Introduction

Depression used to be attributed to a lack of serotonin in the brain. This statement is open to debate, as alternative solutions are entering people's vision and changing our understanding of depression.

People usually believe they understand the causes of chronic depression. A survey shows that over 80% of the public believes the answer is a "chemical imbalance" in the brain. This viewpoint is widely present in pop psychology and cited in research papers and medical textbooks. The book 'Listening to Prozac' describes that using medication that can correct this imbalance to treat depression has life changing value. The book remained on The New York Times bestseller list for several months.

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This imbalanced brain chemical is serotonin. It is an important neurotransmitter, but its' feel good 'effect is actually deified. Serotonin can regulate the central control system in the brain responsible for body temperature, sleep, sexual impulses, and hunger. For decades, serotonin has also been touted as the strongest contender among antidepressant drugs. The principle of commonly used prescription drugs such as Prozac (chemical composition fluoxetine) is to treat chronic depression by increasing serotonin levels.

But the cause of depression is far from the lack of hemostatic drugs. Multiple clinical studies have concluded that the role of serotonin in depression has been overemphasized. Although Prozac has brought relief to many patients' symptoms, in fact, the entire premise of the chemical imbalance theory may be wrong.

If you still believe that depression is simply caused by an imbalance in the chemical serotonin, then that's too bad

A literature review published in the journal Molecular Psychiatry in July 2022 [2] became the latest and perhaps the loudest death knell for the serotonin theory - at least for the simplest form of serotonin theory. An international team of scientists led by Joanna Moncrieff from University College London [3] screened a total of 361 papers from six research fields and evaluated 17 of them in detail. They found no credible evidence to suggest that low levels of serotonin lead to depression - it doesn't even have a correlation with depression. The data does not reliably indicate that individuals with depression have lower levels of serotonin activity compared to the control group. In experiments where researchers artificially reduced the serotonin levels of volunteers, this procedure did not consistently cause depression. Even though researchers have attempted to identify stress as a possible common factor, genetic studies seem to have also ruled out the relationship between genes that affect serotonin levels and depression.

If you still believe that depression is simply caused by an imbalance in the chemical serotonin, that's too bad, "said Taylor Braund, a clinical neuroscientist and postdoctoral researcher at the Black Dog Institute in Australia (who was not involved in this new study). ("Black dog" is a term used by Winston Churchill to describe his own low mood, and some historians speculate that he was referring to depression.)

Serotonin deficiency itself may not lead to depression. The question left for scientists by this discovery is: What exactly causes depression? The evidence shows that there may not necessarily be a simple answer to this question. In fact, this has prompted neuropsychiatrists to rethink what depression may actually be.

The medicine is not symptomatic

The academic attention to the role of serotonin in depression began with a drug to treat tuberculosis. In the 1950s, doctors began prescribing iproniazid, a compound that targets Mycobacterium tuberculosis bacteria in the lungs, to patients. This medicine is not particularly effective in treating tuberculosis infection, but it does bring unexpected and pleasant side effects to some patients. Their lung function and everything else did not improve, but their mood showed a trend of improvement, "said Gerard Sanacola, director of the Depression Research Program at Yale University and a clinical psychiatrist

Researchers were puzzled by this result and began studying how isoniazid and related drugs work in the brains of rats and rabbits. They found that these drugs prevented animals from absorbing compounds called amines, including serotonin - a chemical that transmits information between nerve cells in the brain.

Several renowned psychologists, including the late clinical doctors Alec Coppen [6] and Joseph Schildkraut [7], captured the idea that depression may be caused by long-term serotonin deficiency in the brain. So, the serotonin hypothesis of depression further influenced drug development and neuroscience research in the following decades. In the late 1980s, this led to the invention of selective serotonin reuptake inhibitors (SSRIs), such as Prozac. This type of medication increases the level of serotonin activity by reducing the absorption of serotonin by nerve cells. Today, the serotonin hypothesis remains the most commonly heard explanation when patients with depression are prescribed SSRI drugs.

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To investigate the relationship between serotonin imbalance and depression, Joanna Moncrieff, a psychiatric researcher at University College London, searched for hundreds of

papers in six research fields and published a review of the study in Molecular Psychiatry.

