No Link Between Serotonin and Depression?

If you’re active on social media, you might’ve come across reports of a recent meta-analysis showing no evidence of a causal link between serotonin and depression. And you might’ve also come across far-reaching interpretations about the effectiveness of antidepressants. Not exactly surprisingly, popular interpretations of this study have gone way beyond what the poor paper actually shows. And the reason seems to be more than just “media hyping it up for clicks”.

Disclaimer (because not everyone might read until the end): do not abruptly stop taking antidepressants. Doing so leads to quite serious side effects, including, but not limited to dizziness, nausea, shock-like sensations in the body, increased anxiety and depression symptoms, and in rare cases, psychosis.

The meta-analysis recently published by Joanna Moncrieff and colleagues in the Molecular Psychiatry journal, titled “The serotonin theory of depression: a systematic umbrella review of the evidence“, has sparked a new bout of psychiatry/neuroscience drama. But while drama is my guilty pleasure, carefully diffusing dramatic situations by using established scientific evidence to separate fact from reasonable speculation from wild fantasy is my middle name. And to do that, we will be looking at four things:

What did the scientific community know about chemical imbalance and depression before this meta-analysis came out?
What’s new in this study?
What can we actually claim based on it?
What’s the deal with antidepressants?

What scientists knew

In short, pretty much everything that is presented in the article. You see, this article is an umbrella review. That means the authors conducted a systematic review of other systematic reviews and meta-analyses. In a systematic review, scientists do not perform any new experiments. Instead, they summarize previously published literature selected and evaluated according to a systematic set of criteria. A meta-analysis is also a summary of previous literature, but in addition, it involves statistical analyses on the data collected from these other reports. In other words, an umbrella review is a summary of summaries.

There is a lot of merit in umbrella reviews, as they provide a much better overview of all available evidence and are capable of addressing much broader questions compared to normal systematic reviews (as we will also see for the current one). Because of that, they are typically used in medicine to develop clinical guidelines. At the same time, it also means that the information included in an umbrella review already exists prior to the publishing of that review. And that any expert worth their salt most likely knows about it already.

Which is exactly the case here. The serotonin hypothesis of depression, usually marketed as the “chemical imbalance” theory, fell out of fashion a long time ago. “Chemical imbalance” as a cause of depression (and later of other mental disorders) was first put forward in the 1950s, when during unrelated trials scientists observed that some drugs helped with depressive symptoms. The logical hypothesis was that depressed people had some form of “imbalance” which the drugs corrected. This hypothesis appears to have become mainstream in the ’90s, when pharmaceutical companies began using it in their marketing campaigns for a new type of antidepressant called SSRI (selective serotonin reuptake inhibitor).

But assuming that serotonin concentrations were decreased in people with depression was not enough. Researchers wanted to know exactly what caused that. Generally speaking, there are several mechanisms through which one can end up with less of a particular neurotransmitter:

there’s simply not enough of it produced;
something is blocking its release;
it’s cleared too fast from the synapse.

In all cases, the end result would be the same: we would be measuring a decreased amount of that particular neurotransmitter at the synapse. Of course, going even further, one could even trace a genetic cause for certain defective mechanisms. For depression, a popular candidate gene was initially identified for the last mechanism only. Unfortunately, the research for all three mechanisms followed a typical pattern: initial study reported changes of a certain mechanism in depression→follow-up studies showed conflicting results→subsequent larger studies/meta-analyses found no consistent evidence of effect→hypotheses were refined and/or new ones were generated, methods were improved as well, and the whole cycle started again.

While this is a slow and arduous process, it has also led us to discover that depression is most likely not a single disorder, but multiple disorders in a trenchcoat. In this context, changes in a single neurotransmitter cannot account for the observed heterogeneity. As such, the simplistic serotonergic hypothesis was abandoned. And while research into neurotransmitter changes in depression (not just serotonin, but also dopamine, noradrenaline, glutamate, GABA etc.) continued, the focus hasn’t been on finding the one true substance which causes depression, but on understanding the bigger picture of neurochemical changes and how they relate to the other potential causes and markers of depression.

