Serotonin Reuptake ENHANCER as Anti-Depressant

Also see:
Anti-Serotonin, Pro-Libido
Estrogen, Serotonin, and Aggression
Estrogen, Glutamate, & Free Fatty Acids
Estrogen Increases Serotonin
Omega -3 “Deficiency” Decreases Serotonin Producing Enzyme
Linoleic Acid and Serotonin’s Role in Migraine
Gelatin > Whey
Thyroid peroxidase activity is inhibited by amino acids
Whey, Tryptophan, & Serotonin
Tryptophan, Fatigue, Training, and Performance
Carbohydrate Lowers Free Tryptophan
Protective Glycine
Intestinal Serotonin and Bone Loss
Hypothyroidism and Serotonin
Gelatin, Glycine, and Metabolism
Whey, Tryptophan, & Serotonin
Tryptophan, Sleep, and Depression
Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response.

The predominant theory of depression suggests that a deficiency of serotonin (the “feel good neurotransmitter” or “happy chemical”) is a major player in depression. However, a more unified & integrated approach sees serotonin as prime facilitator of stress and degeneration that synergizes with other stress substances like estrogen, polyunsaturated fats, excitatory amino acids, prolactin, and glucocorticoids to create vicious, stress stimulating loops.

The proven anti-depression effects of tianapetine (Stablon, Coaxil, Tatinol), a selective serotonin reuptake enhancer (SSRE), calls into question the current model of depression since it has the opposite effect of the selective serotonin reuptake inhibitors (SSRI) drugs commonly used to treat depressives. Instead of inhibiting the uptake of serotonin like an SSRI, an SSRE increases uptake of serotonin, lowering serotonin’s activity. Tianeptine is well tolerated, decreases the excitatory effects of glutatmate, prevents or reverse stress-related brain changes, doesn’t cause dependence or withdrawal symptoms, improves memory, and does not impair cognitive function.

SSRI drugs can sometimes cause very adverse side effects including increased symptoms of depression and suicide, as the Boston Globe article “Prozac Revisited” discusses. Making a Killing: The Untold Story of Psychotropic Drugging is a documentary that reveals how the current model for treating depression needs modification.

Tianeptine is referred to as an “atypical” anti-depression treatment. With a different perspective on physiology and the stress response, it’s the SSRI treatments that are atypical. Hopefully, the efficacy of tianeptine will open the mainstream’s consciousness to the stress-promoting effects of serotonin. This new consciousness can lead to a better understanding of other stress-related health problems.

Drugs. 1995 Mar;49(3):411-39.
Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression.
Wilde MI, Benfield P.
Tianeptine is a novel antidepressant agent, both structurally (modified tricyclic) and in terms of its pharmacodynamic profile. Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT) in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebral tissue and plasma, and reduces serotonergic-induced behaviour. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, antagonises stress-induced behavioural deficits and prevents changes in cerebral morphology. The antidepressant efficacy of tianeptine, as shown in 2 trials of patients with major depression or depressed bipolar disorder with or without melancholia, is greater than that of placebo. In patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymic disorder, the antidepressant efficacy of short term (4 weeks to 3 months) tianeptine therapy appears to be similar to that of amitriptyline, imipramine and fluoxetine and may be superior to that of maprotiline in patients with coexisting depression and anxiety. However, submaximal dosages of amitriptyline and maprotiline were used in these studies. Preliminary evidence suggests that tianeptine may also be effective in patients with endogenous depression. Progressive therapeutic improvements have been observed with up to 1 year of tianeptine treatment, and long term therapy may reduce the rate of relapse or recurrence. Tianeptine is effective in the treatment of depression in elderly and post-alcohol-withdrawal patient subgroups. Tianeptine was more effective in reducing psychic anxiety than placebo in patients with major depression or depressed bipolar disorder with or without melancholia. The overall anxiolytic properties of tianeptine in patients with coexisting depression and anxiety appear to be similar to those of amitriptyline, imipramine and fluoxetine and may be superior to those of maprotiline, although submaximal dosages of amitriptyline and maprotiline were used. Studies of tianeptine in patients with primary anxiety have not been conducted. Tianeptine is well tolerated in the short (3 months) and long (up to 1 year) term. The incidence of dry mouth (38 vs 20%), constipation (19 vs 15%), dizziness/syncope (23 vs 13%), drowsiness (17 vs 10%) and postural hypotension (8 vs 3%) are greater with amitriptyline than with tianeptine. Insomnia and nightmares occur in more tianeptine than amitriptyline recipients (20 vs 7%). The relative lack of sedative, anticholinergic and cardiovascular adverse effects with tianeptine makes it particularly suitable for use in the elderly and in patients following alcohol withdrawal; these patients are known to have increased sensitivity to the adverse effects associated with psychotropic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Encephale 1994 Sep-Oct;20(5):521-5.
[Can a serotonin uptake agonist be an authentic antidepressant? Results of a multicenter, multinational therapeutic trial].
Kamoun A, Delalleau B, Ozun M
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%).

