Tianeptine: An Atypical Antidepressant with Multimodal Pharmacology

TL;DR: Clinical trials show that tianeptine is at least as efficacious as first-line antidepres-sant treatments, with improved tolerability as it is significantly less prone to disrupting the patient's normal functionality.

Abstract: Background: Tianeptine is an atypical antidepressant marketed as Stablon since the late 1980’s. While chemically very similar to tricyclic antidepressants, tianeptine was thought to have the apparently paradoxical mechanism of action of enhancing serotonin reuptake. However, recent data highlight a multimodal pharmacology for tianeptine including actions at glutamatergic synapses (inhibiting NMDA receptors and an indirect effect on AM-PA receptors) coupled with agonist effects at mu opioid receptors (-receptors). Objective: We have reviewed clinical and preclinical data for tianeptine to provide a compre-hensive study of its pharmacology. Results: Clinical trials show that tianeptine is at least as efficacious as first-line antidepres-sant treatments, with improved tolerability as it is significantly less prone to disrupting the patient's normal functionality. Tianeptine appears more efficacious in males than females, although these gender-specific differences may be accounted for by pharmacokinetics. Pre-clinical data suggest that the ability to stabilise glutamatergic neurotransmission may underlie tianeptine’s ability to improve cognitive function and anxiety-related symptoms. Alternative-ly, μ-receptor activation of the mTOR signalling pathway could lead tianeptine to be a fast-acting antidepressant. Agonist actions at μ-receptors could also explain the potential abuse li-ability and dependence issues seen with high dose tianeptine. Conclusion: Tianeptine itself is off patent, but it still holds much promise as an experimental tool yielding valuable insights into the molecular mechanisms underlying depression.

Summary

1. Introduction

• Major depressive disorder (MDD) is a highly pervasive disorder, characterised by persistent low mood, low self-esteem and anhedonia.
• In the UK, depression affects 4 million adults, 8.4% of the total population and has been linked with poor health, significant comorbidity and mortality [1-3].
• MDD, therefore, is characterised as a severely debilitating disease with a major impact not only on a person's quality of life but can also place a massive financial strain on a country’s healthcare system.
• All four classes of antidepressants have proven to be catalysts by dramatically improving the quality of life of depressed patients [4].
• These agents, however, are associated with limitations in their onset of action, efficacy, tolerability and safety.

2. Clinical Efficacy of Tianeptine

• The authors have attempted a comprehensive review of all the accessible clinical trial information on tianeptine and their findings are summarized in Table 1.
• In one study, 286 adult patients of both genders were treated with tianeptine for 6 weeks [16].
• Clinical evidence also supports an improvement in cognitive function following treatment with tianeptine.
• There is also strong clinical evidence that tianeptine is beneficial for overcoming treatmentresistant depression when combined with other antidepressants [27-28].
• Patients were diagnosed with MDD and did not respond or partially responded to SSRI monotherapy [27].

2.1 Safety and Tolerability of Tianeptine

• A number of safety studies from various clinical trials have described tianeptine as a welltolerated drug.
• Tianeptine’s safety credentials are furthermore enhanced by the fact that it has a very low overdose risk, therefore, has been classed as a drug with a low abuse potential.
• Undoubtedly, one of the major drawbacks of current antidepressant treatments is the discontinuation symptoms that occur after cessation of treatment.
• Antidepressant therapy is clinically proven to aggravate such problems; results from the same study revealed that patients on antidepressants increased the frequency of sexual dysfunction compared to the untreated patients [35].
• In comparison with TCAs and SSRIs, tianeptine exhibited a lower incidence of sexual dysfunction having a similar rate of untreated patients [35].

