The development of the science of anxiety disorders is clearly not keeping up with the global increase in morbidity. All over the world, The number of people with diseases belonging to this group is increasing (generalized anxiety disorder, panic disorder, phobias, etc.). some types of anxiety disorders, such as social phobia (social anxiety disorder), affect society, perhaps even more than schizophrenia, radically impairing the quality of life of many people.
Anxiety to a greater extent than other mental disorders, have attracted the attention of philosophers. From a philosophical point of view, the meaning of the disease is important, not its biological mechanics. Many great thinkers, from Pascal to Heidegger, have offered their answers to the question of the meaning of anxiety.
In 1871, the Da Costa syndrome (“soldier’s heart”) was described — pain in the heart of a soldier who is afraid of battle. From this point on, the history of scientific research on anxiety begins. Freud spent a lot of effort searching for the meaning of anxiety. For Freud, anxiety is the center of all mental disorders.
In the psychodynamic tradition that grew out of psychoanalysis, illness is interpreted as a visible manifestation of internal struggle. Therefore, the question of the meaning of a symptom is the question of what the body wants to achieve using this symptom, what problem the person copes with using the symptom.
According to Freud, painful anxiety is formed as a result of the displacement of a more fundamental fear. Little Hans, about whom Freud writes, is afraid of horses because of the Oedipus complex, he is afraid and hates his father. Hatred is repressed, turns into anxiety, and anxiety crystallizes into fear of a horse that might bite (castrate) Hans.
To Freud’s interpretation of anxiety can be added many more witty interpretations of this type of symptoms. Almost every twentieth – century psychologist who talked about anxiety offered his own vision of its ontology. The deeper layers of being the author touches, the more solid the theory of anxiety looks. For Otto Rank, anxiety is a manifestation of “fear of life.” Jung’s reaction is to encounter irrational images of the collective unconscious. In Rollo may, it is a manifestation of the conflict between being and non — being.
Prior to the development of relatively effective anxiolytics in the 1960s, anxiety, as psychiatrists put it, was systematically psychologized. Anxiety symptoms were attributed the status of a high-value existential experience. It was customary to talk about anxiety in a psychoanalytic manner: it is a conscious feeling, the causes of which are hidden in the unconscious.
Representatives of the behavioral direction in human research described anxiety and fear differently — in terms of learning theory. According to them, pathological anxiety consists of non-adaptive responses of a living being to a threat: behavioral (running away) and physiological (the reaction of the body, or rather, the nervous system that triggers a cascade of processes in other systems of the body).
The accepted division of fear and anxiety has an important meaning, especially if we study fear and anxiety from a neurobiological point of view. Anxiety is not a reaction to what is happening now, it is a state experienced in anticipation of an exciting event. Fear is usually understood as a reaction to a stressful event that is happening at the moment. Anxiety is undifferentiated fear, and fear is anxiety that takes a specific form.
Accordingly, fear should be studied in one type of experiment, and anxiety in another. Experiments show which neural circuits are activated during anxiety. To do this, the symptoms of anxiety disorders are artificially provoked. Other studies evaluate the neural activity of patients in their normal state. So far, such studies have not provided information about what features are manifested in patients with anxiety disorders in a calm state.
It is important to separate physiological and pathological anxiety. Normal anxiety is a normal biological reaction that is designed to warn a person of possible harm. There is a wide range of types of anxiety that are considered normal. Pathological anxiety is characterized by excess, uncontrollability, and prevalence (i.e., anxiety extends to almost all areas of life).
The symptoms of mood and anxiety disorders are mostly the result of an imbalance of activity in the emotional rather than cognitive centers of the brain (although the “emotion vs cognition” dichotomy is not entirely justified). The highest cognitive centers of the brain are located in the frontal lobe, an evolutionarily newest area of the brain. The prefrontal frontal cortex is responsible for regulatory functions such as planning, decision-making, predicting the consequences of behavior, and understanding and managing social behavior. Various parts of the prefrontal cortex are also involved in the reward system, the body’s response to emotions, and the control of emotional impulses. In a relatively healthy brain, these cortical regions regulate impulses, emotions, and behavior through inhibitory top-down control.
