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.
Is there an alternative to a medication-based approach? If someone takes medication, is there more they can do in order to maximize the effect? Consider seeking the help of a qualified psychotherapist trained in cognitive behaviour therapy.
In addition, our clinic has developed a cognitive behavioral guide to self-care for depression. Though not a substitute for professional face-to-face care, UnDoing Depression may be a useful adjunct to your efforts. The preview is below. For 50% off the regular fee of $140 USD, use coupon code “changeways70” when you visit our host site, here.
We also have courses for professionals and for the public entitled What Is Depression, What Causes Depression, Diagnosing Depression, Cognitive Behavioral Group Treatment of Depression, How to Buy Happiness, and Breathing Made Easy. For the full list with previews and substantial discounts, visit us at the Courses page of the Changeways Clinic website.