Summary
Abstract
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.
Pharmacodynamic Profile
Tianeptine is an antidepressant drug with structural similarities to the tricyclic antidepressant agents but a novel neurochemical profile. The main difference between this and other antidepressant agents is its action on serotonin (5-hydroxytryptamine; 5-HT): tianeptine increases serotonin uptake in the brain and platelets. The behavioural (in animal models) and physical (atrophy of neuronal dendrites) effects of stress on the hypothalamic-pituitary-adrenal axis are reduced by tianeptine, and levels of noradrenaline (norepinephrine) and dopamine are indirectly increased in several regions of the brain. The main metabolite (MC5; pentanoic acid) has some minor antidepressant activity.
Clinical studies indicate that, unlike tricyclic antidepressant agents, tianeptine is not associated with adverse effects on driving skills or cognitive function (such as sedation or impaired memory) and may have slight activating properties, particularly in aspects of attention. Similarly, there appear to be few effects on sleep in healthy volunteers or patients with concurrent depression and alcoholism after withdrawal of alcohol.
Like the selective serotonin reuptake inhibitors (SSRIs) and in contrast with the tricyclic antidepressants, tianeptine has a favourable cardiovascular profile in healthy volunteers and patients with depression, with and without concurrent alcoholism.
Pharmacokinetic Profile
The maximum plasma concentration (Cmax) of tianeptine was 0.3 mg/L, time to Cmax (tmax) was 0.94 hours and bioavailability was 99% after a single oral dose of tianeptine 12.5mg in healthy volunteers. The drug is not subject to first-pass hepatic metabolism. Food decreases Cmax and prolongs tmax but does not affect the extent of absorption. Although the distribution of tianeptine is rapid (distribution half-life 0.7 hours) protein binding is high (95%), resulting in alow volume of distribution (0.5 to 0.8 L/kg) in healthy volunteers.
Tianeptine undergoes extensive extrarenal metabolism and has a short elimination half-life (t1/2β; 2.5 hours in healthy volunteers). The major metabolic pathway of tianeptine is a 2-step β-oxidation process of the aliphatic chain, leading to the formation of 2 main metabolites MC5 and MC3 (propionic acid). MC3 is the main metabolite of tianeptine in urine and MC5 is the main metabolite in plasma. Tianeptine does not undergo cytochrome P450—dependent biotransformation to any significant extent, thus reducing the risk of drug interactions.
The pharmacokinetic profile of a single dose of tianeptine in adults with depression appears similar to that in healthy adult volunteers, although the tmax and t12β were prolonged. Steady-state pharmacokinetics were achieved after 1 month of treatment with tianeptine 37.5 mg/day and were maintained over 3 months. Most values were similar to those seen in depressed patients after a single dose, but the area under the concentration-time curve (AUC) was significantly greater after extended treatment (1.3 vs 1 mg/L · h; p < 0.03).
The pharmacokinetic profile of oral tianeptine was not significantly altered in patients with compromised renal function. However, the t1/2β and AUC of the MC5 metabolite were increased compared with controls, suggesting a decreased clearance of this metabolite in patients with renal failure. Although bioavailability of tianeptine remained high (85%) in elderly individuals, clearance was lower than that reported in younger individuals. The pharmacokinetic profile of tianeptine is not altered in patients with alcoholic cirrhosis and depression.
Therapeutic Efficacy
The clinical antidepressant efficacy of tianeptine 25 to 50 mg/day has been proven against placebo in patients aged 18 to 60 years with major depression (single episode or recurrent) or bipolar disorder (depressed) in 2 double-blind trials. Initial improvements were seen after 7 days, and improvement continued throughout the 6 weeks of study. Improvements from baseline on the Montgomery-Åsberg Depression Rating Scale (MÅDRS) were 44 and 54% with tianeptine and 28 and 38% in placebo recipients (p < 0.05 and p < 0.01, respectively).
Tianeptine 25 to 37.5 mg/day for 1.5 to 3 months had equivalent antidepressant efficacy to fluoxetine 20 mg/day in patients with major depression (single episode or recurrent), bipolar disorder (depressed) or dysthymic disorder in several studies. However, although equivalence was noted in several parameters in elderly patients receiving tianeptine or fluoxetine in one study, reductions from baseline in the MÅDRS scores were statistically significantly greater in those receiving fluoxetine (62 vs 51% in fluoxetine and tianeptine recipients, respectively, compared with 50 vs 51%, respectively, in a study in patients aged 18 to 65 years which used this assessment tool). The antidepressant efficacy of tianeptine 37.5 mg/day (reduction in MÅDRS score of 56%) was equivalent to that of sertraline 50 mg/day (reduction of 54%) after 1.5 months in patients with major depression or bipolar disorder. A study published only in abstract form indicates that tianeptine 37.5 mg/day has similar efficacy to paroxetine 20 mg/day for 3 months (reductions in MÅDRS scores of 62 and 61%, respectively).
