Tianeptine: Challenging Antidepressant Model

 

L-tryptophan is an essential amino acid that is utilised in the brain to create serotonin. It has been stated that those who consume more L-tryptophan in their diet are less likely to commit suicide than those who do not consume much of the amino acid. SSRIs, which are the most common treatment for depression, work by binding to the serotonin transporter, thus preventing the reuptake of serotonin into the presynaptic nerve cells. This process results in more serotonin being available for use in the nerve synapse. Popular examples of SSRIs include fluoxetine (Prozac) and sertraline (Zoloft).

 

Working as a selective serotonin reuptake enhancer (SSRE), Tianeptine acts in the opposite fashion. Rather than preventing the reuptake of serotonin, Tianeptine actually aids this process in the hippocampus and the cortex. Since this process also appears to help to treat depression, Tianeptine has further complicated the understanding that having a deficit of serotonin is the cause of depression.

 

Precisely how Tianeptine works to increase the speed of serotonin reuptake remains unclear, particularly as the drug does not appear to act noticeably at the sites of neurotransmitter receptors or monoamine transporters. It has been presumed that the effect of Tianeptine is dependent upon the changes in neurons and the relationships between them that take place in the longer term – over the period of a few weeks. This theory does however remain conjecture.

 

Tianeptine’s not like other antidepressants: Truly Unique Properties

 

In the summer of 2014, a study revealed that tianeptine operates as a complete agonist at the delta and mu opioid receptors, whilst having no significant impact at the kappa receptors. It is understood that selective kappa agonists usually cause dysphoria and conversely, selective mu agonists in certain parts of the brain (known as hedonic hotspots) usually cause euphoria. The effect of delta opioid receptors however, is not yet known. Opioids that have been widely used for the treatment of psychiatric conditions in the past are known for their addictive properties as well as their effects as mood-improvers. The action of Tianeptine on mu, and to a lesser extent delta opioid, receptors may however offer the key to a drug that brightens the mood without the side effect of dependence.

 

Tianeptine’s action – Challenging the classic Antidepressant model


L-tryptophan
 is an essential amino acid that is utilised in the brain to create serotonin. It has been stated that those who consume more L-tryptophan in their diet are less likely to commit suicide than those who do not consume much of the amino acid. SSRIs, which are the most common treatment for depression, work by binding to the serotonin transporter, thus preventing the reuptake of serotonin into the presynaptic nerve cells. This process results in more serotonin being available for use in the nerve synapse. Popular examples of SSRIs include fluoxetine (Prozac) and sertraline (Zoloft).

 

Working as a selective serotonin reuptake enhancer (SSRE), Tianeptine acts in the opposite fashion. Rather than preventing the reuptake of serotonin, Tianeptine actually aids this process in the hippocampus and the cortex. Since this process also appears to help to treat depression, Tianeptine has further complicated the understanding that having a deficit of serotonin is the cause of depression.

 

Precisely how Tianeptine works to increase the speed of serotonin reuptake remains unclear, particularly as the drug does not appear to act noticeably at the sites of neurotransmitter receptors or monoamine transporters. It has been presumed that the effect of Tianeptine is dependent upon the changes in neurons and the relationships between them that take place in the longer term – over the period of a few weeks. This theory does however remain conjecture.

 

Tianeptine Politics | The Big Pharma Stronghold

 

Tianeptine, Politics and the Pharmaceutical Industry

 

Tianeptine is unique drug with a broad range of possibilities and applications. Not only is it a viable anti-depressant, it’s also used for the treatment and management of a huge range of ailments.  In fact if you haven’t already, go and read our other article on future uses of tianeptine to find out exactly how tianeptine has been proven useful in the treatment of asthma, anxiety, erectile dysfunction and irritable bowel syndrome.  Interestingly, however, tianeptine is NOT available in the USA and remains a ‘niche’ drug even in countries where it is available.  So why does a drug with so much scientifically proven potential remain widely unused and underutilised?  This article addresses the complex truth behind the politics of tianeptine.

 

 

The basic story of Tianeptine in the USA

 

Without getting bogged down in a historical narrative, here’s a brief summary of tianeptine in the USA.  First off, Servier, the maker of tianeptine, wanted to market the drug for disorders other than depression and anxiety.  It wasn’t until the late 1980’s that the company chose to sell it as an anti-depressant and by that time their patent had expired, meaning that other companies could essentially copy the drug.

 

Now, getting a drug into the US market is tough, particularly because the Federal Drug Administration requires assortments of extremely expensive tests and procedures before they will give approval.  Unfortunately, because of the expired patent, Servier calculated that the money it would cost to introduce tianeptine in the US would never be recouped.

 

In essence, why would any company pay huge sums of money when as soon as they get approval any other company in the world can start selling the product on the same ticket?  The answer of course is that they won’t, meaning that tianeptine remains unapproved and officially unavailable in the US.

 

 

The FDA and US Economic Protectionism

 

You might be thinking, ‘hold on, if tianeptine is so useful and has such a successful track record, why can’t the FDA make special considerations?’  Good question!  The answer is simple, US Economic Protectionism.

