Tianeptine

"Coaxil" redirects here. For the transmission line for radio frequency signals, see Coaxial cable.

Tianeptine

Systematic (IUPAC) name
7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid
Clinical data
Trade names	Coaxil, Stablon
AHFS/Drugs.com	International Drug Names
Legal status	Rx-only (many countries) Legal (Unscheduled) (US) Controlled (FR, BH, SG)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	99%
Protein binding	95%
Metabolism	Hepatic
Biological half-life	2.5-3 hours, 4-9 hours (elderly)
Excretion	Renal (65%), Faecal (15%)
Identifiers
CAS Number	66981-73-5 Y
ATC code	N06AX14 (WHO)
PubChem	CID: 68870
IUPHAR/BPS	7558
ChemSpider	62102 Y
UNII	0T493YFU8O Y
KEGG	D02575 Y
ChEMBL	CHEMBL1289110 N
Chemical data
Formula	C21H25ClN2O4S
Molecular mass	436.953 g/mol
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) Y Key:JICJBGPOMZQUBB-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Tianeptine (brand names Stablon, Coaxil, Tatinol, Tianeurax and Salymbra) is a drug used primarily in the treatment of major depressive disorder, although it may also be used to treat asthma or irritable bowel syndrome. Chemically it is a tricyclic antidepressant (TCA), but it has different pharmacological properties than typical TCAs as recent research suggests that tianeptine produces its antidepressant effects through indirect alteration of glutamate receptor activity (i.e., AMPA receptors and NMDA receptors) and release of BDNF, in turn affecting neural plasticity.

Tianeptine has antidepressant and anxiolytic (anti-anxiety) properties with a relative lack of sedative, anticholinergic and cardiovascular adverse effects, thus suggesting it is particularly suitable for use in the elderly and in those following alcohol withdrawal; such persons can be more sensitive to the adverse effects of psychotropic drugs. Recent results indicate possible anticonvulsant (anti-seizure) and analgesic (painkilling) activity of tianeptine via immediate or downstream modulation of adenosine A₁ receptors (as the effects could be experimentally blocked by antagonists of this receptor).

Tianeptine is a low-affinity full agonist at the μ-opioid and δ-opioid receptors with negligible effect at the κ-opioid receptors. μ-Opioid agonists typically induce euphoria, and in accordance, tianeptine does so at high doses well above the normal therapeutic range.

Tianeptine was discovered and patented by The French Society of Medical Research in the 1960s. Currently, tianeptine is approved in France and manufactured and marketed by Laboratories Servier SA; it is also marketed in a number of other European countries under the trade name “Coaxil” as well as in Asia (including Singapore) and Latin America as “Stablon” and “Tatinol” but it is not available in Australia, Canada, New Zealand, the U.K. or the U.S..

Medical uses

Tianeptine shows efficacy against serious depressive episodes (major depression), comparable to amitriptyline, imipramine and fluoxetine, but with significantly fewer side effects. It was shown to be more effective than maprotiline in a group of people 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 or tianeptine therapy showed equivalent panic-blocking effects. Like many antidepressants (including bupropion, the selective serotonin reuptake inhibitors, the serotonin-norepinephrine reuptake inhibitors, moclobemide and numerous others) it may also have a beneficial effect on cognition in people with depression-induced cognitive dysfunction.

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 and moclobemide. 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 reported to be very effective for asthma. In August 1998, 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 persons. 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 person 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 attention-deficit hyperactivity disorder.

Side effects

File:StablonBox.jpg

Stablon box and blister pack.

Compared to other TCAs it produces significantly fewer cardiovascular, anticholinergic (like dry mouth or constipation), sedative and appetite-stimulating effects. A recent review found that it was amongst the antidepressants most prone to causing hepatotoxicity (liver damage), although the evidence to support this concern was of limited quality.

