How Serotonin Reuptake Inhibitors Work: Understanding More Fundamental Mechanisms of Action

Several lines of evidence suggest that in adults, antidepressant therapies enhance neurogenesis in the hippocampus, but how this process occurs has been unclear. These researchers studied the effects of fluoxetine in mice and in humans. They worked out several pathways that begin with the stimulation by fluoxetine of the microRNA miR-16 in serotonergic neurons in raphe and ultimately result in hippocampal neurogenesis.

In a series of experiments in mice, fluoxetine activated raphe miR-16, which decreased raphe levels of the serotonin reuptake transporter (SERT). In turn, these events directly caused brain-derived neurotropic factor (BDNF) and two other signaling molecules to act on the hippocampus. Indirectly, the same events resulted in release of another protein from the raphe nuclei, S100β, which in turn stimulated the locus coeruleus to induce SERT and secrete serotonin. Both the direct and indirect pathways caused decreases in hippocampal miR-16, which sequentially led to increases in both hippocampal SERT and the bcl-2 protein (which promotes neurotrophic function), which in turn stimulated neurogenesis. In nine patients with major depression, 12-week fluoxetine treatment increased levels of the three signaling molecules in cerebrospinal fluid. The interventions were accompanied by improvements in several mouse models of depression, as well as in the patients. See accompanying figure.