Stress elicits adaptive responses from the brain, but it can also lead to maladaptive consequences. For example, stress can precipitate mental illness, including depression. Prolonged stress also causes damage to neurons in the hippocampus. Antidepressant drugs must be evaluated, not only for their ability to potentiate adaptive responses, but also to inhibit maladaptive consequences of stress. Ongoing research in our laboratory has compared the atypical tricyclic antidepressant, tianeptine, with the typical tricyclics, desipramine and imipramine, with respect to the effects of isolation and repeated restraint stress. Tianeptine and desipramine similarly attenuated isolation stress-induced increases in locus coeruleus and midbrain tyrosine hydroxylase mRNA levels and isolation-stress induced decreases in preproenkephalin mRNA levels in striatum and nucleus accumbens. However, tianeptine and imipramine differed in their effects in the cerebral cortex and hippocampus on 5HT2, and 5HT1A receptor levels but, surprisingly, produced similar effects on levels of the serotonin transporter labelled with [3H] paroxetine. Tianeptine also prevented stress-induced reductions in the length and number of branchpoints of dendrites of CA3 pyramidal neurons in hippocampus; comparison with effects of typical tricyclics are ongoing. Tianeptine also blocked effects of corticosterone treatment to reduce branching and length of CA3 dendrites. These actions of tianeptine may be due to interactions between 5HT and excitatory amino acids in the mossy fiber terminals on CA3 pyramidal neurons. Taken together, these results indicate that tianeptine has unique properties compared to some other antidepressant drugs, but shares in common with those drugs the ability to attenuate stress effects on tyrosine hydroxylase gene expression and on the serotonin transporter. It remains to be seen whether these actions are the basis of a common antidepressant action.

Previous experiments have shown that tianeptine, a new psychotropic agent with antidepressant properties, improves performance in several learning and memory tasks in mice. In more recent investigations, tianeptine was found to completely alleviate working memory deficits produced by long-term alcohol intoxication and to prevent abnormal memory loss in aged animals (Jaffard et al, 1991b, 1991c). The aim of this paper was to examine how this last finding may be integrated in our understanding of brain mechanisms involved in memory loss. For this purpose, we present a brief review of experimental data and theories which, at different levels of analysis, seems to be relevant to this issue. Together with the subsequent examination of the conditions in which tianeptine was found to improve long-term retention, we suggest that: i) long-term memory loss would be largely determined by the initial encoding of information, so that ii) tianeptine would help aged animals to use spatial mapping or configural associations more efficiently at the time of initial acquisition. This, in turn, suggests that one of the main brain target sites for tianeptine in enhancing memory is the hippocampal formation.

Tianeptine, whose main neurochemical action is to increase 5-HT uptake, significantly decreased alcohol consumption in rats. During a tianeptine long-term treatment study, gamma-GT levels in depressed alcoholic patients decreased, suggesting that this medication could be useful in alcoholism. The role of tianeptine in the prevention of alcoholic relapses is being evaluated in a double-blind placebo-controlled study. Two hundred non-depressed patients satisfying DSM III-R criteria for Psychoactive Substance Dependence (alcohol – daily intake greater than 80 g) will enter the study after alcohol withdrawal. A minimum score of three on the Short-Mast Questionnaire, mean cell volume above 98 f1 and/or gamma-GT more than twice the upper normal value are required. Patients are treated as out-patients and surveyed for 9 months. The maintenance of abstinence is estimated through clinical and laboratory assessments. The alcohol intake is evaluated in patients who relapse. Efficacy is determined secondarily using Clinical Global Impressions Scale, Hopkins Symptom Check List and visual analogue scales. Somatic complaints are collected using AMDP-5. Preliminary results are presented.

