Friday, June 16, 2023

What does it mean to say that serotonin is implicated in depression?

As I explained in a recent post, psychiatrists find it difficult to give up the serotonin theory of depression. A paper in Molecular Psychiatry, written by multiple authors, many of whose academic psychiatric careers have been dependent on believing a version of the theory, argues that the evidence clearly indicates the serotonin system is implicated in depression. I want to look at what this statement means.

The paper concludes that "acute tryptophan depletion and decreased plasma tryptophan in depression indicate a role for 5-HT [serotonin] in those vulnerable to or suffering  depression, and that molecular imaging suggests the system is perturbed". Note that the paper does not say that depression is caused by low serotonin. The serotonin hypothesis has not been proven, which is what people have often been led to believe. The argument seems to be that further research is justified, I guess particularly in the two areas highlighted of tryptophan depletion and serotonergic molecular imaging.

Any statements in the paper in favour of the serotonin theory of depression are not couched in terms of causation. For example, as in the title of the paper, the serotonin system is said to be implicated in depression, not necessarily a causal factor in depression. The brain contains large numbers of neurones that transmit signals by releasing neurotransmitters, such as serotonin. Of course depression is mediated by the brain. Is any more than this tautologous statement being made by suggesting that the serotonin system is implicated in depression? I guess the serotonin system must be implicated in some way, which is unclear at present, as it is part of total brain processes. But that is very different from suggesting that depression is due to an abnormality of serotonin in the brain.

Moncrieff at al (2023) make this point in their response to this paper, including commenting on other letters written in reply to their original umbrella review. As they say, 
We would agree that many brain processes, including the serotonin system likely play a complex, though poorly understood, role in emotion and behaviour, including depression. Yet such ideas are different from the specific claim that depression is caused by low serotonin levels or serotonin activity (often communicated to patients) that our review specifically examines.

Psychiatrists will continue to find it difficult to give up the serotonin theory of depression because they believe antidepressants are effective. As nearly all antidepressants have an effect on serotonin, as far as they are concerned, this mechanism must be how they work. Questioning whether antidepressants are any better than placebo creates grave concern for the professional viability of psychiatrists, as does debunking the serotonin theory of depression. Psychiatrists need to give up such a vulnerable basis for their practice.


Akhil das said...

antidepressants have shown clear benefit from placebo in multiple RCTs. How do u explain that?

DBDouble said...

The debate about the serotonin theory is not really to do with the separate debate about the efficacy of antidepressants. I have blogged on this elsewhere (eg. see post Essentially the academic debate has not come to a conclusion. My personal view is the small statistically significant difference between antidepressants and placebo in clinical trials is an artefact because of methodological problems.