CNS Drugs. 2008;22(1):15-26.
Neurobiological and clinical effects of the antidepressant tianeptine.
Kasper S, McEwen BS.
The precise neurobiological processes involved in depression are not clear, but it is recognized that numerous factors are involved, including changes in neurotransmitter systems and brain plasticity. Neuroplasticity refers to the ability of the brain to adapt functionally and structurally to stimuli. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, learning, memory and emotions are altered in depression. The mechanisms underlying alterations in neuroplasticity are believed to relate to changes in neurotransmitters, hormones and growth factors. Structural changes in the hippocampus that have been proposed to be associated with depression include dendritic atrophy, reduced levels of cerebral metabolites, decreased adult neurogenesis (generation of new nerve cells) and reduced volume. Increased dendritic branching occurs in the basolateral nucleus of the amygdala. Reduced neuronal size and glial cell density occur in the prefrontal cortex. Clinically, tianeptine is an antidepressant effective in reducing symptoms of depression in mild to moderate-to-severe major depression, including over the long term. Tianeptine is also effective in alleviating the symptoms of depression-associated anxiety. It is generally well tolerated, with little sedation or cognitive impairment. The efficacy profile of tianeptine could be explained by its neurobiological properties observed in animal models. Tianeptine prevents or reverses stress-associated structural and cellular changes in the brain and normalizes disrupted glutamatergic neurotransmission. In particular, in the hippocampus, it prevents stress-induced dendritic atrophy, improves neurogenesis, reduces apoptosis and normalizes metabolite levels and hippocampal volume. Tianeptine also has beneficial effects in the amygdala and cortex and can reverse the effects of stress on neuronal and synaptic functioning. The neurobiological properties of tianeptine may provide an explanation not only for its antidepressant activity, but also for its anxiolytic effects in depressed patients and its lack of adverse effects on cognitive function and memory.

Neuropsychopharmacol Hung. 2008 Dec;10(5):305-13.
[“Atypical” antidepressive mechanisms: glutamatergic modulation and neuroplasticity in case of tianeptine].
[Article in Hungarian]
András S.
Recent neurobiological and clinical studies demonstrated that neuroplasticity, a principal mechanism of neuronal adaptation and survival, was disrupted in major depression and in long-term stress. Increasing research data show, that structural remodeling and maladaptive dysfunction of certain brain regions is a main component of major depressive illness. Tianeptine, an “atypical” antidepressant, which has a pharmacological action different from the “typical” reuptake blocking agents, underlined a re-evaluation of the neurobiological basis of major depression and revealed that the disorder cannot be explained only by the classic monoamine hypothesis. Neuroplasticity hypothesis of major depression brings the possibility to make important contributions to the diagnosis, however, it may helpful in the understanding the detailed subtle drug effects, which cannot be revealed by pure neurochemical mechanisms. In this review, effects of tianeptine on neuroplasticity, neuroprotection, neurogenesis, hippocampal stress response, long term potentiation, and, as well as on the glutamatergic system and other neuronal networks are evaluated.

Eur Psychiatry. 2002 Jul;17 Suppl 3:318-30.
Structural plasticity and tianeptine: cellular and molecular targets.
McEwen BS, Magarinos AM, Reagan LP.
The hippocampal formation, a structure involved in declarative, spatial and contextual memory, undergoes atrophy in depressive illness along with impairment in cognitive function. Animal model studies have shown that the hippocampus is a particularly sensitive and vulnerable brain region that responds to stress and stress hormones. Studies on models of stress and glucocorticoid actions reveal that the hippocampus shows a considerable degree of structural plasticity in the adult brain. Stress suppresses neurogenesis of dentate gyrus granule neurons, and repeated stress causes remodeling of dendrites in the CA3 region, a region that is particularly important in memory processing. Both forms of structural remodeling of the hippocampus are mediated by adrenal steroids working in concert with excitatory amino acids (EAA) and N-methyl-D-aspartate (NMDA) receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, head trauma, and ischemia, and alterations of calcium homeostasis that accompany age-related cognitive impairment. Tianeptine (tianeptine) is an effective antidepressant that prevents and even reverses the actions of stress and glucocorticoids on dendritic remodeling in an animal model of chronic stress. Multiple neurotransmitter systems contribute to dendritic remodeling, including EAA, serotonin, and gamma-aminobutyric acid (GABA), working synergistically with glucocorticoids. This review summarizes findings on neurochemical targets of adrenal steroid actions that may explain their role in the remodeling process. In studying these actions, we hope to better understand the molecular and cellular targets of action of tianeptine in relation to its role in influencing structural plasticity of the hippocampus.

