Source: Journal of Psychiatric Practice

Date: Volume 10(5) September 2004 pp 323-330

Tianeptine : A Facilitator of the Reuptake of Serotonin and Norepinephrine as an Antidepressant?

PRESKORN, SHELDON H. MD

SHELDON H. PRESKORN, MD, is Professor and Chairman, Department of Psychiatry, University of Kansas School of Medicine-Wichita, and Medical Director, Clinical Research Institute, Wichita, Kansas. He has more than 25 years of drug development research experience at all levels (i.e., preclinical through Phase IV) and has been a principal investigator on over 150 clinical trials including every antidepressant marketed in the United States over the last 15 years. Dr. Preskorn maintains a website at http://www.preskorn.com where readers can access previous columns and other publications. This column is the third in this series examining the pharmacology of a number of antidepressants marketed in other countries but not in the United States: reboxetine, milnacipran, and tianeptine. The previous two columns reviewed reboxetine, a norepinephrine (NE) selective reuptake inhibitor (NSRI),1 and milnacipran, a dual norepinephrine and serotonin (SE) reuptake pump inhibitor (DNSRI).2 Duloxetine, which has just been approved for marketing in the United States, will be reviewed in the last column in this series.

Like milnacipran, tianeptine and amineptine (a related molecule) are marketed in France and a few other countries around the world but there is little knowledge of these drugs in the United States and many other English-speaking countries around the world.3 Tianeptine stands out in this series because its apparent mechanism of action contradicts accepted theories concerning the mechanisms of action of antidepressants. In contrast to most, if not all, other putative antidepressants, tianeptine facilitates rather than retards the re-uptake of the biogenic amine neurotransmitters, SE and NE.4,5 The question, of course, is whether tianeptine is an antidepressant. This column reviews the available data so that readers can form their own opinion on that issue as well as on the question of why tianeptine is not available in the United States.

Like the other columns in this series, this one follows a standard format, first presenting a review of the drug’s chemistry, preclinical pharmacology, and metabolism and then giving an overview of its human pharmacology including safety, tolerability, and efficacy. As with the previous columns, an extensive review of the drug’s pre-clinical pharmacology is presented for two reasons. First, this serves to illustrate the amount of preclinical research that is done to evaluate the pharmacology of an investigational antidepressant as part of its development, thus providing an example of the preclinical stage of drug development described in an earlier series of columns on drug development in psychiatry and the human genome project.6 Second, these preclinical studies illustrate the effects that drugs can have on brain function and hence their potential to interact pharmaco-dynamically to alter brain function and thus influence behavior. These considerations are relevant to the issue of drug-drug interactions, another recurrent theme discussed in a number of columns.7

As with other columns in this four-part series, it is worthwhile to review information on tianeptine for several reasons. First, even though it may never be marketed in the United States, it is marketed in other countries. Hence, U.S. clinicians may encounter patients who have been started on this medication elsewhere. In fact, one of my colleagues recently asked me if I knew anything about tianeptine, because she had a patient who had been started on this medication when living in Russia and the person had now moved to Kansas. Second, this column, like the previous ones on reboxetine and milnacipran, will help answer the frequently asked question: Why are some drugs marketed in other countries but not in the United States?

CHEMISTRY

Tianeptine is a 3-chlorodibenzothiazepine nucleus with an aminoheptanoic side chain.8 It can also be chemically described as a substituted dibenzothiazepine nucleus with a long lateral chain.9 There are highly specific structural requirements for molecules in the tianeptine series to be active, including the requirement for an aminocarboxylic chain with an optimal length of six methylene links, a tricyclic nucleus with an electron donor heteroatom in position 5, and an aromatic substitution with a moderate electron-acceptor atom in position 3. These highly specific requirements for the tianeptine series are in marked contrast with the lack of specific requirements for the classical tricyclic antidepressants.8 Tianeptine is chiral with (+) and (-) enantiomers.10 The drug is marketed as a racemic mixture. Both of the enantiomers are active but the (-) enantiomer is more active than the (+) enantiomer.

CENTRAL NERVOUS SYSTEM PHARMACOLOGY

A substantial amount of research, particularly preclinical, has been done with tianeptine. Tianeptine does not bind to α- or β-adrenergic, dopamine, SE, GABA, glutamate, benzodiazepine, muscarinic, or histamine receptors, nor does it affect calcium channels or the neuronal transport protein for NE or dopamine.11,12 Chronic administration of tianeptine also does not alter the density or the affinity of α2, β1, SE-1, SE-2, or GABA receptors or imipramine or benzodiazepine binding sites.11

