Revisiting the SSRI–TRKB Mechanism: Lack of Evidence for Interaction in the Human Brain

Abstract Direct binding of selective serotonin reuptake inhibitors (SSRIs) to the TRKB receptor has been revealed as a novel mode of action for SSRIs. However, micromolar SSRI concentrations are required for this interaction to produce measurable effects in vitro and in vivo in animal models. Here, we highlight that measurements of human blood and cerebrospinal fluid from chronically treated patients reveal only nano- to picomolar SSRI levels. Rodent electrophysiological studies show that micromolar SSRI concentrations disrupt multiple ion channel functions, and we demonstrate that exposure of human neurons to micromolar concentrations leads to significantly reduced activity at 1 µM and complete silencing at 10 µM-concentrations required to exert effects by direct SSRI low-affinity binding to TRKB in animals. Together, clinical measurements, animal electrophysiological studies, and our human neuro-electrophysiology data question whether the low SSRI concentrations achieved in patients have any consequences through their low-affinity binding to TRKB receptors. The micromolar concentrations required for effects elicit by SSRI-TRKB direct interaction are not reached under therapeutic conditions and, as our data show, would instead presumably lead to a near-complete loss of neuronal activity in humans. Competing Interest Statement SI is the founder of Oscillution AB, holds shares in the company, and serves in a management position.