 

At the end of the day Servier is a European company not an American one.  The profits of tianeptine sales would largely be redirected back to Europe and this would be of no benefit to the US economy.  If tianeptine is ever to be approved by the FDA, it will likely only happen AFTER an American made drug that works in the same ways as tianeptine was approved and released into the US marketplace.

 

This may sound slightly conspiratorial, so how about an extremely relevant example?  The most well -known anti-depressant in the world, Prozac, is commonly referred to as the world’s first SSRI. Interestingly, however, numerous SSRI’s had been produced in Europe years beforehand but had been shut out from the American market.  Once Prozac, the all-American anti-depressant, had been approved and marketed, then the European drugs were given approval.

 

 

Larger Problems with the Pharmaceutical Industry

 

Market Protectionism, expensive FDA approval and expired US Patents do offer some explanation of why tianeptine isn’t available by prescription in the United States.  What these reasons don’t explain is why tianeptine is also unavailable in Canada, the United Kingdom and Australia.  Perhaps, then, there are some other factors at play.

 

Tianeptine is in many ways just the tip of the iceberg when it comes to the complex workings of the pharmaceutical industry.  Now, it’s easy when talking about pharmaceuticals to get bogged down in the ‘big pharma conspiracy,’ yet to do so is often intellectually lazy.  As such, any following claims made about the pharmaceutical industry will be directly linked to studies, research and articles for you to pursue and personally verify should you wish to do so.

 

 

Publication Bias

 

One of the biggest issues of pharmaceutical industry is that of ‘publication bias.’  This refers to the unethical influence of pharmaceutical companies on the studies and trials that they sponsor.  Basically the companies exploit a loophole in the legal system.  Companies carrying out their own clinical trials must register them in a database. However, the companies are NOT required to disclose the results of all of their trials.  Pharmaceutical companies therefore can register trials but choose not to disclose any negative results or findings.  In essence the companies can, and do, choose to only publish the results of studies that positively back up the claims made by the company.[i]

 

To put this into practice, it’s completely possible that a pharmaceutical company could sponsor a hundred different trials into the effects of its drug.  Ninety-nine of those trials could show that the drug is worthless, yet the company could still legally claim that the drug worked based on the results they publish from the single positive trial!

 

 

Other duplicitous publication habits[ii]

 

Don’t go believing that the problem of publication bias ends with cherry picking positive studies and hiding negative ones.  Companies have yet more options available to them:

 

  1. They can publish the same positive study numerous times to make it look like lots of different ones.

 

  1. They can ‘bury’ negative data in masses of text but leave it out of published graphs, images and summaries.

 

  1. They can completely ignore people who drop out of the trials.  (i.e. due to side effects or negative reactions to the drug)

 

  1. They can simply not ask any questions or monitor any side effects, therefore removing the obligation to publish them.

 

  1. They can choose not to include people known to respond well to placebo.  This is especially useful in manipulating placebo controlled studies.

 

 

Placebo versus SSRI

 

The manipulation of placebo controlled studies has been highlighted by the work of Irving Kirsch, Associate Director of the Program in Placebo Studies at Harvard Medical School.  He headed up a project analysing every single FDA registered study for the six most common SSRI’s.  What he and his team found was that although SSRI’s did give statistically significant changes to depression scores, these changes were small enough to make LITTLE OR NO CLINICALLY SIGNIFICANT DIFFERENCES in the treatment of depression when compared to placebo administration.

 

The project summarises its findings by saying that there is little reason to prescribe new-generation antidepressant medications to any but the most severely depressed patients unless alternative treatments have been ineffective.”  Kirsch talks at length about his findings in The Emperors new drugs.[iii]

 

Moreover, Kirsch’s team aren’t the only group to conduct this kind of research.  In 2002, Arif Khan spearheaded a team that requested all the FDA data on SSRIs and came to similar results as Kirsch.  Additionally the Journal of the American Medical Association published a meta-analysis in 2010 looking at published data on SSRIs.  They concluded, like Kirsch, that all but the most severely depressed fail to get much benefit from SSRIs beyond the placebo effect.

 

 

Mistrust and Meta-analyses

 

Now, if regulators and practitioners are aware of biased studies, surely they can rely on meta-analyses instead?  Think again…

 

An upcoming issue of the Journal of Clinical Epidemiology contains a review of 185 meta-analyses, and concludes that “a massive number of meta-analyses of antidepressant clinical trials have financial conflicts of interest and are unduly influenced by pharmaceutical companies

 

The review, conducted by Ebrahim[iv] and his colleagues, discovered that 79% of all antidepressant meta-analyses published over the past seven years were linked to or created by the pharmaceutical industry. (For example by funding, sponsorship or authors/researchers who were industry employees and/or had conflicts of interest)

 

The review also revealed that fifty-four meta-analyses (29%) had authors who were employees of the assessed drug manufacturer, and that meta-analyses including an author employed by the manufacturer of the assessed drug were 22-fold less likely to have negative statements about the drug than other meta-analyses.