Tianeptine in vivo, after both acute and repeated treatment, enhances SE uptake in the cortex and hippocampus but not in the mesencephalon and has no direct effect on NE or DA uptake.13 These findings were confirmed in a study in which tianeptine increased but sertraline decreased the concentration of 5-HIAA, the major metabolite of SE formed by oxidation mediated by monoamine oxidase (MAO)-A, particularly in the hippocampus and hypothalamus.14,15

Short-term treatment with tianeptine also increases NE levels in the preoptic area, the parietal sensory cortex, and dorsal raphe and decreases NE turnover in the parietal sensory cortex, dorsal raphe, and parietal motor cortex, indicating that tianeptine can also alter the central NE system, perhaps indirectly through its action on the SE system.16 In addition, short-term tianeptine treatment increased extracellular DA concentration in the nucleus accumbens and, at higher doses, in the frontal cortex but not in the striatum, and the effect on DA was not diminished by marked depletion of SE by intracerebroventricular administration of 5,7-dihydroxytryptamine, suggesting this effect is not dependent on a central SE mechanism.17,18

Microiontophoretic application of tianeptine onto dorsal hippocampus CA3 pyramidal neurons increased their firing frequency. This effect was unchanged by the coadministration of 5,7-dihydroxytryptamine, indicating that the SE transporter is not involved in this effect of tianeptine.19,20 Acute treatment with tianeptine also reduced acetylcholine release from the dorsal hippocampi by 40% and from the frontal cortices by 30%.21 In contrast to the increase in firing of CA3 pyramidal neurons, this effect on acetylcholine release does appear to be mediated by effects on central SE mechanisms, as witnessed by the fact that it is abolished by chemical lesion of the median raphe nucleus and by coadministration of metergoline, a SE receptor blocker.

Sustained treatment with tianeptine did not modify the firing of SE neurons in the dorsal raphe or their responsiveness to intravenous injections of lysergic acid diethylamide (LSD) or 8-OH-DPAT, which are agonists at the somatodendritic SE autoreceptor.22 The firing of hippocampal CA3 pyramidal neurons in response to microiontophoretic application of SE also remained unchanged. However, chronic administration (14 days) of tianeptine did reduce the expression of the SE transporter mRNA and the number of SE transporter binding sites.23,24 This finding is more in line with the effects of antidepressants that are classic SE uptake pump inhibitors and suggests a difference between the acute effects of tianeptine and the chronic adaptive changes, which may be more relevant to its antidepressant properties in man. Sustained treatment with tianeptine also decreases corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) levels, abolishing the stress-induced reduction of hypothalamic CRF concentration and markedly reducing the stress-induced increase in plasma ACTH and corticosterone levels.25,26

In addition to studies of the effect of tianeptine alone, a number of preclinical drug-drug interaction studies have looked at tianeptine in combination with other drugs. In rats, both tianeptine and citalopram reduced in a concentration-dependent manner the inhibitory effect of a 5HT1B receptor agonist on stimulation-induced release of acetylcholine in the hippocampus.27 5HT1B presynaptic heteroreceptors are located on cholinergic terminals in this and other brain structures. Conversely, tianeptine did not antagonize the inhibitory effect of the muscarinic receptor agonist carbachol on K(+)-evoked release, indicating that the effect is most likely not mediated by a direct effect on the cholinergic system.

While tianeptine shares with the classical antidepressants the ability to reduce the expression of the SE transporter mRNA and the number of SE transporter binding sites, it does not modify the efficacy of SE synaptic transmission in the rat hippocampus even after sustained treatment. Nevertheless, tianeptine, like a number of other classical antidepressants, is active in several animal models of depression. It antagonizes stress-induced spatial memory impairment in the rat,28 isolation-induced aggression in mice and behavioral despair in rats,5 hyperactivity in the olfactory bulbectomized rat,29 and rat pup ultrasonic vocalizations, which may be even a better model for anxiety disorders.30

Tianeptine has a number of effects on stress responses. Specifically, it reverses stress-induced deficits in exploratory activity31 and attenuates the behavioral signs of sickness behavior in rats induced by the cytokine inducer lipopolysaccharide (LPS) and the prototypical proinflammatory cytokine, interleukin (IL)-1β.32 Tianeptine shares with several tricyclic antidepressants and fluoxetine the ability to inhibit corticosterone-induced gene transcription.33 Tianeptine prevents atrophy of apical dendrites in the CA3 region of the hippocampus caused by chronic daily restraint stress or by daily administration of corticosterone.34-36

This latter effect does not generalize to all antidepressants: tianeptine produced this effect in several studies, while desipramine, fluoxetine, and fluvoxamine did not.37,38 This neuroprotective effect was not mediated through neurotropic factors such as brain-derived neurotropic factor (BDNF), neurotrophin-3 (NT-3), or basic fibroblast growth factor (bFGF), nor through effects on neuronal developmental factors, GAP-43 or MAP2.34 This finding may be relevant to the ability of tianeptine to improve working and reference memories in rodents.39,40 Tianeptine has been postulated to have a beneficial effect on memory by counteracting the SE-induced inhibition of medial septal neurons.39 These findings suggest a potential role for tianeptine in the treatment of cognitive impairment in the elderly, particularly in those with dementing illness.

