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Friday, 16 December 2011

Medications: What Would a Selective Serotonin Reuptake ENHANCER Do?

In recent years there has been considerable controversy about the Selective Serotonin Reuptake Inhibitors (SSRIs) like citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), and the like.
These drugs are widely thought to operate by reducing the reuptake of serotonin into the sending neuron, thereby leaving more serotonin available in the gap between neurons so that enough can get across and cause the next neuron in line to fire.

Irving Kirsch and others have called this explanation into question, acknowledging that about 60% of people taking SSRIs seem to improve, but questioning whether the popularly-accepted explanation is correct.

If an SSRI helps mood by inhibiting serotonin reuptake, then what if we had a drug that promotes reuptake? Such a drug would open the reuptake pumps wider, reduce the amount of serotonin in the gap between neurons, and reduce the likelihood that the next neuron in line would fire. Presumably, such a drug would increase depression or, at minimum, have no antidepressant effect.

Fine. But is there such a drug?

Yes. It’s called tianeptine. It is a selective serotonin reuptake enhancer (an SSRE). It has been used in Europe and elsewhere for over ten years, and has been the subject of considerable study, including a number of double-blind trials.

Oddly enough, it’s sold as an antidepressant.

In 2002, a meta-analysis (a statistical reanalysis of multiple previous trials) examined five studies of tianeptine versus SSRI. The SSRI was fluoxetine (Prozac) in two cases, paroxetine (Paxil) in two cases, and sertraline (Zoloft) in one (Kasper & Olie, 2002).

The results indicated that there were no significant differences in effectiveness between SSRE and SSRI, except for one measure that leaned in favour of tianeptine. Most studies and reviews considering tianeptine concur that there is ample evidence that tianeptine is approximately as effective as SSRIs (eg., McEwan & Olie, 2005, Brink et al., 2006) and there are scattered reports that it is better tolerated with fewer side effects.

What’s missing from this picture?

What's missing is a nice medication crossover trial. Perhaps people who are given an SSRI and do not respond well will respond better to an SSRE than to another SSRI. As far as I can tell, this hasn’t yet been done.

So what’s up? 

How can tianeptine possibly work? One option is that both SSRI and SSRE are simply placebos, and that it doesn’t matter what you give people, some of them will get better – even if the drugs have opposite chemical effects.

Another option is that the reuptake effect doesn’t really explain the antidepressant effect, and that one or both of these medications works against depression at some other level. And indeed, there are hints that in addition to the SSRE effect, tianeptine operates elsewhere in the brain: on glutamate transmission, on the hippocampus, and possibly by reducing the damaging effects of stress (Kasper & McEwan, 2008).

What the tianeptine data does do is cast the popular explanation of antidepressant action into serious question. It’s hard to claim that antidepressants work by reducing reuptake when an equally effective drug increases reuptake. This is just one line of evidence nailing down the coffin lid of the monoamine hypothesis of depression.

It will be interesting to see what comes of the research into tianeptine. What we can already conclude is that our traditional explanation to patients about how SSRIs work is simply not supported - not by this data, nor by other lines of evidence. To the extent that we continue to give out the story, we are spinning fairy tales.

The truth is: We just don’t know how these medications work on depression – apart from the action of expectancy (the belief that one is receiving an active treatment), which seems to account for a large proportion of the effect.

Is there an additional biochemical margin, an organic benefit to these medications? Perhaps. But at this point there is no consensus about what it is.


Brink, CB, Harvey, BH, & Brand, L (2006).  Tianeptine: A novel atypical antidepressant that may provide new insights into the biomolecular basis of depression.  Recent Patents on CNS Drug Discovery, 1, 29-41.

Kasper, S, & McEwan, BS (2008).  Neurobiological and clinical effects of the antidepressant tianeptine.  CNS Drugs, 22, 15-26.

Kasper, S, & Olie, JP (2002).  A meta-analysis of randomized controlled trials of tianeptine versus SSRI in the short-term treatment of depression.  European Psychiatry, 17, 331-340.

Kirsch, I, et al., (2008).  Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration.  PLoS Medicine, 5(2), e45.

