Serotonin Returns
The Serotonin Hypothesis of Depression May Not Be Dead Yet
Last year, an umbrella review was published that analyzed the evidence on the serotonergic hypothesis of clinical depression. In the review, the authors claimed that after going through decades of clinical research, there was no clear evidence that lower levels of serotonin caused, or were related to the occurrence of clinical depression.
The review obviously seemed like a bombshell piece of evidence on a theory that had become the norm in our everyday understanding of clinical depression. I covered the story here:
In the time since the review was published, concerns have been raised about the methodological solidity of the umbrella review. I will be sharing a simple summary of those concerns here.
Understanding Meta-Analyses
A meta-analysis is considered a solid piece of evidence in scientific literature. As the name suggests, it is an analysis of analyses. In the process, researchers gather the previous studies done in a domain and analyze the overall findings.
A meta-analysis, when done well, can serve as the referral point for future researchers but meta-analyses have one major weakness.
They are only as good as the studies included in the analysis. If poorly designed studies get muddled in with well-designed ones, the overall quality of the meta-analysis reduces.
Inclusion and Exclusion
You may have some simple questions about performing a meta-analysis. Who decided which studies are included and which ones are not? How is this decision made? What happens if a mistake is made?
While I won’t get into the details of how to conduct a meta-analysis, you need to know that scientists use a protocol to select which studies are worth being included in the study and which ones are not.
Interestingly, the authors of the umbrella review used a modified version of this protocol. This modification was made AFTER the process of collecting and analyzing studies had begun.
While it is not damning in itself, it raises questions about the validity of the analysis.
Interpreting Results
Questions have also been raised about the interpretations made from the included studies. In some cases, it was discovered that the authors of the original review made a conclusion that was OPPOSITE to what the research found.
In other studies, they did not follow the validated criteria to decide on the quality of evidence for biomarker studies.
Basically, going away from the valid protocols leaves room for manipulation of results and seeping in of bias.
This seems to be the case in the umbrella review.
Unconvincing Rebuttals
When the concerns with these studies were first published in scientific journals, the original authors of the umbrella review were expected to respond. Their response so far has been less than convincing.
They have resorted to personal attacks against the critics, called them shills for “Big Pharma” and questioned their motivations. They have done little to offer justification or explanation for their actions.
While these rebuttals may work in an online debate or a trolling contest, they don’t really work well in scientific discourse.
So what’s the truth?
This is where facts get muddled with opinion and bias. Honestly, while I was on board the idea that low serotonin levels alone do not cause depression, I found the criticism of the umbrella review valid and the rebuttals to them below par.
The original authors seem to have an axe to grind with antidepressant use instead of trying to generate a better understanding of how depression develops and the role of chemical balance in the same.
We like to think that science is linear and moves from one bombshell discovery to the other. It is not so. Science and scientific knowledge develop over time.
It is no surprise then that humility and being open to criticism are such central qualities to being a good scientist.
While the “chemical imbalance theory” of depression still doesn’t capture the complexity and nuances of neurochemistry and psychopathology, I think the role of serotonin in the same has not yet been completely debunked. (As I previously thought)
Serotonin has made a comeback.
You can read more about the criticisms and what they mean here.
Meta studies are always very interesting and not always super accurate. You are 100% right to shed light on this. One of the things that I've noticed in my research on serotonin is that elevated levels of it can cause health problems. The evidence is pretty clear that high levels of serotonin have a role in cancer.
https://mattcook.substack.com/p/happy-to-horrified-the-lies-of-serotonin
Yes, scientific studies are often less than perfect. They aren't the end all be all some take them to be.