Panic disorder with agoraphobia or without agoraphobia

The main symptom of panic disorder is recurrent panic attacks. Panic attacks are characterized by sudden intense anxiety accompanied by at least four vegetative or cognitive symptoms.

Panic attacks are characterized by rapid development, anxiety reaches its climax within a few minutes. The panic attack ends just as suddenly, lasting no more than 30 minutes, but moderate anxiety can persist for more than an hour.

The DSM-IV identifies three types of panic attacks. Spontaneous panic attacks occur unexpectedly, without warning signs, and are not provoked by any factors. Situational panic attacks are triggered by certain frightening stimuli or the expectation of their possible occurrence. Situationally predisposed panic attacks occupy an intermediate position: they most often occur under the influence of a certain stimulus, but this connection is not always traced. Panic disorder is characterized by spontaneous panic attacks that occur in the absence of any triggering stimuli or situations. Panic disorder can be diagnosed if at least two spontaneous panic attacks occur, and at least one of these attacks must be accompanied by anxious anticipation of subsequent attacks or changes in behavior for at least 1 month.

Patients with panic disorder have a number of comorbid conditions. Of particular interest is the relationship between panic disorder and agoraphobia. Agoraphobia is characterized by fear or anxiety associated with visiting places from which it is difficult to escape. There is no single answer to the question of whether agoraphobia is an independent disorder, but there is no doubt that treatment of agoraphobia is an essential component of the treatment of panic disorder. One of the main problems is the frequency with which agoraphobia occurs without panic disorder and panic attacks. This problem is partly created by epidemiological data, according to which agoraphobia is more common than panic disorders. However, in this chapter the two conditions are considered together, since there are doubts about the validity of these epidemiological data. Almost all patients with agoraphobia suffer from panic attacks, and antipanic therapy can lead to regression of agoraphobia. Even when agoraphobia occurs in the absence of panic attacks, it can be associated with a fear of developing panic-like symptoms.

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Pathogenesis of panic disorder with or without agoraphobia

Although the pathogenesis of panic disorder remains largely unclear, several theories exist. More is known about this disorder than about any of the other disorders discussed in this chapter. The following sections review current theories that are relevant to the treatment of panic disorder (with or without agoraphobia).

Respiratory Theories of Panic Disorder

One theory suggests that a spontaneous panic attack is a kind of "emergency" reaction that occurs in response to a failure in the regulation of breathing. According to this theory, a panic attack is provoked by respiratory failure through the activation of a hypothetical "choking center" in the brain. The neuroanatomical model linked the development of a panic attack with hyperactivation of brainstem structures, which is reflected in changes in respiratory functions, dysfunction of the noradrenergic and serotonergic systems. According to this model, other manifestations of panic disorder are associated with dysfunction of other parts of the brain: for example, anticipatory anxiety - with dysfunction of limbic structures (for example, the amygdala), and restrictive behavior - with disorders in the prefrontal cortex.

Respiratory theories are based on a number of well-known data noted in studies of adult patients with panic disorder. First, complaints of respiratory failure are one of the most important components of the clinical picture of a panic attack. Second, individuals with respiratory diseases who suffer from dyspnea have more pronounced panic-like symptoms than patients without dyspnea. Third, adult patients with panic disorder often have an increased anxiety response when exposed to agents that stimulate the respiratory center, such as carbon dioxide, sodium lactate, and doxapram, a carotid stimulant. Finally, an increased anxiety response is reflected in the physiology of respiration: panic attacks are accompanied by a marked increase in ventilation. Patients with panic disorder have been found to have a number of disturbances in the neurogenic regulation of respiration, including hyperventilation and "chaotic ventilation" when studying respiration in a special chamber. Although it remains unclear to what extent these breathing disturbances are related to anxiety severity, the fact that similar changes are also found during sleep suggests that they are not dependent solely on cognitive factors.

The respiratory model of panic disorder has found application in the treatment of this condition. Drugs that effectively block panic attacks induced by stimulation of the respiratory center are also effective in ordinary panic attacks, while drugs that are effective in generalized anxiety disorder (but not in panic disorder) do not block panic attacks induced by stimulation of the respiratory center. There is evidence of the hereditary nature of respiratory regulation disorders. In mentally healthy relatives of patients with panic attacks, a pathological reaction to inhalation of carbon dioxide was found. Given the reliability and good reproducibility of the noted results, researchers continue to study the relationship between panic disorder and respiratory regulation.

Autonomic Theories of Panic Disorder

A close relationship between the autonomic nervous system and panic disorder has long been suggested. Earlier studies noted a tendency for heart rate to increase in patients with panic disorder, especially in laboratory conditions. This result was attributed to the influence of personal anxiety on the patient's status, since such changes in cardiac activity were less often detected in natural conditions. More recent studies have been based on the study of cardiac indices of the interaction of the parasympathetic and sympathetic systems and the response to noradrenergic drugs. These data confirm that panic disorder may arise from subtle dysfunction of the sympathetic nervous system, the parasympathetic nervous system, or a disruption in the interaction between them.

The most reliable evidence of parasympathetic dysfunction in patients with panic disorder has been obtained from studies of heart rate variability. