The neurobiological properties of tianeptine (Stablon)

Tianeptine is a  antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It’s now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression.
Depression is a complex, heterogeneous disorder, and the mechanisms underlying its pathogenesis are not that clear and are the subject of intensive investigation using pharmacological and genetic tools and animal models. The ‘monoamine hypothesis’ of depression, which involves imbalances in serotonergic, noradrenergic and possibly dopaminergic functions, has dominated notions and explanations of the pathophysiology of depression since the empirical discovery of the antidepressant properties of monoamine oxidase inhibitors and tricyclics about 50 years ago. Although the monoaminergic neurotransmitters serotonin (5-HT), norepinephrine and dopamine (DA) are undoubtedly involved, it is now recognized that monoamine deficits are only part of the story and are not sufficient on their own to explain the mechanism of action of antidepressants. In extension to the chemical hypothesis of depression, contemporary theories suggest that major depressive disorders may be associated not only with an imbalance of neurotransmitters and neuromodulators but also with an impairment of neuroplasticity and cellular resilience, and that antidepressant medications act by normalizing this impairment. The term neuroplasticity describes the ability of the adult and differentiated brain to adapt functionally and structurally to internal and external stimuli and is considered today as a feature of depressive illness. Brain regions that exhibit neuroplastic processes include the hippocampus, amygdala and prefrontal cortex, as they are reported to undergo structural changes in depression, and alterations in these brain regions affect emotions, perceptions, memory and cognitive function. The concept of a serotonergic deficit in depression is particularly challenged by the drug tianeptine, an antidepressant with structural similarities to the tricyclic antidepressant agents but with different pharmacological properties. The efficacy and tolerability of tianeptine are clearly demonstrated in depressed patients. However, the monoamine hypothesis cannot explain these properties. In fact, tianeptine has contributed greatly to our realization of the complexity of the etiology of depression, and to the complexity of central mechanisms triggered by antidepressants. Its mechanisms of action clearly challenge the hypothesis of an immediate modulation of monoamine axes to support the antidepressant actions. Rather, tianeptine triggers a cascade of cellular adaptations that ultimately will lead to the antidepressant efficacy. Among those sustained adaptations, increased phosphorylation of glutamate receptors subtypes in circumscribed brain region appears particularly interesting. Glutamate is the major excitatory neurotransmitter in the brain controlling synaptic excitability and plasticity in most brain circuits, including limbic pathways. Glutamatergic mechanisms are crucial in virtually all key functions perturbed in depressed states. In addition, glutamate is an essential participant in many forms of adaptive plasticity, including: learning and memory. The actions of tianeptine on the glutamatergic system offer new insights into how this compound may be useful in the treatment of depression.
The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation
Molecular Psychiatry (2010) 15, 237–249