But in the mid-1990s, doubts about the serotonin model began to spread. Some researchers have found that SSRI drugs often fail to meet expectations and do not show significant improvements in performance compared to traditional drugs such as lithium *. The research results did not unfold as predicted by the serotonin model, "said Moncliffe.

*Translator's note: Refers to lithium salts, ionic compounds containing lithium ions, commonly used clinically as lithium carbonate.

                                                                    The antidepressant mechanism of SSRIs may not be the same as the serotonin model.

By the early 21st century, few experts believed that depression was solely caused by serotonin deficiency, but no one attempted to conduct a comprehensive evaluation of the evidence. This ultimately prompted Moncliffe to organize such a study. This way, we have a chance to see if this theory is really supported by evidence, "she said.

She and her colleagues found that the serotonin hypothesis is not supported by evidence. But it still has supporters. Last October, a few months after their review article was published, Biological Psychiatry published an online paper [8] claiming to provide specific validation for the serotonin theory. However, other researchers remain skeptical as this study only surveyed 17 volunteers. Moncliffe disagrees with their results and believes that they are not statistically significant.

Another chemical imbalance

Although serotonin levels do not seem to be the main cause of depression, in clinical trials, the effect of SSRI is still somewhat improved compared to placebo. The mechanism behind this improvement is still elusive. John Krystal, the head of the Department of Psychiatry at Yale University and a neuropharmacologist, said, "Even if aspirin can relieve headaches, it does not mean that a lack of aspirin in the body will cause headaches. The work of fully understanding how SSRIs can cause changes in clinical practice is still on the way

       John Krystal, the head of the Department of Psychiatry at Yale University, said that efforts to understand the clinical efficacy of SSRI drugs are "a work on the road.

Speculation about the source of the positive effects of this drug has led to other theories about the source of depression.

Although the name contains the word "selectivity", some SSRIs also change the relative concentration of other chemicals except serotonin. Some clinical psychiatrists believe that one of these compounds may play a real role in inducing or alleviating depressive symptoms. For example, SSRI increases the circulating level of tryptophan in the blood. Tryptophan is a precursor of serotonin, which helps regulate the sleep cycle. Over the past 15 years or so, this chemical has become a powerful antidepressant. "The tryptophan deprivation study provides quite convincing evidence," said Michael browning, a clinical psychiatrist at Oxford University [10].

Some tryptophan deprivation studies [11] found that about two-thirds of people who have just recovered from a depressive episode will relapse after being given a artificially controlled low tryptophan diet. People with a family history of depression are also susceptible to tryptophan deprivation [12]. In addition, tryptophan has a secondary effect of increasing the level of serotonin in the brain.

The latest evidence also shows that tryptophan and serotonin may help regulate the growth of bacteria and other microorganisms in the intestine, and the chemical signals of these microbial populations may affect mood. Although little is known about the exact mechanism of the connection between the brain and the gut, this connection seems to affect brain development. However, since most of the studies on tryptophan deprivation have been on a small scale, this issue is far from conclusive.

Browning said that other neurotransmitters, such as glutamate, which plays an important role in memory formation, and GABA, which inhibits the transmission of information between cells, may play a role in the formation of depression. It is possible that SSRI exerts its therapeutic effect by regulating the content of these compounds in the brain.

Moncliffe believes that if we just look for other chemical imbalance theories that can explain depression, we are just repeating the past, not really a new research direction. She said, "I think such studies still agree with the theory similar to the serotonin hypothesis" - that is, antidepressants can play a role by reversing the abnormalities of certain chemicals in the brain. She believes that the influence of serotonin in the brain is too extensive, so it is difficult to distinguish its direct antidepressant effect from other emotional or sensory changes that temporarily replace our feelings of anxiety or despair.

Gene answer

Not all theories about depression are related to neurotransmitter deficiency. There are also some theories that pay more attention to the gene level.

In 2003, the first sketch of the roughly complete human genome sequence was released, which is widely known as the foundation of the new era of medicine. In the next 20 years, researchers found a series of genes behind the disease, including 200 genes related to the risk of depression [13]. (hundreds of other genes have been found that may increase the risk of disease).

