Evidence for a serotonergic subtype of major depressive disorder: A NeuroPharm-1 study

Abstract Selective serotonin reuptake inhibitors (SSRIs) are the first line pharmacological treatment of Major Depressive Disorder (MDD), but only about half of patients benefit from it. Cerebral serotonin 4 receptor (5-HT 4 R) 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 5-HT 4 R differs between healthy and MDD individuals and if it is associated with successful outcomes of serotonergic treatment of MDD. We [ 11 C]-SB207145 PET-scanned 100 (71 F) untreated patients with moderate to severe MDD and 91 (55 F) healthy controls; 40 patients were re-scanned after 8 weeks treatment. All patients started treatment with the SSRI escitalopram and were followed clinically after 1, 2, 4, 8 and 12 weeks. Treatment response was measured as change from baseline. Before treatment, patients with MDD had 8% lower global 5-HT 4 R binding than controls (95%CI[-13.1%;-2.5%], p<0.001). Non-responders did not differ from controls, whereas remitters had 9% lower binding than controls ([-16.1%;-2.7%], p=0.004). Independent of treatment outcomes, patients reduced their neostriatal 5-HT 4 R binding (−9%, [-12.8%;-5.0%], p<0.001) after serotonergic intervention. Overall, patients with MDD have lower cerebral 5-HT 4 R binding than controls, suggesting that 5-HT 4 R is a biomarker for MDD. The observation that SSRI treatment leads to reduced neostriatal 5-HT 4 R binding supports that the treatment does indeed increase brain 5-HT levels. Patients who remit to SSRIs have lower cerebral 5-HT 4 R prior to treatment than controls whereas non-responders do not differ. We propose that non-responders to SSRI’s constitute a subgroup with non-serotonergic depression. ClinicalTrials.gov Identifier: NCT02869035 Registry name: Treatment Outcome in Major Depressive Disorder URL: https://clinicaltrials.gov/ct2/show/NCT02869035?term=NCT02869035&draw=2&rank=1