In comparative studies with tricyclic or tetracyclic antidepressant agents, the antidepressant efficacy of tianeptine 25 to 50 mg/day (44 to 64% reduction in MÅDRS scores) was equivalent to that of amitriptyline 50 to 100 mg/day for 1 or 1.5 months (53 and 69%), clomipramine 100 to 200 mg/day for 6 months (55%), imipramine 100 to 200 mg/day for 1.5 months (41%) and mianserin 30 to 80 mg/day for 1.5 or 6 months (48 and 50%) in patients with major depression (single episode or recurrent), bipolar disorder (depressed), dysthymic disorder or adjustment disorder. Tianeptine 37.5 mg/day (56% reduction in MÅDRS score) was more effective than maprotiline 75 mg/day for 2 months (47%) in a study of perimenopausal women with anxio-depressive symptoms and less effective than dothiepin 150 to 225 mg/day for 1 month in a small study of patients with depressive disorders.
The anxiolytic efficacy of tianeptine was assessed in several comparative trials of patients with concurrent depression and anxiety. Tianeptine 25 to 50 mg/day appears to have equivalent anxiolytic efficacy to fluoxetine 20 mg/day for 1.5 to 3 months, sertraline 50 mg/day for 1.5 months, amitriptyline 50 to 100 mg/day for 1 to 1.5 months, clomipramine 100 to 200 mg/day for 6 months and mianserin 30 to 80 mg/day for 1.5 or 6 months. Superior anxiolytic efficacy was attributed to tianeptine over maprotiline 75 mg/day for 2 months in a study of perimenopausal women with anxio-depressive symptoms.
Tianeptine 25 to 50 mg/day is effective as long term treatment to prevent relapse or recurrence in patients with depression. It also appears to have potential for use in specific subgroups. The efficacy of tianeptine 25 or 37.5 mg/day was equivalent to that of mianserin 30 mg/day and similar in some but not all parameters to that of fluoxetine 20 mg/day in elderly patients. Patients with chronic alcoholism often develop depression, especially on withdrawal of alcohol. Assessments of antidepressant and anxiolytic efficacy for tianeptine 37.5 mg/day were equivalent to those for amitriptyline 75 mg/day over 1 to 2 months in this patient population.
Improvements in quality-of-life scales with depressed tianeptine recipients were similar to those in patients receiving mianserin or fluoxetine.
Tolerability
The adverse effect profile of tianeptine appears to be similar in many respects to that of the SSRIs, in that cognitive, cardiovascular and bodyweight effects are minimal in comparison with the classical tricyclic antidepressant agents. In fact, in comparisons with placebo, the only symptom appearing significantly more often with tianeptine was headache. In clinical trials, the most common adverse effects seen in patients with depressive disorders receiving tianeptine were gastrointestinal (nausea, constipation, abdominal pain) or CNS (headache, dizziness, change in dreaming) disturbances, which decreased in frequency with continued treatment.
Effects such as dry mouth, hot flushes, somnolence, vertigo, gastrointestinal disturbances, increased bodyweight, increased heart rate and tremor occurred significantly more often in patients receiving tri- or tetracyclic antidepressant agents than in those receiving tianeptine. In studies comparing tianeptine with fluoxetine, paroxetine or sertraline, in contrast, the incidence of most adverse effects was similar; nausea, tremor and palpitations tended to occur more often in fluoxetine recipients, and the incidence of dry mouth tended to be higher in tianeptine recipients. Tianeptine has only rarely been associated with hepatoxicity.
The favourable tolerability profile of tianeptine has been confirmed in long term trials, and in elderly patients (including those with cardiovascular pathology before treatment initiation) and patients with alcoholism. The low incidence of anticholinergic and neurological effects associated with tianeptine is of particular importance in these subgroups, who have increased sensitivity to the adverse effects of psychotropic drugs.
Tianeptine has a wide therapeutic margin; overdosage has been associated with only minor transient adverse effects.
Dosage and Administration
The recommended dosage of tianeptine in patients with depression is 37.5 mg/day orally in 3 divided doses, with meals. The dosage should be reduced in elderly patients and patients with severe renal failure, but dosage reduction is not required in patients with chronic alcoholism or hepatic impairment or those undergoing haemodialysis.
The dosage of tianeptine should be reduced over 1 to 2 weeks when discontinuing treatment, although there is little evidence of psychological or physical dependence on the drug. As with other antidepressants, tianeptine is contraindicated in patients taking monoamine oxidase inhibitors.