Mol Psychiatry. 2005 Jun;10(6):525-37.
Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine.
McEwen BS, Olié JP.
Recent studies have provided evidence that structural remodeling of certain brain regions is a feature of depressive illness, and the postulated underlying mechanisms contribute to the idea that there is more to antidepressant actions that can be explained exclusively by a monoaminergic hypothesis. This review summarizes recent neurobiological studies on the antidepressant, tianeptine (S-1574, [3-chloro-6-methyl-5,5-dioxo-6,11-dihydro-(c,f)-dibenzo-(1,2-thiazepine)-11-yl) amino]-7 heptanoic acid, sodium salt), a compound with structural similarities to the tricyclic antidepressant agents, the efficacy and good tolerance of which have been clearly established. These studies have revealed that the neurobiological properties of tianeptine involve the dynamic interplay between numerous neurotransmitter systems, as well as a critical role of structural and functional plasticity in the brain regions that permit the full expression of emotional learning. Although the story is far from complete, the schema underlying the effect of tianeptine on central plasticity is the most thoroughly studied of any antidepressants. Effects of tianeptine on neuronal excitability, neuroprotection, anxiety, and memory have also been found. Together with clinical data on the efficacy of tianeptine as an antidepressant, these actions offer insights into how compounds like tianeptine may be useful in the treatment of neurobiological features of depressive disorders.

J Psychopharmacol. 2004 Dec;18(4):553-8.
The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder.
Schruers K, Griez E.
Antidepressants that inhibit the reuptake of serotonin (5-HT) are particularly effective in the treatment of panic disorder. Evidence suggests that increased 5-HT availability is important for the anti-panic effect of serotonergic drugs and in maintaining the response to selective serotonin reuptake inhibitors (SSRIs). Tianeptine is an antidepressant with 5-HT reuptake enhancing properties (i.e. the opposite pharmacological profile to that of SSRIs). Therefore, no effect would be expected in panic disorder. The aim of the present study was to compare the effect of tianeptine with that of paroxetine, a selective 5-HT reuptake inhibitor with demonstrated efficacy in panic disorder, on the vulnerability to a laboratory panic challenge in panic disorder patients. Twenty panic disorder patients were treated with either tianeptine or paroxetine for a period of 6 weeks, in a randomized, double-blind, separate group design. The reaction to a 35% CO(2) panic challenge was assessed at baseline and after treatment. Improvement on several clinical scales was also monitored. Tianeptine, as well as paroxetine, showed a significant reduction in vulnerability to the 35% CO(2) panic challenge. In spite of their opposite influence on 5-HT uptake, both tianeptine and paroxetine appeared to reduce the reaction to the panic challenge. These results raise questions about the necessity of 5-HT uptake for the therapeutic efficacy of anti-panic drugs.

Neuropsychobiology. 1997;35(1):24-9.
Placebo-controlled study of tianeptine in major depressive episodes.
Costa e Silva JA, Ruschel SI, Caetano D, Rocha FL, da Silva Lippi JR, Arruda S, Ozun M.
The efficacy and safety of tianeptine were compared, in the course of a multicentre randomised, double-blind, parallel group study, to those of placebo in the treatment of Major Depressions and Bipolar Disorder, Depressed with or without melancholia, without psychotic features. After a 1-week run-in placebo period, 126 depressed out-patients presenting DSM-III-R Major Depression or Bipolar Disorder, Depressed, with a total MADRS score of at least 25, were treated for 42 days with either tianeptine (25-50 mg/day) or placebo. Efficacy assessments were MADRS, CGI, HARS, Zung Depression Self Rating Scale and a VAS. Better efficacy of tianeptine was shown, and confirmed by covariance analyses, in final MADRS scores of the intention-to-treat population, of patients treated for at least 14 days and of completers; also in CGI items 1 and 2, MADRS item 10, and VAS. The results confirmed the efficacy of tianeptine (mean dosage: 37.5 mg/day) in the treatment of Major Depression and Bipolar Disorder, Depressed, with or without melancholia, compared to placebo. Tianeptine’s acceptability did not differ from that of placebo. For adverse events, a higher incidence of headaches was found with tianeptine.