The current operating model for depression in psychiatry is the biopsychosocial model, which views depression as a disorder caused by an interplay between biological, psychological, and social factors. Changes associated with this disorder include altered structural and functional brain connectivity, neuroimmune alterations, problems related to the gut-brain axis, and epigenetic modifications, among others.

In summary, scientists had already abandoned the “chemical imbalance” serotonin theory of depression for quite a while. Of course, a natural question here is “why the hell are we still using antidepressants then?” We’ll talk more about that in the final section, but in short, it’s because they work (at least for some people), and because in spite of numerous efforts, we currently do not have an alternative when it comes to medication. And no, psychotherapy and exercising don’t help everyone either.

What’s new here

This will be a much shorter section because, as you can already see, there wasn’t much new here.

As we’ve highlighted above, the authors of this umbrella review did an incredible amount of work by putting together decades of findings from different research directions. More specifically, they summarized literature from six separate subfields:

serotonin concentration in the cerebrospinal fluid;
presynaptic receptors inhibiting serotonin release;
function of the serotonin transporter responsible for clearing it away from the synapse;
depletion of a serotonin precursor;
genetics of the serotonin transporter;
interaction between stress and the gene encoding the serotonin transporter.

Each study included in the review was also evaluated according to a strict set of criteria in order to determine its quality. From a research perspective, it is highly useful to have this kind of information on the quality of previously published literature, as well as to have one document providing a clear overview of a particular research subdomain (rather than having to sift through to hundreds, if not thousands, of papers).

But in terms of novelty and of “disproving” the serotonin hypothesis…well, they’re mostly just beating a dead horse.

What we can infer from it

We cannot use this umbrella review to claim anything more than what the authors have actually analyzed. Yes, it’s appealing to make other claims based on it, but in science, every hypothesis, no matter how trivial it might seem, needs to be tested. There are enough instances where something “obvious” turns out to work in a surprising way. Still, we can make some inferences by corroborating this study with previously published work which looks at other issues of interest.

For example, albeit inadvertently, this study highlights a problem in the communication between scientists and the public. Although they did not explicitly review this, the authors do mention in the introduction that the “chemical imbalance” theory is still incredibly popular among the general public. In support of this statement, they cite a couple of prior studies where ~80% of the surveyed people believe in this hypothesis. Small caveat though: those studies are from the early 2010s, and it’s reasonable to assume that beliefs about that have changed over the past decade. And a second small caveat: generally, such beliefs are modulated by cultural background, so it’s really a stretch to claim that what holds true in the United States or Australia will generalize to, you know, the rest of the planet. Still, going beyond these things and judging simply by people’s reactions to the current article, it seems that there’s something there.

As it’s often the case, there are multiple reasons for the current public beliefs about depression causes. Of course, one of them is that pharma companies heavily pushed the easy, but completely vacuous term of “chemical imbalance” in their commercials. But that’s only part of the story, especially when taking into account the fact that direct marketing of psychiatric drugs to consumers isn’t a thing in a lot of countries.

Another reason is that some psychiatrists themselves used this explanation. And not necessarily because they believed it to be true, but because it was an effective way of reducing medication-associated stigma and even patient self-blame, which in turn could lead to better outcomes for a disorder where having a negative self-image is part of the problem. Along the same lines, mental health awareness efforts focused on stigma reduction latched onto the biochemical explanation as well.

On top of this, poor outreach efforts from scientists ensured that there was virtually no pushback against a hypothesis that scientists already knew to be false.

And public beliefs about the cause of depression (and mental illness in general) matter quite a lot. Although more specific results are still in need of some clarification, there is a general trend which suggests that a biochemical explanation of depression increases acceptance of antidepressants as a potential treatment, while also making people more pessimistic about the outcome of said treatment. At the same time, it decreases self-blame and increases the willingness to seek help.

Coming back to the current umbrella review though, it becomes apparent that the outrage wasn’t sparked by the serotonin hypothesis being “disproved”, but by what the implications of that seemed to be. In this context, the study authors themselves going online and writing in the The Conversation that “[…] it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe” is particularly problematic.

