2024 marks the 50th anniversary of the publication of the first paper on fluoxetine, and when it comes to fluoxetine, its other name may be better known – Prozac; The drug's Chinese name is often misspelled as "Baizao").
As the first selective Serotonin reuptake inhibitor (SSRIs) to be marketed, fluoxetine became popular after its launch in 1988, and sales increased year after year. Since then, a number of SSRIs have been marketed, and fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram are known as the "five golden flowers" of antidepressants, firmly occupying the market for antidepressants, and SSRIs have also become the first choice for most doctors when giving treatment recommendations.
In 2022, a total of 46 million SSRIs were prescribed in the United Kingdom, of which 21 million belonged to the SSRIs drug sertraline, which was the tenth most prescribed drug that year, while the most prescribed drug atorvastatin in the same year was only 57 million.
The sales volume is huge, the doctors are the first choice, and the patients benefit from it, and it seems that the effectiveness of SSRIs is unquestionable. But in recent years, there has been a lot of controversy about the mechanism of action of SSRIs, which has led to doubts: Do these drugs really work?
The serotonin hypothesis has resurfaced
To judge whether a drug is really effective, we often have to analyze the mechanism of action of the drug and the patient's efficacy. SSRIs stand for serotonin [serotonin (5-HT)] reuptake inhibitors. Serotonin is a class of neurotransmitters that are widely distributed in the brain.
If we think of our brain as clusters of neuronal connections, then serotonin is the messenger of communication between neurons, mediating the transmission of nerve signals and is indispensable for maintaining the normal function of the brain. Serotonin is able to produce "pleasurable" experiences in humans, and it is also involved in regulating body temperature, sleep, libido, and many other physiological functions.
The serotonin hypothesis about depression is based on this: if the level of serotonin in the brain decreases, it may trigger depressive symptoms in humans. SSRIs are a class of drugs that prevent serotonin from being "recycled" to increase the concentration of serotonin in the brain to achieve antidepressant effects.
The stock copyright picture, reprinting and using may cause copyright disputes
The serotonin hypothesis was developed by chance. Invented as an antihistamine allergy drug, imipramine was inadvertently found to have a pleasurable effect in humans, thus becoming the first tricyclic antidepressant, and although tricyclic drugs have been proven to have antidepressant effects, they also have obvious toxic side effects.
Scientists at the time didn't know how these drugs worked, but as research grew, researchers found that tricyclic drugs could bind to receptors for a variety of neurotransmitters, inhibit the reuptake of norepinephrine (NA), serotonin and dopamine by the presynaptic membrane, and increase the concentration of these neurotransmitters in the synaptic cleft to delay the time of action on the corresponding receptors, thus exerting antidepressant effects.
Tricyclic binds to a variety of receptors, meaning it is not selective for these neurotransmitters and means increased side effects. To minimize side effects, researchers focused on a specific protein: serotonin transporters. This also drove the launch of the first SSRIs drug, fluoxetine.
But is serotonin deficiency really the culprit that causes depression? Subsequent researchers do not think so, and a number of clinical studies have shown that the antidepressant effect of serotonin is amplified. Although these drugs have somewhat alleviated depressive symptoms, the premise of the serotonin imbalance hypothesis that a decrease in serotonin triggers depression has been controversial for many years.
In 2022, University College London psychiatrist Joanna Moncrieff and her partners published a review paper in the journal Molecular Psychiatry, which analyzed, integrated and evaluated papers related to the serotonin hypothesis in multiple research areas, and finally concluded that there is no convincing evidence that "reduced serotonin levels cause depression", and there is no direct evidence that serotonin levels are associated with depression; Artificially lowering serotonin levels in the brains of healthy people does not quickly lead to depression.
People have become so accustomed to the idea that depression is related to serotonin imbalances, so much so that the paper's conclusions have caused an uproar and a small earthquake in the field of antidepressants.
A more intuitive way to evaluate the effectiveness of a drug is to treat the patient. SSRIs have accounted for the majority of the market for antidepressants over the past five decades, and their efficacy seems unquestionable in this regard. But multiple previous studies have questioned this.
