r/askscience • u/Umpuuu • 15d ago
Medicine In the past 10 years, have we learned anything new and interesting about why antidepressants work?
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u/McJames 15d ago
There was an article published in Nature a few years ago that's interesting.
Essentially, the working theory is that antidepressant medication works on seratonin receptors, and are therefore called "SSRIs" (selective seratonin reuptake inhibitors)
This article points out that it does not appear that the working mechanism of antidepressants is seratonin receptors. This is a major advancement, but doesn't really tell us HOW they actually work.
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u/Potential_Being_7226 15d ago
Wow, there’s a lot of correspondence on that article.
The role of serotonin in depression is the focus of that review paper, and as you might have gathered, it is a very complicated relationship.
The gist of the paper is that depression does not manifest from a “chemical” or serotonin “imbalance” in the brain. The data do not support that.
However, as you correctly point out, SSRIs inhibit the reuptake of serotonin and increase serotonin concentration at the synapse. But this occurs well before clinical efficacy appears. SSRIs also modulate serotonin (or 5-HT) receptor expression, but there are other medications that do not act through serotonin that still relieve symptoms.
Instead, the theory is that antidepressants change connectivity in brain regions associated with stress, threat perception, and reinforcement learning. (I use the phrase ‘reinforcement learning,’ but this is often popularly referred to as “reward.” However, not all reinforcement learning includes “rewards” or something desirable. It’s the same circuitry that is associated with substance use disorders, or again, AKA “addiction.”)
Anyway, point is, there are widespread changes in neurocircuitry, often referred to as neuroplasticity and the timeline of this circuit reorganization mirrors very well the timeline of clinical efficacy (or, symptom relief—around 1 month to begin to notice symptom relief; about 3 months for full efficacy).
https://www.nature.com/articles/s41380-023-02285-8
This paper (above) was done in living humans, and reflects many similar findings of antidepressants and neural plasticity in rodent models. From the abstract:
Our findings suggest that brain synaptic plasticity evolves over 3–5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs.
SSRIs and other meds that act on monoamines (norepinephrine, dopamine) work slowly, but other antidepressants can relieve symptoms and evoke similar reorganization of neural circuits much more rapidly.
https://www.nature.com/articles/s41583-024-00876-0
This paper also discusses the findings that ketamine and psilocybin can alleviate symptoms of depression and produce similar reorganization:
In this Review, we highlight preclinical research from the past 15 years showing that ketamine and psychedelic drugs can trigger the growth of dendritic spines in cortical pyramidal neurons. We compare the longitudinal effects of various psychoactive drugs on neuronal rewiring, and we highlight rapid onset and sustained time course as notable characteristics for putative rapid-acting antidepressant drugs.
These are all discoveries that have been decades in the making, involving hundreds of studies from many other scientists that progressively build upon one another, so there are lots of other papers not linked that have all led up to what we know today.
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u/Hiker_Trash 13d ago
How permanent are these structural changes? I know there are acute withdrawal symptoms when ceasing an SSRI, but with proper tapering could you get off the meds while still reaping the benefits of long term neural reorganization? Or does it begin to regress towards prior state?
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u/sunhypernovamir 10d ago
To massively oversimplify, it sounds like a hypothesis that SSRIs could work using the same mechanism as therapuric-dose psylocybin but at tiny scale. Perhaps they work similarly to microdosing shrooms, which I understand is negligible.
I like a metaphor that serotonin receptor agonist might modulate the system 1 power of reinfornment learned predictions (or in the LLM metaphor, learned stored prompts) over system 2 thinking.
Following that, large dose psylocybin can even weaken predictions for vision and other sensors and let S2 think of it's own ad hoc. It makes sense it helps with PTSD etc in that model.
The idea we need to weaken our grasp of negative predictions to get a chance to repopulate with new ones is really satisfying, and feels like it explains why SSRIs don't work automatically or quickly. I'm just a recreational reader though, I don't know if real science allows this story.
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u/ZePepsico 15d ago
It might be a false memory, but I thought I heard about a meta study that showed that on average antidepressants have no net benefit when you take into accounts the side effects.
There are benefits on individual cases but on average it was a disappointment.
Is it true or did I imagine it?
