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A balanced 3 way cross-over study involving 12 young healthy volunteers (6 men and 6 women) was used to determine the pharmacokinetic parameters of the antidepressant tianeptine following a single dose administered by oral and intravenous route. The influence of alcohol on the pharmacokinetics of tianeptine when given per os was also investigated. Kinetic parameters of metabolite MC5, the C5 side chain beta-oxidation product of tianeptine, were simultaneously determined. Following intravenous administration total clearance and volume of distribution of tianeptine were 230 +/- 59 ml.min-1 and 0.47 +/- 0.14 l.kg-1 respectively. When given orally, tianeptine was absorbed rapidly (tmax = 0.94 +/- 0.47 h). The mean systemic availability was estimated to be 99 +/- 29%. Tianeptine was eliminated from plasma with a half-life of 2.5 +/- 1.1 h, mainly via extrarenal route since its renal clearance averaged 0.38 +/- 0.47 ml.min-1. Plasma levels of metabolite MC5 were lower than those of the parent drug but decreased with a longer half-life (7.2 +/- 5.7 h). Alcohol co-administration decreased tianeptine absorption rate and lowered tianeptine plasma levels by about 30% but did not affect those of the MC5 metabolite.

Melatonin rhythms were assessed in 49 registered blind individuals by measurement of the urinary metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s). Subjects had different causes of visual loss and were classified as having light perception or better (LP; n = 19) or having no perception of light (NPL; n = 30). Subjects collected four-hourly urine samples (eight-hourly overnight) for 48 h at weekly intervals for 3-5 weeks. The majority of LP subjects (14 of 19) had normally entrained aMT6s rhythms (mean acrophase range, 2.4-6.2 h), 4 were abnormally entrained to 24 h (mean acrophase range, 8.9-1.0 h), and 1 was unclassified. Conversely, most NPL subjects had abnormal rhythms (23 of 30), the incidence of which was greater in uni- and bilaterally enucleated subjects. The majority of NPL subjects (17 of 30) had free-running aMT6s rhythms period range, 24.13-24.79 h), 5 were abnormally entrained to 24 h (acrophase range, 7.2-20.6 h), and 1 was unclassified. Output (micrograms of aMT6s per 24 h) and amplitude (micrograms per h) of aMT6s production did not vary between LP and NPL subjects (mean 24-h output +/- SD, 12.7 +/- 7.5 and 9.4 +/- 6.4 micrograms aMT6s/24 h, respectively; mean amplitude +/- SD, 0.6 +/- 0.4 and 0.5 +/- 0.3 microgram/h, respectively). These results indicate that a higher proportion of NPL subjects have abnormal melatonin rhythms compared to those with LP.

S-20098 has potent and specific agonist properties on melatonin receptors both in vitro and in vivo. Behavioral studies on rodents already showed that repeated intraperitoneal administration of S-20098 could dose-dependently alter the functioning of the circadian clock. To determine whether single administration of S-20098 could alter the circadian rhythms of rodents, we first used the phase-response curve (PRC) approach in two different species: Syrian hamsters and mice (C3H/HeJ). Our results show that the shape, circadian times and extent of the PRC to S-20098 look very similar in mice and hamsters. In both species, the phase advance portion of the PRC to S-20098 is limited to a 3 h window preceding the onset of locomotor activity, but the magnitude of phase shifts is larger in mice. We also tested the phase shifting effects of increasing doses of S-20098 during the interval of maximal sensitivity to this compound. Treatment with S-20098 induces dose-dependent phase shifts, with maximal shifts observed after injections of 20 and 25 mg/kg S-20098 i.p., respectively, in mice and hamsters. Those results are in agreement with the limited distribution of melatonin-binding sites within the circadian clock of adult Syrian hamsters, as compared to other rodents.

The influence of a test meal on the absorption and disposition of tianeptine (Stablon), a new antidepressant, was investigated in 12 healthy subjects in a two-way, randomized, open cross-over study. Single 12.5-mg oral doses of tianeptine were administered following a night of fasting or immediately after a standardized breakfast. When subjects received tianeptine under fasting conditions the lag time before absorption onset, and the time of the maximum plasma concentration were 0.55 +/- 0.26 hours and 1.29 +/- 0.29 hours, respectively. The maximum plasma concentration was 322 +/- 44 ng/mL, and the total area under the curve 994 +/- 248 ng/hr/mL. When tianeptine was given at the end of the meal, several significant changes were found for tianeptine kinetic parameters; the lag time increased by 0.3 hour and the maximum plasma concentration was lowered (decreased by 25%) and occurred later (tmax increased by 0.5 hour). However, no significant change was found in the area under the plasma concentration-time curve. The trend and extent of changes in the MC5 metabolite parameters were similar to those observed for the parent drug. Absorption of tianeptine is slightly delayed and slowed down without modification of its extent when tianeptine is given at the end of a meal. These slight changes are not clinically relevant for an antidepressant administered three times a day. Despite the changes observed, tianeptine may be given at meal times to improve compliance with treatment.

