The authors of this study conducted a search for Russian and English-language articles in databases such as ELibrary.ru, Web of Science, Scopus, Clinical Case, PubMed, and Cochrane Database of Systematic Reviews. The search for articles was carried out by the keywords “agoraphobia”, “anxiety disorders”, and “borderline mental disorders”. The inclusion criteria were as follows: full-text articles in Russian and English, original research, Cochrane reviews, clinical observations, and publication date from 1994 to 2020. The exclusion criteria were abstracts and a publication date before 1994. Therefore, in total, 734 publications were found; 43 publications met the inclusion/exclusion criteria.

Agoraphobia is a disorder characterized by the appearance of fear when the patient is in an open space or in crowded places (shops, bus stops), followed by the formation of behavior to avoid situations that caused fear. According to the classification given in ICD-10, it can be divided into two groups: agoraphobia without anamnestic data for panic disorder and panic disorder with agoraphobia (ICD-10). Some researchers distinguish agoraphobia with an early and late (after 65 years) debut [1].

The prevalence of panic disorder is estimated at about 2% of the population per year or about 2–5% of the population during their lifetime [2][3]. Among these patients, from one-third to half have agoraphobic symptoms, although in clinical samples, the percentage is even higher [4]. Such a fairly high percentage of the occurrence of agoraphobia in the population makes this topic relevant for research.

The results of recent studies show the presence of comorbidity between agoraphobia and other disorders of the anxiety spectrum. In particular, agoraphobia occurs in 0.8% of people who have had a panic attack, and in 1.1% with panic disorder [2]. It has also been shown that a third of patients with panic disorder and major depressive disorder develop agoraphobia [5].

It is important to note that comorbidity increases the severity of the disease and reduces the effectiveness of the treatment. The nosologies listed above are grouped into a group of borderline mental disorders that have a high percentage of occurrence in the population [6]. Some of them, in particular PTSD (post-traumatic stress disorder), may be factors shaping the development of agoraphobia, therefore it is important to strive to reduce the frequency of prevalence of these nosologies [7].

Another factor in the importance of work in this direction is the fact that agoraphobia significantly aggravates the course of panic disorder and worsens the quality of life of patients, assessed on the SF-36 scale [8].

Taking into account the prevalence of the disease and a decrease in the quality of life in patients, the selection of effective therapy for panic-agoraphobic conditions plays an important role [9][10].

It can be noted that the position of agoraphobia as a separate nosology has been very “precarious” for a long time. In particular, there was a question about the secondary formation of agoraphobia in relation to panic disorder. Or is it a separate nosological unit, as it was originally indicated in the ICD?

Agoraphobia was first described by Westphal in 1871, and before the advent of the DSM-III-R (Diagnostic and Statistical Manual for Mental Disorders, third edition, revised), it was defined as a fairly common anxiety disorder or the so-called phobic neurosis. Subsequently, agoraphobia was included in ICD-9 as an independent syndrome manifested by multiple fears, and in ICD-10, it occupies the same status (ICD-10, 1995).

In the USA, where the main classification system for mental disorders is the DSM, the definition of agoraphobia prevails as “a feeling of fear with avoidant behavior formed when staying alone or among people in places from which it is difficult to get out or get medical help in an emergency”. It is possible to say that this definition is similar to the definition of panic disorder and the definition of agoraphobia given in ICD-10. However, the definition of agoraphobia in the DSM is closer to panic disorder than to phobias. Agoraphobia with panic attacks should be encoded as its initial phase, when there are repeated panic attacks, which, in turn, leads to the development of fear of such an attack and, accordingly, avoidance of situations and places that can provoke such an attack. If there is no history of panic attacks, then the diagnosis sounds like agoraphobia without panic attacks. However, according to the DSM, it is required that the avoidant behavior be the result of anxiety about the development of a panic attack, that is, in any case, a link between panic disorder or attack and agoraphobia is indicated, which is the difference between this classification and ICD-10. Thus, in the DSM-III-R, agoraphobia was defined as a response to situations in which a panic attack took place. However, the evolution of subsequent revisions of the DSM followed the path of increasing recognition of agoraphobia outside the design of panic attacks or panic disorder. In the DSM-V classification, published in 2013, significant changes were made to the category of anxiety disorders, including agoraphobia and panic disorder. In particular, they were divided into two separate diagnoses, that is, when formulating a diagnosis, two different codes should be used. It can be said that the diagnostic criteria for agoraphobia have undergone only minor changes. In particular, it is necessary to confirm the occurrence of fear in two or more situations in order to exclude other phobias (APA, 2013).