In the course of the international development of tianeptine (T), depressed patients were recruited by 15 centres from Belgium, Italy, Portugal, Spain and Switzerland in a double-blind parallel group study versus placebo (P) and imipramine (I). Efficacy and safety of tianeptine are evaluated in the treatment of major depressions (single episode or recurrent) and depressed bipolar disorders. The initial severity of the depression is controlled by a MADRS score equal to or greater than 25. Rapid placebo responded are excluded during a placebo pre-inclusion period (duration: 1 week). After an increasing daily dose period (3 days), depressed patients are treated, until the 14th day (D14), at a constant daily dose (T: 37.5 mg; I: 150 mg; P: 3 capsules). After D14 and until the end of the 6th week, a flexible dosage can be used in accordance with the therapeutic efficacy and/or the potential adverse events (T: 25–50 mg; I: 100–200 mg; P: 2–4 capsules). The antidepressant efficacy is regularly evaluated by rating scales (MADRS, HSCL). Anxiety linked to depression is evaluated by the Hamilton Anxiety Rating Scale. The safety is controlled by clinical examination, laboratory parameters and a check-list of side-effects. Preliminary results are presented and discussed showing the interest of surveillance of trials in progress.

Tianeptine is a clinically effective anti-depressant with the unusual profile of increasing 5-HT uptake, thereby decreasing the synaptic availability of 5-HT. In the social interaction test of anxiety in the rat, withdrawal from chronic diazepam treatment produced a significant anxiogenic response that was reversed by acute administration of tianeptine (2.5–10 mg/kg). These doses were without significant effect in the vehicle-treated rats. Exposure of rats to cat odour resulted in anxiogenic responses in the plus-maze and social interaction tests and in decreased exploration. These changes were not reversed by 5 days treatment with tianeptine (2.5–10 mg/kg). Thus, tianeptine may not he effective in all anxiety states, but could be particularly useful in treating patients withdrawn from benzodiazepines.

Tianeptine has been shown to be an effective antidepressant versus reference drugs and to be better tolerated than amitriptyline, without the latter's anticholinergic side-effects. Its good acceptability has been confirmed in long-term use (1 year) in large patient groups. In an open pilot trial in endogenous melancholia, tianeptine showed the same activity as would be expected of a conventional antidepressant. This is being verified in a double-blind trial versus maprotiline. In a separate open study, it has demonstrated a potential to prevent relapse and recurrence in depressed patients treated for 1 year. These results are currently being tested versus placebo.

The acceptability and efficacy of tianeptine were evaluated in three open trials in a total of 549 elderly patients, 426 of whom were treated for 3 months and 188 for 1 year. The therapeutic effect was that expected from an effective antidepressant, with a marked response after treatment for one month. In the geriatric trial, where patients were primarily dysthymic, continuation of treatment after 6 months consolidated the improvement already observed. Tianeptine also had a favorable long-term effect in chronic refractory depression. Drop-outs due to side-effects were few (4.4%), despite the high risk population. All pre-treatment complaints improved on tianeptine. The high frequency of somatic complaints expressed before treatment confirmed the extent to which depression is somatised in the elderly. Concomitant physical disease present in 87% of patients did not restrict the use of tianeptine. The fact that tianeptine has a low incidence of anticholinergic effects and no affinity for either H1 or α1 receptors makes it a particularly easy drug to use in elderly subjects who are sensitive to the side-effects of psychotropic agents.

A study was performed in young healthy volunteers in order to test the possible action of tianeptine, a new antidepressant drug, on cognitive performances. Attention tests, memory tests, a non-verbal inductive reasoning test and a sleep questionnaire were used in this double-blind placebo-controlled crossover study. The two one-week drug administration periods were separated by a one-week wash-out period. The methodology permitted us to evaluate the learning effect during the familiarization with the tests and to clear the results of the study from this parameter which could possibly distort analysis. For this large range of tests, the results showed that tianeptine did not affect the level of functioning of the volunteers after their familiarization with the tests. These results are in contrast with those obtained by different authors with classical tricyclic antidepressants.

