Understanding why serotonin does not cause depression

Allan Young, one of the co-authors of the recent article that indicated that serotonin is implicated in depression (see last post), is quoted in Herald Scotland (see analysis article) as saying that “Any criticism of the chemical imbalance theory truly misunderstands why it was developed and used by researchers and clinicians”. I’m not quite sure what he means by this. As I understand it, the motivation to continue the serotonin hypothesis is to encourage people to take their antidepressant medication. How people have understood the serotonin hypothesis (chemical imbalance theory) is that depression is caused by low serotonin. Young says this theory is too simplistic. But I’m not sure what he believes instead.

He suggests the theory was developed to explain how “brain changes occur in depression in a more accessible way”. Again, it’s not clear what he means by this. But this seems to be the crux of the problem. Are the brain changes in depression any different from ‘normal’? Depression is a personal condition. Of course it’s mediated by the brain. That’s commonsense and not rocket science. People don’t need a chemical imbalance theory to understand that.

Young's convinced that “brain changes do occur in the brain of depressed people”. He seems to be saying that these changes cause depression. He’s got muddled that people are their brains (eg. see previous post). Of course I have a brain. If I was depressed I would still have a brain. But that brain is not me, whether I’m depressed or not. It doesn’t cause my depression.

The conclusion of the umbrella review by Moncrieff et al was that there is no convincing evidence to support the theory that depression is caused by low serotonin. Young says this conclusion is wrong. It isn’t! Psychiatrists like Young need to move on from an outdated, misguided physical disease model of mental illness. Otherwise he won’t understand why the serotonin theory of depression needs debunking, even the less simplistic version he wants to promote, whatever that is.

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.