The limbic system (emotional processing structures of the brain) is evolutionarily older than the frontal cortex. The parts of the brain that are included in it are responsible for processing information about the state of the body. The hippocampus is one of the structures of the limbic system that is involved not only in memory processes, but also in the control of stress centers in the brain. The oldest structure of the limbic system, the amygdala, processes emotionally significant external stimuli and initiates the corresponding behavioral response. Her area of responsibility includes fear and aggression, as well as the formation and recovery of emotional and fear-related memories.
Abnormal connections between the cortex and the limbic system, specifically between the amygdala and the anterior cingulate cortex and between the amygdala and the orbitofrontal cortex, are to blame for the development of anxiety disorders. Research on the biology of anxiety revolves around the amygdala, which works together with a complex network that includes other elements of the limbic system and the prefrontal cortex. All this complex is involved in emotional processes that are triggered when an adaptive or pathological response to an external stimulus is formed.
It is in this system of neural connections that the neurobiological explanation of the psychological characteristics of anxious people is sought. The exaggeration of the probability of a bad event is due to abnormalities in the prefrontal cortex neural networks that are responsible for calculating the probability of a threat. Increased attention to the threat at the biological level corresponds to increased amygdala activity. An inadequate response to an imaginary threat, when fear is caused by safe stimuli, becomes possible due to a violation in the connections between the amygdala and the prefrontal cortex. In the same place, in the connections of the amygdala with the cortex, there is a neurobiological substrate of avoiding behavior characteristic of phobias.
Violation of the connection between the cortex and the limbic system is expressed in the fact that the cortex, in simplified terms, does not calm the emotions that are bubbling in the limbic system. The amygdala in anxiety disorders is inadequately aroused in response to external stimuli. The cortex, in turn, is activated in a way that is not necessary to slow down the amygdala. A person is overcome by emotions, and very unpleasant ones (panic, fear, anxiety).
Based on these data, neuroscientist Joseph Ledoux proposed an interesting hypothesis about the place of psychotherapy in the treatment of anxiety. For those who have the most influential factor in the development of the disease is amygdala hyperactivity, psychotherapy aimed at correcting conscious attitudes is not suitable. Conversely, if abnormal activity in the prefrontal cortex plays a major role (i.e., at a higher anatomical level), psychotherapy that works with cognitive strategies can be very effective.
Russian physiologist Ivan Petrovich Pavlov (the same one who experimented on dogs) did a lot to understand the causes of anxiety. So, in the group of anxiety disorders and stress-related disorders, there are diseases that occur in accordance with the Pavlovian model of conditioned reflexes: post-traumatic stress disorder, phobias, social anxiety disorder. In all these diseases, anxiety and fear arise as a response to a stimulus that is not really followed by “punishment”. A rat trained to be electrocuted after a sound will be afraid of the sound even when it is not followed by an electric shock. This kind of training is described in sufficient detail in the language of neuroscience. The key here is the process of turning short-term memory into long-term memory. Anxiety as a result of training is triggered in harmless situations, turning these situations into “dangerous” ones.
At the same time, it should be taken into account that in the described experiment with a rat, it is used to model defensive behavior. We don’t know anything about the rat’s fear. Her experiences in any experiment on the subject of fear and anxiety are unknown to us.
This shows the lack of laboratory models of fear. The behavior of a living being is not a definite indication of its mental state. If a person drinks, it does not mean that he feels thirsty.
The behavioral response that the amygdala is responsible for is not fear, but a response to a threat. The experience common to anxiety disorders — fear, anxiety — appears as a result of cognitive interpretation of the work of defense mechanisms. Fear is a conscious experience. The experience of fear or anxiety involves consciousness and the functioning self. If there is no “I”, then there is no danger, because the danger is always aimed at someone. Therefore, it is impossible to identify with human fear what happens to an animal that meets something threatening. We don’t know anything about the mind of a lab rat, and we have every right to doubt that it even has one.
