Serotonin has nothing to do with it?
Depression doesn't seem to be associated with low serotonin levels
According to a large-scale review conducted by scientists from University College London, decades of research have not provided clear evidence that serotonin levels or its activity are responsible for depression.
A new umbrella review of previously published meta-analyses and systematic reviews, published this summer in the journal Molecular Psychiatry (Moncrieff et al., The serotonin theory of depression: a systematic umbrella review of the evidence), suggests that depression is most likely not caused by a chemical imbalance, and also questions the effect of antidepressants. Most antidepressants are selective serotonin reuptake inhibitors (SSRIs), which were originally supposed to work by blocking the reuptake of serotonin by its secreting neurons, which leads to an increase in the amount of serotonin in the synaptic cleft. There is no other generally accepted pharmacological mechanism by which antidepressants affect the symptoms of depression.
Joanna Moncrieff, professor of psychiatry at University College London and lead author of the review, commented on its results:
"It is always difficult to prove a negative result, but I think we can say with confidence that after a huge number of studies conducted over several decades, there has never been convincing evidence that depression is caused by disorders associated with serotonin, especially lower levels or reduced serotonin activity. The popularity of the theory of depression as a result of "chemical imbalance" coincided with a huge increase in the use of antidepressants. The number of prescriptions for antidepressants has increased dramatically since the 1990s: currently one in six adults in England and 2% of teenagers receive antidepressants. Many people take antidepressants because they have been led to believe that their depression has a biochemical cause, but this new study shows that this belief is not supported by evidence."
The purpose of the summary review was to cover all serotonin and depression studies published in the most important areas of knowledge. Tens of thousands of people participated in the studies included in the review.
The study, which compared the levels of serotonin and its breakdown products in blood or brain fluids, did not reveal a difference between people with diagnosed depression and healthy participants from the control group.
Studies of serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, have shown weak and contradictory results indicating higher levels of serotonin activity in people with depression. However, the researchers suggest that the results are probably explained by the fact that people with depression took antidepressants. Unfortunately, such effects have not been reliably excluded.
The authors also reviewed studies in which serotonin levels were artificially reduced in hundreds of people by excluding from their diet the amino acid necessary for the production of this neurotransmitter. These studies have been cited as demonstrating that serotonin deficiency is associated with depression. However, a meta-analysis conducted in 2007 and a sample of recent studies showed that reducing serotonin levels in this way did not cause depression in hundreds of healthy volunteers. There was very weak evidence in a small subset of people with a family history of depression, but only 75 participants participated in this study, and later data was inconclusive.
In very large studies involving tens of thousands of patients, variations of genes, including the serotonin transporter gene, were studied. They found no differences in these genes between people with depression and healthy control groups. These studies also looked at the impact of stressful life events and found that they have a strong impact on the risk of people falling into depression — the more stressful life events a person has experienced, the more likely he is to fall into depression. A well-known early study found a link between stressful events, the type of serotonin transporter gene that a person had, and the likelihood of depression. But larger and more comprehensive studies show that this was a false discovery.
All these results combined led the authors to conclude that "there is no evidence to support the hypothesis that depression is caused by a decrease in serotonin activity or concentration."
The authors also found evidence that people taking antidepressants had lower levels of serotonin in their blood. They concluded that some data are consistent with the possibility that long-term use of antidepressants reduces the concentration of serotonin. The researchers say that this may mean that the increase in serotonin levels that some antidepressants cause in the short term may lead to compensatory changes in the brain, which in the long term give the opposite effect.
Although the study did not consider the effectiveness of antidepressants, the authors consider it necessary to further research treatment methods that could focus on managing stressful or traumatic events in people's lives, for example, through psychotherapy, along with other practices such as exercise.
"We believe," explained Professor Moncrieff, "that patients should not be told that depression is caused by low levels of serotonin or a chemical imbalance, and they should not be convinced that antidepressants act by acting on these unproven abnormalities. We don't understand what exactly antidepressants do to the brain, and providing people with this kind of misinformation prevents them from making an informed decision about whether to take antidepressants or not."
"During my training in psychiatry," said the co—author of the review, Dr. Mark Horowitz, a practicing psychiatrist and clinical research fellow in psychiatry at University College London, "I was taught that depression is caused by low serotonin levels, and I myself taught this to students in my lectures. Participating in this study has opened my eyes, and I feel like everything I thought I knew has been turned upside down. One of the interesting aspects in the studies we studied was how much influence adverse life events have on depression. Apparently, after all, a bad mood is a reaction to how people live, and it cannot be reduced to a simple chemical equation."
Professor Moncrieff added:
"Thousands of people suffer from the side effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop taking them, but the number of prescriptions continues to grow. We believe that this situation is partly caused by the false belief that depression is caused by a chemical imbalance. It is time to inform the public that this belief is not based on science."