The effect of chronic alcoholism (with or without associated moderate cirrhosis) on the disposition of the antidepressant tianeptine, which is devoid of substantial first-pass metabolism, was examined in 21 patients and 11 age-matched controls. Pharmacokinetic parameters for tianeptine and its C5 acid analogue metabolite (MC5 metabolite) were estimated by non-compartmental analysis. The area under the curve (AUC) for tianeptine, following a 12.5mg single oral dose, was decreased by 31% in chronic alcoholics and increased by only 14% in cirrhotics, compared to controls. These changes did not attain statistical significance. The trend of changes in the AUC for the MC5 metabolite was similar to that observed for the parent drug. No statistical difference was found in the terminal half-life for both tianeptine and its MC5 metabolite between patients and controls. On the basis of this study, it appears unnecessary to modify the proposed dosage regimen used in clinical trials (tianeptine sodium salt 12.5mg 3 times daily) in chronic alcoholics with or without associated moderate cirrhosis.

Summary— The pharmacokinetics of the tricyclic antidepressant amineptine (Survector®) and its main metabolite were studied in 12 young healthy adults (6 men, 6 women; mean age 35.8 yr). Plasma samples were taken over 24 h following a single oral dose of 100 mg amineptine chloryhdrate. Plasma levels of both compounds were determined by means of high performance liquid chromatography. Amineptine was rapidly absorbed. Mean peak plasma concentrations of amineptine and its metabolite occurred 1 h and 1.5 h, respectively, after product administration. The mean apparent volume of distribution was large: 2.4 l.kg−1. Elimination was rapid; the mean half-lives of the 2 compounds were short: 0.8 h for amineptine and 2.5 h for the metabolite. The mean apparent plasma clearance of amineptine was high (124.8 l.h−1). When the results were adjusted for body weight and surface area, no significant difference in pharmacokinetic parameters was found between men and women. Given its pharmacokinetic characteristics there is no risk of amineptine accumulation and thus it is a particularly easy drug to manage. A standard dosage of amineptine was defined for use in healthy young adults.

129 chronic alcoholic patients, withdrawn from alcohol and presenting major depression or dysthymic disorder, were treated for 4-8 weeks under double-blind conditions either with a new antidepressant, tianeptine (37.5 mg per day), or with amitriptyline (75 mg per day). Both groups presented steady improvement of the symptoms of depression during treatment, as scored on the Montgomery and Asberg Depression Rating Scale and the Hopkins Symptom Checklist self-evaluation; for the latter scale, the improvement was significantly greater in the tianeptine group. In addition to the improvement of mood, tianeptine also produced significant reduction of the somatic complaints of the depressed patients. Furthermore, tianeptine possesses anxiolytic activity, as shown by the change of the Hamilton Anxiety Rating Scale global score, similar to that produced by amitriptyline. The anxiolytic activity of tianeptine was not accompanied by any impairment of vigilance, unlike that of amitriptyline. Tianeptine produced rare, mild anticholinergic effects. The results obtained show that tianeptine is an effective anxiolytic antidepressant, with better safety than amitriptyline, suitable for use in the treatment of mood disorders following alcohol withdrawal.

The study concerns the use of a new antidepressant, tianeptine, as a treatment of depressive and/or amotival syndrome, in 30 drug addicts, detoxified from opiates. From a thymoanaleptic point of view, 85% of the patients exhibit a positive result after 28 days of treatment with 37.5 mg/day. These good results are confirmed by the evolution of the Hamilton Depression Rating Scale global score, which significantly decreases from D0 to D14 and from D14 to D28. The acceptability of the antidepressant is good. Anticholinergic side-effects are very uncommon. Tianeptine appears devoid of any obvious psychostimulant or sedative effect. The drug compliance, estimated by counting the tablets, is very satisfying: there is no tendency to a spontaneous increase of dosing. The follow-up of the patients after drug cessation has not shown any symptoms suggesting psychological or physical dependence towards the drug. During this study in subjects particularly predisposed to the abuse of psychoactive drugs, tianeptine has not induced anything suggesting the possibility of drug abuse or tolerance.