Statistically, SSRIs may have a significant effect on depressive symptoms, but a careful analysis of data from clinical studies reveals that placebo has also worked so well in clinical trials of these drugs that the clinical significance of SSRIs is questionable.
In addition, SSRIs may increase the risk of certain adverse events compared to placebo: data suggest that the use of SSRIs is associated with an increased risk of epilepsy and fractures; There is also an increased risk of bleeding events when combined with certain medications. There does not appear to be a significant difference in the effect of SSRIs on mortality.
However, some research suggests that there may be a link between the use of SSRIs and an increased risk of suicide. In 2007, a student hanged himself during a clinical trial of Duloxetine, another antidepressant by Eli Lilly and Company, which caused a lot of controversy about the drug. In the same year, in response to a lawsuit allegedly concealing clinical data related to antidepressants, GlaxoSmithKline chose to make the results of clinical trials public so that all information could be publicly accessed. Eli Lilly and Company, under pressure, also decided to release clinical results.
There is a heated debate about the possible link between SSRIs therapy and increased risk of suicide. Researchers say it is difficult to assess whether this increased risk is due to the fact that treatment takes time to take effect or because SSRIs directly affect mood when the patient population is more vulnerable.
In this way, SSRIs have been questioned in recent years, so why are they still selling so well, and are prescriptions snowflakes being prescribed?
There are conflicting views on depression in the academic community
As the second generation of antidepressants after tricyclic antidepressants, SSRIs are still the main force in the current battlefield of treating depression, and there is certainly a reason why SSRIs have endured, although there are more drugs with new mechanisms on the market after SSRIs.
Part of the reason is obvious: SSRIs are effective for many patients. While there are differences between individuals, this person-to-person difference is medically quite normal. Eero Castrén from the University of Helsinki, Finland, commented: "Despite the controversy surrounding the efficacy of SSRIs, this drug still plays an important role clinically. The efficacy of antidepressants does have a lot to improve. This effect does not apply to some people and some symptoms, but for many patients, they do work, even very effectively. There are many medications for high blood pressure, and they don't work for a lot of people. But no one complained about it. Castrén argues that the stigma surrounding depression makes antidepressant medications more controversial.
There are also researchers who believe that this is because there is a conflict between the views of the natural and social sciences on depression: researchers in the field of biochemistry want to understand what happens in our brains during depression and whether we can use these processes to help patients. At the same time, researchers in the field of sociology have pointed out that drugs can only treat the symptoms of depression, which may obscure or distract people from the social context in which depression arises.
Moncrieff, the author of the controversial paper, argues that serotonin and depression are being linked far more than they should. "There's always been a strong desire in the medical community to see depression as a physiological illness and to believe that we have a treatment that biochemical can treat depressed mood," she said. ”
If depression is merely a physical illness and can be treated, it can be very beneficial for pharmaceutical companies and psychiatrists, because the large number of antidepressant prescriptions means huge profits. The situation is also a peace of mind for policymakers, as it avoids patients coping with "widespread social discontent" in other ways. Know that the high incidence of depression is often associated with poor social realities. So, Moncrieff thinks it's these things that are holding us back from thinking more deeply and exploring how SSRIs work.
It sounds reasonable, if you're a politician and when depression is high in the population, you can just turn the problem to the experts, to the doctors and the scientists who are looking at how to treat it, without having to think "Why are so many people unhappy in our society?" And not to mention the question, "Does this have to do with the economic downturn in society, with the current state of poverty and inequality?" "We are shifting the consequences of our social and economic policies to the medical realm, ignoring the realities behind these policies – high unemployment, housing and economic insecurity, and so on," Moncrieff concluded. ”
It's just a matter of time
After the publication of Moncrieff's review in 2022, the existence and use of SSRIs have been challenged like never before. Many people use this paper as a waving banner to attack SSRIs and existing psychiatry.
This kind of offensive rhetoric is dangerous, and while we already know that SSRIs aren't perfect, they work in at least some patients, and for some, the effect is a panacea. When the public accepts this type of rhetoric and resists SSRIs, the people who really need these drugs are put in a dangerous position.