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References
McConville BJ, Chaney RO, Browne KL, et al. Newer antidepressants: beyond selective serotonin reuptake inhibitor antidepressants. Pediatr Clin North Am 1998; 45(5): 1157–71
Wilde MI, Benfield P. Tianeptine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression [published erratum appears in Drugs 1995 Jul; 50(1): 156]. Drugs 1995 Mar; 49: 411–39
Labrid C, Mocaër E, Kamoun A. Neurochemical and pharmacological properties of tianeptine, a novel antidepressant. Br J Psychiatry 1992 Feb; 160 Suppl. 15: 56–60
Ansseau M. The paradox of tianeptine. Eur Psychiatry 1993; 8 Suppl. 2: 89s–93s
Chamba G, Lemoine P, Flachaire E, et al. Increased serotonin platelet uptake after tianeptine administration in depressed patients. Biol Psychiatry 1991 Sep 15; 30: 609–17
Datla KP, Curzon G. Behavioural and neurochemical evidence for the decrease of brain extracellular 5-HT by the antidepressant drug tianeptine. Neuropharmacology 1993 Sep; 32: 839–45
De Simoni MG, De Luigi A, Clavenna A, et al. In vivo studies on the enhancement of serotonin reuptake by tianeptine. Brain Res 1992 Mar 6; 574: 93–7
Fattaccini CM, Bolaños-Jimenez F, Gozlan H, et al. Tianeptine stimulates uptake of 5-hydroxytryptamine in vivo in the rat brain. Neuropharmacology 1990 Jan; 29: 1–8
Kato G, Weitsch AF. Neurochemical profile of tianeptine, a new antidepressant drug. Clin Neuropharmacol 1988; 11 Suppl 2: S43–50
Koshikawa N, Kitamura M, Tomiyama K, et al. Chronic treatment with tianeptine attenuates the behavioural effects induced by 5-HTP, but not the effects on hippocampal 5-HT concentrations. Neurosci Res Commun 1998; 22(2): 107–16
Koshikawa N, Mocaër E, Stephenson JD. The effects of tianeptine on wet-dog shakes, fore-paw treading and a flexor reflex in rats are consistent with enhancement of 5-hydroxytryptamine uptake. Eur J Pharmacol 1991 May 30; 198: 51–7
Marinesco S, Poncet L, Debilly G, et al. Effects of tianeptine, sertraline and clomipramine on brain serotonin metabolism: a voltammetric approach in the rat. Brain Res 1996 Oct 14; 736: 82–90
Mennini T, Mocaer E, Garattini S. Tianeptine, a selective enhancer of serotonin uptake in rat brain. Naunyn Schmiedebergs Arch Pharmacol 1987 Nov; 336: 478–82
Ortiz J, Mocaër E, Artigas F. Effects of the antidepressant drug tianeptine on plasma and platelet serotonin concentrations in the rat. Eur J Pharmacol 1991 Jul 9; 199: 335–9
Ortiz J, Mariscot C, Alvarez E, et al. Effects of the antidepressant drug tianeptine on plasma and platelet serotonin of depressive patients and healthy controls. J Affect Disord 1993 Dec; 29: 227–34
Piñeyro G, Deveault L, Blier P, et al. Effect of acute and prolonged tianeptine administration on the 5-HT transporter: electrophysiological, biochemical and radioligand binding studies in the rat brain. Naunyn Schmiedebergs Arch Pharmacol 1995 Feb;351: 111–8
Whitton PS, Sarna GS, O’Connell MT, et al. The effect of the novel antidepressant tianeptine on the concentration of 5-hydroxytryptamine in rat hippocampal dialysates in vivo. Neuropharmacology 1991 Jan; 30: 1–4
Broqua P, Baudrie V, Laude D, et al. Influence of the novel antidepressant tianeptine on neurochemical, neuroendocrinological, and behavioral effects of stress in rats. Biol Psychiatry 1992 Feb 15; 31: 391–400
Broqua P, Baudrie V, Chaouloff F. Differential effects of the novel antidepressant tianeptine on L-5-hydroxytryptophan (5-HTP)-elicited corticosterone release and body weight loss. Eur Neuropsychopharmacol 1992 Jun; 2: 115–20
Bueno L, Fioramonti J, Rettori MC. Inhibition of stress-induced colonic motor alterations by tianeptine [abstract no. 782]. 9th World Congress of Psychiatry; 1993 Jun 6–12; Rio de Janeiro, 200
Conrad CD, Galea LA, Kuroda Y, et al. Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. Behav Neurosci 1996 Dec; 110: 1321–34
Conrad CD, LeDoux JE, Magariños AM, et al. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav Neurosci 1999 Oct; 113: 902–13
Curzon G, Datla KP. Effects of tianeptine on behavioural and neurochemical responses to immobilization stress. Eur Psychiatry 1993; 8Suppl. 2: 61s–6s
Curzon G, Kennett GA, Sarna GS, et al. The effects of tianeptine and other antidepressants on a rat model of depression. Br J Psychiatry 1992 Feb; 160 Suppl. 15: 51–5
