Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge

• Published in: Biological psychiatry (1969) 2023-06, Vol.93 (12), p.1089-1098
• Main Authors: Erritzoe, David, Godlewska, Beata R., Rizzo, Gaia, Searle, Graham E., Agnorelli, Claudio, Lewis, Yvonne, Ashok, Abhishekh H., Colasanti, Alessandro, Boura, Iro, Farrell, Chloe, Parfitt, Hollie, Howes, Oliver, Passchier, Jan, Gunn, Roger N., Politis, Marios, Nutt, David J., Cowen, Philip J., Knudsen, Gitte M., Rabiner, Eugenii A.
• Format: Article
• Language: English
• Subjects: 5-HT2A receptors; Adolescent; Adult; Amphetamine; Brain - diagnostic imaging; Brain - metabolism; Depression; Depressive Disorder, Major - diagnostic imaging; Depressive Disorder, Major - metabolism; Dextroamphetamine; Female; Humans; Kinetics; Major depression; Male; Middle Aged; Positron emission tomography (PET); Positron-Emission Tomography - methods; Receptor, Serotonin, 5-HT2A - metabolism; Serotonin; Serotonin - metabolism; Young Adult
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2022.10.012

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. 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. 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). 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.