 

Worryingly then, the very studies that are designed to review and analyse research for mistakes and bias have become just as biased as the research that they’re designed to review.

 

Pharma funding and lobby groups

 

At this point you might be wondering exactly how scientific studies can become biased on such a significant and widespread level.  The answer, unfortunately, is that large channels of money and favour are in action between researchers, businesses and politicians.

 

Thanks to the work of the Centre for Responsive Politics[v] it is possible for anyone, including you, to search for the exact amounts of money transferred between clients, lobby groups and politicians across America.  (The site is called opensecrets.org should you wish to verify any figure in this article.) The results of such searches can be somewhat terrifying.

 

Take for example the total amounts of money spent on lobbying in America’s biggest industries.  The totals below are from 1998-2015[vi]

 

IndustryTotal
Pharmaceuticals/Health Products$3,201,510,687
Insurance$2,234,393,387
Electric Utilities$2,040,702,304
Electronics Mfg & Equip$1,853,271,085
Business Associations$1,842,908,662
Oil & Gas$1,750,255,336
Misc Manufacturing & Distributing$1,442,304,755
Education$1,419,264,645
Hospitals/Nursing Homes$1,332,519,332
Telecom Services$1,291,783,209
Securities & Investment$1,287,877,075
Civil Servants/Public Officials$1,235,147,415
Real Estate$1,233,235,907
Health Professionals$1,221,036,450
Air Transport$1,144,829,349
Misc. Issues$947,286,635
Automotive$905,452,098
Defence Aerospace$902,567,485
Health Services/HMOs$880,161,913
TV/Movies/Music$867,424,016

 

You’ll notice that the pharmaceutical industry is the single biggest spender on lobbying in the United States, spending $3.2 billion over seventeen years in order to sway legal and political decisions in its favour.

 

The oil and energy industries often get a lot of bad press for this type of behaviour, yet the reality is that both of these industries spend less than half the money that the pharmaceutical industry does.

 

Medicare, Chuck Grassley and Buying Support

 

Here is a prime example of how decisions can be swayed through the purchase of political support.

 

You might remember that back in 2007 a bill to let Medicare negotiate drug prices with manufacturers was controversially blocked.  This meant the government lost the opportunity to potentially save billions of dollars. The biggest voice opposing the bill was Senator Chuck Grassley, a republican candidate from Iowa.  However, if you head back to opensecrets.org and look at Mr. Grassley’s sources of political fundraising you’ll find that across the last decade the medical industry has been one of his biggest sources of funding.[vii]

 

Apologies to Senator Grassley is he feels he’s being singled out here, because the reality is that he’s one of hundreds if not thousands of US politicians to have done this.  Again, head over to opensecrets.org and do the research yourself.  See how deep the rabbit hole goes.

 

 

Returning to the discussion of Tianeptine – An Unfortunate Reality

 

Whether we like it or not the drug industry is a mammoth, and the anti-depressant industry alone is worth an estimated $150 billion.  Drug’s like tianeptine represent a viable, inexpensive alternative to SSRI’s and because of this they cannot (at least in the eyes of drug industry shareholders) be allowed to enter common usage.  Through a combination of legal action, lobbying, scientific falsehood and clever marketing, tianeptine has been forced to remain on the side-lines specifically because it threatens the pockets of a very loud and powerful minority.

 

What this means for you, and for medicine as a whole, is that although tianeptine may be a better alternative for the treatment of various ailments, it won’t be prescribed by your local doctor any time soon.  Indeed for many sufferers of depression, anxiety or even chronic asthma for that matter, SSRI’s will remain the go-to prescription despite the alarming number of side effects.

 

In the future then, if medicine is to take steps forward and start pursuing drugs based on efficacy rather than economics, serious changes are needed to the processes through which studies are conducted and reviewed.  Lastly, if you happen to look into tianeptine or any other non-mainstream drugs, this article has hopefully demonstrated to you the value of double checking the credentials and funding of the information you find.

 

Notes for Further Reading

 

[i] http://blogs.plos.org/speakingofmedicine/2010/11/01/publication-duty-for-big-pharma/

[ii] http://www.uncommonhelp.me/articles/antidepressants-dirty-little-secret/

[iii] Irving Kirsh, The Emperor’s New Drugs: Exploding the Antidepressant Myth (2009 Bodley Head)

[iv] Ebrahim, S., Bance, S., Athale, A., Malachowski, C., & Ioannidis, J. P. (2015). Meta-analyses with industry involvement are massively published and report no caveats for antidepressants. Journal of Clinical Epidemiologyhttp://www.jclinepi.com/article/S0895-4356(15)00429-1/abstract

[v] https://en.wikipedia.org/wiki/Center_for_Responsive_Politics

[vi] http://www.opensecrets.org/lobby/top.php?indexType=i

[vii] http://www.opensecrets.org/politicians/summary.php?cycle=2014&type=I&cid=n00001758&newMem=N

Tianeptine’s Future Uses | Asthma, IBS, Fibromyalgia & ED

 

Future Uses of Tianeptine

 

You’re probably aware of Tianeptine’s successful usage as an anti-depressant and anti-anxiety medication.  You may not know, however, just how versatile tianeptine is.  In fact various pieces of research have suggested future uses for the drug ranging from the treatment of asthma through to prevention of erectile dysfunction.  This article explores some of the biggest possible future usages of tianeptine as well as the science behind these possibilities.

