A first-year student who complains of pronounced weakness and unprecedented difficulties in studying. A woman who has recently become a mother, but does not feel any joy from the smile of her child. The head of the firm who wakes up at 5 am with insane anxiety and suicidal thoughts. An old man who suffered a stroke and became depressed and apathetic after it. It’s hard to believe, but all these people suffer from the same disease — depression.

From the point of view of psychiatry, depression is a serious disease that significantly worsens a person’s life and is associated with a high risk of suicide.

There are several approaches to classifying mood disorders. In one of the models used before the 1960s, all affective disorders were regarded as different manifestations of the same disease. Currently, the most popular model is the one that separates mood disorders according to their polarity. With this approach, two groups are distinguished: bipolar disorders (depression at one pole, mania at the other pole) and unipolar (only depression).

The problems with studying unipolar depression are similar to the problems with studying almost all mental disorders. Depression is a natural phenomenon that is quite difficult to observe from the outside, as is customary in nature science. In General, the entire emotional sphere is difficult to study at the level of neuroscience. It’s not just that the limbic system of the brain, which is responsible for emotions, is very complex and connected to almost all other parts of the brain. To create a biological map of emotions, you have to rely on the descriptions of mood and well-being that a person gives about their subjective experience. The neurobiology of emotions is designed to compare subjective experiences with objective neural facts observed in the brain. The complexity of this task has slowed and continues to slow the development of the neurobiology of affective disorders.

Key events in the history of depression research occurred when psychiatrists began to conduct diagnostics more carefully. At some point, it became clear that manic-depressive psychosis (now known as bipolar disorder) is diagnosed too often, and in many cases there are isolated depressive episodes without mania in between. This is a very important point, because depending on the polarity of the mood disorder, treatment tactics and further prognosis are currently being determined.

The theory of depression, as in the case of the doctrine of other major mental disorders, arose after effective medications were mastered. Research has moved from working antidepressants to creating a concept that explains their effects and describes the biological background of symptoms of depression. At the same time, the substances that showed an antidepressant effect initially belonged to classes of drugs that are far from psychiatry — anti-tuberculosis and antihistamines.

The prehistory of modern depression science began far from Western psychiatry. In the 1930s, Indian doctors introduced reserpine, a means to lower blood pressure. Reserpine is made from the root of rauwolfia, which in India was used to treat snake bites. In the 1950s, reserpine began to be used in the West and soon noticed that it produces a sedative effect.

Sometimes reserpine had a bad effect on the mental state of patients. In some cases, it increased depression. These cases presumably include the medical history of Ernest Hemingway, whose depression worsened while taking reserpine.

Laboratory animals reacted strangely to reserpine. At first, there was a transient activation phase, and then a prolonged deceleration began. It turned out that reserpine increases the level of monoamines (serotonin, norepinephrine, dopamine, etc.) in the gap between neurons — substances associated with affective processes. However, then the enzyme monoamine oxidase (MAO) released by the body reduces this level. As a result, there is a long-term, lasting several days, monoamine deficiency. If the animals were given not only reserpine, but also the antidepressant iproniazid, the inhibition phase did not occur. The antidepressant itself did not cause activation, it only stopped the decrease in monoamine levels, slowing the effect of MAO.

Iproniazid was developed as a drug for the treatment of tuberculosis. In 1952, the antidepressant effect of this substance was accidentally revealed. Life magazine published an article about success in the treatment of tuberculosis, accompanied by a photo with dancing patients who felt an amazing surge of energy after taking iproniazid.

Research on the effects of reserpine and iproniazid in the 1950s helped sketch the future theory of depression. In the early 1960s, the understanding of the processes that occur in the brain under the influence of antidepressants expanded. Scientists realized that antidepressants affect monoamines in two ways: they prevent MAO from decomposing them (IMAO group antidepressants) or increase their level (tricyclic antidepressants).

It was not clear why amphetamine, which increases monoamine levels, does not work against depression. Amphetamine first raises the mood to the level of euphoria, and then brings the person down into the abyss of depression. It was assumed that different substances have different effects on different neurotransmitters. Something has a stronger effect on norepinephrine, something on serotonin.

In 1965, an article was published in the United States with the main thesis in the science of depression — the effect of antidepressants is explained by the fact that they increase the level of norepinephrine in the brain.

In 1967, British scientist Alex Koppen published a paper on the role of another monoamine, serotonin. In 1969, the Lancet published a landmark article by Russian psychopharmacologist Izyaslav Lapin on the same topic. Based on these publications, it was concluded that all known effective treatment for depression, whether it is antidepressants or electroconvulsive therapy, is associated with increased serotonin levels.