”Even if aspirin can relieve headache, this does not mean that lack of aspirin in the body will lead to headache. “

"People need to understand that there are genes that cause depression, but only recently have researchers begun to consider factors other than psychology and the environment," Christo said

However, our understanding of genetics is not perfect. Christo noted that twin studies have shown that genetic factors may account for 40% of the risk of depression. But the genes found so far can only explain about 5%.

In addition, just carrying the depression gene does not mean that individuals will definitely suffer from depression. Genes also need to be activated in some way through internal or external conditions.

Srijan Sen, a neuroscientist at the University of Michigan [14], said: "people sometimes mistakenly distinguish environmental factors from genetic factors. But for most common characteristics, genetic and environmental factors play an important role."

In order to study the genetic basis of depression, Sen's laboratory mapped the genome of the subjects and carefully observed how individuals with different genetic characteristics responded to environmental changes. (recently, they studied the stress caused by the new crown epidemic.) different genetic variations can affect whether individuals become depressed due to sleep deprivation, physical or mental abuse, social isolation and other stresses.

                          Research shows that in the brain of patients with chronic depression, the "white matter" of brain nerve fibers shows less connectivity.

                                                                                 However, the reason for this difference is not clear.

Environmental impacts such as stress sometimes cause "epigenetic" changes in the genome, affecting subsequent gene expression. For example, Sen's lab studied epigenetic changes in the terminal caps of chromosomes, the telomeres that affect cell division. Other laboratories have studied the change of a chemical label called methylation groups, which can turn genes on or off. Epigenetics can sometimes be passed down from generation to generation. Sen said: "the impact of the environment is as biological as the impact of genes, but the two are from different sources."

The study of these genes may help us find the best treatment for patients in the future. Some genes can lead some people to get better results in cognitive behavioral therapy (CBT), while for others, SSRI or ketamine may be more effective. However, Sen believes that the correspondence between genes and patients' response to treatment is not clear.

Products of neural connections

Genetic differences may make some people more prone to depression, and also cause differences in nerve connections and brain structure. A large number of experiments have shown that individuals have differences in the ways in which brain neurons interconnect to form functional pathways [15], and these pathways will affect mental health.

Jonathanreple and Susanne meinert from Goethe University in Frankfurt, Germany, are exploring why there are fewer connections in the brain of patients with chronic depression,

                                                            which they believe may be caused by neural plasticity or inflammation.

At a recent academic conference, the team led by Jonathan reple, a psychiatry researcher at Goethe University in Frankfurt, Germany [16] described how they scanned the brains of volunteers with severe depression and found that their brain structure was different from that of non depression control group. For example, the "white matter" of brain nerve fibers in patients with depression shows fewer connections. (however, there is no clear "white matter" watershed that can be used to judge what is a bad mental state. Ripple points out that a person cannot be diagnosed as depression by scanning his brain.)

After six weeks of treatment in the depression group, ripple's team performed another round of brain scans. This time, they found that the overall level of neural connectivity in the brain of patients with depression increased with symptom relief. This increase in connectivity does not require any treatment for patients, but can be achieved as long as the mood improves.

One possible explanation for this change is the phenomenon of neural plasticity. Ripple said, "neuroplasticity means that the brain can actually create new connections and change existing connections." if depression occurs because there are too few connections in the brain or some connections are lost, using neuroplasticity to increase connectivity may help improve people's mood.

chronic inflammation

However, ripple cautioned that there was another explanation for the phenomenon observed by his team. The brain connections of patients with depression may be damaged due to inflammation. Chronic inflammation slows the body's ability to recover, and in nerve tissue, it gradually weakens synaptic connections. The loss of this connection is considered to be one of the causes of mood disorders.

There is sufficient evidence to support this theory. When psychiatrists evaluated the prevalence of chronic inflammatory diseases such as lupus and rheumatoid arthritis, they found that "all groups have a higher than average prevalence of depression." said Charles Nemeroff, a neuropsychiatric at the University of Texas at Austin [17]. Of course, knowing that they have incurable degenerative diseases may lead to depression, but researchers suspect that inflammation itself is also a factor.