 

A quick heads-up, this article assumes that you know what tianeptine is, its current usage as an anti-depressant and the possible mechanisms through which it works.  (If not then check out this article to find out – insert link to prior article)

 

 

Tianeptine for the treatment of ‘at risk’ populations

 

One of the primary benefits of Tianeptine is that it has the same antidepressant and anti-anxiety properties[i] of other medications but with a relative lack of side effects.  Specifically tianeptine does not have any cardiovascular, sedative or anticholinergic adverse effects that would have significant negative impacts on the elderly.  Long term use of anti-cholinergic medication for example has been shown to increase the risk of both mental and physical decline.[ii]  In older adults study results even suggest that anti-cholinergic drugs appear to increase the risk of death[iii]  What’s more, there are also studies suggesting that they can contribute to memory problems[iv] including dementia.[v]

 

Studies have also shown tianeptine to be effective in the treatment of depression in individuals with post-traumatic stress disorder.[vi] In relation to PTSD, tianeptine was found to be most effective in chronic cases.  It has additionally been proven to be at least as effective as moclobemide and fluoxetine[vii] yet far less dangerous in terms of side-effects and addiction potential.  Fluoxetine, for example, has been shown to double an individual’s likelihood of developing insomnia, nausea, diarrhoea, rashes and itchiness as well as to increase likelihood of suicide or suicidal thoughts by 50-100%.[viii]  This last point is especially concerning in the treatment of individuals with PTSD given that they present a high risk group for suicidal behaviours.

 

 

Tianeptine for the treatment of Asthma

 

Most anti-depressants cause an anti-inflammatory effect in bronchi.  They have also been linked to bronchodilation.  The sum of these effects is that anti-depressants could theoretically be useful in the treatment of severe asthma.  However, traditional SSRI’s (Selective Serotonin Reuptake Inhibitors) come with complex side-effects that often outweigh the benefit of the asthma treatment.  Moreover, as serotonin may indeed cause bronchoconstriction the drug may be self-cancelling.  In other words traditional anti-depressants are ineffective in the treatment of asthma.

 

On the other hand antidepressants that combine anti -inflammatory and bronchodilating properties with minor side effects could turn out to be promising drugs in treating asthma.” [ix]  Tianeptine just so happens to be one of these drugs.  Specifically tianeptine is useful because it actually enhances serotonin reuptake rather than inhibit it.  This means that with tianeptine there is no bronchoconstrictive side-effect and it can work as a highly effective treatment for asthma.

 

Tianeptine as a treatment for asthma is much more than just hypothesis.  In fact its effectiveness has been proven through numerous vigorous studies.  In 1997, the Central University of Venezuela’s Institute of Experimental Medicine began a year-long randomized controlled trial of children with asthma.  At the end of the trial the children who had received tianeptine all showed decreases in clinical rating of asthma as well as increased lung function.[x] Basically because tianeptine reduced free serotonin levels the bronchoconstrictive effects of that serotonin were reduced.  This same institute went on to conduct two double-blind placebo-controlled crossover trials (about as scientifically vigorous as a study can get) as well as a seven year open-label study involving more than twenty-five thousand participants.  Each of these studies demonstrated tianeptine to be highly effective in the treatment of asthma.[xi]

 

 

Tianeptine for the treatment of Irritable Bowel Syndrome

 

Tianeptine may also prove useful in the treatment of irritable bowel syndrome, especially in cases of severe abdominal pain for which amitriptyline would usually be prescribed ‘off-label’.  A recent clinical trial[xii] compared the effectiveness and side effects of tianeptine and amitriptyline in the treatment of Irritable bowel syndrome as found them to be equally as effective.  However, tianeptine produced significantly less side effects such as constipation and dry mouth.  What’s more, amitriptyline has a much higher toxicity and can be particularly dangerous in overdose[xiii], meaning that tianeptine presents a safer alternative.

 

                                          

Tianeptine to treat pain due to Fibromyalgia

 

There have also been some promising developments in regards to tianeptine’s ability to treat pain associated with fibromyalgia.[xiv]  Specifically a 24 week study in 2007 divided participants into a ‘treatment’ group and a placebo ‘control’ group.  The study recorded pain scores, impact questionnaires, tender point scores and a depression anxiety inventory.  They found that the group treated with tianeptine demonstrated noticeable reductions in pain, anxiety and negative impacts of fibromyalgia.  With fibromyalgia still remaining a complex and poorly understood phenomenon any medications that can make headway in this area could prove extremely useful.