The researchers warn that anyone considering giving up antidepressants should, given the risk of side effects after withdrawal, seek medical advice. According to a large-scale review conducted by scientists from University College London, decades of research have not provided clear evidence that serotonin levels or its activity are responsible for depression.
A new umbrella review of previously published meta-analyses and systematic reviews, published this summer in the journal Molecular Psychiatry, suggests that depression is most likely not caused by a chemical imbalance, and also casts doubt on the effects of antidepressants. Most antidepressants are selective serotonin reuptake inhibitors (SSRIs), which were originally supposed to work by blocking the reuptake of serotonin by its secreting neurons, which leads to an increase in the amount of serotonin in the synaptic cleft. There is no other generally accepted pharmacological mechanism by which antidepressants affect the symptoms of depression.
Joanna Moncrieff, professor of psychiatry at University College London and lead author of the review, commented on its results:
"It is always difficult to prove a negative result, but I think we can say with confidence that after a huge number of studies conducted over several decades, there has never been convincing evidence that depression is caused by disorders associated with serotonin, especially lower levels or reduced serotonin activity. The popularity of the theory of depression as a result of "chemical imbalance" coincided with a huge increase in the use of antidepressants. The number of prescriptions for antidepressants has increased dramatically since the 1990s: currently one in six adults in England and 2% of teenagers receive antidepressants. Many people take antidepressants because they have been led to believe that their depression has a biochemical cause, but this new study shows that this belief is not supported by evidence."
The purpose of the summary review was to cover all serotonin and depression studies published in the most important areas of knowledge. Tens of thousands of people participated in the studies included in the review.
The study, which compared the levels of serotonin and its breakdown products in blood or brain fluids, did not reveal a difference between people with diagnosed depression and healthy participants from the control group.
Studies of serotonin receptors and the serotonin transporter, the protein targeted by most antidepressants, have shown weak and contradictory results indicating higher levels of serotonin activity in people with depression. However, the researchers suggest that the results are probably explained by the fact that people with depression took antidepressants. Unfortunately, such effects have not been reliably excluded.
The authors also reviewed studies in which serotonin levels were artificially reduced in hundreds of people by excluding from their diet the amino acid necessary for the production of this neurotransmitter. These studies have been cited as demonstrating that serotonin deficiency is associated with depression. However, a meta-analysis conducted in 2007 and a sample of recent studies showed that reducing serotonin levels in this way did not cause depression in hundreds of healthy volunteers. There was very weak evidence in a small subset of people with a family history of depression, but only 75 participants participated in this study, and later data was inconclusive.
In very large studies involving tens of thousands of patients, variations of genes, including the serotonin transporter gene, were studied. They found no differences in these genes between people with depression and healthy control groups. These studies also examined the impact of stressful life events and found that they have a strong impact on the risk of people falling into depression — the more stressful life events a person has experienced, the more likely he is to fall into depression. A well-known early study found a link between stressful events, the type of serotonin transporter gene that a person had, and the likelihood of depression. But larger and more comprehensive studies show that this was a false discovery.
All these results combined led the authors to conclude that "there is no evidence to support the hypothesis that depression is caused by a decrease in serotonin activity or concentration."
The authors also found evidence that people taking antidepressants had lower levels of serotonin in their blood. They concluded that some data are consistent with the possibility that long-term use of antidepressants reduces the concentration of serotonin. The researchers say that this may mean that the increase in serotonin levels that some antidepressants cause in the short term may lead to compensatory changes in the brain, which in the long term give the opposite effect.
Although the study did not consider the effectiveness of antidepressants, the authors consider it necessary to further research treatment methods that could focus on managing stressful or traumatic events in people's lives, for example, through psychotherapy, along with other practices such as exercise.
"We believe," explained Professor Moncrieff, "that patients should not be told that depression is caused by low levels of serotonin or a chemical imbalance, and they should not be convinced that antidepressants act by acting on these unproven abnormalities. We don't understand what exactly antidepressants do to the brain, and providing people with this kind of misinformation prevents them from making an informed decision about whether to take antidepressants or not."
"During my training in psychiatry," said the co—author of the review, Dr. Mark Horowitz, a practicing psychiatrist and clinical research fellow in psychiatry at University College London, "I was taught that depression is caused by low serotonin levels, and I myself taught this to students in my lectures. Participating in this study has opened my eyes, and I feel like everything I thought I knew has been turned upside down. One of the interesting aspects in the studies we studied was how much influence adverse life events have on depression. Apparently, after all, a bad mood is a reaction to how people live, and it cannot be reduced to a simple chemical equation."
Professor Moncrieff added:
"Thousands of people suffer from the side effects of antidepressants, including the severe withdrawal effects that can occur when people try to stop taking them, but the number of prescriptions continues to grow. We believe that this situation is partly caused by the false belief that depression is caused by a chemical imbalance. It is time to inform the public that this belief is not based on science."
The researchers warn that anyone considering giving up antidepressants should, given the risk of side effects after withdrawal, seek medical advice.
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