The links between serotonin and depression put to the test by science

Let’s board a time machine: we are in 1967 when the article entitled Biochemistry of affective disorders is published in the scientific literature by Alec Coppen. It was he who first presented the idea that depression and other disorders might have a biological explanation. In the viewfinder, monoamines (including dopamine and serotonin), a family of neurotransmitters whose functions are different. If the proposed model does not elude the environmental causes of these disorders, it focuses on the strictly biochemical aspect of their explanation. The idea that there would be a loss of neurotransmitters which would induce disorders, is already present.

While the article is innovative in that it proposes quantifiable causes for affective disorders, the evidence it has to support its view is slim. What prompts the author to suggest that these disorders have biochemical bases is the fact that treatments ” physical are working. He then takes as an example the case of a patient depressive, retarded and anorexic” and suggests that he has regained a normal state after seizures induced by Electric power. Of course, he does not stop there in the demonstration. But most of the studies cited include few patients, which limits the theory to a clearly exploratory stage.

Since then, many studies have been carried out with the aim of uncovering the biochemical bases of depression, focusing in particular on serotonin. If this theory seems validated for many media and for health professionals who are not specialists in the subject, there are still questions about it in the scientific community. It is with this in mind that a recent systematic review published in Nature fits in, arguing that this theory is simply not supported by empirical evidence.

Why is this important?

As we have just mentioned, this theory has a special status because of its wide media coverage since the 1990s and the marketing of serotonin reuptake inhibitors. This can greatly affect people’s beliefs about the supposed causes of depression. For example, in Australia, 67% of the population attribute depression has neurobiological causes. However, most people also consider that there are psychosocial causes.

Some consider the ultimate proof of this theory to be the clinical effectiveness of serotonin reuptake inhibitors. However, the latter is regularly the subject of criticism, whether in matter effect size, relative efficacy depending on the severity of the depression and even mechanisms of action. A good overview of these reviews can be found in this meta-analysis who studied extensive clinical data transmitted to the Food and Drug Administration. With all these elements, it is therefore necessary to check the status of this theory in the literature. Is it validated by robust, consensus-based evidence? Is it refuted? Or should it be the subject of broader investigations?

The burden of proof lies with the scientists who support this theory

Within their systematic review, the authors studied the question of the link between serotonin and depression by taking into account the level of plasma serotonin and its metabolite main urinary: theacid 5-hydroxy-indolacetic, the level and activity of a synaptic serotonin receptor, the level and activity of serotonin transporters, the effect of a reduction in tryptophan — I’amino acid precursor of serotonin — on the onset of depression, the level of expression of a gene of interest, in particular the one leading to the production of protein transporting serotonin, and the interaction between this gene and the stress. The authors excluded studies on animal models and on patients with specific conditions (physical pathologies or very specific depression such as childhood or postpartum depression).

Regarding serotonin and its urinary metabolite, the review suggests that the associations are not statistically significant when multiple regressions are performed, taking into account the importance of other key variables. A few studies have also investigated this link by measuring the aforementioned variables in the cerebrospinal fluid — the preferred site for this type of measurement, but very invasive — and found no association. On the side of the receptors, of which more than 14 have been identified, the review focuses on studies of only one of them, since it is currently the only one whose possible role in the occurrence of depression. No association is detectable between healthy and depressed patients. Also, several studies are unfortunately methodologically biased, since they include patients undergoing treatment.

For the carrier, the studies do not find associations and when they find some, they suffer from a colossal methodological bias which is that most of the patients included have a history of takingantidepressants. It’s a common problem in depression studies that was already limiting findings in the days of Alec Coppen. The studies of depletion, which focus on lowering the amount of tryptophan, suffer from the same bias, and in more qualitative studies, find no effect on participants’ mood. Finally, regarding the isolated genetic component and its relationship to stress, if previous studies suggest links between a genetic polymorphism and depression, larger and more methodologically robust studies fail to find the same results. These links are therefore strongly questioned.

What future for the theory of neurobiological imbalance?

Given the elements presented, the theory of neurobiological imbalance does not seem to be supported by the evidence. However, several things need to be clarified. The first is that this theory could still explain other types of depression. As we have seen, studies including this type of patient were excluded from the systematic review. Second, perhaps other markers will give conflicting evidence in the future, such as the 13 receptors whose functions we still don’t know well today. Third, no matter how reliable this theory is, it does not call into question theaxiom suggesting that depression has biological causes.

Therefore, even if this theory is false, it does not rehabilitate the anachronistic ideas, unfortunately still too widespread, considering that depression is due to a lack of willpower. Unfortunately, partial biological determinism, even when known, does not appear to reduce stigma in populations with psychiatric disorders. In conclusion, therefore, it is incumbent on the proponents of this theory to produce more convincing evidence to support it. The medical community must also re-examine some of the pharmacological treatments whose controversial clinical efficacy rests on this theory.