 

 

Tianeptine to treat Depression and Erectile Dysfunction

 

In 2006 the Journal of Sexual Medicine published original research on the topic of tianeptine for the treatment of depression and erectile dysfunction.[xv]  The research was based on a placebo controlled double blind randomised study of 68 men over 8 weeks.  The participants answered questionnaires on depression/anxiety, sexual inventory and quality of life/erectile function.  The results of the study indicated that tianeptine was 72.7% successful in reducing depression, improving quality of life and reducing erectile dysfunction.

 

In Conclusion – A better alternative

 

You’ve probably noticed that the ailments tianeptine could treat in the future already have medications to treat them in the present.  This has led some companies to question the drug’s worth.  However, the future potential of tianeptine lies not in its ability to treat previously untreated ailments, but rather to BETTER treat ailments that we are already medicating today.  Specifically, tianeptine appears to offer a safer treatment alternative with significantly less side effects than many of today’s more popular medications.  As more awareness of tianeptine is generated there’s no doubt that its popularity will grow as a preferential medication for a variety of ailments.

 

 

[i] Defrance, R; Marey, C; Kamoun, A (1988). “Antidepressant and anxiolytic activities of tianeptine: an overview of clinical trials.”. Clinical Neuropharmacology. 11 Suppl 2: S74–82. PMID 2902922.

[ii]  Fox, C; Smith, T; Maidment, I; Chan, WY; Bua, N; Myint, PK; Boustani, M; Kwok, CS; Glover, M; Koopmans, I; Campbell, N (September 2014). “Effect of medications with anti-cholinergic properties on cognitive function, delirium, physical function and mortality: a systematic review.”. Age and ageing 43 (5): 604–15. doi:10.1093/ageing/afu096PMID 25038833.

[iii] Ruxton, K; Woodman, RJ; Mangoni, AA (2 March 2015). “Drugs with anticholinergic effects and cognitive impairment, falls and all-cause mortality in older adults: A systematic review and meta-analysis.”. British journal of clinical pharmacology. PMID 25735839.

[iv] Talan, Jamie (July–August 2008). “Common Drugs May Cause Cognitive Problems”. Neurology Now 4 (4): 10–11. doi:10.1097/01.NNN.0000333835.93556.d1. Retrieved 2008-08-17.

[v] “Study suggests link between long-term use of anticholinergics and dementia risk”Alzheimer’s Society. 2015-01-26. Retrieved 2015-02-17.

[vi] Aleksandrovskiĭ IuA, Avedisova AS, Boev IV, Bukhanovkskiĭ AO, Voloshin VM, Tsygankov BD, Shamreĭ BK.  ‘Efficacy and tolerability of coaxil (tianeptine) in the therapy of posttraumatic stress disorder’ https://www.ncbi.nlm.nih.gov/pubmed/16329631

[vii] Onder, E; Tural, U; Aker, T (April 2006). “A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake”. European Psychiatry 21 (3): 174–9. doi:10.1016/j.eurpsy.2005.03.007.PMID 15964747.

[viii] Stone MB, Jones ML (November 17, 2006). “Clinical Review: Relationship Between Antidepressant Drugs and Suicidality in Adults” (PDF). Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee (PDAC). FDA. pp. 11–74.

[ix] G Krommydas, K Gourgoulianis, V Raftopoulos, E Kotrotsiou. Antidepressants And Asthma Treatment. The Internet Journal of Pulmonary Medicine. 2005 Volume 6 Number 1.

[x] Lechin, F; van der Dijs, B; Lechin, AE (November 2004). “Treatment of bronchial asthma with tianeptine”. Methods and Findings in Experimental and Clinical Pharmacology26 (9): 697–701. doi:10.1358/mf.2004.26.9.872567PMID 15632955.

[xi] Ibid.,

[xii] Sohn, W; Lee, OY; Kwon, JG; Park, KS; Lim, YJ; Kim, TH; Jung, SW; Kim, JI (September 2012). “Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open-label, non-inferiority, randomized controlled study”. Neurogastroenterology & Motility 24 (9): 860–e398. doi:10.1111/j.1365-2982.2012.01945.xPMID 22679908.

[xiii] Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.

[xiv] http://www.isrctn.com/ISRCTN16400909

[xv] Hany El-Shafey MD1, Ahmad Atteya MD2, Samir Abu el-Magd MD3, Ahmad Hassanein MD1, Ahmad Fathy MD1 andRany Shamloul MD, ‘Tianeptine Can Be Effective in Men with Depression and Erectile Dysfunction,’ The Journal of Sexual Medicine. Volume 3, Issue 5, pages 910–917, September 2006

Tianeptine Sulphate Dosage – The Complete Guide [2016]

Tianeptine Sulphate, Dosage, Complete Guide

 

Tianeptine is a member of the class of drugs known as tricyclic antidepressants (TCAs). It has been found to have anxiolytic and mood altering effects. Despite being a tricyclic drug, tianeptine has a significantly different pharmacologic profile than the average TCA and is thought to produce effects through action at several unique receptors. Tianeptine has found use in the treatment of asthma and irritable bowel syndrome (IBS) and may affect neural plasticity (learning).