Delbende C, Contesse V, Mocaër E. The novel antidepressant, tianeptine, reduces stress-evoked stimulation of the hypothalamo-pituitary-adrenal axis. Eur J Pharmacol 1991 Sep 24; 202: 391–6
Delbende C, Mocaër E, Rettori M, et al. Effect of the antidepressant tianeptine on the activity of the hypothalamo-pituitary-adrenal axis. Eur Psychiatry 1993; 8Suppl.2: 49s–54s
Delbende C, Tranchand Bunel D, Tarozzo G, et al. Effect of chronic treatment with the antidepressant tianeptine on the hypothalamo-pituitary-adrenal axis. Eur J Pharmacol 1994 Jan 14; 251: 245–51
Fontanges R, Mimouni J, de Grieve X, et al. Effect of tianeptine on neuroendocrine, enzyme and behavioral responses to restraint stress in male rats. Eur Psychiatry 1993; 8Suppl. 2: 67s–73s
Guillaume V, Magnan E, Cataldi M, et al. Effect of tianeptine on the hypothalamic control of the corticotrophic response to stress. Eur Psychiatry 1993; 8Suppl.2: 55s–60s
Luine V, Villegas M, Martinez C, et al. Repeated stress causes reversible impairments of spatial memory performance. Brain Res 1994 Mar 7; 639: 167–70
Magariños AM, Deslandes A, McEwen BS. Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. Eur J Pharmacol 1999 Apr 29; 371: 113–22
McEwen BS, Angulo J, Gould E, et al. Antidepressant modulation of isolation and restraint stress effects on brain chemistry and morphology. Eur Psychiatry 1993; 8Suppl. 2: 41s–8s
McEwen BS, Conrad CD, Kuroda Y, et al. Prevention of stress-induced morphological and cognitive consequences. Eur Neuropsychopharmacol 1997 Oct; 7Suppl 3: S323–8
Mennini T, Taddei C, Codegoni A, et al. Acute noise stress reduces [3H]5-hydroxytryptamine uptake in rat brain synaptosomes: protective effects of buspirone and tianeptine. Eur J Pharmacol 1993 Sep 14; 241: 255–60
Sacchetti G, Bonini I, Waeterloos GC, et al. Tianeptine raises dopamine and blocks stress-induced noradrenaline release in the rat frontal cortex. Eur J Pharmacol 1993 May 19; 236: 171–5
Watanabe Y, Gould E, Daniels DC, et al. Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol 1992 Nov 3; 222: 157–62
Whitton PS, Sarna GS, Datla KP, et al. Effects of tianeptine on stress-induced behavioural deficits and 5-HT dependent behaviour. Psychopharmacology 1991; 104(1): 81–5
Frankfurt M, McKittrick CR, McEwen BS, et al. Tianeptine treatment induces regionally specific changes in monoamines. Brain Res 1995 Oct 23; 696: 1–6
Invernizzi R, Pozzi L, Garattini S, et al. Tianeptine increases the extracellular concentrations of dopamine in the nucleus accumbens by a serotonin-independent mechanism. Neuropharmacology 1992 Mar; 31: 221–7
Tanda G, Carboni E, Frau R, et al. Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential? Psychopharmacology 1994; 115: 285–8
Vaugeois JM, Corera AT, Deslandes A, et al. Although chemically related to amineptine, the antidepressant tianeptine is not a dopamine uptake inhibitor. Pharmacol Biochem Behav 1999 Jun; 63: 285–90
Kelly JP, Leonard BE. The effect of tianeptine and sertraline in three animal models of depression. Neuropharmacology 1994 Aug; 33: 1011–6
Mocaër E, Rettori MC, Kamoun A. Pharmacological antidepressive effects and tianeptine-induced 5-HT uptake increase. Clin Neuropharmacol 1988; 11 Suppl. 2: S32–42
Nowakowska E, Kus K, Chodera A, et al. Behavioural effects of fluoxetine and tianeptine, two antidepressants with opposite action mechanisms, in rats. Arzneimittelforschung 2000 Jan; 50: 5–10
Lacroix P, Rocher N, Deslandes A. Antidepressant effects of tianeptine, of its two enantiomers and its predominant metabolite in the learned helplessness test in rats [abstract]. Eur Neuropsychopharmacol 1996 Sep; 6 Suppl. 4: 70
Oluyomi AO, Datla KP, Curzon G. Effects of the (+) and (−) enantiomers of the antidepressant drug tianeptine on 5-HTP-induced behaviour. Neuropharmacology 1997 Mar; 36: 383–7
File SE, Andrews N, Zangrossi Jr H. Tianeptine counteracts the anxiogenic effects of benzodiazepine withdrawal, but not those of exposure to cat odour. Eur Psychiatry 1993; 8Suppl. 2: 75s–80s
File SE, Mabbutt PS. Effects of tianeptine in animal models of anxiety and on learning and memory. Drug Dev Res 1991; 23(1): 47–56
Uzbay IT, Çinar MG, Aytemir M, et al. Analgesic effect of tianeptine in mice. Life Sci 1999; 64: 1313–9
