Tianeptine

Mechanism of action

Recent studies suggest that tianeptine acts as a full agonist at the mu-type opioid receptor (MOR),. The mu opioid receptors are currently being studied as effective targets for antidepressant therapies. It is believed that the clinical effects of tianeptine are owed to its modulation of these receptors. In addition to its actions on the opioid receptor, previous studies have owed its action to its effect on the serotonin receptor,, dopamine (D2/3) receptors, and glutamate receptors,, as discussed below: Tianeptine has challenged the monoaminergic hypothesis of depression, as well as the widely supported monoaminergic mechanisms whereby the action of most known antidepressants have been explained. Specifically, this drug is thought to persistently alter glutamate receptor bursting of the hippocampal CA3 commissural associational synapse. Current research suggests that tianeptine produces its antidepressant effects through the modulation of glutamate receptor activity (for example, AMPA receptors and NMDA receptors) and affect the release of brain-derived neurotrophic factor (BDNF), which impacts neural plasticity. More recent studies by support the role of tianeptine in the modulation of glutaminergic activity in the amygdala, the emotional region of the brain associated with memories. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, and thus prevents stress-related behavioral issues. In rodents, the stress of acute restraint increases extracellular levels of glutamate in the basolateral amygdala an effect that was inhibited by tianeptine. Interestingly, the SSRI fluoxetine increased extracellular glutamate levels in the basolateral amygdala regardless of stress conditions. These data demonstrate that the mechanism of action of tianeptine is distinct from SSRIs and support the hypothesis that the mechanism of action of tianeptine relates to alteration of glutaminergic activity in the amygdala and the hippocampus. In addition to the above mechanisms, tianeptine is a unique antidepressant and anxiolytic medication that stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in brain tissue. Although the monoaminergic neurotransmitters serotonin (5-HT), noradrenaline (NA) and dopamine (DA) are proven to be related to the occurrence of depressive disorders, it is now recognized that monoamine deficits are not sufficient to explain the mechanism of action of antidepressant medications.

Pharmacodynamics

Analyses in large-scale epidemiologic surveys have shown that the anxiety disorders are widely comorbid with major depression. This makes antidepressant with anxiolytic properties particularly unique and attractive. Tianeptine is effective in reducing depressive symptoms in mild to severe major depressive disorder and also alleviates anxious symptoms associated with depression without the need for coadministration of an anti-anxiety medication. These findings, however, are met with controversial data. In a study of healthy volunteers, Tianeptine-treated subjects were less accurate at identifying facial expressions, suggesting a lack of improvement in the psychomotor symptoms of depression. The tianeptine group also showed reduced memory and reduced attentional vigilance to various stimuli.

Pharmacokinetics

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