Panic disorder is a chronic disease, as a result of which patients need long-term therapy [11]. At the same time, it was shown that agoraphobia was a predictor of an unfavorable outcome in people with panic disorder [11]. The presence of agoraphobia in such patients aggravates the clinical course of panic disorder and increases the likelihood of having one or more concomitant mental disorders compared to patients with panic disorder, but without agoraphobia. It has been shown that after a panic attack, 37% of patients demonstrate avoidance behavior of moderate severity, and 81% of these patients form such behavior in less than a year [12]. The researchers identified risk factors that increase the risk of developing agoraphobic symptoms, such as the early age of the onset of panic attacks [13], female gender [14], and belonging of the underlying disease to the group of the anxiety spectrum [12]. According to domestic researchers, the predominant gender of patients with panic disorder and agoraphobia is female, and the age of onset of the disease is 21–30 (32.4%) and 31–40 (35.3%) years, which corresponds to the data of foreign scientists [15].

Generalized anxiety disorder is a mental pathology that demonstrates a high degree of comorbidity with other nosologies. In particular, it was shown that the probability of morbidity during life with major depressive disorder in generalized anxiety disorder is 62.4%, agoraphobia — 25.7%, and panic disorder — 23.5% [16].

In various Russian studies, the comorbidity of agoraphobia and somato-vegetative type of generalized anxiety disorder has been shown, which is manifested by short-term somatized anxiety reactions during the day. Among other disorders that are comorbid to anxiety disorder, of interest is irritable bowel syndrome, which leads to the development of agoraphobia. This is due to the fact that patients are afraid to experience the manifestations of this syndrome in public, which forms an avoidant behavior [17].

Studies have shown that the comorbidity of depression and panic disorder with agoraphobia is associated with increased anxiety, hypochondria, feelings of “inadequacy”, social isolation, as well as the inefficiency of treatment, difficulties of psychosocial rehabilitation, and an increase in the frequency of hospitalization [18]. Also, the severity of depressive symptoms (guilt, hopelessness) increases in the presence of panic disorder with agoraphobia [19]. Sareen et al., 2005 [20] showed that panic disorder with agoraphobia was associated with a history of suicide attempts. This is very important, since a suicide attempt in the anamnesis is regarded as a predictor of further suicide attempts. Some researchers believed that the presence of a suicide attempt in patients suffering from major depressive disorder was not associated with the presence of panic disorder, since the presence of anxiety and hypochondria was regarded as a protective factor against suicidal behavior, since these patients were more afraid of death [21]. Other researchers believed that there was a connection between psychomotor agitation and suicidal ideas, which contradicts the hypothesis of anxiety as a protective factor against suicide [22]. The key point in these hypotheses is the presence of a link between depressive and anxiety spectrum disorders.

For a long time, it has been investigated which factors associated with panic-agoraphobic symptoms can lead to an increased risk of suicidal behavior, in addition to the influence of depression. Patients with comorbidity of anxiety and depression may commit suicide more often than patients without anxiety, as this is a way to get rid of their worrying symptoms [20]. Panic attacks during depression significantly impair social functioning, which in turn can lead to suicidal ideation.

It should be noted that there is a reverse effect of depression on agoraphobia; in particular, there is an increase in the severity of phobic symptoms [23].

Thus, there is a complex pathogenetic relationship between panic-agoraphobic symptoms and depression. In this regard, the study of this issue is very important, as it will help reduce the likelihood of suicidal behavior.

Studies have shown high comorbidity between panic disorder and PTSD. Thus, panic disorder occurs in 7.3–18.6% of men and 12.6–17.5% of women suffering from PTSD [24]. More recent studies have shown that 35% of patients with PTSD suffered panic attacks within a year, which led to increased comorbidity with other anxiety spectrum disorders and deterioration of social functioning [25].

The relationship between PTSD and panic disorder is emphasized in connection with the emergence of a circular model of the development of feelings of fear, which postulates a similar etiology of anxiety disorders based on this emotion [26]. Applying this hypothesis to PTSD and panic disorder, it is possible to say that in a situation that triggers a reminder of a physical threat, a person experiences tachypnea, heart pain, and fear of death. The hypothesis of the circular formation of a sense of fear is in good agreement with the assumption that panic during a traumatic event becomes part of a conditioned reflex that can start at a certain moment, demonstrating the above symptoms [27]. At the same time, agoraphobic symptoms may form when patients avoid those places that cause a panic attack and experience anxiety about its likely development [13].