Presse Med. 1996 Mar 16;25(9):461-8.
[Major depressive episodes in patients over 70 years of age. Evaluation of the efficiency and acceptability of tianeptine and mianserin].
[Article in French]
Brion S, Audrain S, de Bodinat C.
OBJECTIVES:
The aim of this multicenter study was to compare the efficacy, acceptability and impact on quality of life of tianeptine (T) and mianserine (M) in patients over 70 years of age with major depression.
METHODS:
Fulfilment of the DSM IIIR criteria for major depression with a total Montgomery and Asberg depression rating scale (MADRS) of at least 25 and a Hamilton anxiety rating scale (HARS) of at least 18 were required for inclusion. The 315 men and women enrolled in the study were given, by double blind assignment, either T: 37.5 mg/day, T: 25 mg/day or M: 30 mg/day. Treatment duration was 6 months in all three groups and follow-up continued for 3 months after withdrawal of tianeptine or mianserine. The main efficacy criterion was the MADRS score evaluated at each of 6 visits at day 15 (D15) and month 1 (M1), M2, M4, M4.5 and M6. The HARS score was another efficacy criterion. Overall assessment of efficacy and acceptability was done at each visit by the patient and the investigator. Both the patient and the physician estimated global effectiveness on a quality of life scale at M1, M3, M6 and M9.
RESULTS:
In the intention-to-treat population (n = 299), the antidepressant efficacy of tianeptine and mianserine was not significantly different, whether assessed as effect on anxiety or on quality of life. Scores however tended to be better in the T: 37.5 mg group. Acceptability was good as shown by the low number of adverse events in all 3 groups, but at D15, the incidence of impaired vigilance or equilibrium was significantly lower in the T: 25 mg group than in the M: 30 mg group, emphasizing the advantage of tianeptine in decreasing the risk of falling. Physician-assessed tolerance and acceptability was significantly different at M3 (p = 0.014) and at M6 (p = 0.028) in favor of T: 37.5 mg, indicating that though increasing dosage does not improve efficacy, there is no risk of poorer acceptability.
CONCLUSION:
These findings reconfirm the antidepressive efficacy, acceptability and safety of tianeptine. They also confirm the anxiolytic aspect associated with the antidepressive effect of tianeptine without any sedative effect. Tianeptine is particularly well indicated in the treatment of depression in elderly or very elderly subjects.

CNS Drugs. 2002;16(1):65-75.
Efficacy and safety of tianeptine in major depression: evidence from a 3-month controlled clinical trial versus paroxetine.
Waintraub L, Septien L, Azoulay P.
OBJECTIVE:
This study was performed to compare the efficacy and safety of tianeptine and paroxetine in the treatment of major depression. Anxiolytic drug use was systematically reported to provide an indirect evaluation of the anxiolytic activity of both treatments. Zopiclone use was assessed to provide an indirect evaluation of the possible hypnotic activity of both treatments.
DESIGN AND SETTING:
This was a 3-month controlled, randomised, double-blind clinical trial which involved 82 centres in France.
PATIENTS:
277 outpatients who met DSM-IV criteria for major depression.
INTERVENTIONS:
Patients were treated with either tianeptine (12.5mg three times daily) or paroxetine (20mg once daily plus two placebo capsules). The drug dosages could be doubled after 3 weeks if required by the patient’s medical state.
MAIN OUTCOME MEASURES AND RESULTS:
There was a significant decrease in the Montgomery-Asberg Depression Rating Scale score in both groups (from 28.9 at baseline to 11 at endpoint in the tianeptine group, and from 29.6 to 11.6 in the paroxetine group) after 3 months of treatment. No significant difference was evident between the groups. Secondary criteria confirmed the antidepressant efficacy of both medications, with no difference between tianeptine and paroxetine (Hamilton Depression Rating Scale global score at endpoint, Clinical Global Impression final scores, number of responders, delay-to-response, rate of dosage doubling at day 21). The anxiolytic and hypnotic consumption rates decreased in both groups, with no significant difference between the groups. There was no significant difference in clinical safety parameters.
CONCLUSION:
Tianeptine appears to be as effective and as safe as paroxetine for the ambulatory treatment of major depression.