Medical researchers have found that for some patients, inflammation can trigger depression. Interferon alpha, sometimes used to treat chronic hepatitis C and other diseases, fills the immune system with proteins called cytokines. This molecule promotes a series of reactions from mild swelling to septic shock. Therefore, interferon alpha can cause severe systemic inflammatory response. A sudden influx of inflammatory cytokines can lead to loss of appetite, fatigue, and a decrease in mental and physical activity - all symptoms of severe depression. Patients taking interferon often report sudden depression, sometimes severe.

If the neglected chronic inflammation leads to depression in many people, researchers also need to determine the source of inflammation. Autoimmune diseases, bacterial infections, high stress, and some viruses (including the virus that causes covid-19) may trigger persistent inflammatory reactions. Viral inflammation can extend directly to brain tissue. Therefore, in order to design effective anti-inflammatory treatment for depression, we may also need to know which causes inflammation.

At present, we still do not know whether treating inflammation alone is enough to alleviate depression. Clinicians are still trying to analyze the causal relationship between inflammation and depression. "It's like some kind of chicken egg or egg chicken problem," Nemerov said.

General theory

More and more scientists are advocating to redefine the word "depression" as a umbrella term to refer to a series of diseases, just as oncologists now believe that cancer is used to refer to a group of different but similar malignant tumors. Just as the prevention or treatment of each kind of cancer should be related to their respective root causes, the treatment of depression may also need to be different from person to person.

If there are different types of depression, even though they may show similar symptoms, such as fatigue, loss of interest, appetite changes, suicidal thoughts, insomnia or sleepiness, they may be caused by a completely different mixture of environmental and biological factors. Chemical imbalance, genes, brain structure and inflammation may all play a role to some extent. "After five or ten years, we may not discuss depression as a single problem," Sen said.

Therefore, in order to effectively treat depression, medical researchers may need to have a detailed understanding of the germination of depression. Nemerov looks forward to the day when the golden standard of medical care is not just a single treatment. It will be a set of diagnostic tools that can find out the best treatment for different patients with depression, and the best treatment may be cognitive behavioral therapy, lifestyle change, neuromodulation, avoiding depression gene trigger, talk therapy, drugs or a combination of several.

This prediction may upset some doctors and drug developers, because it is obviously easier to use a universal strategy. However, "understanding the true complexity of depression can lead us to the most effective way in the end," Christo said. He also said that in the past, clinical psychiatrists were like explorers who landed on an unknown island. They set up tents and were very comfortable. "Now we find that there is actually a whole continent to be explored."

Postscript

Yinshangmoyu: when trying to understand a disease with complex manifestations, the overly simplified mechanism explanation may need to be deliberated again and again - especially for brain mental diseases, and depression is no exception. As described in this article, depression may have the characteristics of "pedigree distribution" like autism, but facing its complexity, though difficult, is the most likely way to create value. "Out of the comfort zone", this sentence may also apply to depression researchers who are now on the way of "paradigm shift".

References:

1. https://www.sciencedirect.com/science/article/pii/S266656032200038X?via%3Dihub

2. https://www.nature.com/articles/s41380-022-01661-0

3. https://www.ucl.ac.uk/psychiatry/people/joanna-moncrieff95/

4. https://www.unsw.edu.au/staff/taylor-braund

5. https://medicine.yale.edu/profile/gerard-sanacora/

6. https://academic.oup.com/ijnp/article/22/6/371/5498496

7. https://www.nature.com/articles/1301474

8. https://www.biologicalpsychiatryjournal.com/article/S0006-3223(22)01704-8/fulltext

9. https://medicine.yale.edu/profile/john-krystal/

10. https://www.psych.ox.ac.uk/team/michael-browning

11. https://www.nature.com/articles/4001949

12. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(96)07044-4/fulltext

13. https://www.nature.com/articles/s41593-021-00860-2

14. https://medicine.umich.edu/dept/psychiatry/srijan-sen-md-phd

15. https://www.sciencedirect.com/science/article/pii/S1084952121001208?via%3Dihub

16. https://www.kgu.de/einrichtungen/kliniken/zentrum-fuer-psychische-gesundheit/psychiatrie-psychosomatik-und-psychotherapie/team/leitung/univ-prof-dr-med-jonathan-repple

17. https://dellmed.utexas.edu/directory/charles-nemeroff