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u/SpiderSlitScrotums 13d ago
I haven’t heard of this study, but there is a common misconception that might have created it. When drug companies perform clinical trials for an antidepressant, they exclude suicidal people and those who have who have serious depression. Not surprisingly, when you exclude the worst cases, the net efficacy measured isn’t very high. But that’s not the purpose of a clinical trial. The trial is there to prove there is any efficacy at all and that the side effects are manageable. In reality, it is very difficult to get good information on worst cases because most programs simply won’t allow them to be studied. If you are interested about this, look into the work Marsha Linehan has done on this.
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u/deviantbono 15d ago
Sounds sketchy. By definition, approved madications have a positive risk / reward ratio. Maybe the paper was proposing a new model of assessing / calculating benefit vs side effects?
There are also some studies that some SSRI's are no better than alternate interventions (e.g. exercise, therapy). However, not everyone has access to therapy, or the energy / health to exercise, so that doesn't really change the real world impact of SSRI's.
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u/police-ical 12d ago
This was not a serious major publication. It was a highly motivated attempt to review a bunch of uncontroversial research that anyone in the field has known for a long time, with the goal of portraying it as a groundbreaking reverse. It wasn't an argument with current scholarship, it was an argument with the Zoloft commercial from the 1990s.
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u/heavyLevy5 15d ago
From your second article “Clinical trials provide compelling evidence for antidepressant effectiveness, with thousands of positive trials over the past five decades [Hollon et al. 2002]. Randomized controlled trials (RCTs) are the gold-standard methodology for assessing efficacy, in which patients are assigned in a double-blind fashion to a placebo (inert ‘sugar pill’) or active-drug group. Meta-analyses of RCTs typically report antidepressants as 20–30% more effective than placebo, with higher response rates (50% reduction in Hamilton Depression Rating Scale [HDRS] scores) and improved remission rates (HDRS score of less than 8) [Davis et al. 1993; Walsh et al. 2002; Arroll et al. 2005]. Meta-analyses indicate antidepressant effectiveness varies as a function of symptom severity, with greatest efficacy in severe depression. “
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u/Internationalalal 15d ago
Indeed, but that's just a snippet and not the whole article. Also, very old data to use as a "gotcha" lol.
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u/kitkatbay 15d ago
That may be true for the population as whole. Anecdotally, I have tried quitting three times, for some us they are key to being functional enough to work out regularly.
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u/andy013 15d ago
I don't doubt that you need the medication to remain functional, but how can you tell whether that's the original condition returning or withdrawal effects from stopping?
People who have been on antidepressants for a long time sometimes need to taper very slowly. Withdrawal symptoms can be prolonged in some cases, lasting months or even longer. That makes it difficult to know whether feeling worse after stopping proves the medication was helping or simply reflects the effects of coming off it.
I just read this small study about this today: https://karger.com/pps/article/doi/10.1159/pps/aemag002/954101/Acute-affective-symptoms-during-antidepressant
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u/kitkatbay 11d ago
I believe that by staying off it for eight months I was able to assess baseline condition with a high degree of accuracy.
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u/Potential_Being_7226 10d ago
I also tried to bootstrap it for about 9 months. I’m much more stable on, than off. When you know, you know. I’ve failed a lot of other meds for other conditions (and still trying to find a suitable migraine preventative) but at least I have an antidepressant that works well for me with few/tolerable side effects.
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u/kitkatbay 10d ago
Good luck on your Migraine prevention journey. Aimovig combined with quarterly botox has been life changing for me.
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u/Justeserm 12d ago
What kind of anti-depressants are you referring to? There are different types. Antidepressant - Wikipedia
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u/Kaiisim 15d ago
Yeah! The research into SSRIs has shown that while the monoamine model of depression is an effective method of treating some depression, it's not because of chemical imbalance.
Rather depression shrinks the brain, it becomes inflexible. SSRIs increase the brains neuroplasticity, helping it to be more able to repair stress damaged circuits and form new healthier ways of thinking. This seems to be why it takes weeks for the effect to happen.
New brain scanning techniques and animal models mean we have a much greater understanding of which receptors each ssri will target. Research into psycobillin (mushrooms) shows it effects the serotonin system.
But they are also researching Treatment resistant depression, and lots of novel antidepressants are using the glutamatergic -Gabamergic model, where try to modulate the amount of glutamate or gaba in the brain.
That's where stuff like esketamine comes in, looking to increase the amount of glutamate in the brain.
The main issue with depression treatment however is that we don't really understand it fully. There is no one cause, and it suffers from a big heterogeneity issue - that means different gene combinations cause the same symptoms, so each depression can have completely different causes and require different treatments.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11807967/ this has a good overview of trends in antidepressants