CNS Drugs. 2001;15(3):231-59.
Tianeptine: a review of its use in depressive disorders.
Wagstaff AJ, Ormrod D, Spencer CM.
Tianeptine is an antidepressant agent with a novel neurochemical profile. It increases serotonin (5-hydroxytryptamine; 5-HT) uptake in the brain (in contrast with most antidepressant agents) and reduces stress-induced atrophy of neuronal dendrites. Like the selective serotonin reuptake inhibitors (SSRIs) and in contrast with most tricyclic antidepressant agents, tianeptine does not appear to be associated with adverse cognitive, psychomotor, sleep, cardiovascular or bodyweight effects and has a low propensity for abuse. Tianeptine has a comparatively favourable pharmacokinetic profile. It is not subject to first-pass hepatic metabolism, has high bioavailability and limited distribution, and is rapidly eliminated. While this offers advantages for tianeptine over the tricyclic antidepressant agents in terms of dose titration, treatment changes and potential drug interactions, its rapid elimination makes adherence to dosage schedules more important. Tianeptine differs from most antidepressants in that it is not primarily metabolised by the hepatic cytochrome P450 system, indicating less likelihood of drug-drug interactions; this is of particular interest for elderly patients. Tianeptine, in dosages of 25 to 50 mg/day, has been investigated in patients with major depression, depressed bipolar disorder, dysthymia or adjustment disorder. It has equivalent antidepressant efficacy to several classical antidepressant agents (amitriptyline, clomipramine, imipramine, mianserin) and the SSRIs fluoxetine (in most patients), paroxetine and sertraline. Comparison with maprotiline indicated superior efficacy for tianeptine but dothiepin appeared superior in another study. Extended treatment with tianeptine decreases the incidence of relapse/recurrence of depression. Tianeptine appears to be as effective as fluoxetine, sertraline, amitriptyline, clomipramine and mianserin and more effective than maprotiline in improving associated anxiety in patients with depressive disorders. Depression and anxiety symptoms in alcohol dependant patients also respond well to tianeptine. The adverse effects associated with tianeptine are similar in many respects to those of the SSRIs and minimal in comparison with the tricyclic antidepressants. The most common adverse effects are nausea, constipation, abdominal pain, headache, dizziness and changes in dreaming. Anticholinergic effects occur less often with tianeptine than with tricyclic agents. Hepatoxicity is rare. The dosage should be decreased in elderly patients and those with severe renal failure, but adjustment is not necessary in patients with alcoholism or hepatic impairment, or those undergoing haemodialysis. Conclusions: The antidepressant efficacy and favourable tolerability and pharmacokinetic profiles of tianeptine in patients with depression, including those with associated anxiety, have been proven; the data indicate that it may have additional potential in specific subgroups of depressed patients such as the elderly and those with chronic alcoholism.

J Sex Med. 2006 Sep;3(5):910-7.
Tianeptine can be effective in men with depression and erectile dysfunction.
El-Shafey H, Atteya A, el-Magd SA, Hassanein A, Fathy A, Shamloul R.
INTRODUCTION:
Erectile dysfunction (ED) and depression are highly prevalent medical disorders affecting men of diverse cultures throughout the world. Tianeptine is a new antidepressant drug with less adverse effects on sexual functions.
AIM:
To evaluate the efficacy of tianeptine in the treatment of mild to moderate depression with ED.
METHODS AND MAIN OUTCOME MEASURES:
A randomized, double-blind, placebo-controlled, crossover trial. Subjects were assigned either tianeptine or matching placebo, each for 8 weeks. All patients were followed up on monthly basis where they were asked to complete three assessment questionnaires, namely, Anxiety and Depression Scale, Brief Sexual Inventory, and Quality-of-life and erection questionnaire. All patients were asked a global assessment question. Treatment-responsive subjects were defined as study participants who had scores 1-16 on the Anxiety and depression Scale, showed normal erectile function on the Brief Sexual Inventory, and answered “yes” to the global assessment question.
RESULTS:
Of the 237 consecutive men complaining of ED of >6 months and screened for this study, 110 patients met our inclusive criteria; 42 declined to participate. The remaining 68 patients were randomly assigned to treatment. Significant improvement (P < 0.05) was observed during the active drug phase in all three assessments questionnaires, in comparison with the placebo phase. Forty-eight patients (72.7%) of the subjects during the active drug phase were classified as responders, while 19 (27.9%) of the subjects during placebo phase were classified as responders.
CONCLUSIONS:
Tianeptine could be considered an effective therapy for the treatment of depression and ED. Further large-scale multicentered studies are warranted.