Taken together, the extensive preclinical pharmacology described above suggests that tianeptine is a unique and pharmacologically interesting CNS medication with a number of potential uses and implications beyond being an antidepressant. Unfortunately, as discussed later, tianeptine has not been studied as rigorously in phase I-III studies as one would like in order to fully understand and exploit its human pharmacology.

PRECLINICAL METABOLISM

Tianeptine is converted by hamster, mouse, and rat CYP enzymes into a reactive metabolite. 41 That finding has been extended to human liver microsomes and involves glucocorticoid inducible CYP enzymes, possibly CYP 3A but not CYP 2D6 or CYP 1A2.42 Based on further studies in animals, high doses of tianeptine (360 times the human therapeutic dose) produced covalent binding to liver, lung, and kidney proteins, depleted hepatic glutathione by 60%, and increased SGPT levels fivefold.43 The significance of this finding to humans, including its possible predictive value for the potential for idiosyncratic and immunoallergic reactions, has not been determined.

Tianeptine inhibits both β-oxidation and tricarboxylic acid cycle in the mouse. At higher doses (600 times the human oral dose), tianeptine in the mouse inhibits the oxidation of medium- and short-chain fatty acids and causes microvesicular steatosis in the liver.44 Again, the implications of these findings for humans are uncertain; however, severe and prolonged impairment of mitochondrial β-oxidation can cause microvesicular steatosis and may in severe cases cause liver failure, coma, and death.45 As discussed in the section on adverse effects below, there have been cases of hepatotoxicity with microvesicular steatosis reported in patients treated with tianeptine.

HUMAN METABOLISM

Tianeptine does not undergo first pass metabolism during absorption from the gastrointestinal (GI) tract, and has high bioavailability and a low volume distribution.46 There is a modest food effect with increased time to the maximum peak (by 0.5 hour) and lower peak concentrations by 25%; however, the magnitude of these effects are of doubtful clinical significance.47 Tianeptine is highly bound to plasma protein (approximately 95%), particularly to human serum albumin, and has saturable binding to α1-acid glycoprotein.48 High non-esterified fatty acids (NEFA), which are seen in patients with chronic renal failure, increased the unbound fraction of tianeptine threefold.48

Tianeptine is rapidly eliminated from the body and is primarily cleared via the kidneys.4,49 It has a short half-life of 2.5 hours.46 The major metabolites are analogs of tianeptine with a C5 and C3 lateral chain and a N-demethylated derivative.46

Given the importance of the kidneys in the clearance of tianeptine, a number of studies have been done in volunteers with various degrees of impaired renal function. There was a 1-hour prolongation of the half-life in elderly subjects and in patients with renal failure.46,48 However, the terminal half-life of the C5 metabolite was almost tripled in patients with chronic renal failure (i.e., creatinine clearance less than 19 ml/min).48 Based on preclinical evidence that the C5 metabolite is pharmacologically active, the dose of tianeptine should be reduced in such patients. In addition, tianeptine and its C5 metabolite show low dialyzability so that hemodialysis is unlikely to be an effective method to speed the elimination of tianeptine after an overdose.48

Given that cirrhosis secondary to alcoholism is a significant health concern in France as well as in the rest of the world, a number of studies have been done examining the interactions between tianeptine and alcohol and between tianeptine and various hepatic conditions.50,52 Acute alcohol administration decreased the absorption rate of tianeptine and lowered its plasma levels by approximately 30% but did not affect the pharmacokinetics of the C5 metabolite.52 The pharmacokinetics of tianeptine in individuals with significant alcohol-induced hepatitis did not differ from what is seen in normal controls to any degree that is likely to be clinically relevant.

The pharmacokinetics of tianeptine are similar in elderly (72-81 years old) versus young volunteers, but the C5 metabolite levels were higher, suggesting the need for a possible dose reduction.53 Women have a modestly lower (31%) volume of distribution compared to males, but the magnitude of this effect is of dubious clinical significance.54

SAFETY AND ADVERSE EFFECTS

While the acute putative antidepressant mechanism of action of tianeptine differs radically from other antidepressants, its side-effect profile is similar to that of other newer antidepressants, particularly in terms of having low abuse potential and a low risk of adverse effects on the cardiovascular system, the cholinergic systems, sleep/arousal, cognition, psychomotor functioning, and weight.4,55

