Pharmacotherapeutic class: OTHER ANTIDEPRESSANTS. ATC code: N06AX14.
Pharmacology: Pharmacodynamics: Mechanism of action: Tianeptine is an antidepressant: Tianeptine has the following characteristics in animals: tianeptine increases the spontaneous activity of pyramidal cells in the hippocampus and accelerates their recovery after functional inhibition, tianeptine increases the rate of serotonin re-uptake by neurons in the cortex and hippocampus.
In vitro, tianeptine has no affinity for monoaminergic receptors and does not inhibit serotonin (5-HT), noradrenaline (NA) or dopamine (DA) re-uptake. Tianeptine can modulate synaptic glutamatergic neuro-transmission.
The specific contribution of each effect to the antidepressant activity is unknown.
Clinical efficacy and safety: Four double-blind, placebo-controlled trials were performed to evaluate the short-term efficacy of tianeptine in the treatment of major depressive episodes in adults: one at fixed doses (37.5 mg, 75 mg) and two with possibility to adjust the dosage to a higher or lower dose (initial dose 37.5 mg, then 25, 37.5 or 50 mg) and one in elderly patients (311 patients aged 65 years and above; ~100 patients by treatment arm, including ~20 patients above 75 years in each arm) with a potential dose increase according to patient improvement after 2 weeks of treatment (25 mg then 25mg or 50 mg). In the adult studies, primary endpoint was change in MADRS total score from baseline for the fixed and flexible dose trials.
At the end of treatment (6 weeks), the efficacy of tianeptine was significant in the two flexible dose trials but not in the fixed dose trial. In a trial, imipramine, used as an active comparator, demonstrated the sensitivity of the trial. In the elderly study (potential dose increase trial), after 8 weeks of treatment, significant efficacy of tianeptine was demonstrated on the primary endpoint (HAMD total score change from baseline). The active control, escitalopram, used in this trial showed assay sensitivity.
The maintenance of the antidepressant efficacy was evaluated in a relapse and recurrence prevention trial. Patients considered as responding to treatment by the investigator (6 weeks of "open" treatment with tianeptine at a daily dosage of 2 to 4 tablets, i.e. 25 to 50 mg daily) were randomised to tianeptine or placebo for an additional duration of 16.5 months. Tianeptine showed a statistically significant efficacy superiority with respect to placebo (p < 0.001) on the main criterion of the trial: prevention of relapse or recurrence measured by the time to their onset. The incidence of relapse after 6 months of double-blind follow-up was 6% for tianeptine and 22% for placebo. The incidence of relapse or recurrence after 18 months of double-blind follow-up was 16% for tianeptine and 36% for placebo.
Pharmacokinetics: Absorption: Gastrointestinal absorption is rapid and complete.
Distribution: Distribution is rapid and is associated with protein binding of nearly 94 %, primarily to albumin.
Biotransformation: Tianeptine is extensively metabolised by the liver, primarily by beta-oxidation, without CYP450 involvement. Its main metabolite, pentanoic acid (MC5), is active and less potent than tianeptine.
Elimination: The elimination of tianeptine is characterised by a short terminal half-life of 3 h, most of the metabolites are excreted in the urine.
Elderly, very elderly and fragile patients: In elderly patients, tianeptine plasma concentrations increased by 30% and those of MC5 were nearly doubled after single or repeated administration, compared to that of younger patients (see Dosage & Administration).
In very elderly (87 ± 5 years) or fragile (45 ± 9 kg), a significant increase of Cmax and exposure (area under the curve, AUC) to tianeptine and MC5 were observed after a single administration (see Dosage & Administration).
Patients with severe renal failure (ClCr < 19 ml/min): The pharmacokinetics of tianeptine remain unchanged but the exposure to MC5 is nearly doubled after single and repeated administration (see Dosage & Administration).
Patients with severe liver cirrhosis (Class C, Child-Pugh Score): Exposure to tianeptine and MC5, after the administration of a 12.5 mg dose, are increased compared to that of adult depressive patients (see Dosage & Administration).
In case of milder cirrhosis, such as chronic alcoholics, the effects on the pharmacokinetic parameters are insignificant (see Dosage & Administration).
Toxicology: Preclinical safety data: Non-clinical data from conventional genotoxicity and carcinogenesis studies have not revealed any specific risk for humans.
In the fertility study, an increase in pre-implantation losses was observed at the maternotoxic dose of 45 mg/kg/day (i.e. 12 times the human dose determined with respect to the body surface).
Tianeptine is not teratogenic in rats and rabbits.
In the peri- and post-natal study, a lactic secretion dysfunction and an increase in post-implantation and post-natal losses have been observed in rats at the maternotoxic dose of 45 mg/kg/day (i.e. 12 times the human dose determined with respect to the body surface).