3.1 Brain Structure and Neurotrophic Effects

• Neuroplasticity is the ability of the adult and differentiated brain to adapt functionally and structurally to internal and external stimuli [37].
• Specifically, a study involving 16 patients with depression revealed that in all cases the volume of the left side of the hippocampus was 19% smaller when compared to 16 nondepressed patients [41].
• 2 Synaptic Plasticity Synaptic plasticity is the ability of neurones to undergo activity-dependent alterations in synaptic function in order to determine how the synapse will respond to afferent activity [48].
• More specifically the use of animal models has revealed that acute and chronic stress inhibits the ability of the hippocampus and the prefrontal cortex to undergo long-term potentiation (LTP) [50-51].
• Tianeptine (10mg/kg) successfully enhanced synaptic function in the hippocampus [52-53] and prefrontal cortex [53] while maintaining normal synaptic function in the amygdala [54] of male Sprague-Dawley rats; the potentiation of LTP was reported to occur immediately after tianeptine administration.

3.3 Memory and Cognition

• A functional consequence of MDD and stress involves impairment of cognitive and memory function.
• Impairment in memory function is believed to occur due to damage to the hippocampus by stress and its related hormones [50, 55]; particularly damage in the region is associated with altered spatial memory.
• Fascinatingly, evidence from the same experiment suggests that tianeptine improves memory without affecting the stress-induced rise in glucocorticoid suggesting that tianeptine does not interfere with activation of the hypothalamic-pituitary-adrenal axis following stress [56].
• These effects of tianeptine are consistent with findings obtained from adrenalectomised rats [55].
• During MDD the amygdala is thought to be dysregulated, with fear-related learning being impaired [57-58].

4.1 Actions at the Serotonin Reuptake Transporter

• One molecular target of tianeptine is the serotonin reuptake transporter (SERT) – a transporter which mediates reuptake of serotonin in neurones [62].
• SSRIs have been proposed to inhibit SERT by interacting with the C-terminal part of SERT containing the transmembrane domains 10 and 12; specifically they form dipole-dipole interactions or hydrogen bonds with the benzene ring of the Tyr95 and make the transporter adopt a conformation that decreases the affinity for serotonin or reduces its rate of transport [62-63].
• Similarly to other classes of antidepressant, tianeptine was anticipated to interfere with neurotransmission of the serotonin system, due to its apparent mechanism of action.
• Initially, this notion was shown to be true by experiments that revealed that acute and sustained administration of tianeptine (10mg/kg) decreased the synaptic availability of serotonin in rat brains [66, 68].
• The validity of these studies has been questioned due to the technical limitations that could not be avoided at the time [70].

4.3 Interactions with -receptors

• Clinically, recommended dosing with tianeptine is 37.5 mg/day.
• These effects were independent of any serotonin mediated actions of tianeptine [109] and could account for the apparent abuse and dependency seen at higher doses of tianeptine.
• These authors suggested that the high dose tianeptine and amitriptyline interacted with opioid receptors since naloxone effectively reversed these effects.
• Activation of both - and -receptors could also contribute to the antidepressant actions of tianeptine.

5. Pharmacokinetics of Tianeptine

• In healthy individuals, the pharmacokinetic properties of tianeptine have been extensively studied.
• Only MC5 is known to possess pharmacological activity [124].
• Taking into account the pivotal role of the kidneys in the clearance of tianeptine, individuals with impaired kidney function exhibit altered tianeptine pharmacokinetic properties.
• Moreover, there seems to be a dramatic heightening of the terminal half-life of the metabolite MC5 in patients with renal failure [124].
• Tianeptine has been associated with gender-specific differences in efficacy which may be attributable to gender differences in pharmacokinetics.

6. Conclusion

• Clinically tianeptine is as efficacious as SSRIs with more rapid improvements in cognitive function and anxiety relieving properties.
• What is more, in terms of safety and tolerability tianeptine is particularly attractive since clinical studies have shown it to be less hazardous and significantly less prone to disrupting the patient’s normal functionality.
• Tianeptine is an atypical antidepressant acting at SERT to stimulate serotonin reuptake, although this mechanism is unlikely to explain tianeptine’s antidepressant properties.
• One more plausible mechanism by which tianeptine produces its antidepressant and neurorestorative properties is via modulation of the glutamatergic system which is achieved by an effect upon the glycine site of the NMDA receptor; inhibiting its function, and mTOR signalling by indirectly enhancing AMPA-related signalling.
• Tianeptine itself is off patent, but it still holds much promise as an experimental tool, yielding valuable insights into the molecular mechanisms underlying depression.