Therefore, understanding how personality traits are associated with the occurrence of panic disorder and agoraphobia is an important step in studying the etiology of the latter. Researchers have shown that cluster C (“anxiety” group) of psychopathies, especially avoidant and dependent, are associated with anxiety disorders, in particular with panic disorder and agoraphobia [28]. It should be noted that some researchers dispute the point of view that these types of personality disorders are predisposing factors for panic disorder and agoraphobia, based on retrospective data on the premorbid personality structure of patients with anxiety disorders. Other researchers believe that in the early stages of the course of panic disorder, the symptoms of the disease cannot affect the deformation of personality [29]. This point of view can be confirmed by the fact that effective therapy for panic disorder and agoraphobia can neutralize pathoharacterological personality traits [30].

It is known that the personal characteristics of patients can have a significant impact on the prognosis of therapy. Thus, in a study by Ozkan and Altindag, 2005 [31], it was shown that those patients whose characterological features reached the severity of psychopathic, panic disorder was characterized by a more severe course, agoraphobic symptoms were more often associated, and the risk of suicide was higher.

Among the factors shaping personality, in addition to genetically determined personality traits, education plays an important role. Russian researchers have shown that the inharmonious type of upbringing was very often applied to patients with agoraphobia. The most frequent style is “hyper-responsibility and hyper-care” (50.98%), which correlates with social anxiety and social phobia. The next most common (24.11%) parenting style was the so-called “Cinderella”, as a result of which patients are characterized by a complex of guilt and dependence, and the prohibition on the manifestation of negative emotions led to the somatization of anxiety1.

After a panic attack, patients often develop anxiety about waiting for a repeat attack, which is actualized when it is necessary to stay in a situation that can trigger a phobic reaction (anxiety, a feeling of tension in the body, tachycardia, difficulty breathing). These manifestations could be accompanied by the development of hypochondriac disorders. The fear for health is of the nature of obsessive hypochondria with an understanding of the morbidity and unreasonableness of the phobia and the fight against it, but sometimes hypochondria can take on the character of a predominant idea. The latter option is distinguished by the absence of a critical attitude toward one's condition [18].

In the study by Pose2, it was also revealed that all the patients suffering from agoraphobia had comorbidity with disorders of the hypochondriac spectrum: from the degree of fixation to the obsessive nature. Neurotic hypochondria was characterized by the concreteness of nosophobia with somato-vegetative manifestations. The clinical picture was characterized by a change of syndromes, such as hypochondriacal manifestations and pathocharacterological personality change, which overlapped the phobia picture. Subsequently, the clinical picture of neurotic development was determined by an obsessive-phobic and hypochondriac complex. Interestingly, according to the results of this work, it was revealed that a super-valuable type of hypochondriac disorders was formed in patients with personality disorders. Thus, in the case of anxiety, anankastic and dependent personality disorders, hypochondriacal development with accentuation of perfectionism, change of priorities and values and “breaking of the life curve” was revealed. The hysterical personality had a more favorable course. There was a partial reduction of hypochondria with the restoration of the previous level of functioning. Thus, one can say that the presence of a hysterical radical in the personality structure is prognostically favorable, while an anankastic, anxious, or dependent radical is unfavorable. At the same time, the clinical picture of hypochondria determines the dynamics of the course of agoraphobia. With neurotic hypochondria, long-term remissions without psychopathological disorders were observed, and with super-valuable hypochondria, a continuous course with the generalization and complication of the clinical picture due to the formation of comorbid connections.

Foreign studies of this kind were conducted in the eighties. Hypochondria was considered a somatic manifestation of impaired self-perception, and agoraphobia — a defensive reaction and an attempt to restore impaired self-perception. It has also been shown that patients can tolerate panic attacks earlier without understanding their psychological etiology, but they can be the key moment in the formation of hypochondria or anxious temperament.

Although the main time of studying the comorbidity of anxiety disorders and schizophrenia belongs to the early years of the nosological approach in psychiatry, for a long time this topic was ignored by both clinicians and researchers [32]. This was probably due to the fact that for a long time, it was indicated in the DSM diagnostic criteria that an anxiety spectrum disorder could be diagnosed if there was no connection with a disorder of the first axis, in particular schizophrenia, which led to a low diagnosis of this nosology in patients with schizophrenia [33]. However, with the advent of DSM-III-R, the diagnosis of comorbid anxiety disorder was allowed, if its manifestations were not associated with the underlying mental illness. The second reason for the increased interest in this problem at the moment is that the presence of comorbid anxiety disorder negatively affects the rehabilitation of patients and their degree of functioning [34]. Thus, the treatment of anxiety spectrum disorders in patients with schizophrenia is necessary, as it increases the likelihood of achieving a favorable result [35]. In a meta-analytical study by Achim et al., 2009, which included 52 studies with a total of 4,032 patients, the frequency of anxiety spectrum disorders in patients with schizophrenia was shown. The authors have proved that the average prevalence of agoraphobia in this cohort of patients is 5.4%, the 95% confidence interval ranges from 0.2% to 10.6% [36].