Curr Neuropharmacol. 2008 December; 6(4): 311–321.
Tianeptine: An Antidepressant with Memory-Protective Properties
Phillip R Zoladz, Collin R Park, Carmen Muñoz, Monika Fleshner, and David M Diamond
The development of effective pharmacotherapy for major depression is important because it is such a widespread and debilitating mental disorder. Here, we have reviewed preclinical and clinical studies on tianeptine, an atypical antidepressant which ameliorates the adverse effects of stress on brain and memory. In animal studies, tianeptine has been shown to prevent stress-induced morphological sequelae in the hippocampus and amygdala, as well as to prevent stress from impairing synaptic plasticity in the prefrontal cortex and hippocampus. Tianeptine also has memory-protective characteristics, as it blocks the adverse effects of stress on hippocampus-dependent learning and memory. We have further extended the findings on stress, memory and tianeptine here with two novel observations: 1) stress impairs spatial memory in adrenalectomized (ADX), thereby corticosterone-depleted, rats; and 2) the stress-induced impairment of memory in ADX rats is blocked by tianeptine. These findings are consistent with previous research which indicates that tianeptine produces anti-stress and memory-protective properties without altering the response of the hypothalamic-pituitary-adrenal axis to stress. We conclude with a discussion of findings which indicate that tianeptine accomplishes its anti-stress effects by normalizing stress-induced increases in glutamate in the hippocampus and amygdala. This finding is potentially relevant to recent research which indicates that abnormalities in glutamatergic neurotransmission are involved in the pathogenesis of depression. Ultimately, tianeptine’s prevention of depression-induced sequelae in the brain is likely to be a primary factor in its effectiveness as a pharmacological treatment for depression.

Mol Psychiatry. 2010 Mar;15(3):237-49. Epub 2009 Aug 25.
The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation.
McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E.
Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine’s mechanism of action with a focus on the glutamatergic system, which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.

Br J Psychiatry Suppl. 1992 Feb;(15):66-71.
Long-term administration of tianeptine in depressed patients after alcohol withdrawal.
Malka R, Lôo H, Ganry H, Souche A, Marey C, Kamoun A.
Alcohol interferes with the central metabolism of the catecholamines and especially with indolamines (5-HT). Thus, the use of an antidepressant such as tianeptine, whose main neurochemical effect is to increase the reuptake of 5-HT, seems to be particularly indicated for the continued treatment of depressed patients after alcohol withdrawal. This study evaluated the therapeutic efficacy and acceptability during long-term administration of tianeptine in depressed patients (major depressive episode or dysthymic disorder) in a multicentre trial, after withdrawal from alcohol abuse or dependence. The results relate to 130 depressed patients, who abstained from alcohol and received treatment for a year. Only one patient dropped-out because of side-effects, and medication was interrupted in 5% of subjects because of alcoholic relapses. Prescribed in the long term, tianeptine did not produce orthostatic hypotension, changes in bodyweight, or alterations in the ECG. All changes found in haematological and biochemical investigations suggested an improvement in patients’ physical state. This, and other studies, indicate that tianeptine appears to have the potential to be a safe antidepressant, which might be particularly useful in those patients who are susceptible to the side-effects of psychotropic drugs.

J Clin Psychopharmacol. 2003 Apr;23(2):155-68.
Clinical and neurobiological effects of tianeptine and paroxetine in major depression.
Nickel T, Sonntag A, Schill J, Zobel AW, Ackl N, Brunnauer A, Murck H, Ising M, Yassouridis A, Steiger A, Zihl J, Holsboer F.
Selective serotonin reuptake inhibitors (SSRIs) are widely used as effective pharmacological agents to treat depressive disorders. In contrast to the SSRIs, which block the presynaptic serotonin (5-HT) transporter and by this route increase the concentration of serotonin in the synaptic cleft, the antidepressant tianeptine enhances the presynaptic neuronal reuptake of 5-HT and thus decreases serotonergic neurotransmission. Both SSRIs and tianeptine are clinically effective; however, their opposite modes of action challenge the prevailing concepts on the need of enhancement of serotonergic neurotransmission. To better understand the differences between these two opposite pharmacological modes of action, we compared the changes induced by tianeptine and paroxetine on psychopathology, the hypothalamic-pituitary-adrenocortical (HPA) system, and cognitive functions in a double-blind, randomized, controlled trial including 44 depressed inpatients over a period of 42 days. Depressive symptomatology significantly improved in all efficacy measures, with no significant differences between tianeptine and paroxetine. There was a trend toward better response to the SSRI among women. Assessment of the HPA system showed marked hyperactivity before the beginning of treatment, which then normalized in most of the patients, without significant differences between the two antidepressants. Cognitive assessments showed no significant differences between the two drugs investigated. The results of the current study suggest that the initial effect, i.e., enhancement or decrease of 5-HT release, is only indirectly responsible for antidepressant efficacy, and they support the notion that downstream adaptations within and between nerve cells are crucial. The normalization of the HPA system as a common mode of action of different antidepressants seems to be of special interest.