Adverse Effects

The most common adverse effects include nausea, constipation, abdominal pain, headache, dizziness, and altered dreaming.4 The following adverse effects were more common with amitriptyline than tianeptine: dry mouth (38% vs. 20%), constipation (19% vs. 15%), dizziness/syncope (23% vs. 13%), drowsiness (17% vs. 10%), and postural hypotension (8% vs. 3%). However, insomnia and nightmares were more common with tianeptine than amitriptyline (20% vs. 7%).56 Another report based on 1,458 outpatients on 37.5 mg/day of tianeptine who were followed for 3 months by 392 general practitioners in an open-label study found that fewer than 5% of patients stopped prematurely due to adverse effects and that none of the adverse effects was clinically severe and/or serious. No cardiovascular, hematological, hepatic, or other biochemical abnormalities were found nor was there any evidence of abuse, dependence, or withdrawal symptoms.57

Hepatotoxicity has been reported but is rare. In one such patient, there were hypersensitivity manifestations suggestive of an immunoallergic mechanism and histological evidence of microvesicular steatosis. Discontinuation of tianeptine was followed by complete recovery.58 This case was possibly due to oxidation of tianeptine to reactive metabolites and the inhibition of mitochrondial β-oxidation of fatty acids.

The cardiovascular effects of tianeptine have been assessed in specific placebo-controlled trials in healthy volunteers59 and by analysis of heart rate, blood pressure, and ECG data in five trials involving 3,300 depressed patients.60 Based on these studies, tianeptine does not affect heart rate, blood pressure, ventricular function (i.e., cardiac output), or intracardiac conduction; these studies included elderly patients, patients with alcoholism, and patients with pre-existing cardiac abnormalities. There were few instances of orthostatic hypotension.

In a placebo-controlled and mianserin-controlled crossover study in healthy volunteers, tianeptine, in contrast to mianserin, did not affect several measures of alertness, vigilance, and ability to react in clinically important situations such as driving, as measured by brake-reaction time, choice reaction time, critical flicker fusion, or self-assessed ratings of sedation.61

Overdose

There are limited published data on the tianpetine overdose risk. In a long-term maintenance study, seven patients attempted suicide by tianeptine overdose and all had uneventful recoveries.62 In addition to this report, there was a case study of a patient who abused tianeptine for stimulant effect taking 150 tablets daily (i.e., 50 times the recommended dose) for an unspecified period of time.63 No severe toxicity, including hepatotoxicity, was observed. This patient initially experienced nausea, vomiting, abdominal pain, anorexia with weight loss, and constipation but these adverse effects progressively disappeared despite continued and even escalating drug use. When tianeptine was abruptly discontinued in this patient, she experienced a mild withdrawal syndrome consisting of mylagia and cold sensation.

Drug-Drug Interactions

In a study testing the effects of antipsychotics, benzodiazepines, and a number of other drugs on tianeptine’s plasma protein binding, only salicylic acid at high plasma concentrations was found to be able to displace tianeptine from its binding sites and thus possibly potentiate its effects.51 Only limited drug-drug interaction studies have been published with tianeptine. One reported no interaction either way between tianeptine and oxazepam,64 as would be expected since oxazepam does not require oxidative drug metabolism for its elimination.

Tianeptine significantly reduced the wet dog shakes induced by 5-hyroxytrytophan, which would reduce the likelihood of the serotonin syndrome in the event that tianeptine is inadvertently used with other drugs capable of causing the serotonin syndrome.65

CLINICAL USE/THERAPEUTIC INDICATIONS

Efficacy for Acute Treatment

Like reboxetine1 and milnacipran2 and consistent with its primarily European development, most of the published trials of tianeptine have been active rather than placebo-controlled and results were not published in full with rigorous peer review, compromising the ability to critically assess efficacy.

A summary report of three multicenter, randomized, double-blind, placebo-controlled trials involving a total of 556 patients has been published.66 One of these studies was conducted in Brazil and has been published separately.67 In this Brazilian study involving 126 depressed outpatients meeting DSM-III-R criteria for major depression or bipolar disorder (depressed phase), tianeptine, 25-50 mg/day, produced a 58% response rate compared with 41% for placebo and statistically significantly superior (p < 0.01) reduction in the final Montgomery-Asberg Depression Rating Scale (MADRS) scores. In a second study in 186 patients with major depression or bipolar disorder (depressed phase), there was a statistically significantly greater reduction (p < 0.05) in the final MADRS scores both in patients treated with tianpetine (37.5 mg/day) and with imipramine (150 mg/day) compared with those who received placebo. The response rates were 56% for tianeptine, 48% for imipramine, and 32% for placebo.66 In the largest study involving 244 patients with major depression, tianeptine at doses of 37.5 and 75 mg/day did not produce superior response compared with placebo; however, the placebo response rate was more than 65%.66 The other published studies in major depression have been active- rather than placebo-controlled.

