Tianeptine


Tianeptine, sold under the brand names Stablon, Tatinol, and Coaxil among others, is an atypical tricyclic antidepressant which is used mainly in the treatment of major depressive disorder, although it may also be used to treat anxiety, asthma, and irritable bowel syndrome.
Tianeptine has antidepressant and anxiolytic effects with a relative lack of sedative, anticholinergic, and cardiovascular side effects. It has been found to act as an atypical agonist of the μ-opioid receptor with clinically negligible effects on the δ- and κ-opioid receptors. This may explain part of its antidepressant and anxiolytic effects; however, it is thought that tianeptine also modulates glutamate receptors, and this may also explain tianeptine's antidepressant/anxiolytic effects.
Tianeptine was discovered and patented by the French Society of Medical Research in the 1960s. It was introduced for medical use in France in 1983. 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 and Latin America as Stablon and Tatinol but it is not available in Australia, Canada, New Zealand, Italy or the United Kingdom. In the US, it is an unregulated drug sold under several names and some of these products have been found to be adulterated with other recreational drugs. It is commonly known by the nickname "gas station heroin".

Medical uses

Depression and anxiety

Tianeptine shows efficacy against serious depressive episodes, 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 on paroxetine or tianeptine therapy showed equivalent panic-blocking effects. Like many antidepressants it may also have a beneficial effect on cognition in people with depression-induced cognitive dysfunction. A 2005 study in Egypt showed tianeptine to be effective in men with depression and erectile dysfunction.
Tianeptine has been found to be effective in depression, in people with Parkinson's disease, and with post-traumatic stress disorder for which it was as safe and effective as fluoxetine and moclobemide.

Other uses

A clinical trial comparing its efficacy and tolerability with amitriptyline in the treatment of irritable bowel syndrome showed that tianeptine was at least as effective as amitriptyline and produced fewer 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 who 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 an under-25,000 person open-label study lasting over seven years, both showing effectiveness.
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.

Contraindications

Known contraindications include the following:
  • Hypersensitivity to tianeptine or any of the tablet's excipients.

    Side effects

Compared to other tricyclic antidepressants, it produces significantly fewer cardiovascular, anticholinergic, sedative and appetite-stimulating effects. Unlike other tricyclic antidepressants, tianeptine does not affect heart function.
μ-Opioid receptor agonists can sometimes induce euphoria, as does tianeptine, occasionally, at high doses, well above the normal therapeutic range. Tianeptine can also cause severe withdrawal symptoms after prolonged use at high doses which should prompt extreme caution.

By frequency

Sources:
;Common
  • Headache
  • Dizziness
  • Insomnia/nightmares
  • Drowsiness
  • Dry mouth
  • Constipation
  • Nausea
  • Abdominal pain
  • Weight gain
  • Agitation
  • Anxiety/irritability
;Uncommon
;Rare

Pharmacodynamics

Atypical μ-opioid receptor agonist

In 2014, tianeptine was found to be a μ-opioid receptor full agonist using human proteins. It was also found to act as a full agonist of the δ-opioid receptor, although with approximately 200-fold lower potency. The same researchers subsequently found that the MOR is required for the acute and chronic antidepressant-like behavioral effects of tianeptine in mice and that its primary metabolite had similar activity as a MOR agonist but with a much longer elimination half-life. Moreover, in mice, although tianeptine produced other opioid-like behavioral effects such as analgesia and reward, it did not result in tolerance or withdrawal. The authors suggested that tianeptine may be acting as a biased agonist of the MOR and that this may be responsible for its atypical profile as a MOR agonist. However, there are reports that suggest that withdrawal effects resembling those of other typical opioid drugs do manifest following prolonged use at dosages far beyond the medical range. In addition to its therapeutic effects, activation of the MOR is likely to also be responsible for the abuse potential of tianeptine at high doses that are well above the normal therapeutic range and efficacy threshold.
In rats, when co-administered with morphine, tianeptine prevents morphine-induced respiratory depression without impairing analgesia. In humans, however, tianeptine was found to increase respiratory depression when administered in conjunction with the potent opioid remifentanil.

Glutamatergic, neurotrophic, and neuroplastic modulation

Research suggests that tianeptine produces its antidepressant effects through indirect alteration and inhibition of glutamate receptor activity and release of, in turn affecting neural plasticity. 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.

Serotonin reuptake enhancer

Tianeptine is no longer labelled a selective serotonin reuptake enhancer antidepressant.
Tianeptine had been found to bind to the same allosteric site on the serotonin transporter as conventional TCAs. However, whereas conventional TCAs inhibit serotonin reuptake by the SERT, tianeptine appeared to enhance it. This seems to be because of the unique C3 amino heptanoic acid side chain of tianeptine, which, in contrast to other TCAs, is thought to lock the SERT in a conformation that increases affinity for and reuptake of serotonin. As such, tianeptine was thought to act a positive allosteric modulator of the SERT, or as a "serotonin reuptake enhancer".
Although tianeptine was originally found to have no effect in vitro on monoamine reuptake, release, or receptor binding, upon acute and repeated administration, tianeptine decreased the extracellular levels of serotonin in rat brain without a decrease in serotonin release, leading to a theory of tianeptine enhancing serotonin reuptake. 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 in extracellular levels of serotonin in rats. However, coadministration of tianeptine and the selective serotonin reuptake inhibitor fluoxetine inhibited the effect of tianeptine 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 any case, the collective research suggests that direct modulation of the serotonin system is unlikely to be the mechanism of action underlying the antidepressant effects of tianeptine.