In the Russian school of psychiatry, it is customary to distinguish a sluggish type of schizophrenic process, which in the American school is considered a schizotypal personality type. The endogenous process in this case is characterized by the absence of pronounced positive symptoms, but against the background of a “slow” course [37]. Some researchers consider agoraphobia within the framework of a defect formed as a result of a sluggish process3 [40].

According to various Russian studies, the debut of agoraphobia in patients with schizophrenia occurs at a mature age. The main plot of the phobia is the fear of staying in a confined space alone and the fear of independent movement on the street. Interestingly, agoraphobic symptoms were formed not only against the background of panic disorder, but also in patients with synesthesia [38].

In Germany, Schneider and Altman, 2001 conducted a large retrospective epidemiological study MUCPA (Multicentre Study of Psychiatric Comorbidity in Alcoholics), the purpose of which was to determine the prevalence of comorbid psychiatric disorders among people suffering from alcoholism. The study included 556 patients suffering from alcoholism (patients who also used other psychoactive substances were excluded from the study). Therefore, anxiety disorders were found in 42.3% of the examined people. Generalized anxiety disorder was diagnosed in 42.3%, agoraphobia — in 12.9%, social phobia — in 13.1%, and panic disorder — in 13.7% of all the cases [39].

According to Tomasson and Vaglum (1996), in the case of agoraphobia/panic disorder, the risk of repeated treatment for alcoholism after detoxification in persons is 6 times higher than with two previous treatments [40].

In Russian studies, it has been shown that the picture of panic disorder with agoraphobia becomes heavier when a patient has chronic alcoholism (in particular, the frequency of seizures increases), while the presence of agoraphobic symptoms leads to a relapse of alcoholic illness, which is explained by taking alcohol to relieve symptoms [35]. The same authors have shown that in the presence of chronic alcoholism, agoraphobic symptoms in panic disorder develop faster, and the quality of remission is significantly lower than in patients without alcohol dependence.

Russian researchers have identified a high frequency of dependence on tranquilizers, while this phenomenon is more common in people with an unfavorable course of agoraphobia4.

Summarizing the above-mentioned information, it can be noted that agoraphobia is still an urgent task for both clinicians and researchers. An analysis of the literature showed that, probably, due to the dominance of “American” views on this nosology, it was inextricably considered secondary to panic disorder. In turn, this led to a lack of data on agoraphobic symptoms. However, even from this material, it is clear that this disorder is a serious problem for a psychiatrist due to the fact that it is not rare, while it aggravates the clinical picture of other mental illnesses. In particular, as it has been mentioned earlier, it increases the risk of suicidal behavior in depression, reduces the effectiveness of therapy for schizophrenic spectrum disorders and the quality of life of patients, leads to a relapse of chronic alcoholism, and also increases the likelihood of developing dependence on tranquilizers.

1. Pose, I.B. Clinical and psychological predictors of the unfavorable course of agoraphobia with panic disorder: Abstract of the dissertation for the degree of Candidate of Medical Sciences. Moscow State Medical University named after A.I. Evdokimov. Moscow, 2012. 177 p. 2. Pose, I.B. Clinical and psychological predictors of the unfavorable course of agoraphobia with panic disorder: Abstract of the dissertation for the degree of Candidate of Medical Sciences. Moscow State Medical University named after A.I. Evdokimov. Moscow, 2012. 177 p. 3. Kolutskaya E.V. Obsessive-phobic disorders in schizophrenia and disorders of the schizophrenic spectrum: Abstract of the dissertation for the degree of Candidate of Medical Sciences. The Scientific Center of Mental Health of the Russian Academy of Medical Sciences. Moscow, 2001. 152 p. 4. Pose. I.B. Clinical and psychological predictors of the unfavorable course of agoraphobia with panic disorder: Abstract of the dissertation for the degree of Candidate of Medical Sciences. Moscow State Medical University named after A.I. Evdokimov. Moscow, 2012. 177 p.