) from Innovation Fund Denmark (Grant No. 4108-00004B [to GMK]), and a Medical Research Council Project grant (to OH) and an MRC Programme grant (Grant No. MR/K022202/1 [to PJC]).
Funding Information:
The study was sponsored by Imanova Ltd. (now Invicro), London, United Kingdom, and the Danish Innovation Fund (NeuroPharm grant) and was approved by the local ethics committees (reference No. 17/EE/0484) and the Administration of Radioactive Substances Advisory Committee (reference No. RPC 630/3764/-37465). All participants provided written informed consent. PET and magnetic resonance scans of the brain were carried out at the Invicro Imaging Centre, Hammersmith Hospital, London, United Kingdom.
Funding Information:
DE has within the last 2 years received fees for scientific advisory work from the following (novel psychedelic) companies: Mydecine, Field Trip Health, Entheon, SmallPharma Ltd, Aya Biosciences, Clerkenwell Health, and Mindstate Design Lab; and has received an honorarium fee from each of Compass Pathways and Lundbeck for a talk about psychedelic science. GR, GES, YL, JP, RNG, and EAR are all employees of Invicro, an imaging company that performs contract work for a large range of pharmaceutical and biotech companies (>30 industry partners over the past 2 years). IB has received editor fees from Elsevier. OH is a part-time employee and stock holder of Lundbeck A/s, and has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan, and has a patent for the use of dopaminergic imaging. AHA was funded by National Institute of Health Research Academic Clinical Fellowship and Kings College London scholarship (the funders had no role in this study). PJC is co-applicant on an MRC grant which involves collaboration with Pfizer, and holds a patent on behalf of Oxford University for the use of ebselen in patients with resistant depression. DJN reports speaking honoraria for Lundbeck and Otsuka (both more than 2 years ago). MP is employed by the University of Exeter and has received grant funding for research projects from Michael J Fox Foundation for Parkinson's Research, Invicro, City Electrical Factors, F. Hoffmann-La Roche AG, Glaxo Wellcome R&D Ltd, Piramal Imaging, European Commission, CHDI Foundation, IBA Pharma S.A., Eli Lilly & Company; honoraria for editing a book from Elsevier; and consultancy fee for advisory board from F. Hoffmann-La Roche AG. GMK has received honoraria as a speaker for H Lundbeck and Sage Biogen, and as a consultant for Sanos. BRG, CA, AC, CF, HP report no biomedical financial interests or potential conflicts of interest.
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