By frequency

Sources:

Common (>1% frequency)

• Headache (up to 18%)
• Dizziness (up to 10%)
• Insomnia/nightmares (up to 20%)
• Drowsiness (up to 10%)
• Dry mouth (up to 20%)
• Constipation (up to 15%)
• Nausea
• Abdominal pain
• Weight gain (~3%)
• Agitation
• Anxiety/irritability

Uncommon (0.1-1% frequency)

• Bitter taste
• Flatulence
• Gastralgia
• Blurred vision
• Muscle aches
• Premature ventricular contractions
• Micturition disturbances
• Palpitations
• Orthostatic hypotension
• Hot flushes
• Tremor

Rare (<0.1% frequency)

• Hepatitis
• Hypomania
• Euphoria
• ECG changes
• Pruritus/allergic-type skin reactions
• Protracted muscle aches
• General fatigue

Abuse and addiction potential

Abuse of tianeptine is rare and thus far has only been seen in persons with pre-existing multi-substance abuse disorders. 141 cases of abuse were identified in France between 1989 and 2004, correlating to an incidence of 1 to 3 cases per 1000 persons treated with tianeptine and 45 between 2006 and 2011. 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 person. The severity of the withdrawal is dependent on the daily dose, with high doses being extremely difficult to quit.

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 persons. 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 has been intravenously injected by drug users in 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. Thus, in Russia tianeptine (sold under the brand name “Coaxil”) is a Schedule III controlled substance in the same list as the majority of benzodiazepines and barbiturates.

Contraindications

Known contraindications include the following:

• Treatment with monoamine oxidase inhibitors (MAOIs) 14 days or less prior to treatment with tianeptine. Due to the potential for cardiovascular effects (including hypertension and cardiovascular collapse), convulsions, hyperthermia (high body temperature) and death.
• Hypersensitivity to tianeptine or any of the tablet's excipients.
• Being under the age of 15 years.

In vitro tianeptine and its two principal metabolites have no effects on monoamine uptake, release or neurotransmitter receptor binding.

Mechanism of action

Initial studies found that upon acute and repeated administration, tianeptine decreased the extracellular levels of serotonin in rat brain without a decrease in serotonin release and it was hence called a (selective) serotonin reuptake enhancer. In vitro tianeptine and its two principal metabolites showed no effects on monoamine uptake, release or neurotransmitter receptor binding in rats. The (−) enantiomer is more active in this sense than the (+) enantiomer. However, 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. However, coadministration of tianeptine and the selective serotonin reuptake inhibitor 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, although it has been shown that fluoxetine can be partially substituted for tianeptine in animal studies.

In contrast to most 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.

Some researchers hypothesize that tianeptine has a protective effect against stress induced neuronal remodeling. There is also action on the NMDA and AMPA receptors. 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.

Although several related compounds are disclosed in the original patent, it is unclear whether these share tianeptine's unique pharmacological effects. Amineptine, the most closely related drug to have been widely studied, is a dopamine reuptake inhibitor with no significant effect on serotonin levels.

Tianeptine has been found to be an efficacious μ-opioid receptor agonist (K_i (human) of 383 ± 183 nM and EC₅₀ (human) of 194 ± 70 nM). The same study revealed that it is also a δ-opioid receptor agonist, although with much lower potency. These actions are responsible for the abuse potential of the drug at high doses well above the normal therapeutic range.

Development

Under the code names JNJ-39823277 and TPI-1062, tianeptine was previously under development for the treatment of major depressive disorder in the U.S. and Belgium. Phase I clinical trials were completed in Belgium and the U.S. in May and June 2009, respectively. For reasons that are unclear, development of tianeptine was discontinued in both countries in January 2012.

Brand names

Brand names include:

• Stablon (AR, AT, BR, FR, IN, ID, MY, MX, PT, SG, TH, TR, VE)
• Coaxil (CZ, HU, PL, RU, UA)
• Tatinol (CN)
• Tianeurax (DE)
• Zinosal (ES)

Synthesis

Prepn: C. Malen et al., DE 2011806  corresp to U.S. Patent 3,758,528 (1970, 1973 both to Sci. Union et Cie-Soc. Franc. Rech. Med.).

See also

• Amineptine
• Tricyclic antidepressant
• List of antidepressants
• Reuptake enhancer

External links

• Tianeptine.com