Jaffard R, Mocaer E, Poignant J-C, et al. Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on alcohol-induced alternation deficits in mice. Behav Pharmacol 1991 Feb; 2: 37–46
Béracochéa D, Deslandes A, Jaffard R. A comparison between the effects of tianeptine and paroxetine on memory deficits induced by long-term ethanol consumption in mice [in French]. Encephale 1994 Jan–Feb; 20: 13–6
Daoust M, Compagnon P, Legrand E, et al. Tianeptine, a specific serotonin uptake enhancer, decreases ethanol intake in rats. Alcohol Alcohol 1992 Jan; 27: 15–7
File SE, Andrews N, al-Farhan M. Anxiogenic responses of rats on withdrawal from chronic ethanol treatment: effects of tianeptine. Alcohol Alcohol 1993 May; 28: 281–6
Saletu B, Grunberger J, Anderer P, et al. Comparative pharmacodynamic studies with the novel serotonin uptake-enhancing tianeptine and -inhibiting fluvoxamine utilizing EEG mapping and psychometry. J Neural Transm 1996; 103: 191–216
Sommers DK, Van Wyk M, Snyman JR. Changes in the prolactin response to dexfenfluramine following tianeptine treatment. Med Sci Res 1997; 25(7): 477–8
Checkley S. Neuroendocrine mechanisms and the precipitation of depression by life events. Br J Psychiatry 1992; 160Suppl. 15: 7–17
Curzon G. Serotonergic mechanisms of depression. Clin Neuropharmacol 1988; 11Suppl. 2: S11–20
Delbende C, Delarue C, Lefebvre H, et al. Glucocorticoids, transmitters and stress. Br J Psychiatry 1992 Feb; 160Suppl. 15: 24–34
Fromenty B, Freneaux E, Labbe G, et al. Tianeptine, a new tricyclic antidepressant metabolized by β-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice. Biochem Pharmacol 1989; 38(21): 3743–51
Poirier MF, Galinowski A, Amado-Boccara I, et al. Effects of tianeptine on attention, memory and psychomotor performance using neuropsychological methods in young healthy volunteers. Eur Psychiatry 1993; 8Suppl. 2: 95s–102s
Toon S, Holt BL, Langley SJ, et al. Pharmacokinetic and pharmacodynamic interaction between the antidepressant tianeptine and oxazepam at steady-state. Psychopharmacology 1990; 101: 226–32
von Frenckell R, Ansseau M, Dulcire C, et al. Effects of tianeptine on vigilance and memory in young healthy volunteers. Psychiatr & Psychobio 1990; 5: 375–80
Ridout F, Hindmarch I. A double-blind placebo-controlled investigation into the effects of tianeptine and mianserin on psychomotor performance and driving skills [abstract]. Eur Neuropsychopharmacol 1999 Sep; 9 Suppl. 5: S240
Mendlewicz J. Sleep EEG study of acute administration of tianeptine in ten young healthy volunteers. A double-blind placebo-controlled study. Servier. C-1574-214-BEL, volume 1/6; 1994 (Data on file)
Macher JP, Minot R, Duval F, et al. Neuroelectrophysiologic studies in alcoholic patients, undergoing withdrawal and depressed, and treated by tianeptine [in French]. Presse Med 1991 Nov 14; 20: 1853–7
Juvent M, Douchamps J, Delcourt E, et al. Lack of cardiovascular side effects of the new tricyclic antidepressant tianeptine. A double-blind, placebo-controlled study in young healthy volunteers. Clin Neuropharmacol 1990 Jan–Feb; 13: 48–57
Petrova E, Akopov G. Predictors of therapeutic efficacy of tianeptine in the treatment of panic disorders [abstract]. Neuropsychobiology 1997; 35(3): 167
Invernizzi G, Aguglia E, Bertolino A, et al. The efficacy and safety of tianeptine in the treatment of depressive disorder: results of a controlled double-blind multicentre study vs. amitriptyline. Neuropsychobiology 1994; 30: 85–93
Lasnier C, Marey C, Lapeyre G. Cardiovascular tolerance to tianeptine [in French]. Presse Med 1991 Nov 14; 20: 1858–63
Lôo H, Malka R, Defrance R, et al. Tianeptine and amitriptyline: controlled double-blind trial in depressed alcoholic patients. Neuropsychobiology 1988; 19: 79–85
Malka R, Lôo H, Ganry H, et al. Long-term administration of tianeptine in depressed patients after alcohol withdrawal. Br J Psychiatry 1992 Feb; 160Suppl. 15: 66–71
Salvadori C, Ward C, Defrance R, et al. The pharmacokinetics of the antidepressant tianeptine and its main metabolite in healthy humans — influence of alcohol co-administration. Fundam Clin Pharmacol 1990; 4: 115–25
Grislain L, Gele P, Bertrand M, et al. The metabolic pathways of tianeptine, a new antidepressant, in healthy volunteers. Drug Metab Dispos 1990 Oct; 18: 804–8
