From the article: One reason is that they apparently had the wrong theory for decades: ... [...] There is apparently some relationship with serotonin, though? Nevertheless, they are pursuing a...
From the article:
2024 marks 50 years since researchers published the first paper on the first SSRI, fluoxetine, which came to market as Prozac in 1988. Today, SSRIs are widely used to treat depression: in England in 2022, 46 million prescriptions for SSRIs were dispensed, with 21 million of those for the SSRI sertraline, making it the 10th most prescribed drug that year. That compares to 57 million prescriptions for the most prescribed drug, atorvastatin, in the same year.
As such it might seem strange that researchers like Hashemi still don’t fully understand how SSRIs work, and why they work better for some patients than others. In fact, researchers have struggled to balance the drugs’ benefits with their shortcomings for decades. In 2004, Chemistry World reported findings that they only work slightly better than taking an inactive placebo. At the same time, concerns around increased risk of suicide among patients, especially children, taking SSRIs came to prominence. SSRIs also have other potentially serious side effects.
...
One reason is that they apparently had the wrong theory for decades:
In the 1960s, researchers looking to minimise side effects focused in on one specific protein: the serotonin transporter protein. This protein mops up serotonin molecules that neurons have released into the synapse gap and transports them back to where they came from. Drugs like fluoxetine are designed to block this reuptake process and raise serotonin levels in the synapse, giving SSRIs their name. But evidence has since shown that serotonin transporter blocking is likely not the most important action of the original lucky antidepressants finds.
For example, various studies have shown that serotonin levels don’t directly correlate with depression. In 1994, researchers stopped untreated depressed people eating tryptophan, the amino acid our body makes serotonin from. The patients’ depression didn’t rapidly worsen. For some, it did worsen, but more slowly than the scientists would have expected if serotonin was directly responsible. The difference between these patients may relate to why SSRIs work better for some people than others.
...
The SSRI controversy turned into widespread shock in 2022, thanks to a review paper by psychiatrist Joanna Moncrieff from University College London and colleagues. We’ve become so used to the idea that depression is linked to a serotonin imbalance that their conclusion there is no evidence for low serotonin levels causing depression stunned the world. ‘We’ve never known how [SSRIs] work,’ Moncrieff says. While they may raise serotonin levels in the short term, Moncrieff argues that this is changing our brain’s baseline chemistry. She compares the effect to that of drinking alcohol.
[...]
Many people have taken Moncrieff’s 2022 paper as a reason to attack SSRIs and psychiatry in general, Hashemi notes. ‘We know [SSRIs are] not perfect,’ she says. ‘Nobody loves them. But they work, and they work quite well for a subset of patients. The public is becoming susceptible to quite dangerous anti-SSRI rhetoric that can really be harmful to the people who need them. I think we have to be really clear that that’s not based on science.’
There is apparently some relationship with serotonin, though?
Yet Hashemi accepts that not fully understanding the chemical and physiological reasons makes it difficult to explain some SSRI quirks, like the differences between individuals. However, she notes that some people who don’t respond to SSRIs have a specific version, or polymorphism, of the gene carrying instructions for how to make the serotonin transporter protein. This is one topic her team is intending to study with its mini-brains.
Nevertheless, they are pursuing a different explanation:
While Castrén notes that most patients don’t care exactly how SSRIs work, his team has helped find a promising new potential explanation. The scientists have focused on the role of Brain Derived Neurotrophic Factor (BDNF) protein. BDNF helps keep neurons alive as well as enabling plasticity, the process in which neurons grow and change their connections. In the 1990s, researchers found that in tests on animals that simulate depression reduced BDNF secretion leads to fewer synapses. Injecting BDNF straight into their brains could increase the number of synapses, and reverse depression-like behaviour.
In the early 2000s researchers found SSRIs promote neurons to grow in brain areas such as the prefrontal cortex, Castrén highlights. ‘We thought that this is an indirect effect of the actual serotonin,’ he says. In recent years, Castrén’s team has found that antidepressants bind directly with the receptor protein on neurons that recognises BDNF, called TrkB. ‘For plasticity, and in mice for antidepressant-like behavioural responses, binding to TrkB seems to be necessary,’ Castrén says. ‘In our mind, the critical things that antidepressants do is bind to TrkB.’
Interesting. Given that depression doesn't describe an explicit condition (in the same way that a broken arm explicitly refers to a bone fracture), I'd always figured serotonin imbalance wasn't...
Interesting. Given that depression doesn't describe an explicit condition (in the same way that a broken arm explicitly refers to a bone fracture), I'd always figured serotonin imbalance wasn't the only cause. Hence the unpredictable efficacy of SSRIs, while still being extremely helpful to some folks, along with the other troubles researching serotonin imbalance.
But this seems to be suggestive of a more unifying theory.
Seems depression as a result of issues with brain plasticity is gaining ground as a recognized theory. It's the same reasoning behind the efficacy of ketamine as an anti-depressant as well, though I don't recall if that mechanism of action also involves TrkB or not. My neurochem starts to peter out around proteins.