Experiments with Pavlovian conditioning, on which the modern scientific understanding of anxiety disorders is based, are organized in accordance with the functionalist concept of consciousness and subjective experience. Only the stimulus and reaction are objectively observed. It is not necessary to introduce into this system a third intermediate element, the subjective experience that occurs in response to a stimulus. However, it is with a complaint about this experience — a sense of anxiety — that the patient turns to the doctor.
The amygdala is called the center of fear, but it would be more correct to call it the center of defensive reactions. If we agree that fear and anxiety require the awareness that the “I” is in a threatening situation, then the amygdala is clearly not enough to create an anatomical map of fear. For a conscious experience of fear, other parts of the brain must be involved in addition to the amygdala.
These areas of the brain are located in the cortex, where neurons are connected by many complex connections. Rats do not have such a system of neural connections. Therefore, the rat does not have the concept of a terrible thing. The human brain, which, thanks to the developed cortex, is able to work with abstractions, creates concepts not based on statistical patterns. “Here I was electrocuted ten times, this is a bad place,” the rat conceptualizes. A person can do without accumulating statistical data about the situation, he can analyze the situation by other signs. Before entering a room where he will be electrocuted, a person is able to notice some signs that this is a bad place that threatens his “I”. This ability to build abstractions and start from the concept of “I” in their perception of the world qualitatively distinguishes the subjective world of a person from the subjective world of a rat, if there is one.
The problem with studying human anxiety based on animal models is precisely this: different types of living creatures have different types of fear. Admittedly, a strictly biological approach that ignores the specific human phenomenology of anxiety helps answer many questions. For example, starting from the biological concept of fear, you can understand why anxiety disorders are so widespread. From an evolutionary point of view, it is more profitable to be afraid in a safe situation than not to be afraid in a dangerous situation. Evolution encourages those who exaggerate the danger. Pathological activity of the limbic system is a manifestation of a healthy, i.e. evolutionarily justified, reaction of the body. The amygdala takes control of the nervous system from the cortex, so that the person immediately escapes from the threat, and does not plunge into complex reflections about the meaning of life.
But for all the advantages of modeling anxiety in animals, it has an important drawback. It takes medicine away from the essence of the disease. The results of such studies are transferred to people as if human anxiety is the same as a certain type of behavior observed in animals.
Anxiety is no exception in psychiatry, as it is treated with substances that affect neurotransmitters, just like many other diseases. In the neurobiology of anxiety, serotonin, a neurotransmitter that acts on several receptors, is usually put first. It is assumed that there are serotonin receptors, the work of which in certain neurons, in certain regions of the brain (prefrontal cortex, limbic system) affects the level of anxiety. Accordingly, the emotional stability and response of the brain to external threats depend on serotonin.
There is evidence that norepinephrine and dopamine are also involved in the development of anxiety. In addition, increased activity in areas of the brain that process emotions in patients with anxiety disorder may be caused by a weakening of the inhibitory effects of GABA or activation of excitatory neurotransmission of glutamate.
In the Central nervous system, classical neurotransmitters are often packaged and released along with neuropeptides, many of which work in limbic areas where they can affect stress and emotional processes. Among the neuropeptides associated with psychopathology are oxytocin and vasopressin, as well as corticotropin-releasing hormone (in the Chapter on depression, we wrote that it is a “conductor of stress” that triggers the body’s response to strong external stimuli).
An attentive reader may wonder about the difference between the neurobiology of depression and the neurobiology of anxiety. After all, serotonin, norepinephrine and dopamine play an important role in both cases. In both cases, the neural network connecting the limbic system and the prefrontal cortex does not work well. What is the difference, then?
On the one hand, in practice, depression and anxiety disorders really often accompany each other. In people with a family history of depression, anxiety disorder can develop before the first depressive episode in adolescence, acting as a harbinger of bad mood.
On the other hand, it is also important what other systems in the brain, in addition to serotonin, do not work as they should. If you look at these disorders separately, depression is characterized by more extensive neurotransmitter and neuroendocrine damage, compared with anxiety disorders. Moreover, it is important to know in which area of the brain, in which serotonin receptors, and in which neural pathways the disorder lies. Depending on these and many other factors, a particular mental phenomenon develops — depression, anxiety, or something else.
