It is understood how most drugs work their magic. But for some it remains a mystery. Among the most mysterious is a group of widely used antidepressants called selective serotonin reuptake inhibitors (ssris), the best known of which is Prozac.
For decades, doctors believed that ssris worked by increasing levels of serotonin, a chemical that carries signals between neurons in the brain. This assumption was based on the hypothesis that lack of serotonin causes depression. But a growing number of researches suggest that the theory does not hold up, a conclusion drawn from a set of newly published reviews of this work in Molecular Psychiatry.
This super study, led by Joanna Moncrieff of University College London, covers several lines of research on the link between serotonin and depression. One looks at the levels of serotonin and its degradation products in the blood and spinal cord fluid, taking them as indicators of the amount in the brain, which is not safe to measure directly in living people. Work in this line, the review concludes, shows no difference between clinically depressed and healthy.
Neurons reabsorb serotonin after they have done their job. ssris blocks this, leaving more of the molecule available. Thus, another study examined serotonin-responsive receptor proteins and the transporters through which it is reabsorbed. This occasionally found evidence of increased serotonin activity in people with depression, contrary to what might be expected. Dr. Moncrieff believes this can result from the use of antidepressants, something that is not always taken into account when compared to and without depression.
A third line of research depends on the fact that serotonin is made from tryptophan, a substance that the body cannot synthesize and therefore must ingest from food. In these experiments, participants ’serotonin levels are reduced by depriving them of tryptophan. Dr. Moncrieff’s team concluded that reducing serotonin in this way did not produce depression in hundreds of healthy volunteers.
Finally, the researchers analyzed large genetic analyzes. These found no differences between the genes that regulate the serotonin transporter in those with depression and those that do not.
If serotonin is not the cause of depression, this raises questions about ssris. These do help some new patients, but not others. And they come at a cost. Possible side effects include loss of libido and inability to reach orgasm. It can also be difficult to stop taking it, leaving some who are recovering from depression to depend on it for life.
Clinical practice is already changing to emphasize dealing with the environmental triggers of depression, such as adversity and poor coping skills, rather than deploying drugs. But it would still be good to understand in advance who will benefit from the ssris and who will not. Without the serotonin hypothesis, doctors return, in this sense, to the case. ■
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