In an overview briefly summarizing 5 double-blind, active but not placebo-controlled studies, tianeptine was found comparable in efficacy and better tolerated than reference antidepressants, mainly amitriptyline, in patients with either DSM-III major depression, single or recurrent (without melancholia and psychotic features) or dysthymic disorder with or without an additional diagnosis of alcohol abuse or dependence.68 One of these was a 6-week, multicenter trial conducted in Italy involving 300 inpatients or outpatients with DSM-III major depression. There was no difference in efficacy but tianeptine produced fewer adverse effects.69 There was also a study that compared tianeptine and fluoxetine in 387 patients with major depression, recurrent depressive disorder, or bipolar affective disorder based on ICD-10 criteria. There was no difference on any efficacy parameter and the response rate was 58% and 56% for tianeptine and fluoxetine, respectively.68

There have also been some trials of tianeptine in patient populations not typically studied in U.S. registration trials. A placebo-controlled trial reported greater improvement with tianeptine in patients with psychasthenia.70 A maprotiline-controlled trial in 83 menopausal or premenopausal women with anxiodepressive disorder reported statistically superior (p < 0.01) response and better tolerability in the patients treated with tianeptine.71 In a 4-8 week, random assignment, double-blind study involving 129 chronic patients with alcoholism and comorbid major depression or dysthymia, tianeptine (37.5 mg/day) produced comparable efficacy but was better tolerated in comparison to amitriptyline (75 mg/day).72 In a 6-week, double-blind, random assignment study in 265 outpatients with DSM-III dysthymic disorder with manifest anxiety, tianeptine (37.5 mg/day) produced comparable efficacy to amitriptyline (75 mg/day), with treatment response rates of 78% versus 83%, respectively.73

There have also been some studies in elderly patients. In a 12-week, double-blind, random assignment study in 237 elderly patients (> 65 years of age) with DSM-III-R major depression, fluoxetine (20 mg/day) produced a higher remission rate (MADRS ≤ 10) compared with tianeptine (37.5 mg/day) (p < 0.01).74 There have been two other open-label trials in elderly patients, with one trial published twice.75-77 In these studies, tianeptine was well tolerated.

In addition to acute efficacy trials, there have also been relapse prevention studies. While most were open label, a double-blind, placebo-controlled study has been reported.78 In this study, 286 patients meeting DSM-III-R criteria for recurrent major depression (i.e., at least one previous episode in the last 5 years) were initially treated open label with tianeptine, 37.5 mg/day, for 6-weeks; the 185 responders were then randomly assigned in a double-blind fashion to either continue tianeptine or be switched to placebo and followed for 18 months. By 18 months, the relapse rate in the placebo-treated patients was 36% versus 16% in the patients treated with tianeptine. In addition to this study, there have been open-label studies of several patients maintained on tianeptine for more than 1 year with maintenance of response in over 80% and no late emergent unexpected adverse effects.62,79 Finally, there was an interesting, albeit open-label, study of 130 patients treated with tianeptine for both major depression and comorbid alcoholism.80 Only one patient dropped out because of late-emergent adverse effects and 5% because of relapse of their alcoholism.

Dosing Recommendations

Doses of tianeptine used in most of the clinical trials have been between 25 and 50 mg/day, with 37.5 mg/day appearing to be the most efficacious for most patients.

Onset of Action

There have been no published studies demonstrating a faster onset of action for tianeptine than other antidepressants currently marketed in the United States.

CONCLUSION

Like the previous columns on reboxetine1 and milnacipran,2 this review illustrates the substantial effort that can go into developing a drug, which nevertheless fails to gain approval for marketing in the United States. Such an effort costs money and takes time off the patent life. The portfolio of studies with tianeptine reviewed here, if performed today in the United States, would cost hundreds of millions of dollars-illustrating the risky nature of drug development.

This review also illustrates the specific stages through which a drug goes in clinical development. Each stage is designed to yield information to make Go, No Go decisions about whether the drug is likely to have sufficient efficacy relative to any safety or tolerability concerns to gain market approval. Based on its preclinical studies, tianeptine does reach the brain and does have novel effects on both central NE and SE uptake pumps (i.e., facilitating rather than inhibiting these uptake pumps).

Given this novel pharmacology, it would be particularly helpful if reliable surrogate markers for antidepressant response in man existed to provide more cost-effective and time-effective guidance for antidepressant drug development. Unfortunately, such surrogate markers do not currently exist or at least are not widely accepted. As has generally been the case, the pharmacodynamic translational studies with tiapneptine in humans have been limited to assessing the side effects of the drug, its effects on the cardiovascular system, and most importantly its potential antidepressant effects.