 

Potential Benefits of Tianeptine

 

Tianeptine has been primarily used to treat depression, with some off-label use in the treatment of asthma and IBS. Following reports of improved cognition and euphoria from patients, researchers began to find that tianeptine had unique properties not seen with other TCA drugs. Subsequent research, particularly into interactions with receptors, indicates that tianeptine may dramatically affect human cognition, mood, and learning with very few side effects.

 

Depression, Stress, and Neuroplasticity

 

Neuroplasticity is a term used to describe the brain’s ability to adapt and change structure in response to learning and novel situations. In short, increased neuroplasticity is associated with easier learning and better cognitive performance while decreased neuroplasticity has opposite effects. Depression contributes to decreased neuroplasticity, so it should come as no surprise that depression impacts cognitive performance and that antidepressants can improve neuroplasticity.

 

One of the major factors contributing to depression is anxiety, which is provoked by stress. Multiple studies over many years have confirmed that stress and anxiety are detrimental to learning. Indeed, anyone who has ever been peppered with questions in a high-pressure environment (e.g. testing, medical students on wards, etc.) can attest to the cognitive impairment that results from stress. The problem is even worse than that, however. Stress can actually induce neuronal remodeling and affect established brain chemistry. There is evidence that stress, if allowed to persist, can actually lead to permanent mental impairment.

 

Antidepressants and other neuromodulatory compounds can protect against stress-induced neuronal remodeling. While the benefits of antidepressants on neuronal function have been known for some time, renewed interest has developed due to reports regarding tianeptine. There is good evidence to indicate that tianeptine inhibits pathological changes in glutamine transmission in the amygdala and hippocampus[1]. By doing this, tianeptine can reduce the effects of stress on the brain, making it easier to work in, function in, and survive high-stress environment.

 

Receptor Activation

 

Tianeptine has myriad receptor interactions that produce a wide range of effects. Beyond elevating mood and reducing anxiety, the molecule has also been found to have anticonvulsant and analgesic effects. It is also thought to induce euphoria, an effect that may explain the drug’s antidepressant effects despite a relatively mild serotonin effect.

 

What is clear about tianeptine is that it is a complex drug involved in multiple receptor interactions. Pinning down the precise effects of tianeptine as a result of specific receptor interactions has been difficult. Here is what has been discovered about the drug thus far.

 

Glutamate Receptors

Glutamate is a non-essential amino acid that plays an important role in neurotransmission and neural activation. In fact, glutamate is the most abundant excitatory neurotransmitter in the vertebrate nervous system and is heavily involved in learning and memory[2]. There are several different glutamate receptors in the central nervous system (CNS), including the NMDA receptor and the AMPA receptor.

 

NDMA receptor activation plays a vital role in learning and memory as well as in alertness. Many anesthetic drugs, like ketamine and nitrous oxide, reduce NMDA receptor activity. When activity is increased, as is the case with tianeptine binding, the NMDA receptor enhances memory and learning through a Hebbian mechanism. This essentially means that it promotes synaptic development and thus enhances the formation of connections between one neuron and another.

 

AMPA receptor activation mediates fast synaptic transmission in the CNS. This effect plays a significant role in long-term potentiation (LTP), which is the process of strengthening of synapses based on recent patterns of activity. In other words, AMPA receptor activation helps to strengthen synaptic connections and thus helps to make newly learned tasks and facts more permanent. It is a factor in long-term memory formation.

 

Tianeptine alters glutamate activity at both of the above receptors and, in so doing, may boost memory and learning. It also promotes the release of brain-derived neurotrophic factor (BDNF), which promotes nerve and synapse growth and is associated with the formation of new memories and the protection of existing brain structure[3], [4]. BDNF is heavily associated with the cognitive-enhancing effects of physical activity[5].

 

Adenosine A 1  Receptors

Adenosine A 1  receptors are thought to inhibit cholinergic neurons in the basal forebrain, an effect associated with increasing sleepiness and decreased alertness[6]. The receptors have also been associated with anticonvulsant and analgesic activity. Stimulants tend to antagonize (suppress activity) A1 receptors while sedatives tend to increase activity and thus reduce seizure activity and raise seizure thresholds (i.e. the amount of aberrant brain activity needed to trigger a seizure).

 

Tianeptine appears to modify the downstream effects of A 1  receptors, which means the drug works not at the receptor itself, but by modifying the chain of events that follows after receptor activation. In so doing, tianeptine may be able to suppress seizure activity and produce analgesic effects without producing the reduction in alertness associated with these events.

 

µ-Opioid and ?-Opioid Receptors

The µ-opioid receptor is heavily associated with analgesia (pain relief) and euphoria. Morphine is the prototypical µ-opioid receptor agonist. The ?-opioid receptor is primarily associated with analgesia as well as with respiratory depression. Tianeptine is a heavy agonist of both receptors, which would explain most of the drug’s analgesic properties, but may also help to explain its anxiolytic and antidepressant effects.