The classical biochemical hypothesis of depression posits a functional deficit in central neurotransmitter systems, particularly serotonin (5-HT) and/or noradrenaline. The major support for this theory was that antidepressants increase the amount of neurotransmitters in the synaptic cleft, by inhibiting reuptake mechanisms (tricyclics) or inhibiting enzymatic catabolism (MAOIs). 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 reuptake, such as fluvoxamine, fluoxetine, citalopram, sertraline, paroxetine, etc. Numerous clinical studies have demonstrated the antidepressant activity of such types of agents, supporting 5-HT deficit as the main origin of depression. Tianeptine is active in classical animal models of antidepressants. Its antidepressant efficacy has been established in controlled trials involving a large number of patients. Several biochemical studies however demonstrated that tianeptine induces in acute as well as in chronic conditions, a presynaptic increase of 5-HT reuptake, both in animal and human platelets and animal CNS. Therefore, as a 5-HT reuptake enhancer, tianeptine exhibits a mechanism of action totally opposite to 5-HT reuptake blockers such as fluoxetine but, paradoxically, both mechanisms of action are associated with a therapeutic activity in depressive disorders. Several hypotheses to explain these paradoxical findings and different methodologies to test them clinically are proposed.

The effects of the novel antidepressant tianeptine, after acute or chronic administration, were compared in normal and restraint-stressed (30 min or 2 h) Wistar rats. Tianeptine, at the dose of 10 mg/kg, did not exert any effect in non-stressed rats. However, in animals restrained for 30 min, tianeptine reduced the increase of circulating ACTH and β-endorphin levels without modification of corticosterone. Moreover, it antagonized the deficit of vertical exploratory activity in an open field. In rats restrained for 2 hours, a single injection of tianeptine suppressed the stress-induced increase of TAT hepatic activity and moderately attenuated the deficit of activity in the open field. This effect was less marked and not statistically significant after chronic treatment.

The novel antidepressant drug tianeptine had an antidepressant-like effect on a rat model of depression based on the deficit in open field activity observed on the day after 2 h immobilization. Thus, tianeptine (10 mg/kg ip) given 2 h after the end of the immobilization period led to the deficit being opposed. Similar results were obtained using rats previously given 10 mg/kg of the drug per day for 13 days and a final dose 2 h after the end of immobilization. Other workers have found that tianeptine attenuates stress-induced activation of the hypothalamo-pituitary-adrenal axis. Possible relationships between these findings are discussed together with the paradoxical co-existence of the antidepressant properties of tianeptine with its ability to decrease the availability of 5-HT to receptors.

Stress-induced stimulation of corticotropic function involves the activation of hypothalamic corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which can be measured by improved methods of neuroendocrine investigation. The antiserotoninergic tricyclic antidepressant, tianeptine, reduces the corticotropic response to stress, as shown by a reduction in hypothalamo-hypophyseal portal CRH and AVP levels.

The effect of the antidepressant agent, tianeptine, on the hypothalamo-pituitary-adrenal (HPA) axis was studied in adult male rats under basal and stressed conditions. Chronic treatment with tianeptine (10 mg/kg; 2 weeks; twice a day) induced a significant decrease of hypothalamic CRF (–12%) and pituitary ACTH concentrations (–21%), suggesting that tianeptine reduces the activity of hypothalamic CRF neurons and pituitary corticotrophs. The possible effect of tianeptine in the neuroendocrine response to stress was thus investigated. Rats were submitted to restraint stress for 30 min; under these conditions ACTH and corticosterone levels were considerably increased. A single injection of tianeptine was found to significantly reduce stress-evoked elevations of plasma ACTH and corticosterone. Time-course experiments, consisting of administering tianeptine 1–3 h before immobilization stress, revealed that the maximum inhibitory effect of tianeptine occurs about 2 h after injection of the antidepressant. Administration of various doses of tianeptine (from 2.5 to 20 mg/kg) showed that the effect of the drug was dose-dependent; the maximum effective dose being 10 mg/kg. Taken together, these data indicate that tianeptine may exert original ‘anti-stress’ activity.