While its apparent novel acute mechanism of action has raised questions about the simplest version of the biogenic amine theory of antidepressant efficacy, the clinical trials with tianeptine have not been sufficient to lead to approval as an antidepressant in most countries, including the United States, which generates by far the largest revenue for antidepressants anywhere in the world. Hence, failure to win approval for U.S. marketing significantly limits return on investment for an antidepressant.

In the case of tianeptine, its patent life may have run out before the company could develop the resources to more actively purse the development of the drug in the United States. In this regard, tianpetine, like reboxetine and a number of other antidepressants, is chiral, raising the possibility that one of its enantiomers could be the object of a development program. If confidence in tianeptine’s apparent novel mechanism of action were sufficiently high, its structure could also provide a platform for the development of structural analogs with sufficient patent life to warrant more extensive development efforts. Time will tell whether any of these possibilities will come to pass with this interesting molecule.

Readers interested in further discussion of drug development in psychiatry, particularly with regard to antidepressants, are referred to earlier series of columns. 6,7

References

1. Preskorn SH. Reboxetine: A norepinephrine selective reuptake pump inhibitor. J Psychiatr Practice 2004;10:57-63.

2. Preskorn SH. Milnacipran: A dual norepinephrine and serotonin reuptake pump inhibitor. J Psychiatr Pract 2004;10:119-26.

3. Mitchell PB. Novel French antidepressants not available in the United States. Psychopharmacol Bull 1995;31:509-19.

4. Wagstaff AJ, Ormrod D, Spencer CM. Tianeptine: A review of its use in depressive disorders. CNS Drugs 2001;15:231-59.

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

6. Preskorn SH. Modern drug development and the Human Genome Project. Series of columns published in the Journal of Psychiatric Practice (www.preskorn.com/column4/html).

7. Preskorn SH. The case studies series. Series of columns published in the Journal of Psychiatric Practice ( http://www.preskorn.com/column1/html ).

8. Kroeze WK, Kristiansen K, Roth BL. Molecular biology of serotonin receptors structure and function at the molecular level. Curr Top Med Chem 2002;2:507-28.

9. Labrid C, Mocaer E, Kamoun A. Neurochemical and pharmacological properties for tianeptine, a novel antidepressant. Br J Psychiatry Suppl 1992;15:56-60.

10. Oluyomi AO, Datla KP, Curzon G. Effects of the (+) and (-) enantiomers of the antidepressant drug tianeptine on 5-HTP-induced behavior. Neuropharmacology 1997;36:383-7.

11. Kato G, Weitsh AF. Neurochemical profile of tianeptine, a new antidepressant drug. Clin Neuropharmacol 1988;11:S43-S50.

12. 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 1993;63:285-90.

13. Mennini T, Mocaer E, Garattini S. Tianeptine, a selective enhancer of serotonin uptake in rat brain. Naunyn Schmiedebergs Arch Pharmacol 1987;336:478-82.

14. De Simoni MG, De Luigi A, Clavenna A, et al. In vivo studies on the enhancement of serotonin reuptake by tianeptine. Brain Res 1992;574:93-7.

15. 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;736:82-90.

16. Frankfurt M, McKittrick CR, McEwen BS, et al. Tianeptine treatment induces regionally specific changes in monoamines. Brain Res 1995;696:1-6.

17. Invernizzi G, Pozzi L, Garattini S, et al. Tianeptine increases the extracellular concentration of dopamine in the nucleus. Neuropharmacology 1992;31:221-7.

18. Sacchetti G, Bonini I, Waeterloos GC, et al. Tianeptine raises dopamine and blocks stress-induced noradrenaline release in the rat frontal cortex. Eur J Pharm 1993;236:171-5.

19. Kamoun A, Labrid C, Mocaer E, et al. Tianeptine an uncommon psychotropic drug. Encephale 1989;15:419-22.

20. Pineyro 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;351:111-8.

21. Bertorelli R, Amoroso D, Girotti P, et al. Effect of tianeptine on the central cholinergic system: Involvement of serotonin. Naunyn Schmiedebergs Arch Pharmacol 1992;345:276-81.

22. Pineyro G, Deveault L, de Montigny C, et al. Effect of prolonged administration of tianeptine on 5-HT neurotransmission: An electrophysiological study in the rat hippocampus and dorsal raphe. Naunyn Schmiedebergs Arch Pharmacol 1995;351:119-25.

23. Watanabe Y, Sakai RR, McEwen BS, et al. Stress and antidepressant effects on hippocampal and cortical 5-HT1A and 5-HT2 receptors and transport sites for serotonin. Brain Res 1993;615:87-94.

