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

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 & PLUSMN; 13 years, Hamilton Depression Rating Scale score 21 & PLUSMN; 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 & PLUSMN; 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 signifi-cantly reduced in the HC group (1.04 & PLUSMN; 0.31 vs. 0.87 & PLUSMN; 0.24, p , .001) but not in the MDE group (0.97 & PLUSMN; 0.25 vs. 0.92 & PLUSMN; 0.22, not significant). DBPND of the MDE group was significantly lower than that of the HC group (HC: 15% & PLUSMN; 14% vs. MDE: 6.5% & PLUSMN; 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.