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Tianeptine

Clinical data
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	N06AX14 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	70-99%
Metabolism	Hepatic
Elimination half-life	2.5 hours
Excretion	Renal
Identifiers
IUPAC name (RS)-7-(3-chloro-6-methyl-6,11-dihydrodibenzothiazepin-11-ylamino)heptanoic acid S,S-dioxide
CAS Number	66981-73-5
PubChem CID	68870
ChemSpider	62102
UNII	0T493YFU8O
KEGG	D02575
ChEMBL	ChEMBL1289110
CompTox Dashboard (EPA)	DTXSID7048295
ECHA InfoCard	100.131.750 100.069.844, 100.131.750
Chemical and physical data
Formula	C21H25ClN2O4S
Molar mass	436.953 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES Clc1cc2c(cc1)C(c3c(N(C)S2(=O)=O)cccc3)NCCCCCCC(=O)O
InChI InChI=1S/C21H25ClN2O4S/c1-24-18-9-6-5-8-16(18)21(23-13-7-3-2-4-10-20(25)26)17-12-11-15(22)14-19(17)29(24,27)28/h5-6,8-9,11-12,14,21,23H,2-4,7,10,13H2,1H3,(H,25,26) Key:JICJBGPOMZQUBB-UHFFFAOYSA-N
(what is this?)  (verify)

Tianeptine (INN) was discovered by The French Society of Medical Research in the 1960s. Under the trade-names (Stablon, Coaxil, Tatinol, Tianeurax) it is a drug used for treating major depressive episodes (mild, moderate, or severe). It has structural similarities to the tricyclic antidepressants, but it has different pharmacological properties. Tianeptine is a selective serotonin reuptake enhancer (SSRE), opposite to the action of SSRIs. One review points to the cancellative effects of tianeptine and fluoxetine coadministration on serotonin reuptake. Another suggests that long-term administration of tianeptine has no effect on serotonin pathways. Tianeptine enhances the extracellular concentration of dopamine in the nucleus accumbens and modulates the D₂ and D₃ dopamine receptors. There is also action on the NMDA and AMPA receptors. Recent reviews point to this pathway as a hypothesized mechanism of action, based on tianeptine's effect of reversing impaired neuroplasticity associated with stress.

Tianeptine reduces the effects of serotonin in the limbic system and the pre-frontal cortex, giving rise to a mood elevation, unlike the mood blunting associated with SSRIs. Like SSRIs, however, tianeptine's onset-of-action delay is approximately 2–6 weeks with improvements sometimes noticeable in as soon as one week. Its short-lived, but pleasant, stimulant effect experienced by some patients is shared with its predecessor, amineptine, whose side effects related to dopamine reuptake inhibition resulted in Servier's research into tianeptine. Suggested dosage is three times daily, due to its short duration of action.

Tianeptine has strong antidepressant and anxiolytic properties with a relative lack of sedative, anticholinergic and cardiovascular adverse effects, thus suggesting it is particularly suitable for use in elderly patients and in those following alcohol withdrawal; such patients can be more sensitive to the adverse effects of psychotropic drugs. Recent interesting results indicate anticonvulsant and analgesic activity of tianeptine and its possible interaction with adenosine A₁ receptors.

Currently, tianeptine is approved in France and manufactured and marketed by Laboratoires Servier SA; it is also marketed in a number of other European countries under the trade name “Coaxil” as well as in Asia and Latin America as “Stablon” and “Tatinol” but it is not available in the UK or US.

Uses

Approved

Tianeptine shows efficacy against serious depressive episodes (major depression), comparable to amitriptyline, imipramine and fluoxetine, but with far fewer side effects. It was shown to be more effective than maprotiline in a group of patients with co-existing depression and anxiety. Tianeptine also displays significant anxiolytic properties and is useful in treating a spectrum of anxiety disorders including panic disorder, as evidenced by a study in which those administered 35% CO₂ gas (carbogen) on paroxetine (Paxil) or tianeptine (Stablon) therapy showed equivalent panic-blocking effects.

Investigational and ongoing research

Tianeptine has been reported to be very effective for asthma starting in August 1998, when Dr. Fuad Lechin and colleagues at the Central University of Venezuela Institute of Experimental Medicine in Caracas published the results of a 52-week randomized controlled trial of asthmatic children; the children in the groups that received tianeptine had a sharp decrease in clinical rating and increased lung function. Two years earlier, they had found a close, positive association between free serotonin in plasma and severity of asthma in symptomatic patients. As tianeptine was the only agent known to both reduce free serotonin in plasma and enhance uptake in platelets, they decided to use it to see if reducing free serotonin levels in plasma would help. By November 2004, there had been two double-blind placebo-controlled crossover trials, and a 25,000+ patient open-label study lasting over seven years, all showing effectiveness. A 2005 study in Egypt demonstrated tianeptine to be effective in men with depression and erectile dysfunction. Tianeptine also has anticonvulsant and analgesic effects, and a clinical trial in Spain that ended in January 2007 has shown that tianeptine is effective in treating pain due to fibromyalgia. Tianeptine has been shown to have efficacy with minimal side effects in the treatment of ADD/ADHD.

A clinical trial has been conducted to compare its efficacy and tolerability with amitriptyline in the treatment of irritable bowel syndrome. The results of this trial showed that tianeptine was at least as effective as amitriptyline and produced less prominent adverse effects such as dry mouth and constipation.

Tianeptine has been found to be effective in depression in Parkinson's disease and in post-traumatic stress disorder of which it was as safe and effective as fluoxetine (Prozac, an SSRI) and moclobemide (Aurorix, a RIMA).