24. Kuroda Y, Watanabe A, McEwen B. Tianeptine decreases both serotonin transporter mRNA and binding sites in rat brain. Eur J Pharmacol 1994;268:R3-R5

25. Delbende C, Contesse V, Mocaer E, et al. The novel antidepressant tianeptine reduces stress-evoked stimulation of the hypothalamo-pituitary-adrenal axis. Eur J Clin Pharmacol 1991;202:391-6.

26. 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;251:245-51.

27. Bolanos-Jimenez F, de Castro RM, Fillion G. Antagonism by citalopram and tianeptine of presynaptic 5-HTiB heteroreceptors inhibiting acetylcholine release. Eur J Pharmacol 1993;242:1-6.

28. Conrad C, 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;110:1321-34.

29. Kelly JP, Leonard BE. The effect of tianeptine and sertraline in three models of depression. Neuropharmacology 1994;33:1011-6.

30. Olivier B, Molewijk HE, van der Heyden JA, et al. Ultrasonic vocalizations in rat pups: Effects of serotonergic ligands. Neurosci Biobehav Rev 1998;23:215-27.

31. Borqua 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;31:391-400.

32. Castanon N, Bluthe RM, Dantzer R. Chronic treatment with the atypical antidepressant tianeptine attenuates sickness behavior induced by peripheral but not central lipopolysaccharide and interleukin-1beta in the rat. Psychopharmacology 2001;154:50-60.

33. Budziszewska B, Jaworska-Feil L, Kajta M, et al. Antidepressant drugs inhibit glucocorticoid receptor-mediated gene transcription-a possible mechanism. Br J Pharmacol 2000;130:1385-93.

34. Kuroda Y, McEwen BS. Effect of chronic restraint stress and tianeptine on growth factors, growth-associated protein-43 and microtubule-associated protein 2 mRNA expression in the rat hippocampus. Brain Res Mol Brain Res 1998;59:35-9.

35. Conrad C, LeDoux JE, Magarinos AM, et al. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav Neurosci 1999;113:902-13.

36. Watanabe Y, Gould E, Daniels DC, et al. Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol 2003;222:157-62.

37. McEwen BS, Conrad C, Kuroda Y, et al. Prevention of stress-induced morphological and cognitive consequences. Eur Neuropsychopharmacol 1997;7:S323-S328

38. Magarinos 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;371:113-22.

39. Bassant MH, Lee BH, Jazat F, et al. Comparative study of the effects of tianeptine and other antidepressants on the activity of medial septal neurons in rats anesthetized with urethane. Naunyn Schmiedebergs Arch Pharmacol 1991;344:568-73.

40. Nowakowska E, Kus K, Chodera A, et al. Behavioural effects of fluoxetine and tianeptine, two antidepressants with opposite action mechanisms, in rats. Arzneimittelforschung 2000;50:5-10.

41. Letteron P, Descatoire V, Tinel M, et al. Metabolic activation of the antidepressant tianeptine. I. Cytochrome P-450-mediated in vitro covalent binding. Biochem Pharmacol 1998;38:3241-6.

42. Larrey D, Tinel M, Letteron P, et al. Metabolic activation of the new tricyclic antidepressant tianeptine by human liver cytochrome P450. Biochem Pharmacol 1990;40:545-50.

43. Letteron P, Labbe G, Descatoire V, et al. Metabolic activation of the antidepressant tianeptine. II. In vivo covalent binding and toxicological studies at sublethal doses. Biochem Pharmacol 1989;38:3247-51.

44. Fromenty B, Freneaux E, Labbe G, et al. Tianeptine, a new tricyclic antidepressant metabolized by beta-oxidation of its heptamoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice. Biochem Pharmacol 1989;38:3743-51.

45. Fromenty B, Pessayre D. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol Ther 1995;67:101-54.

46. 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;11:S90-S96.

47. Dresse A, Rosen JM, Brems H, et al. Influence of food on tianeptine and its main metabolic kinetics. J Clin Pharmacol 1988;28:1115-9.

48. Zini R, Morin D, Salvadori C, et al. Tianeptine binding to human plasma proteins and plasma from patients with hepatic cirrhosis or renal failure. Br J Clin Pharmacol 1990;29:9-18.

49. Grislain L, Gele P, Bertrand M, et al. The metabolic pathways of tianeptine, a new antidepressant, in healthy volunteers. Drug Metab Dispos 1990;18:804-8.

50. Royer RJ, Royer-Morrot MJ, Paille F, et al. Tianeptine and its main metabolite pharmacokinetics in chronic alcoholism and cirrhosis. Clin Pharmacokinet 1989;16:186-91.

51. Zini R, Morin D, Salvadori C, et al. The influence of various drugs on the binding of tianeptine to human plasma proteins. Int J Clin Pharmacol Ther Toxicol 1991;29:64-6.