It so happened that in the United States, scientists focused on norepinephrine, and in Europe-on serotonin. In the American journal Science, there are more publications about the role of norepinephrine in the development of depression, while the serotonin theory was more often discussed in the pages of the British journal Lancet.

Proponents of the first theory believed that the increase in serotonin is nothing more than a side effect, the main thing is an increase in norepinephrine. The problem that the authors of the noradrenaline theory knew about, but did not focus on it, is the lack of an antidepressant effect in cocaine, although this substance, from a biochemical point of view, does the same thing as antidepressants, i.e. increases the level of catecholamines — noradrenaline and dopamine.

In the late 1960s, a compromise was formed-antidepressants increase serotonin, which improves mood, and increase norepinephrine, which increases energy.

The monoamine model of depression varies depending on how much weight is given to a particular class of monoamines. There is a theory that the norepinephrine system does not work normally if the serotonin system is broken. Until now, it is impossible to say with certainty that a deficiency of a particular neurotransmitter is a necessary and sufficient condition for depression.

Over time, the science of depression turned to other chemicals (acetylcholine, GABA, glutamate, glycine) and secondary mediators (molecules that act not between nerve cells, but inside the cell), but serotonin and norepinephrine remained in the foreground for a long time. In the 1980s, the introduction of a new type of antidepressant — selective serotonin reuptake inhibitors — gave a decisive advantage to the serotonin theory.

The therapeutic effect of drugs that affect monoamine levels sets benchmarks for depression research. Monoamines occupied about the same place in the study of the psyche as the four liquids in the ancient humoral theory (blood, black bile, yellow bile, and phlegm). In ancient times, melancholy was explained by an imbalance of black bile, since the XX century-an imbalance of norepinephrine and serotonin.

The monoamine theory of depression has become so popular due to several factors. The first of them lies both in the plane of science and in the plane of business. The pharmacological revolution of the 1950s is a multidimensional phenomenon that can be understood as a long-awaited breakthrough in psychiatry and as the opening of a new market filled with a new type of goods. By products, we mean psychotropic drugs that are suitable for outpatient treatment. The relevance of the monoamine theory of depression is easy to understand if you put yourself in the position of a medical representative who is charged with increasing sales of antidepressants.

The authors of the noradrenaline and serotonin theories of depression recognized that they offered a well-functioning model, rather than an exhaustive explanation of everything related to depression. Scientists have managed to make a biological reduction of melancholy, to describe the pathological mood drop using biological terminology. But the description did not close the question of the nature of depression, and the effect of antidepressants remained only partially understood.

Since the 1960s, doctors have been surprised by the delayed effect of antidepressants: biochemically, they act immediately, but for some reason the clinical effect has to wait several weeks. The delayed effect was explained by the fact that depression changes the number of receptors in brain cells. You need to return to normal not only the number of neurotransmitters, but also the number of receptors, and this takes time.

Understanding exactly how antidepressants work is not the same as understanding the causes of depression. Perhaps the drugs do not affect the cause of the disease, but compensate for the deficiency caused by the disease. In this case, this does not mean that psychiatrists treat depression with bad medications, it means that the strength of the scientific understanding of depression should not be exaggerated.

In medicine, it happens that a medicine that passes by the cause of suffering helps to eliminate suffering. For example, diuretics are prescribed for heart failure, and although they do not affect the heart, but the kidneys, they help people with a diseased cardiovascular system.

From the point of view of medical history, the conceptualization of depression could not fail to occur in the 1950s and 1960s, during the rise of clinical neuroscience. People have long tried to talk about the psyche in the language of biology, but only with the discovery of neurotransmission mechanisms did this conversation acquire a pragmatic dimension. Depression was defined as a biological phenomenon, and patients with depression received relatively effective medications.

A powerful argument of biological psychiatry at that time in favor of the material nature of depression was the phenomenon of post-stroke depression. The development of post-stroke depression is a frequent (30-60 %) complication of stroke, which seriously restricts the rehabilitation of patients and worsens the prognosis of patients in the future. Neurologists have noted that damage to the frontal lobe in stroke most often contributes to the development of post-stroke depression. This is because the frontal lobe is an important part of the emotion processing system and has a large number of connections to other areas of the brain (for example, the thalamus, cingulate cortex, and hippocampus). It is probably because of damage to the frontal lobe that stroke survivors experience emotional disorders.

A person can be born into a great family, successfully graduate from University, get a high-paying job, find their soul mate and be basically a cheerful person, but an ordinary atherosclerotic plaque stuck in a small vessel of a certain area of the brain will make them hate themselves and the world around them.