Because while we might be able to infer that there is a communication problem about this issue and we can corroborate this inference with previous literature findings, we can absolutely not draw conclusions about antidepressant effectiveness, let alone safety from this study. This statement doesn’t mean that antidepressants are good or bad. In fact, even if antidepressants were complete and utter trash, we still couldn’t make any claims about that based on this study for a simple reason: the study did not look at effectiveness or safety of antidepressants in treating major depressive disorder!

The deal with antidepressants

Of course, it’s natural to ask, if there is no evidence for a serotonin imbalance in depression and given that antidepressants, in particular SSRIs, work by increasing the serotonin concentration, doesn’t that mean that these antidepressants are trash?

Well, not exactly. Again, by looking at other literature which examines these specific questions, we know that SSRIs kind of work, and while we don’t understand very well how, there is evidence for several mechanisms of action. But let’s discuss these things separately.

In terms of SSRI effectiveness, that has been assessed, first and foremost, in clinical trials. What that means is that they have been tested against placebo and shown to do better. The problem here is that they are not doing that much better. Still, it was enough to get them approved, especially as SSRIs have fewer side effects compared to tricyclic antidepressants, i.e. the ones before. Since then, many more studies and reviews have been conducted on this topic, and relatively similar results have emerged. What’s more, these studies have shown that a combination of SSRIs and psychotherapy is more effective than medication alone.

Regarding mechanism of action, the story is a bit more complicated. Pharmacologically speaking, SSRIs increase the concentration of serotonin at the synapse by blocking the activity of the serotonin transporter (the one cleaning up a serotonin party). This happens relatively fast after ingestion. But we also know that people need to take SSRIs for a couple of weeks before seeing any effects. If SSRIs acted (only) through this direct mechanism of action, we would expect improvements on much shorter timescales.

Because that’s not the case, scientists have looked for alternative mechanisms for quite some time already. Unfortunately, there is no consensus one way or another, but current evidence suggests at least two other indirect mechanisms for SSRI effects. The first one hints at antiinflammatory effects of SSRIs. Coupled with the finding that, at least for some people, there seems to be a link between inflammation and depression, this is a promising direction. The second suggests that SSRIs might boost neuroplasticity (the ability of the brain to change and adapt). This could even explain why SSRIs work better in combination with psychotherapy: the medication makes it easier for the brain to learn certain habits that are taught in psychotherapy.

Clearly, although we’ve come a long way since SSRIs were first introduced in the ’60s, we still need more research into the mechanisms of action of SSRIs and we need to reevaluate the side effects/benefits trade-off provided by this medication. As our understanding of depression has evolved, and as other potential treatment options become available (such as transcranial stimulation), this progress needs to be reflected in how depression is handled.

But while all of this is going on, we cannot simply give up on SSRIs. And I mean that quite literally. In the context of the current discussion, a dangerous idea has transpired: that people should simply stop taking this medication. Don’t get me wrong, if you weren’t already on it and would like to have a more in-depth discussion with your doctor based on this information, that’s up to you. But if you’re already taking SSRIs and suddenly stop them because some random person on TV or on the internet said so, you’re in for a rude awakening. Because discontinuing this medication abruptly will lead to some pretty nasty side effects, from fatigue, dizziness, nausea and/or vomiting to more serious ones such as shock-like sensations in your body, suicidal thoughts, increased anxiety, and in rare cases, even psychosis. That is why it’s crucial you talk to your doctor first, so you can come up with a safe plan of tapering off the medication together.

Conclusion

To sum up, the meta-analysis by Joana Moncrieff and colleagues has caused a ruckus with respect to the serotonin hypothesis of depression. But most of it wasn’t actually warranted, because the idea that depression is not caused by a “chemical imbalance” is already mainstream in the scientific community. Still, the study has brought to light a communication problem between scientists and the public, and this should definitely be addressed.

Regarding antidepressants, the study authors themselves have made some unethical, bold, and scary claims which are not supported by the evidence they have presented. While SSRIs are not ideal, there is evidence they work better than placebo and scientists are trying to uncover the mechanisms behind that. Finally, abruptly discontinuing this medication comes with important side effects and it’s definitely not a decision to be made without your doctor.

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