Pharmacokinetic and pharmacodynamic interaction between the antidepressant tianeptine and oxazepam at steady-state.

To assess if any pharmacokinetic or pharmacodynamic interaction at steady-state occurs between the new antidepressant tianeptine and a benzodiazepine (oxazepam) following multiple oral dosing of both drugs, 12 healthy male volunteers entered a balanced three-way double blind cross-over study. Tianeptine (12.5 mg) and/or oxazepam (10 mg) were given three times daily for 4 days. Pharmacokinetic data within a dosing interval at steady-state showed that there were no statistically significant changes in the pharmacokinetics of either tianeptine (and its two major metabolites) or oxazepam when both drugs were co-administered. Psychometric data showed that there was no synergistic negative interaction between the two drugs and that their combination may result in beneficial effects on "alertness" and "happiness".

Tianeptine and alcohol dependence.

Several arguments are in favour of the use of antidepressant drugs in alcohol-dependent patients, especially those acting on the serotoninergic system: (1) neurochemical data indicate the interaction between alcohol and 5-HT metabolism, (2) pharmacological studies show an improvement in the behaviour of alcoholized animals treated with antidepressants, (3) depression is a frequent disease in alcoholic patients. Tianeptine has been shown to be active in the treatment of depression in patients with history of alcohol abuse or dependence. In a first double-blind study performed versus amitryptiline, depression after withdrawal was improved by tianeptine, and biological abnormalities usually related to chronic alcohol intake tended to decrease. Similar results were found in an open study carried out on 277 alcoholic patients treated for 1 year. As these patients were depressed, no definite conclusion could be drawn from these results in respect of a specific action of tianeptine on alcohol dependence. Thus, a multicentre double-blind study has been performed which compared tianeptine (12.5 mg t.i.d) and placebo in 342 non-depressed patients fulfilling DSM-III-R criteria for Psychoactive Substance Dependence (alcohol). Other inclusion criteria were: daily alcohol intake higher than 80 g, minimum score of 3 on the Short-Mast Questionnaire, mean corpuscular volume above 98 fl and/or gamma Gt more than twice the upper limit of normal. The patients were treated for 9 months. The intention-to-treat population and the per protocol population were made up of 327 patients and 111 patients, respectively. The main efficacy criterion was the absence of alcoholic relapse (abstinence) defined by the patient's statements, the investigators clinical judgement and some biological parameters: alcohol blood levels, gamma Gt levels. Secondary criteria were the evolution of the alcohol consumption in the patients who relapsed, cumulative abstinence duration, a visual analogue scale for the evaluation of the appetence for alcohol and the clinical global impressions scale. The statistical analysis showed no difference between both groups in respect of the maintenance of abstinence (intention-to-treat and per protocol populations). In spite of the methodological problems of the studies in dependence (choice of the inclusion and efficacy criteria, especially), the preliminary results obtained with the serotoninergic antidepressants were not confirmed in the different trials performed in the maintenance of alcohol abstinence. The indication of tianeptine should be restricted to the treatment of depressive syndromes, which have a high lifetime prevalence in the alcoholic patient, and which have a noticeable role on the alcoholic relapse.

Analysis of the side effects of tianeptine.

The evaluation of clinical and paraclinical safety of tianeptine was performed in (a) clinical pharmacology studies assessing night sleep EEG organization; electrocardiographic stability by continuous 24-h recordings (Holter's method); ocular tonus in patients with stabilized glaucoma; salivary flow; prolactin secretion; photodynamic dermatologic reactions; cerebral electrical activity; hematologic, hepatic, renal and main metabolic parameters; separately, withdrawal phenomena and addictive potential were searched for in drug addicts; (b) double-blind controlled studies versus reference compounds. The results confirm that the therapeutic safety of tianeptine is satisfactory with respect to clinical side effects and paraclinical parameters. Tianeptine does not induce sedation and thus does not disturb the recovery of active life. It does not induce anticholinergic effects (dry mouth, constipation, etc.), even in elderly subjects. It is devoid of heart and blood pressure side effects including postural hypotension tachycardia, ECG abnormalities, and especially atrioventricular or intraventricular conduction disorders. Moreover, tianeptine does not disturb the hematologic, renal, hepatic parameters, even in alcoholic patients in the detoxification period. It does not induce physical or psychological signs of dependence when discontinued, even in alcoholic patients or drug addicts. No abuse of tianeptine and no tolerance were noted in detoxified opiate addicts.

[Can a serotonin uptake agonist be an authentic antidepressant? Results of a multicenter, multinational therapeutic trial]. / Un stimulant de la capture de sérotonine peut-il être un authentique antidépresseur? Résultats d'un essai thérapeutique multicentrique multinational.

