Project Summary
Unfortunately, fewer than half of patients with major depression achieve full remission following first-line treatment with a selective serotonin reuptake inhibitor (SSRI), creating a pressing need for new therapeutic approaches to address treatment-resistant depression. One strategy for improving treatment response recognizes the underlying mechanistic heterogeneity in major depressive disorder (MDD) and the associated need for focused treatments targeting biologically distinct subgroups of patients.
Tianeptine is an atypical antidepressant that has been used clinically in Europe, Asia, and South America since the late 1980s in millions of patients, but was never submitted for FDA approval and thus is not available in the US. Its efficacy in humans is well documented, and comparable to that of several commonly used classes of antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). However, tianeptine’s molecular mechanism of action had remained unknown until recently. Work in our laboratory has shown that tianeptine acts as a selective agonist of the mu opioid receptor (MOR), signaling in a manner analogous to enkephalins and endorphins, the endogenous opioid peptides. In collaboration with the Hen laboratory, using both genetic knockout and pharmacological inhibition in mouse models for the study of depression, we have collected strong evidence that MOR is the direct molecular target by which tianeptine exerts its antidepressant effects, an entirely unique mechanism among existing antidepressants.
Significant evidence implicates dysfunction of endogenous opioid signaling pathways as a key biological deficit in some depressed patients. We hypothesize that a subgroup of depressed patients with deficient opioid receptor signaling will better respond to pharmacological interventions specifically targeting this biological mechanism.
Importantly, despite targeting MOR, at clinical doses tianeptine does not produce euphoria. In addition, in mice tianeptine administration does not lead to tolerance or withdrawal, in marked contrast to treatment with classical MOR ligands such as morphine. Our lab is working to understand the molecular mechanisms underlying tianeptine’s antidepressant activity and relative freedom of side effects and to develop novel antidepressants based on the mechanism of MOR agonism.