52. Salvadori C, Ward C, Defrance R, et al. The pharmacokinetics of the antidepressant tianeptine and its main metabolite in healthy humans-influence of alcohol coadministration. Fundam Clin Pharmacol 1990;4:115-25.

53. Demotes-Mainard F, Galley P, Manciet G, et al. Pharmacokinetics of the antidepressant tianeptine at steady state in the elderly. J Clin Pharmacol 1991;31:174-8.

54. Grasela TH, Fiedler-Kelly JB, Salvadori C, et al. Development of a population pharmacokinetic database for tianeptine. Eur J Clin Pharmacol 1993;45:173-9.

55. Loo H, Deniker P. Position of tianeptine among antidepressive chemotherapies. Clin Neuropharmacol 1988;11:S97-S102.

56. Wilde MI, Benfield P. Tianeptine: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression. Drugs 1995; 49:411-39. Erratum in: Drugs 1995;50:156.

57. 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.

58. Lebricquir Y, Larrey D, Blanc P, et al. Tianeptine-an instance of drug-induced hepatotoxicity predicted by prospective experimental studies. J Hepatol 1994;21:771-3.

59. 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;13:48-57.

60. Lasnier C, Marey C, Lapeyre G, et al. Cardiovascular tolerance to tianeptine (article in French). Presse Med 1991;20:1858-63.

61. Ridout F, Hindmarch I. Effects of tianeptine and mianserin on car driving skills. Psychopharmacol 2001;154:356-61.

62. Loo H, Ganry H, Dufour H, et al. Long-term use of tianeptine in 380 depressed patients. Br J Psychiatry (Suppl) 1992;15:61-5.

63. Vandel P, Regina W, Bonin B, et al. Abuse of tianeptine. A case report. Encephale 1999;25:672-3.

64. 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.

65. Datla KP, Curzon G. Behavioural and neurochemical evidence for the decrease of brain extracellular 5-HT by the antidepressant drug tianeptine. Neuropharmacology 1993;32:839-45.

66. Ginstet D. Efficacy of tianeptine in major depressive disorders with or without melancholia. Eur Neuropsychopharmacol 1997;7:S341-S345.

67. Costa e Silva JA, Ruschel SI, Caetano D, et al. Placebo-controlled study of tianeptine in major depressive episodes. Neuropsychobiology 1997;35:24-9.

68. Guelfi JD. Efficacy of tianeptine in comparative trials versus reference antidepressants: An overview. Br J Psychiatry (Suppl) 1992;15:72-5.

69. 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 multicenter study vs. amitriptyline. Neuropsychobiology 1994;30:85-93.

70. Grivois H, Deniker P, Ganry H. Efficacy of tianeptine in the treatment of psychasthenia: A study versus placebo. Encephale 1992;18:591-8.

71. Chaby L, Grinsztein A, Weitzman JJ, et al. Anxiety-related and depressive disorders in women during the premenopausal and menopausal period: Study of the efficacy and acceptability of tianeptine versus maprotiline. Presse Med 1993;22:1133-8.

72. Loo H, Malka R, Defrance R, et al. Tianeptine and amitriptyline: Controlled double-blind trial in depressed alcoholic patients. Neuropsychobiology 1988;19:79-85.

73. Guelfi JD, Pichot P, Dreyfus JF. Efficacy of tianeptine in anxious-depressed patients: Results of a controlled multicenter trial versus amitriptyline. Neuropsychobiology 1989;22:41-8.

74. Guelfi JD, Bouhassira M, Bonett-Perrin E, et al. The study of the efficacy of fluoxetine versus tianeptine in the treatment of elderly depressed patients followed in general practice. Encephale 1999;25:265-70.

75. Andrusenko MP, Sheshenin VS, Iakovleva OB. Use of tianeptine (Coaxal) in the treatment of late-life depression. Zh Nevrol Psikhiatr Im S S Korsakova 1999;99:25-30.

76. Saiz-Ruiz J, Montes JM, Alvaraz E, et al. Treatment with tianeptine for depressive disorders in the elderly. Actas Luso Esp Neurol Psiquiatr Cienc Afines 1997;25:79-83.

77. Saiz-Ruiz J, Montes JM, Alvarez E, et al. Tianeptine therapy for depression in the elderly. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:319-29.

78. Dalery J, Dagens-Lafant V, De Bodinat C. Value of tianeptine in treating major recurrent unipolar depression: Study versus placebo for 16 1/2 months of treatment. Encephale 1997;23:56-64.

79. Loo H, Ganry H, Dufour H, et al. Role of tianeptine in the prevention of depression relapse and recurrence: First estimations. Presse Med 1991;20:1864-8.

80. Malka R, Loo H, Ganry H, et al. Long-term administration of tianeptine in depressed patients after alcohol withdrawal. Br J Psychiatry (Suppl) 1992;15:66-71.