Perhaps what we're starting to find is that -- biologically speaking -- depression is predominantly a plasticity issue, but there's multiple routes which can trigger problems. This is not to undermine the significance of social, cultural, and societal issues that could contribute though.
When reading an article about medical terms that need to stop being used (that was directed at medical professionals), "chemical imbalance" was one of them. For most of these chemicals, we have no...
When reading an article about medical terms that need to stop being used (that was directed at medical professionals), "chemical imbalance" was one of them. For most of these chemicals, we have no baseline for what a "balance" would look like!
Not trying to nitpick you, more so elaborating on how little we know about how these drugs work.
Agreed, a term without the implicit norm would be preferable. Did that article suggest an alternative? I used imbalance as the original post did and I figured it'd be more familiar.
Agreed, a term without the implicit norm would be preferable. Did that article suggest an alternative? I used imbalance as the original post did and I figured it'd be more familiar.
I don't know enough to do any more than link and speculate. But my guess is that "plasticity" is more or less of an issue depending on how happy you are with your life? If you don't need to...
I don't know enough to do any more than link and speculate. But my guess is that "plasticity" is more or less of an issue depending on how happy you are with your life? If you don't need to change, it doesn't come up. But when there's a shock (like losing your job or a divorce) then you might suddenly need to change.
We don't call it depression unless you have trouble recovering from that.
It's food for thought and there may be an association. But unfortunately there are folks that are depressed despite having everything go right, so to speak. And like a big part of enjoying life is...
It's food for thought and there may be an association. But unfortunately there are folks that are depressed despite having everything go right, so to speak. And like a big part of enjoying life is learning new things and gaining fresh experiences, no? Even things as minor as eating a new dish or watching a movie, being able to engage with and internalize these requires us to be able to change and adapt. That's structural plasticity.
Functional plasticity is a bit more straightforward. It describes rerouting functions from damaged regions to undamaged regions. Consider a stroke patient's recovery for example.
It's also noteworthy that depression can also be a symptom of plenty of other biological conditions as well. I got put on my SSRI despite suspicious blood tests that indicated potential...
It's also noteworthy that depression can also be a symptom of plenty of other biological conditions as well. I got put on my SSRI despite suspicious blood tests that indicated potential hypothyroidism, which I was later formally diagnosed with and which includes depression as one of its major symptoms. Though in my case I also have an anxiety disorder that the SSRI helps with, doctors really need to be cognizant of these other potential causes of depression and ruling them out during diagnosis.
From the article:
One reason is that they apparently had the wrong theory for decades:
...
[...]
There is apparently some relationship with serotonin, though?
Nevertheless, they are pursuing a different explanation:
Interesting. Given that depression doesn't describe an explicit condition (in the same way that a broken arm explicitly refers to a bone fracture), I'd always figured serotonin imbalance wasn't the only cause. Hence the unpredictable efficacy of SSRIs, while still being extremely helpful to some folks, along with the other troubles researching serotonin imbalance.
But this seems to be suggestive of a more unifying theory.
Seems depression as a result of issues with brain plasticity is gaining ground as a recognized theory. It's the same reasoning behind the efficacy of ketamine as an anti-depressant as well, though I don't recall if that mechanism of action also involves TrkB or not. My neurochem starts to peter out around proteins.
Perhaps what we're starting to find is that -- biologically speaking -- depression is predominantly a plasticity issue, but there's multiple routes which can trigger problems. This is not to undermine the significance of social, cultural, and societal issues that could contribute though.
Thanks for sharing!
When reading an article about medical terms that need to stop being used (that was directed at medical professionals), "chemical imbalance" was one of them. For most of these chemicals, we have no baseline for what a "balance" would look like!
Not trying to nitpick you, more so elaborating on how little we know about how these drugs work.
Agreed, a term without the implicit norm would be preferable. Did that article suggest an alternative? I used imbalance as the original post did and I figured it'd be more familiar.
I don't know enough to do any more than link and speculate. But my guess is that "plasticity" is more or less of an issue depending on how happy you are with your life? If you don't need to change, it doesn't come up. But when there's a shock (like losing your job or a divorce) then you might suddenly need to change.
We don't call it depression unless you have trouble recovering from that.
It's food for thought and there may be an association. But unfortunately there are folks that are depressed despite having everything go right, so to speak. And like a big part of enjoying life is learning new things and gaining fresh experiences, no? Even things as minor as eating a new dish or watching a movie, being able to engage with and internalize these requires us to be able to change and adapt. That's structural plasticity.
Functional plasticity is a bit more straightforward. It describes rerouting functions from damaged regions to undamaged regions. Consider a stroke patient's recovery for example.
It's also noteworthy that depression can also be a symptom of plenty of other biological conditions as well. I got put on my SSRI despite suspicious blood tests that indicated potential hypothyroidism, which I was later formally diagnosed with and which includes depression as one of its major symptoms. Though in my case I also have an anxiety disorder that the SSRI helps with, doctors really need to be cognizant of these other potential causes of depression and ruling them out during diagnosis.