The classical biochemical hypothesis of depression posits a functional deficit in central neurotransmitter systems particularly serotonin (5-HT) and noradrenaline. The major role suggested for 5-HT in this theory led to the development of a large number of compounds which selectively inhibit 5-HT uptake. Numerous clinical trials have demonstrated the antidepressant efficacy of such types of serotoninergic agents, supporting 5-HT deficit as the main origin of depression. Therefore, everything seemed clear: depression was caused by 5-HT deficit. Tianeptine is clearly active in classical animal models predictive of antidepressant activity, and is also active in behavioral screening tests: it antagonizes isolation induced aggression in mice and behavioral despair in rats. Biochemical studies have revealed that in contrast to classical tricyclic antidepressant, tianeptine stimulates 5-HT uptake in vivo in the rat brain. This somewhat surprising property was observed in the cortex and the hippocampus following both acute and chronic administrations. This increase in 5-HT uptake has also been confirmed in rat platelets after acute and chronic administrations. Moreover, in humans, a study in depressed patients demonstrated that tianeptine significantly increased platelet 5-HT uptake after a single administration as well as after 10 and 28 days of treatment. The antidepressant activity of tianeptine has been evaluated in controlled studies versus reference antidepressants. Another study aiming to compare the antidepressant efficacy of tianeptine versus placebo and versus imiporamine is presented. 186 depressed patients were included in this trial. They presented with either Major Depression, single episode (24.6%) or Major Depression recurrent (66.8%) or Bipolar Disorder (depressed) (8.6%).(ABSTRACT TRUNCATED AT 250 WORDS)

[Therapeutic effects of tianeptine in patients with depression and anxiety disorders with or without associated alcoholism]. / Effets thérapeutiques de la tianeptine chez des patients déprimés et anxieux avec ou sans alcoolisme associé.

Tianeptine is a new tricyclic antidepressant. Double blind studies comparing tianeptine with imipramine and amitriptyline have shown the effectiveness of tianeptine's antidepressor action, its properties of non-specific symptoms related to behaviour disorders (anxiety, inhibition ...) and its action on somatic complaints expressed by depressed patients. Tianeptine is an effective antidepressant in cases of depression with anxiety or alcoholism and also leads to good therapeutic response in cases of dysthemia. In depressions with melancholy and endogenous criteria, the expected percentage of responding patients has been observed with tianeptine. A reinforcement of the therapeutic effect has been demonstrated after 6 months of treatment. Its excellent clinical and parclinical acceptability, especially in long term treatment of patients at risk such as elderly depressed patients or alcoholic patients, makes tianeptine a first intention antidepressant.

[Cardiovascular tolerance to tianeptine]. / Acceptabilité cardiovasculaire de la tianeptine.

The cardiovascular effects of tianeptine were assessed by a specific placebo-controlled trial in healthy volunteers and by heart rate, blood pressure and electrocardiogram data analyses in five studies enrolling depressed patients. In two of these studies the effects of tianeptine were compared to those of amitriptyline. The three other studies were performed as open, long-term trials (up to one-year treatment) in large populations of patients (more than 3,300 patients). The findings show that tianeptine does not modify heart rate, blood pressure, conduction or ventricular function. Tianeptine was well tolerated in depressed patients and induced no significant changes at the current dosage in treatment periods from three-months to one-year even in elderly patients, patients with cardiovascular abnormalities or alcoholic patients. Fewer cases of orthostatic hypotension were observed than with other antidepressants. Suicide attempts with tianeptine overdosage did not lead to death due to cardiovascular complications.

[Tianeptine in episodes of major depression with melancholia and signs of endogenicity]. / Etude de la tianeptine dans les épisodes dépressifs majeurs avec mélancolie et signes d'endogénéité.

The effectiveness and good acceptability of tianeptine have been demonstrated in episodes of major depression without melancholia or signs of psychosis which are the valided indications of the tianeptine. In a way of research program, a multicenter study was conducted in 30 patients with D.S.M. III criteria for major depression with melancholia and signs of endogenicity as defined by the Newcastle scale. The patients were treated in a double-blind trial for 42 days. Administration of a placebo for 4 days prior to beginning the study was designed to eliminate rapid responders to placebo. The antidepressant effectiveness was evaluated on the Hamilton (HDRS), Montgomery and Asberg (MADRS) and global clinical impression (GCI) scales. The effect was satisfactory and statistically significant. Seventeen of the 30 patients (57 percent) included in this study improved with tianeptine (CGI-item 2). Results were comparable whatever the diagnosis established on DSM III criteria: bipolar depression, major depression, recurrent or isolated forms. The acceptability evaluated from patient complaints, measurement of blood pressure and laboratory tests was very satisfactory. Treatment was withdrawn in 14 patients with no subsequent withdrawal symptoms. These findings show that tianeptine can be prescribed with success for major depression episodes with melancholia (DSM III) and signs of endogenicity, although it cannot be concluded that patients should be given this treatment in first intention for this type of depression.