Prog Neuropsychopharmacol Biol Psychiatry. 1998 Feb;22(2):319-29.
Tianeptine therapy for depression in the elderly.
Saiz-Ruiz J, Montes JM, Alvarez E, Cervera S, Giner J, Guerrero J, Seva A, Dourdil F, López-Ibor JJ.
1. Depression is frequent in the elderly but difficult both to diagnose and treat due to a number of distinctive features. 2. Tianeptine is a novel antidepressant with a reverse mode of action to that of the selective serotonin reuptake inhibitors yet with proven efficacy and safety. 3. 63 elderly patients (mean age:68.8 years; range:65-80 years) with depressive symptoms (major depression:55.6%; dysthymia:44.4%) were included in a 3-month open multicenter study with tianeptine (25 mg daily). 4. 43 patients (68.2%) completed the study. There were no drop-outs due to side-effects. Total Montgomery and Asberg Depression Rating Scale scores were significantly decreased (p < 0.01) on day 14, with a response rate of 76.7%. 5. Improvements were also observed in anxiety and cognitive performance. Side-effects were seen in only 11.7% of patients, with no changes in laboratory or ancillary safety parameters. Tianeptine is thus effective and well tolerated in this category of patient.

Encephale. 1997 Jan-Feb;23(1):56-64.
[Value of tianeptine in treating major recurrent unipolar depression. Study versus placebo for 16 1/2 months of treatment].
[Article in French]
Daléry J, Dagens-Lafant V, De Bodinat C.
OBJECTIVES:
The aim of this study was to assess the efficacy of tianeptine vs placebo in the long-term treatment of unipolar major recurrent depression.
METHOD:
286 patients who met DSM-III-R criteria for major depression with a Hamilton Depression Rating Scale (HDRS-21 items) score > or = 17, and with a history of at least one previous episode within the last 5 years, were treated in an open trial with tianeptine for 6 weeks. 185 patients who responded to treatment at day 42 (intent-to-treat) were randomly assigned to tianeptine 37.5 mg/day (n = 111), or placebo (n = 74). Among these patients 173 were strict responders to tianeptine (per-protocol-population), as defined in the present study by a 50% reduction in the HDRS score, a global score lower than 15 and confirmation by clinical evaluation. Both groups were comparable except for the severity of the depressive episode (significantly more severe in the tianeptine group (33%) than in the placebo group (18%)) (p = 0.018). Relapses and recurrences were defined by a HDRS score > or = 15, and/or a CGI score > or = 4, the recurrences being confirmed by the clinician. Patients were subsequently evaluated at day 63, and the 3rd, 6th, 9th, 12th, 15th and 18th month.
RESULTS:
Special attention was given to the number of relapses and recurrences, and to the delay of onset (Kaplan Meier Method). Between day 42 and 18th month (intent-to-treat group), the rate of relapses and recurrences was significantly higher in the placebo group (36%), than in the tianeptine group (16%) (p = 0.002). Long term comparison of the rate of patients without recurrence or relapse, also showed a significant difference in favour of tianeptine (p < 0.001). The difference between teh 2 groups increased within time. Secondary analysis of relapses and recurrence in the intent-to-treat group showed a significantly higher rate of relapses for the placebo group (p = 0.002); the rate of patients without recurrences in the long term appeared to be at the limit in the intent-to-treat group (p = 0.067) but significant in the per-protocol-group, in favour of tianeptine (p = 0.36). Furthermore, no difference was observed between the 2 groups, in terms of tolerance. Secondary effects attributed to treatment by investigators were rare and benign in each group.
CONCLUSIONS:
These data support the use of tianeptine in the long term treatment of unipolar major recurrent depression. Relapses and recurrences were 2 to 3 times less frequent with tianeptine as compared to placebo. Furthermore, prolonged treatment with tianeptine appeared to be very well tolerated.