Royer RJ, Albin H, Barrucand D, et al. Pharmacokinetic and metabolic parameters of tianeptine in healthy volunteers and in populations with risk factors. Clin Neuropharmacol 1988; 11Suppl. 2: S90–6
Bouver I, Farinotti R, Gelé P, et al. Metabolism of tianeptine after single and multiple dosing in man [abstract no. 31.02.35]. Psychopharmacology 1988; 96 Suppl.: 275
Riché C. The pharmacokinetics of tianeptine and its MC5 metabolite on repeated dosing in depressed adults. Servier. PMH 1574 01 021; Aug, 1991 (Data on file)
Salvadori C, Merdjan H, Brouard R, et al. Tianeptine and its main metabolite. Disposition in chronic renal failure and haemodialysis. Fundam Clin Pharmacol 1990; 4: 663–71
Royer RJ, Royer-Morrot MJ, Paille F, et al. Tianeptine and its main metabolite pharmacokinetics in chronic alcoholism and cirrhosis. Clin Pharmacokinet 1989 Mar; 16: 186–91
Carlhant D, Le Garrec J, Guedes Y, et al. Pharmacokinetics and bioavailability of tianeptine in the elderly. Drug Invest 1990; 2(3): 167–72
Demotes-Mainard F, Galley P, Manciet G, et al. Pharmacokinetics of the antidepressant tianeptine at steady state in the elderly. J Clin Pharmacol 1991 Feb; 31: 174–8
Jeanniot JP. A study of the pharmacokinetics of tianeptine and its metabolite MC5 in the elderly depressed patient after single and repeated administration of tianeptine sodium salt. Servier. P2.R.90.22.01574.HPK; Jun, 1991 (Data on file)
Dresse A, Rosen JM, Brems H, et al. Influence of food on tianeptine and its main metabolite kinetics. J Clin Pharmacol 1988 Dec; 28: 1115–9
Mocquard MT, Proust L, Deslandes A, et al. Identification of the enzymes involved in the primary pathways of tianeptine using human in vitro models [abstract]. Eur Neuropsychopharmacol 1998 Nov; 8Suppl. 2: S206
Ansseau M, Wauthy J, von Frenckell R, et al. Gradually increased doses of tianeptine: maximal tolerated dose and linearity of the pharmacokinetics [abstract]. An Psiquiatria 1992; 8Suppl. 1: 56
Ansseau M. Tolerance and pharmacokinetic study following single oral increasing doses of tianeptine sodium salt in healthy male volunteers. Servier. P2.R.92.10.01574.HPK; Jan, 1993 (Data on file)
Grasela TH, Fiedler-Kelly JB, Salvadori C, et al. Development of a population pharmacokinetic database for tianeptine. Eur J Clin Pharmacol 1993; 45(2): 173–9
Grasela TH, Fiedler-Kelly JB, Salvadori C, et al. Predictive performance of pre-marketing tianeptine pharmacokinetic parameters as applied to post-marketing data [abstract]. Clin Pharmacol Ther 1993 Feb; 53: 215
Les Laboratoires Servier. Tianeptine prescribing information. Neuilly-sur-Seine, France, 2000
Brion S, Audrain S, de Bodinat C. Episodes of severe depression in subjects over 70 years of age. Efficacy and acceptability of tianeptine and mianserine [in French]. Presse Med 1996; 25(9): 461–8
Faltus F, Novotny V. Comparison of efficacy of tianeptin and fluoxetin in treatment of depressive syndrome. Institut de Recherches Internationales Servier, 2000. (Data on file)
Cassano GB, Heinze G, Lôo H, et al. A double-blind comparison of tianeptine, imipramine and placebo in the treatment of major depressive episodes. Eur Psychiatry 1996; 11(5): 254–9
Costa e Silva JA, Ruschel SI, Caetano D, et al. Placebo-controlled study of tianeptine in major depressive episodes. Neuropsychobiology 1997; 35: 24–9
Montgomery SA. Clinically relevant effect sizes in depression. Eur Neuropsychopharmacol 1994; 4 (3 Special issue): 283–4
Kamoun A, Delalleau B, Ozun M. Can a serotonin uptake agonist be an authentic antidepressant? Results of a multicenter, multinational therapeutic trial [in French]. Encephale 1994 Sep–Oct; 20: 521–5
Guelfi JD, Pichot P, Dreyfus JF. Efficacy of tianeptine in anxious-depressed patients: results of acontrolled multicenter trial versus amitriptyline. Neuropsychobiology 1989; 22: 41–8
Paes de Sousa M, Figueira L, Ferreira L, et al. Efficacy and acceptability of tianeptine in the long-term treatment of major depression. Double blind trial: tianeptine vs clomipramine. Portugal: Servier Especialidades Farmacticas, Lda. 2000. (Data on file)
Svestka J, Synek O. Tianeptine versus dosulepine in the treatment of acute depressive disorders. A controlled study [poster]. 13th Congress of the European College of Neuropsychopharmacology; 2000 Sept 9–13; Munich, Germany