Modern MRI studies in patients with post-stroke depression have revealed a decrease in the volume of gray matter in the prefrontal cortex, limbic system, sensory cortex, and additional motor area. Scientists have shown that post-stroke damage to the frontal lobe can disrupt connections to the limbic system and other parts of the brain, both by weakening them and by over-amplifying them.

The left prefrontal cortex and anterior cingulate cortex, which are closely related to the reward system, play a special role in this process. The deterioration of the connection between these zones in patients with post-stroke depression leads to a decrease in the function of the reward system and the development of anhedonia — a reduced ability to enjoy. Many studies also point to the role of damaged amygdala-anterior cingulate cortex connections in increasing negative emotions and social isolation in patients with post-stroke depression.

Also, in patients with post-stroke depression, there was a decrease in the volume of gray matter in the right hippocampal gyrus. The hippocampal gyrus is involved in the formation of short-term memory and emotional control. Increased connectivity between it and the right anterior cingulate cortex may help speed up the transmission of negative emotions. Excessive activation of the hippocampal gyrus increases the negative aspects of emotional memory, thereby making patients more anxious and pessimistic.

The history of neurology and psychiatry began with the study of people who had experienced brain damage, after which certain symptoms appeared. Establishing a link between the injury and the symptom allowed for a basic explanation of the cause of the disease. The study of post-stroke depression is an example of this approach.

Of course, the biological explanation for depression is not limited to monoamines and specific brain regions. Observations of hormones and the hypothalamic-pituitary-adrenal axis (the system that regulates the body’s response to stress) led to the study of the neuroendocrine aspect of depression.

Since the 1980s, elevated levels of cortisol, the stress hormone, have been considered a fundamentally important biological correlate of depression, along with monoamine imbalances. Constantly elevated levels of cortisol are very toxic to the brain and lead to a worsening of the course of depression. Unfortunately, cortisol-lowering drugs have not been shown to be effective in clinical trials. This may be due to the fact that increased activity of stress systems is not typical for many subtypes of depression, such as menopausal, atypical or seasonal. While clinical trials of new drugs for the treatment of depression, including drugs that reduce cortisol levels, often indiscriminately include all patients with this diagnosis. Depression, like many other mental disorders, is very heterogeneous, and perhaps cortisol-lowering drugs would help 20-30% of patients whose depression is more related to cortisol and the body’s stress system. For other patients, you need to look for drugs with a different mechanism of action.

It turns out that the modern pharmaceutical industry is looking for a “compromise” drug that helps most patients with depression. However, without dividing patients with depression into biological subgroups, most drugs do not pass clinical trials with placebo control, and the entire psychopharmacological industry finds itself in a creative crisis.

By the 2000s, the understanding of the neuroendocrine aspects of depression had expanded. The leading role in the development of depressed mood passed from cortisol to corticotropin-releasing hormone-the “conductor of stress”. It turned out that it triggers the entire cascade of reactions in response to stressors and, with a prolonged increase in its level, suppresses the action of monoamines. The increase in cortisol is only a consequence of the whole system. However, as with cortisol, drugs that block corticotropin-releasing hormone receptors have only shown an effect in a small proportion of patients.

Another interesting hormone — oxytocin-is involved in many processes in the human body, but most often it is associated with feelings of attachment, childbirth and breast-feeding. Women with low oxytocin levels during pregnancy show a weaker emotional connection with their children and a higher risk of postpartum depression.

Perhaps another hormone is important for depression — estrogen, which is considered a powerful regulator of neural processes such as mood and cognitive activity. Among the many factors that affect the development of depression, there is a place of reduced sensitivity of the hypothalamus receptors to estrogen. This feature explains the depressed mood of young mothers.

According to various data, depression affects 10-15 % of mothers both during pregnancy and in the postpartum period. This type of depression is most likely associated with hormonal changes. The researchers hoped that studying postpartum depression would lead to the discovery of a new therapeutic target. However, there were no high-profile discoveries in this area. Birth and postpartum depression are treated with antidepressants, and the birth itself is considered only a provoking factor.

Children whose mothers suffered from birth or postpartum depression have an increased risk of various behavioral and mood disorders. However, the transmission of psychopathology from generation to generation depends more on genetics than on prenatal stress. Maternal depression during pregnancy is associated with low birth weight, and low weight, in turn, is associated with the risk of developing depression. Among all children with low birth weight, those who have relatives with depression in their family are at the highest risk. Genetic variants that mediate the relationship between birth weight and children’s socio-emotional development have been identified, including classic “psychiatric genes” such as the serotonin Transporter gene and the D4 dopaminergic receptor gene. In the future, when parents, as in the movie “Gattaca”, will be able to set the genetic parameters of their children, it is better to choose the right versions of these genes to protect the child from a predisposition to self-destruction.