Full text

Citation for published version:
Bailey, SJ, Almatroudi, A & Kouris, A 2017, 'Tianeptine: An atypical antidepressant with multimodal
pharmacology', Current Psychopharmacology, vol. 6, no. 2, pp. 94-110.
https://doi.org/10.2174/2211556006666170525154616
DOI:
10.2174/2211556006666170525154616
Publication date:
2017
Document Version
Peer reviewed version
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The final publication is available at Bentham Science via https://doi.org/10.2174/2211556006666170525154616
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Tianeptine: an atypical antidepressant with multimodal pharmacology
*Sarah J. Bailey, Abdulrahman Almatroudi and Andreas Kouris
Department of Pharmacy and Pharmacology, University of Bath, Claverton Down,
Bath BA2 7AY, UK.
Corresponding author:
Dr Sarah Bailey
Department of Pharmacy and Pharmacology
University of Bath
Claverton Down
Bath
BA2 7AY
S.Bailey@bath.ac.uk
TEL: 01225 386842
FAX: 01225 386114
KEY WORDS: depression, anxiety, serotonin, glutamate, -opioid receptor, gender, mTOR
CONFLICT OF INTEREST:
No funding was provided for this study. None of the authors have any conflict of interest.
AK was a pharmacology undergraduate; AA was a PhD student funded by the
Government of Saudi Arabia; all authors worked in the Department of Pharmacy and
Pharmacology at the University of Bath.
ACKNOWLEDGEMENTS: All authors contributed substantially to the research, drafting
and revision of the manuscript. No other persons were involved in the preparation of the
manuscript.

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Abstract
Background: Tianeptine is an atypical antidepressant marketed as Stablon since the late
1980’s. While chemically very similar to tricyclic antidepressants, tianeptine was thought to
have the apparently paradoxical mechanism of action of enhancing serotonin reuptake.
However, recent data highlight a multimodal pharmacology for tianeptine including actions
at glutamatergic synapses (inhibiting NMDA receptors and an indirect effect on AMPA
receptors) coupled with agonist effects at mu opioid receptors (-receptors). Objective:
We have reviewed clinical and preclinical data for tianeptine to provide a comprehensive
study of its pharmacology. Results: Clinical trials show that tianeptine is at least as
efficacious as first-line antidepressant treatments, with improved tolerability as it is
significantly less prone to disrupting the patient's normal functionality. Tianeptine appears
more efficacious in males than females, although these gender-specific differences may
be accounted for by pharmacokinetics. Preclinical data suggest that the ability to stabilise
glutamatergic neurotransmission may underlie tianeptine’s ability to improve cognitive
function and anxiety-related symptoms. Alternatively, -receptor activation of the mTOR
signalling pathway could lead tianeptine to be a fast-acting antidepressant. Agonist actions
at -receptors could also explain the potential abuse liability and dependence issues seen
with high dose tianeptine. Conclusion: Tianeptine itself is off patent, but it still holds much
promise as an experimental tool yielding valuable insights into the molecular mechanisms
underlying depression.