McEwan, BS, & Olie, JP (2005).  Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant:  Tianeptine.  Molecular Psychiatry, 10, 525-537.

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  1. Your article is very balanced. In this rather polarized debate between believers and non-believers of anti-depressants, this is very welcome.
    Although my believes in this matter are strongly on Kirsch's side, (I am a non-believer) I would like to see more consensus within the scientific community on this.
    Kirsch did throw more that just a pebble in the pool. Ripples on the surface were picked up by a lot of media. A broad discussion has started, which is good, but there are some serious adverse effects to this.
    For the patients the water suddenly has turned very muddy and blurry. Who should they trust? What should they believe and rely on?
    A woman I know reacted very distressed when she saw a documentary that basically said the pills she depended on were just expensive sugar pills. It wasn't so much she felt betrayed by others - her main concern was that she could no longer trust her own judgement. She felt betrayed by herself. She had felt an immediate difference in state-of-mind when she took the first pill. Was it all just her imagination?
    I tried to reassure here that it was not just her imagination, as drug trials with mice had shown that the animals on anti-depressants tried for a much longer time to free themselves from being suspended by their tail.
    But I added to this that Kirsch' assessment of trial data showed that is was very unlikely that this initial 'drive' or 'boost' that was created by the drugs had any effect on getting rid of a depressive state-of-mind in the long run.
    But even as I said this to her, I wasn't quite sure that the effect of the drug she felt wasn't just a strong placebo-effect after all.

    I think general opinion on efficacy of antidepressants is slowly changing. Believers are starting to doubt.
    One indication of this is the fact that in Belgium, the spokesperson of the Belgian Pharmaceutical Industry ( acknowledged in March 2011 that antidepressants are overused and misused, especially in mild to moderate depression (while quickly adding that he thought it was not being prescribed enough for severe depression). If you look at the website of to see what companies they represent, this was quite a statement!
    Other indications I see are the way antidepressants are described in language. Drug efficacy is often expressed in very conditional and speculative language (might be, could be, is considered to be,...).
    In fact, if you only look at the way the SSRI-SSRE paradox (it is indeed a scientific schoolbook paradox), is being handled in terms of language, you don't have to google too long to find some nice examples of language use that illustrate the unease among believers.
    The Wikipedia article on SSREs states that SSREs "work in marked contrast to other antidepressants such as SSRIs". An almost humourous understatement, but at the same time it is nevertheless a (though be it very hesitant) acknowledgement of the paradox.
    Even more concrete than a wiki-article, I found a question by a patient looking for more efficient medication. She stated it as follows:
    "Since SSRE works in a somewhat inverse way as compared to SSRI, can SSRE help ?"
    Even here, I dare detect a reluctant acknowledgment of the paradox. It's my interpretation of her words of course, but if I'm right, it's a nice example of how patients are dealing with doubt. They let it penetrate drop by drop.
    I assume that's the safest way to proceed.
    Give dumbo some time to adjust. Abrupt changes only have happy endings in Disney cartoons.

  2. I have a sneaky suspicion that SSRE pills help depression by giving you more REM sleep at night, so you'd feel more awake and alert, and SSRI give you less REM sleep (according to a fact list I found), so you'g feel more groggy and unable to function as well, I believe that serotonin re-uptake has a direct effect or is a main reason for(etc.), REM sleep. I think more studies should be done on the effects of Anti-depression on ones sleep.

    1. There are a lot of studies into this. You are broadly wrong, however; SSRIs effects on sleep are not directly related to the action on the serotonin. However, a great many of them have anticholinergic and antihistamine side effects, both of which are known to cause sleep disturbance. However, more likely is that circadian rhythm disturbances exist prior to medication; see the success of aglomelatine, which is active at the melatonin receptors in addition to its antidepressant effects

      for more:
      Clinical Management of Depression: The Keys to Success, Journal of Psychopharmacology, vol 24, no 8, supplement - august 2010

  3. SSRI antidepressants can be distinguished from placebo in controlled trials, sometimes as early as the first week of the course, so it couldn't be the placebo effect responsible for their action.

    Papakostas et al 2006
    Posternak and Zimmerman 2005
    Stassen et al 1996
    Taylor et al 2006