Current research has also shown a link between maternal depression during pregnancy and increased functional connectivity of the amygdala-the emotional center of the brain-with the left temporal cortex and insular lobe, as well as the cingulate gyrus and prefrontal cortex in an infant at 6 months of age. This is a pattern similar to that seen in adolescents and adults with clinical depression.

Another theory of depression is inflammatory, or rather, neuroinflammatory. The immune system is actively involved in the brain. Microglia, which is the storage of immune cells in the nervous system, contributes to the process of neuroinflammation by releasing various inflammatory substances and reactive oxygen species. High levels of inflammatory biomarkers, especially interleukin-6, are found in depression [34]. It is most often seen in patients who are resistant to classic antidepressants and have been abused in childhood. A troubled childhood, surprisingly, has biological consequences — cruelty to children changes their brains, which in the future affects their mental health.

A number of studies have shown that adult survivors of childhood trauma have elevated levels of many other immune biomarkers, such as C-reactive protein, tumor necrosis factor, and various interleukins. There is also evidence that frequent infectious diseases in childhood may be associated with an increased risk of depression in adulthood.

However, no matter how strong the stressful impact on a person at any age, the genetic predisposition to depression is crucial. Large-scale epidemiological studies conducted in the 1980s showed that individuals with family-related disorders are more than twice as likely to develop depressive States.

In particular, in a study of 62 families that lasted from 1982 to 2015, it was found that children of parents with depression not only had twice the risk of mood disorders and suicidal ideation, but also the risk of substance dependence. The descendants of two generations who suffered from depression are at the highest risk of developing depression.

“Out-of-family” forms of depression (i.e., depression was observed only in parents, and grandparents were healthy) had a lower prevalence, as well as a later age of development. It was also found that patients with a family burden of depression are characterized by a more severe course of the disease and a higher frequency of relapses.

The first results of studies of depression using classical methods of genetics suggested that this family aggregation of depression has a genetic character.

The results of large analyses of family and twin studies in the 2000s showed that the heritability of depression ranges from 31 % to 42 %. This is almost half the heritability of schizophrenia and bipolar disorder.

However, epidemiological studies show a higher prevalence of depression among women, which indicates a link between genetic factors of depression and gender. The heritability of depression is significantly higher in women than in men. Probably, at a comparable level of genetic influence, the gender factor acts as a strong” trigger ” of genetic risk.

From the point of view of modern genetics, depression is a disease of an extremely complex polygenic nature. A large number of genes are associated with depression, but due to the relatively small sample sizes, studies conducted to date do not allow us to get a complete picture of the genetic factors involved.

A modern analysis of data from the three largest genome-wide studies of depression (246,363 patients with depression and 561,190 control subjects) revealed 269 genes suspected to be associated with depression. The most significant gene was the SORCS3 gene, which is associated with the work of synapses in the brain. It is noteworthy that this gene is also associated with Alzheimer’s disease.

Additional analysis showed that genes with significant polymorphisms were particularly active in neurons in the frontal and anterior cingulate cortex. Common genetic variants between depression and other mental and somatic diseases were also identified. Data on genetic correlations between depression and schizophrenia, bipolar disorder, as well as coronary heart disease, increased levels of fat (triglycerides), increased adipose tissue, and the ratio of waist and hip volumes were confirmed.

Other interesting genetic correlations were found. It turned out that depression is associated with early menopause. This indicates a common genetic architecture of depression and features of the regulation of female reproductive mechanisms that lead to early menopause and the time shift of other stages of the development of the reproductive system. In addition, genetic correlations were found between depression and Crohn’s disease, an inflammatory bowel disease.

Finally, genetic research has forced a different view of traditional concepts of depression. It turned out that the genes of components of the serotonin system associated with the therapeutic effect and side effects of serotonin antidepressants are not directly related to the cause of depression. Apparently, the effectiveness of serotonin antidepressants and the appearance of depression are caused by different genetic pathways. However, these pathways, according to scientists, can still intersect through common intermediate genes.

Modern genetics returns to the issues discussed in the 1960s and 1970s, but at a higher scientific level. Monoamines are indeed linked to depression in some way, and serotonin antidepressants do make life easier for people with this disorder. However, these facts do not indicate the true cause of depression, which has yet to be discovered.