 

Tianeptine appears to produce relatively few effects on serotonin and norepinephrine levels, something that sets it apart from the other TCA drugs. Its antidepressant effects are thought to relate more to its µ-opioid and ?-opioid activities. These differences may help to explain why tianeptine can be more effective in refractory depression than other TCAs and why it lacks many of the side effects typical of TCAs.

 

Monoamine Transporters

Monoamine transporters regulate levels of monoamine neurotransmitters like adrenaline, dopamine, serotonin and melatonin. Drugs that directly inhibit monoamine oxidase, an enzyme that breaks down monoamines, have been used as antidepressants in the past, but have generally been abandoned due to high rates of side effects and a vast array of adverse food and drug interactions.

 

It was originally thought that tianeptine produce its antidepressant effects by altering regulation of monoamine transmitters to alter levels of serotonin and other neurotransmitters associated with mood. It turns out that tianeptine likely has a very low affinity for monoamine transporters[7]. This hypothesis is supported by the fact that tianeptine administration has almost no effect on serotonin levels in studies on rats[8]. The lack of effect on serotonin and other monoamines further indicates that its µ-opioid and ?-opioid activities are the primary means by which tianeptine elevates mood.

 

Dopamine D 2  and D 3 Receptors

Tianeptine has no direct effects on dopamine receptors (there are five receptors in all), yet it does potentiate D­2 and D 3  receptors in the CNS system[8]. It also modestly enhances dopamine release. The combined effects result in improved mood and improved activity in the brain’s reward center. It is unclear how these effects are achieved, but they tend to mimic effects seen with early-generation TCAs (without the same side effects)[9].

 

Tianeptine Sodium vs Sulphate

 

Early production of tianeptine resulted in a sodium moiety in the TCA ring. It was originally developed and patented by the French Society of Medical Research, but has since been manufactured by Laboratories Servier SA in France, which sells tianeptine under the trade names Coaxil, Stablon, and Tatinol.

 

The production of tianeptine sulphate was a calculated move by a U.S.-based nootropic company to address the fact that tianeptine isn’t sold in many “western” markets. By changing the basic molecular structure, it is possible to skirt patent laws. In general, no company would take this risk, but it was deemed acceptable because Servier is not actively pursuing marketing of tianeptine in the United States, Australia, Canada, New Zealand, or the United Kingdom. Because the drug is effective in treating a variety of conditions, it is unclear why Servier has not pursued marketing in the lucrative “western” markets. Regardless, they have not pushed their patent protections and so it continues to be manufactured and sold as tianeptine sulphate rather than sodium to individuals who can benefit from it.

 

Anecdotal reports suggest that the sulphate form of the drug make it more effective than the sodium form. Users report gentler dose-response curves, easier dosing, less highs and lows in mood, and no crash when the drug is discontinued. There is some speculation that the more gradual onset of action of the sulphate form of the drug may make it less addictive, which is generally true for any drug[10].

 

Dosing Tianeptine

 

Tianeptine sodium is generally prescribed at a dose of 12.5 mg and taken three times per day. Unlike other TCAs and selective serotonin reuptake inhibitors (SSRIs), tianeptine doses do not need to be increased slowly and a taper when the medication is discontinued is not required.

 

Off-prescription use of tianeptine sulphate results in people using anywhere from 100 mg to 3000 mg without substantial side effects. Side effects that may occur at very high doses include anorexia, nausea, vomiting, and constipation[11]. The latter effect is a result of tianeptine’s opioid receptor activity. Withdrawal symptoms do occur, but are generally mild. The most common withdrawal symptoms include myalgia (muscle pain) and feeling cold.

 

Many people start out taking 20 mg of tianeptine sulphate twice per day (40 mg total) and then increase the dose to 60 mg total (20 mg in the morning and 40 mg in the evening). Doses up to 100 mg per day are common, while doses higher than 100 mg per day are relatively rare[12].

 

Though many users claim the drug has a slower onset of action and longer duration of action (allowing for the twice-per-day dosing), there are people who claim the opposite and find that effects last only a few hours. As with any drug, there are likely fast and slow metabolizers of tianeptine sulphate and thus some people may require more frequent dosing than others[13], [14].

 

Many people find that coming of off tianeptine sulphate is a more gradual process than what they experienced with tianeptine sodium. This allows people to re-dose before “falling off the cliff” and experiencing complete cessation of the drug’s effects.  Many people who have taken the sodium version recommend multiplying the total dose by 3.3 and then dividing that by two to get an initial twice-daily dosing of tianeptine sulphate.

 

Tianeptine Side Effects

 

The side effects of tianeptine are surprisingly limited. Compared to other TCAs and even the SSRI class of antidepressants, tianeptine is almost free of side effects. Despite its mild side effect profile, it is important not to mix tianeptine with monoamine oxidase inhibitors or other antidepressants as the combinations could be life threatening. Tianeptine should also not be mixed with anesthetics and its use should cease 24-48 prior to surgical intervention requiring anesthetics or hypnotics. Here are a few of the more common side effects associated with tianeptine.

