Evidence for a Serotonergic Subtype of Major Depressive Disorder

Background: First line pharmacological treatment of Major Depressive Disorder (MDD) is selective serotonin reuptake inhibitors (SSRIs), but only 1/3 of patients obtain remission. Cerebral serotonin 4 receptor (5-HT4R) binding measured with positron emission tomography (PET) is inversely related to serotonin levels and can serve as a proxy for brain serotonin levels. We here determine if a successful outcome of serotonergic treatment in MDD is linked to a serotonergic deficit. Methods: We [11C]-SB207145 PET-scanned 100 untreated patients with moderate to severe MDD and 91 healthy controls; 40 patients were re-scanned after 8 weeks treatment. All patients were started on SSRI and were followed up clinically after 1, 2, 4, 8 and 12 weeks. Treatment response was measured as change from baseline in Hamilton depression rating scale 6 score. Findings: Before treatment, patients with MDD had 8% lower global 5-HT4R binding than controls (95% confidence interval [-13·1%;-2·5%], p<0·001). Non-responders did not differ from controls ([-11·5%;4·0%], p=0.31), whereas remitters had 9% lower binding than controls at baseline ([-16·1%;-2·7%], p=0.004). The probability that a remitter had a lower baseline 5-HT4R neocortex binding compared to a non-responder was 0.63 [0.43;0.84] with p=0.20.Independent of treatment outcomes, patients reduced their neostriatal 5-HT4R binding (-9%, [-12·8%;-5·0%], p<0·001, N=40) after serotonergic intervention. Interpretation: Patients with MDD who remit to SSRIs have lower cerebral 5-HT4R levels than controls whereas non-responders do not differ, suggesting the presence of a serotonergic subtype of MDD. While SSRI intervention decreased neostriatal 5-HT4R, the change was not associated with the individual clinical outcome. Our data suggest that non-responders to SSRI’s constitute a subgroup with non-serotonergic depression. Trial Registration: Registered as a clinical trial before initiation (NCT02869035). Funding Statement: Key economic support was granted from the Innovation Fund Denmark, Research Fund of the Mental Health Services - Capital Region of Denmark, Independent Research Fund Denmark, G.J. Foundation, Research Council of Rigshospitalet, Augustinus Foundation, Savvaerksejer Jeppe Juhl og hustru Ovita Juhls Mindelegat, Lundbeck Foundation and the H. Lundbeck A/S. H. Declaration of Interests: GMK has received honoraria as expert advisor for Sage Therapeutics and as speaker for Jannsen. VGF has served as consultant for SAGE therapeutics. MBJ has given talks sponsored by Boehringer Ingelheim and Lundbeck Pharma. All other authors declare no conflict of interest. Ethics Approval Statement: The study protocol was approved by all relevant authorities (the Health Research Ethics Committee of the Capital Region of Denmark (H15017713), the Danish Data Protection Agency (04711/RH-2016-163) and Danish Medicines Agency (EudraCT- 2016-001626-34)). All participants provided written informed consent prior to inclusion.