As we move from the root cause of the disease (variation in genes) to the symptoms, the number of genetic, epigenetic, environmental, and other factors affecting brain biology increases. The complexity of this system is demonstrated by neuroimaging genetics, which correlates the structural and functional characteristics of the brain with different genes. For example, genetic variants of the serotonin Transporter and MAO (see the Chapter on depression) are associated with individual differences in emotional processing and activation of the prefrontal cortex in depression. Dysfunction in the prefrontal cortex increases the risk of not only depression, but also other mental disorders.
Neuroimaging genetics demonstrates unique problems due to the network nature of the brain: each genetic variant has multiple effects in several brain regions, with the effects of some genes depending on the effects of other genes. Each region of the brain interacts with other regions through multiple neural circuits. Because of this, one disease can have many different symptoms.
A turning point in the history of anxiety treatment was the invention of the tranquilizer meprobamate, which was named after the American city of Milltown. The emergence of Milltown occurred at a historical point where consumer needs met the possibilities of pharmacology. This was the 1950s, when new pills were viewed with great optimism, because humanity had just witnessed a great victory over infections thanks to the introduction of antibiotics. Another touch to understand the time context — the cold war is in the yard, the Americans are seriously preparing to move to underground bunkers after a nuclear strike. Consumer culture is simultaneously under the influence of the optimistic mood that science gives, and under the shadow of anxious forebodings and public fears.
The company that invented Milltown was slow to launch the drug. Invented in 1950, it appeared in pharmacies only in 1955. The fact is that just at this time, the rule was established that such drugs should be sold by prescription. Marketers conducted a survey of doctors and found that most of them will not write prescriptions for medication for anxiety. However, the fears of marketers were in vain. Milltown became a sensation in the medical market. In the United States, 35 million prescriptions were written in 1957 alone (one prescription per second). You could see signs in pharmacies: “Milltown is over”, “Milltown will be tomorrow”.
The success of Milltown can be explained from a cultural point of view. It was another realization of the dream that the quality of life can be changed with the help of modern chemistry. It was then, without irony, that they began to write about “pills for happiness”. Interestingly, Milltown was not opposed to psychotherapy; on the contrary, a 1955 article stated that it helps the patient open up in a dialogue with a psychotherapist.
Milltown showed other players in the pharmaceutical market where millions are made — not on drugs for arthritis and hypertension. The Corporation that best captured the wind direction is Hoffman La-Roche. In 1960, it launched Librium (chlordiazepoxide), the first benzodiazepine tranquilizer, which implemented its action through the main inhibitory neurotransmitter — GABA. The logic is simple: the more active the GABA system works, the more inhibited the centers of “cheerfulness” in the brain and the weaker the anxiety becomes. A few years later, the Librium formula was changed to produce valium (diazepam), probably the most famous tranquilizer.
This is a feature of the history of anti-anxiety medications. They were developed in the heat of competition. The commercial success of valium eclipsed the success of all psychotropic drugs, and not only psychotropic. In Western countries, valium was the best-selling medicine in 1968-1987. In 1978 alone, 2.3 billion tablets were sold.
In the 1960s, public criticism of tranquilizers unfolded in the United States. First, the idea of “happiness pills” is not supported by countercultural youth who are rebelling against the lifestyle of the average American, programmed for everyday success and grabbing anything to stay afloat in the financial and everyday sense of the word. Second, in the 1960s, confidence in pharmacology was weakening.
The US government, meanwhile, is launching the so-called “war on drugs”, a crusade against recreational use of any psychotropic substances. Since the late 1960s, tranquilizers have taken their place in the image system of the “toxic”, non-ecological lifestyle of modern man. The puritanical view of the human psyche did not fit well with the achievements of modern psychiatry.
In the 1970s, the media ignited a new topic related to tranquilizers — addiction. Many stories of ordinary people who were “hooked” on valium by doctors are published. In 1979, Senator Edward Kennedy initiated a Senate inquiry into benzodiazepines, and at the first hearing said the following: “The main problem with drugs in the United States now, not counting alcohol, is diazepam.