In fact, from another perspective, Moncrieff and colleagues' review article provides an opportunity to reflect on the serotonin hypothesis. This hypothesis, which originated by chance 50 years ago, is very simple, attributing depression to the effects of serotonin alone, but as research has progressed, we have learned that depression is a very complex disorder that is related to many factors and involves many physiological mechanisms. To understand the role of serotonin in this complex pathophysiology of depression, we need to look deeper, and these studies use new technologies and methods.
The stock copyright picture, reprinting and using may cause copyright disputes
In addition to the complex physiological mechanism of depression itself, which makes it difficult to explore the mechanism, serotonin itself is also a complex scientific issue. We now know that serotonin is a complex and versatile neurotransmitter with receptors that can be divided into seven subfamilies (5-HT1 to 5-HT7), and at least fourteen receptor subtypes have been identified that function presynapsively and postsynapsely, respectively, and also contain a transporter.
This complexity gives it a variety of physiological functions, which poses a challenge to directly study the function of human serotonin, which needs to be studied with the help of advanced neuroimaging techniques. The specific structure and function of these different subtypes of receptors have not yet been studied, let alone how they behave in disorders such as major depressive disorder. So much so that until now, what was known about the role of serotonin in depression was based almost entirely on circumstantial evidence.
However, there has been a lot of good news recently, such as a study based on positron emission tomography that showed that patients with depression had reduced serotonin release compared to healthy controls. This study provides direct evidence for the first time that serotonin reduction is associated with depression.
At the same time, a range of new tools and techniques have been developed to study the role of serotonin in mood, behavior, and cognitive regulation, which are not discussed in the work of Moncrieff et al. New research points to serotonin playing an important role in complex brain systems that are affected in major depressive disorder and involve the effects of antidepressant treatment.
While some new technologies, such as optogenetics, are still in their infancy and rely on animal models, cognitive neuroscience has developed more advanced methods to study serotonin, a key neurotransmitter that underpins brain function. For example, studies have shown that people with depression are more likely to notice, understand, and remember negative information than positive information, and this bias is related to the susceptibility and maintenance of depression.
SSRIs can help reverse this bias, with studies showing that patients treated with citalopram had a reduced ability to recognize negative emotions and an increased ability to remember positive emotions after 7 days of administration compared to placebo.
At the neurological level, treatment with SSRIs can quickly reverse the amygdala's overreaction to negative information, which is also related to the antidepressant effects of these drugs. Thus, from a cognitive neuroscience perspective, serotonin can modulate key neuropsychological processes associated with depression, which may help explain how antidepressant drug therapy works beyond a narrow neurochemical focus.
The stock copyright picture, reprinting and using may cause copyright disputes
There is also a growing recognition that depression is one of the world's most serious public health problems, and scientists are working together to ensure timely detection, accurate diagnosis, and aggressive treatment of people with depression.
The concept of treatment-resistant depression (TRD) has gradually attracted attention in recent years, and there are still different interpretations of the concept of TRD, but it is generally considered that TRD refers to a disease state in which patients with depression have not met the criteria for clinical remission after receiving antidepressant therapy with two different mechanisms of action for a full course of treatment (at least >6 weeks). It occurs in about 1/5 of patients with depression.
For TRD, in addition to the traditional regimen of changing drug therapy, scientists have also found new treatment options, such as intravenous ketamine in a subanesthetic state that can produce a large and significantly rapid antidepressant effect, and studies in TRD patients have also confirmed this result, which is undoubtedly exciting news, and more new mechanisms of drugs are being explored.
Conflict does not mean bad, truth is always clearer in debate, and science is never afraid of controversy, but will find the right direction in constant discussion. At least now that we know the complexities of depression, antidepressant medication may be useful beyond a narrow neural focus and connected to a broader neural network. To fully understand the role of SSRIs, or to fully understand depression, we still need more patience.
Parastoo Hashemi of Imperial College London (UK) in the United Kingdom believes scientists will solve the mystery of SSRIs, citing as an example that it took scientists 80 years to figure out how aspirin works. "Maybe people have lost patience with the research process for SSRIs, but that doesn't mean the scientific community won't go all out and continue to work. There are also many researchers working around the clock trying to unravel the mysteries that we may not have the technology to do now. But we will, it's only a matter of time. ”
Source: Popular Science China