Contraindications

According to Servier International, tianeptine is contraindicated in children under 15 years of age, people taking MAOIs, and pregnant or lactating women. However, as of 2005, there are no studies published showing increased risk of birth defects.

Side effects

Tianeptine was both studied for short-term (3 month) and long-term treatment (12 months) and equally well tolerated. The studies encompassed 1,300 to nearly 3,000 patients each.

Side effects are as follows (amitriptyline vs tianeptine):

• Dry mouth (38% vs 20%)
• Constipation (19% vs 15%)
• Dizziness/syncope (23% vs 13%)
• Drowsiness (17% vs 10%)
• Postural hypotension (8% vs 3%)
• Insomnia and vivid dreams (7% vs 20%)

Costa e Silva and colleagues at the Jardim Botanico in Rio de Janeiro, Brazil reported a greater frequency of headaches in the tianeptine group as compared with placebo.

Sema Gülen Yıldırım and colleagues reported in 2004 of a case of hypomania caused by tianeptine.

Interestingly, tianeptine along with its two metabolites (S8849, S3139) does not affect the reuptake of monoamines (DA, 5-HT, and noradrenaline) in vitro. Results from in vivo studies confirm that serotonin reuptake is enhanced — while dopamine and noradrenaline are unaffected — suggesting a mechanism independent of SERT. No data is available regarding effects of the drug on postsynaptic receptors.

Usual doses

The recommended dosage is three 12.5 mg tablets daily, one in the morning, one at midday, and one in the evening before the main meals of the day. In chronic alcoholics, whether cirrhotic or not, no alteration of dosage is necessary. In subjects over 70 years of age, and in subjects with renal insufficiency, the dosage should be restricted to two tablets per day.

Coping with suicide risks

As is generally true for activating/nonsedating antidepressants, particularly agitated patients or those developing increase of energy together with suicidal thoughts before remission occurs will normally need initial comedication (1 to 4 weeks) with an effective sedating drug such as a benzodiazepine, barbiturate or neuroleptic. Additionally, hospitalisation of these patients is desirable (close observation possible). These measures to lower the risk of suicide should be continued until remission of depression is stable.

Abuse and addiction potential

Abuse of tianeptine is rare and thus far has only been seen in patients with pre-existing multi-substance abuse disorders. 141 cases of abuse were identified between 1989 and 2004, correlating to an incidence of 1 to 3 cases per 1000 patients treated with tianeptine. The main reason for abuse is to achieve an anxiolytic effect. According to Servier, cessation of treatment with tianeptine is difficult, due to the possibility of withdrawal symptoms in a patient.

One patient reportedly consumed a total of 240 12.5 mg tablets (3000 mg) per day for several months and was later successfully detoxified in an inpatient setting. The report indicated that a tolerance was developed and there were physical withdrawal symptoms.

In 2007, according to French Health Products Safety Agency, tianeptine's manufacturer Servier agreed to modify the drug's label, following problems with dependency.

Singapore's Ministry of Health has restricted the use of tianeptine to psychiatrists due to its abuse potential, while Bahrain has classified it a controlled substance due to increasing reports of misuse and abuse by patients. In September 2012, France began treating Stablon as a controlled substance. Its use now requires a "secure prescription" form in France, just as is required for narcotics.

Tianeptine (under the brand name “Coaxil”) has been intravenously injected by drug users in Armenia and Russia. This method of administration reportedly causes an opioid-like effect and is sometimes used in an attempt to lessen opioid withdrawal symptoms. Tianeptine tablets contain silica and do not dissolve completely. Often the solution is not filtered well thus particles in the injected fluid block capillaries, leading to thrombosis and then severe necrosis.

Mechanism of action

Initial studies found that upon acute and sustained administration, tianeptine decreased the extracellular levels of serotonin. However tianeptine has low affinity for serotonin transporters, so this effect appears to be indirect. Further, the validity of the data from older studies has been contested on the basis of technical limitations; more recent studies found that long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of serotonin in rats, and tianeptine also had no effect on spontaneous firing rate of serotonergic neurons. However, coadministration of tianeptine and fluoxetine inhibited tianeptine's effect on long-term potentiation in hippocampal CA1 area. This is considered an argument for the opposite effects of tianeptine and fluoxetine on serotonin uptake.

In contrast to SSRIs and tricyclic antidepressants, tianeptine modestly enhances the mesolimbic release of dopamine and potentiates CNS D2 and D3 receptors, but it is also unclear how this occurs because tianeptine has no affinity for the dopamine transporter or the dopamine receptors D1, D2, D3, D4 and D5.

My researchers hypothesis tianeptine has a protective effect against stress induced neuronal remodeling. In animal models, tianeptine inhibits the pathological stress-induced changes in glutamatergic neurotransmission in the amygdala and hippocampus. It may also facilitate signal transduction at the CA3 commissural associational synapse by altering the phosphorylation state of glutamate receptors. With the discovery of the rapid and novel antidepressant effects of drugs such as ketamine, many believe the efficacy of antidepressants is related to promotion of synaptic plasticity. This may be achieved by regulating the excitatory amino acid systems that are responsible for changes in the strength of synaptic connections as well as enhancing BDNF expression, although these findings are based largely on preclinical studies.

See also

• Selective serotonin reuptake enhancer

References

1. ^ Royer RJ, Albin H, Barrucand D, Salvadori-Failler C, Kamoun A (1988). "Pharmacokinetic and metabolic parameters of tianeptine in healthy volunteers and in populations with risk factors". Clinical Neuropharmacology. 11 Suppl 2: S90–6. PMID 3180120.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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External links

• Tianeptine.com

Template:Nootropics

• Selective serotonin reuptake enhancers
• Dibenzothiazepines
• Organochlorides
• Servier
• Euphoriants