3
1. Introduction
Major depressive disorder (MDD) is a highly pervasive disorder, characterised by
persistent low mood, low self-esteem and anhedonia. In the UK, depression affects 4
million adults, 8.4% of the total population and has been linked with poor health, significant
comorbidity and mortality [1-3]. MDD, therefore, is characterised as a severely debilitating
disease with a major impact not only on a person's quality of life but can also place a
massive financial strain on a country’s healthcare system.
The prevalence of the monoamine hypothesis as a causative factor of depression has
driven the development of therapies that aim at restoring the neurochemical imbalance in
noradrenaline, serotonin and dopamine. The principle classes of antidepressants utilised
to restore this neurochemical alteration are the monoamine oxidase inhibitors (MAOIs),
tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and
serotonin noradrenaline reuptake inhibitors (SNRIs).All four classes of antidepressants
have proven to be catalysts by dramatically improving the quality of life of depressed
patients [4]. These agents, however, are associated with limitations in their onset of action,
efficacy, tolerability and safety. These antidepressants have a delayed time of onset as
they usually take four to six weeks to exhibit a therapeutic benefit [5]. Problems with the
efficacy of antidepressant therapy include drug resistance where between one and two-
thirds of patients will not respond to the first antidepressant prescribed and 15 to 33
percent will not respond to multiple interventions [6-7]. In terms of tolerability,
antidepressants that interfere with the serotonin system can lead to emotional detachment
[8] and interfere with normal sexual function [9] thus discouraging patients from complying
with therapy. Finally, in terms of safety, even though antidepressants are generally
regarded as safe, they have been associated with life-threatening side-effects including
cardiovascular effects [10] and, controversially, an increased risk of suicide [11-12].
Tianeptine is an atypical antidepressant with a novel mechanism of action. Marketed since
the late 1980’s as Stablon, tianeptine is available in Europe, Latin America, and Asia as a
treatment for MDD although it is not available in the UK or North America [13]. Here we
review the evidence demonstrating the clinical efficacy and potential advantages of
tianeptine as an antidepressant, alongside recent advances in understanding its unique

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multimodal psychopharmacology which could shed light on the molecular mechanisms
underlying depression.
2. Clinical Efficacy of Tianeptine
We have attempted a comprehensive review of all the accessible clinical trial information
on tianeptine and our findings are summarized in Table 1. The clinical efficacy of
tianeptine has been assessed in a vast number of clinical trials, including two small term
placebo controlled double blind studies; their purpose being the assessment of the efficacy
of tianeptine in adult patients of both genders with unipolar or bipolar depression [14-15].
Treatment of both male and female patients (n=129) with tianeptine (37.5 mg/day) for 42
days resulted in a reduction in the Montgomery-Asberg depression scale (MADRS) of
62.3% as compared to placebo (48.5%) [14].The efficacy of tianeptine has also been
shown in long-term studies to assess remission and relapse. In one study, 286 adult
patients of both genders were treated with tianeptine for 6 weeks [16]. The patients that
responded to tianeptine (n=185) were then randomly assigned to tianeptine (37.5 mg/day,
n=111) or placebo (n=74) for up to 18 months and were assessed for their rate of relapse
and reoccurrence by using the Hamilton depression rating scale and the CGI scale [16].
The results of the trial revealed that by the 18-month timepoint, in tianeptine treated
patients, the rate of relapse and reoccurrence was lower (16%) compared to placebo
(36%) [16].
Most of the clinical studies investigating the antidepressant efficacy of tianeptine have
compared its efficacy in parallel with other classes of antidepressants. In double-blind
studies of 4-24 weeks duration, tianeptine (37.5mg/day) showed similar efficacy as the
TCAs amitriptyline (75 mg/day) [17-18] and imipramine (150 mg/d) [15], the atypical
antidepressant mianserin (60mg/day) [19] but also the SSRIs fluoxetine (20mg/day) [20]
and paroxetine (20mg/day) [21]. Additionally, in a meta-analysis comparison with SSRIs,
tianeptine was shown to be just as efficacious during the same treatment period of 6
weeks [22].

Frequently asked questions

Q1. What are the contributions in this paper?

Tianeptine this paper is an atypical antidepressant with a novel mechanism of action, acting at SERT to stimulate serotonin reuptake, although this mechanism is unlikely to explain Tianeptine 's antidepressant properties.