Svestka J, Synek O. Tianeptine versus dosulepine in the treatment of acute depressive disorders. A controlled study [abstract]. Eur Neuropsychopharmacol 2000 Sep; 10Suppl. 3: S252–3
Chaby L, Grinsztein A, Weitzman JJ, et al. Anxio-depressive disorders in menopausal and pre-menopausal women. Double blind study of tianeptine versus maprotiline [in French]. Presse Med 1993 Jul 3–10; 22: 1133–8
Ansseau M, Bataille M, Briole G, et al. Controlled comparison of tianeptine, alprazolam and mianserin in the treatment of adjustment disorders with anxiety and depression. Human Psychopharmacology 1996; 11(4): 293–8
Donoghue J, Taylor DM. Suboptimal use of antidepressants in the treatment of depression. CNS Drugs 2000 May; 13: 365–83
Bakish D, Habib R, Hooper CL. Mixed anxiety and depression: diagnosis and treatment options. CNS Drugs 1998 Apr; 9(4): 271–80
Alby JM, Ferreri M, Cabanne J, et al. Efficacy of tianeptine (Stablon™) for the treatment of major depression and dysthymia with somatic complaints. Acomparative study versus fluoxetine (Prozac™) [in French]. Ann Psychiatr 1993; 8(2): 136–44
Faltus F, Novotny V. Tianeptine for the treatment of major depressive episode: a double-blind study versus fluoxetine [poster]. 42nd Czech-Slovak Psychopharmacological Conference; 2000 Jan; Jesenik Spa, Czech Republic
Guelfi JD, Bouhassira M, Bonett-Perrin E, et al. Study of the efficacy of fluoxetine versus tianeptine in the treatment of elderly depressed patients followed in general practice [in French]. Encephale 1999 May–Jun; 25: 265–70
Lôo H, Saiz-Ruiz J, Costa-e-Silva JACE, et al. Efficacy and safety of tianeptine in the treatment of depressive disorders in comparison with fluoxetine. J Affect Disord 1999 Dec; 56: 109–18
Waintraub L, Septien L, Azoulay P. Efficacy and safety of tianeptine in major depression: evidence from a 3-month controlled clinical trial versus paroxetine [abstract]. Eur Neuropsychopharmacol 2000 Apr; 10Suppl. 2: S51
Szádóczky E, Füredi J. Efficacy and acceptability of tianeptine and sertraline in acute treatment phase of depression. Neuropsychopharmacologia Hungarica 2000; II(4): 171–7
Lôo H, Ganry H, Dufour H, et al. Long-term use of tianeptine in 380 depressed patients. Br J Psychiatry 1992 Feb; 160Suppl. 15: 61–5
Delalleau B, Dulcire C, Le-Moine P, et al. Analysis of the side effects of tianeptine. Clin Neuropharmacol 1988; 11Suppl. 2: S83–9
Dalery J, Dagens-Lafont V, De Bodinat C. Efficacy of tianeptine vs placebo in the long-term treatment (16.5 months) of unipolar major recurrent depression [in French]. Encephale 1997 Jan–Feb; 23: 56–64
Rouillon F, Steru L, Wood S. Methodological approaches to the long-term study of antidepressants. Eur Psychiatry 1996; 11: 109–15
Raffaitin F Efficacy and acceptability of tianeptine in the elderly: a review of clinical trials. Eur Psychiatry 1993; 8Suppl.2: 117s–24s
Malauzat D, Danic C, Peyrouzet J-M, et al. The importance and need to prolong antidepressant treatment after the resolution of depression in elderly patients [in French]. Psychol Med 1990; 22(9): 903–22
Chapuy P, Cuny G, Delomier Y, et al. Tianeptine and depression in 140 elderly patients treated for 1 year [in French]. Presse Med 1991 Nov 14; 20: 1844–52
Guelfi JD, Dulcire C, Le Moine P, et al. Clinical safety and efficacy of tianeptine in 1,858 depressed patients treated in general practice. Neuropsychobiology 1992; 25: 140–8
Ducrocq F. Depression and sexual disorders [in French]. Encephale 1999 Sep–Oct; 25: 515–6
Balleyguier C, Stérin D, Ziol M, et al. Acute mixed hepatitis caused by tianeptine (letter) [in French]. Gastroenterol Clin Biol 1996; 20: 607–8
Le Bricquir Y, Larrey D, Blanc P, et al. Tianeptine — an instance of drug-induced hepatotoxicity predicted by prospective experimental studies. J Hepatol 1994 Nov; 21: 771–3
Rifflet H, Vuillemin E, Rifflet I, et al. Acute painful and febrile hepatic involvement related to ingestion of tianeptine (letter) [in French]. Gastroenterol Clin Biol 1996; 20: 606–7
Bourgeois M, Delalleau B, Féline A, et al. Tianeptine in episodes of major depression with melancholia and signs of endogenicity [in French]. Presse Med 1991 Nov 14; 20: 1837–43
Vandel P, Regina W, Bonin B, et al. Abuse of tianeptine. A case report [in French]. Encephale 1999 Nov–Dec; 25: 672–3