 

  • Constipation
  • Diarrhea
  • Indigestion
  • Vomiting
  • Dry mouth
  • Fatigue
  • Insomnia
  • Changes in appetite
  • Dizziness
  • Respiratory depression
  • Sleepiness
  • Blurred vision
  • Decreased sex drive
  • Headache
  • Itching[15]

 

Summary

 

Tianeptine is a prescription drug with multiple effects. Though a member of the class of TCAs, tianeptine has a substantially different mechanism of action and a unique side-effect profile. Tianeptine has antidepressant, anxiolytic, analgesic, and cognitive enhancing effects. It is currently used in the treatment of depression, but is actively being investigated for use in several other conditions.

 

Resources

 

[1] S. Kasper and B. S. McEwen, “Neurobiological and clinical effects of the antidepressant tianeptine,” CNS Drugs, vol. 22, no. 1, pp. 15–26, 2008.

[2] R. Sapolsky, Biology and Human Behavior: The Neurological Origins of Individuality, 2nd ed. The Teaching Company, 2005.

[3] S. E. Slack, S. Pezet, S. B. McMahon, S. W. N. Thompson, and M. Malcangio, “Brain-derived neurotrophic factor induces NMDA receptor subunit one phosphorylation via ERK and PKC in the rat spinal cord,” Eur. J. Neurosci., vol. 20, no. 7, pp. 1769–1778, Oct. 2004.

[4] T. Ng, S. M. Teo, H. L. Yeo, M. Shwe, Y. X. Gan, Y. T. Cheung, K. M. Foo, M. T. Cham, J. A. Lee, Y. P. Tan, G. Fan, W. S. Yong, M. Preetha, W.-J. K. Loh, S.-L. Koo, A. Jain, G. E. Lee, M. Wong, R. Dent, Y. S. Yap, R. Ng, C. C. Khor, H. K. Ho, and A. Chan, “Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer,” Neuro-Oncol., Aug. 2015.

[5] S. Gomes da Silva and R. M. Arida, “Physical activity and brain development,” Expert Rev. Neurother., pp. 1–11, Aug. 2015.

[6] D. Elmenhorst, P. T. Meyer, O. H. Winz, A. Matusch, J. Ermert, H. H. Coenen, R. Basheer, H. L. Haas, K. Zilles, and A. Bauer, “Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study,” J. Neurosci. Off. J. Soc. Neurosci., vol. 27, no. 9, pp. 2410–2415, Feb. 2007.

[7] B. Haenisch and H. Bönisch, “Interaction of the human plasma membrane monoamine transporter (hPMAT) with antidepressants and antipsychotics,” Naunyn. Schmiedebergs Arch. Pharmacol., vol. 381, no. 1, pp. 33–39, Jan. 2010.

[8] B. S. McEwen, S. Chattarji, D. M. Diamond, T. M. Jay, L. P. Reagan, P. Svenningsson, and E. Fuchs, “The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation,” Mol. Psychiatry, vol. 15, no. 3, pp. 237–249, Mar. 2010.

[9] “Effect of repeated treatment with tianeptine and fluoxetine…?: Behavioural Pharmacology,” LWW. [Online]. Available: http://journals.lww.com/behaviouralpharm/Fulltext/2002/03000/Effect_of_repeated_treatment_with_tianeptine_and.4.aspx. [Accessed: 14-Sep-2015].

[10] “Tianeptine Sulfate is VASTLY SUPERIOR to Tianeptine Sodium • /r/Nootropics,” reddit. [Online]. Available: https://www.reddit.com/r/Nootropics/comments/30w63b/tianeptine_sulfate_is_vastly_superior_to/. [Accessed: 14-Sep-2015].

[11] P. Vandel, W. Regina, B. Bonin, D. Sechter, and P. Bizouard, “[Abuse of tianeptine. A case report],” L’Encéphale, vol. 25, no. 6, pp. 672–673, Dec. 1999.

[12] “Tianeptine Sulfate – post your dose? • /r/Nootropics,” reddit. [Online]. Available: https://www.reddit.com/r/Nootropics/comments/34vjs2/tianeptine_sulfate_post_your_dose/. [Accessed: 14-Sep-2015].

[13] “Ceretropic Stocks Tianeptine Sulphate • /r/Nootropics,” reddit. [Online]. Available: https://www.reddit.com/r/Nootropics/comments/2z4e8w/ceretropic_stocks_tianeptine_sulphate/. [Accessed: 14-Sep-2015].

[14] “Anyone tried the new tianeptine sulfate? • /r/Nootropics,” reddit. [Online]. Available: https://www.reddit.com/r/Nootropics/comments/2zobah/anyone_tried_the_new_tianeptine_sulfate/. [Accessed: 14-Sep-2015].

[15] “Coaxil Drug Information – uses, side effects, precaution for Coaxil.” [Online]. Available: http://www.diseasesatoz.com/medications/coaxil.htm. [Accessed: 21-Aug-2015].