[Fluoxetine is Prozac, an SSRI]
Hum Psychopharmacol. 2002 Aug;17(6):299-303.
Tianeptine and fluoxetine in major depression: a 6-week randomised double-blind study.
Novotny V, Faltus F.
In a 6-week, multicentre, randomised, double-blind controlled study, tianeptine (37.5 mg/day) and fluoxetine (20 mg/day) were compared for efficacy and safety in 178 patients with major depression. No significant difference was shown between the two drugs, either in terms of efficacy (MADRS, CGI, COVI) or in terms of safety, except for the CGI ‘severity of illness’ which was lower at the end point with tianeptine than with fluoxetine. The percentages of responders (as defined by a 50% decrease of the MADRS score from baseline to end point) were 75% with tianeptine and 67% with fluoxetine, showing the efficacy of both drugs. In conclusion, both tianeptine and fluoxetine are effective and well-tolerated treatments for major depression.

BMJ Case Rep. 2012 Oct 9;2012.
Tianeptine in combination with monoamine oxidase inhibitors for major depressive disorder.
Tobe EH.
Major depressive disorder may respond to monotherapy with monoamine oxidase inhibitors (MAOIs) or tianeptine. Literature search showed no reports of MAOIs combined with tianeptine. The method included was clinical case history. A 59-year-old woman had partial improvement of depression with the MAOI tranylcypromine combined with topiramate, trazodone and ziprasidone. The patient had further improvement of depression symptoms after addition of tianeptine. No adverse events were evident. The combination of MAIOs and tianeptine may be effective for refractory major depressive disorder.

Neuropsychobiology. 1992;25(3):140-8.
Clinical safety and efficacy of tianeptine in 1,858 depressed patients treated in general practice.
Guelfi JD, Dulcire C, Le Moine P, Tafani A.
1,927 outpatients were included by 392 general practitioners in an open study in order to evaluate the safety of tianeptine in the ambulatory treatment of depression. The results of 1,858 depressed patients without melancholia and psychotic features, fulfilling DSM III criteria of Major Depressive Episode or Dysthymic Disorder, could be analysed. 1,458 patients completed the 3-month treatment period. The group treated with 37.5 mg/day of tianeptine showed improvement on the Montgomery-Asberg Depression Rating Scale. With regard to the clinical tolerance of tianeptine, somatic complaints were rarely reported and adverse events necessitating premature termination of treatment (4.8% of included patients) were without clinical severity. Cardiovascular, haematologic, hepatic and biochemical safety were verified. No signs of dependence and no specific withdrawal symptoms were found after discontinuation of treatment.

Psychiatr Prax. 2003 May;30(4):221-2.
[Therapy resistant major depression: improvement of symptomatology after combining antidepressants with Tianeptine (Stablon)].
[Article in German]
Niederhofer H.
OBJECTIVES:
In common, depressive disorders are treated with various antidepressants, the number of which is enormously increasing. Nevertheless, in some cases therapy resistance is observed. In these cases, neuroleptics are used as an alternative. Recently, Tianeptin (Stablon) has also been used for the treatment of depressive disorders.
METHOD:
We report a 32-year old “therapy resistant” depressive female. Monotherapy with antidepressants and Tianeptin (Stablon) was ineffective.
RESULTS:
Finally, a combination of antidepressants and Tianeptin (Stablon) was effective and lowered the HAMD-Score significantly.
DISCUSSION:
A combination of antidepressants and Tianeptin (Stablon) seems to be an effective new Option for the treatment of “therapy resistant” major depressions.

Eur Neuropsychopharmacol 1997 Oct;7 Suppl 3:S323-S328.
Prevention of stress-induced morphological and cognitive consequences.
McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM, McKittrick C.
Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals, and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may contribute to these changes, since the elevations of glucocorticoids in Cushing’s syndrome and during normal aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats at the cellular level, and we have been investigating underlying mechanisms in search of agents that will block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as well as impairment of initial learning of a radial arm maze task. Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells, we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced impairment of radial maze learning. Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or corticosterone, and that the final common path may involve interactive effects between serotonin and glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus. We discuss the implications of these findings for treating cognitive impairments and the risk for dementia in the elderly.