Henry JA, Rivas CA. Constraints on antidepressant prescribing and principles of cost-effective antidepressant use. Part 1: depression and its treatment. Pharmaco Economics 1997 May; 11: 419–43
Wittchen H-U, Knäuper B, Kessler R. Lifetime risk of depression. Br J Psychiatry 1994; 165Suppl. 26: 16–22
Sambunaris A, Hesselink JK, Pinder R, et al. Development of new antidepressants. J Clin Psychiatry 1997; 58Suppl. 6: 40–53
Roose SP, Spatz E. Treatment of depression in patients with heart disease. J Clin Psychiatry 1999; 60Suppl. 20: 34–7
Andrews JM, Nemeroff CB. Contemporary management of depression. Am J Med 1994 Dec 19; 97Suppl. 6A: 24S–32S
Montejo-González AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex & Marital Therapy 1997 Fall; 23(3): 176–94
ASHP Commission on Therapeutics. ASHP therapeutic position statement on the recognition and treatment of depression in older adults. Am J Health System Pharm 1998 Dec 1; 55: 2514–8
Frackiewicz EJ, Sramek JJ, Cutler NR. Gender differences in depression and antidepressant pharmacokinetics and adverse events. Ann Pharmacother 2000 Jan; 34: 80–8
Montgomery SA, Dufour H, Brion S, et al. The prophylactic efficacy of fluoxetine in unipolar depression. Br J Psychiatry 1988; 153Suppl. 3: 69–75
Kupfer DJ, Frank E, Perel JM, et al. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1992; 49: 769–73
Montgomery SA, Dunbar G. Paroxetine is better than placebo in relapse prevention and the prophylaxis of recurrent depression. Int Clin Psychopharmacol 1993; 8: 189–95
Doogan DP, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry 1992; 160: 217–22
Rouillon F Anxiety with depression: a treatment need. Eur Neuropsychopharmacol 1999 Jul; 9 Suppl. 3: S87–92
Bremner JD. Does stress damage the brain? [in English]. Biol Psychiatry 1999; 45(7): 797–805
Salzman CS. Practical considerations for the treatment of depression in elderly and very elderly long-term care patients. J Clin Psychiatry 1999; 60Suppl. 20: 30–3
Malka R. Role of drug therapies in the treatment of alcoholism: alcohol and anxiety — alcohol and depression. Clin Neuropharmacol 1988; 11Suppl. 2: S69–73
Schulberg HC, Katon WJ, Simon GE, et al. Best clinical practice: guidelines for managing major depression in primary medical care. J Clin Psychiatry 1999; 60Suppl. 7: 19–26
Ballenger JC, Davidson JRT, Lecrubier Y, et al. Consensus statement on the primary care management of depression from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry 1999; 60 Suppl. 7: 54–61
Bouhassira M, Allicar MP, Blachier C, et al. Which patients receive antidepressants? A ‘real world’ telephone study [in English]. J Affect Disord 1998; 49(1): 19–26
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Various sections of the manuscript reviewed by: G.B. Cassano, Department of Psychiatry, University of Pisa, Pisa, Italy; C.D. Conrad, Department of Psychology, Arizona State University, Tempe, Arizona, USA; C. Delbende, Laboratoire de Biologie Animale, Université des Sciences et Technologies de Lille, Villeneuve d’Ascq, France; G. Invernizzi, 1a Cattedra di Clinica Psichiatrica, Università Degli Studi di Milano, Milan, Italy; A.P. Kashyap, Department of Psychiatry, Waitemata Health, Waitakere Hospital, Auckland, New Zealand; N. Koshikawa, Department of Pharmacology, Nihon University School of Dentistry, Tokyo, Japan; M.C. Mauri, 1a Cattedra di Clinica Psichiatrica, Università Degli Studi di Milano, Milan, Italy; S. Montgomery, London, England; E. Nowakowska, Department of Pharmacology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
Data Selection
Sources: Medical literature published in any language since 1995 on tianeptine, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search term was ‘tianeptine’. EMBASE search term was ‘tianeptine’. AdisBase search terms were ‘tianeptine’ or ‘S 1574’. Searches were last updated December 2000.
Selection: Studies in patients with depressive disorders who received tianeptine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Tianeptine, depression, pharmacodynamics, pharmacokinetics, therapeutic use.
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Wagstaff, A.J., Ormrod, D. & Spencer, C.M. Tianeptine. Mol Diag Ther 15, 231–259 (2001). https://doi.org/10.2165/00023210-200115030-00006
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DOI: https://doi.org/10.2165/00023210-200115030-00006