” as A result, by the 1990s, public opinion in the United States had changed so much that tranquilizers were treated as drugs, and their users, respectively, as drug addicts.
These days, the first line of treatment for anxiety disorders is antidepressants, which work primarily on serotonin rather than GABA. If tranquilizers are expected to have a rapid effect on anxiety, then treatment with antidepressants is expected to have a long remission with a good prognosis. A tranquilizer will certainly help ease a panic attack, but it will not affect the risk of developing further attacks.
The neurobiology of anxiety disorders has significantly overtaken psychopharmacology. Drugs with a fundamentally different mechanism of action and effectiveness that would be higher than that of antidepressants, tranquilizers, and pregabalin  have not yet been invented. In contrast to the 1950s and 1960s, when drug development largely depended on random discoveries, modern scientists are moving from identifying neurobiological abnormalities (therapeutic targets) to searching for substances that normalize brain function.
Studies of twins using neuroimaging have shown that reducing the volume of the hippocampus increases susceptibility to stress. The hippocampus is known to actively communicate with the amygdala and hypothalamus, areas of the brain that control various physiological and behavioral manifestations of anxiety. Apparently, due to a decrease in the volume of the hippocampus, its inhibitory effect is weakened, the stress centers are overly activated and send more alarm signals to the adrenal glands, which is why more cortisol is released. Cortisol, which is very toxic to the hippocampus, kills its cells. The vicious circle closes — the hippocampus decreases, anxiety increases. It is not yet clear what causes the initial reduction in the volume of the hippocampus.
It is clear that anxiety disorders, like mood disorders, arise under the influence of two groups of factors: hereditary predisposition and environmental influence.
Molecular genetic studies have shown that the heritability of such a characteristic trait as anxiety is about 45 % in the population, and anxiety disorders — 30-50 %. The contribution of non-genetic factors is estimated quite high: 50-70 %.
Environmental factors (such as prolonged stress) are likely to contribute to the development of anxiety disorders through epigenetic changes  that increase the risk of developing anxiety in the womb. In untreated mothers with an anxiety disorder, the functioning of a region of the glucocorticoid receptor gene changes, which increases the risk of developing an anxiety disorder in their children. This is probably due to the fact that the stress hormone cortisol acts specifically on glucocorticoid receptors.
It is noteworthy that the monoamine oxidase type A gene (this is the substance that the first antidepressants acted on) is involved in the mechanism by which early Psychotrauma affects subsequent psychopathology. In boys who were abused as children, carrying a low-level variant of the MAO-A gene increases the likelihood of developing antisocial behavior and anxiety disorders in adulthood. However, abused boys with a highly active variant of the MAO-A gene do not have an increased risk of psychopathology in adulthood.
Most genetic research in the neurobiology of mood and anxiety disorders centers around genes involved in the regulation of the monoamine system. A small but significant increase in anxiety was found in people with a specific variant of the serotonin Transporter gene. When people were shown scared and angry faces, they had increased bilateral amygdala activity. In addition, patients with anxiety disorder showed a decrease in connectivity between the amygdala and cingulate gyrus, as well as a decrease in the volume of gray matter in these brain structures.
Neurochemists have also shown that depression and anxiety disorders increase the production of a serotonin Transporter, which is why serotonin released by one neuron does not have time to contact the receptors of the next neuron. It is believed that the activity of serotonin neurons in symptoms of anxiety can be either reduced or increased. In particular, high levels of serotonin in the amygdala are manifested by panic attacks. In the future, I hope, scientists will understand all the nuances of the functioning of the serotonin system and the brain as a whole in anxiety disorders.
Ongoing research supports the hypothesis that genetic predisposition may be common among mood and anxiety disorders, with individual clinical symptoms being the product of both genetics and external influences. In particular, epigenetic factors can allow for an extremely complex range of interactions between genes, the environment, society, and individual experience.
Anxiety disorders are among the most common mental disorders. Effective treatment of these conditions will make humanity much happier.