Tianeptine

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

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. Although not well studied with tianeptine, it has been shown for tricyclic antidepressants that they may cause cardiac arrhythmias.

By frequency

Sources:

Recreational use and addiction potential

Recreational use of tianeptine is rare and thus far has only been seen in persons already using multiple substances for recreational purposes. 141 cases of recreational use 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 recreational use 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 recreational potential, while Bahrain has classified it a controlled substance due to increasing reports of misuse and recreational use 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:

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:

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.).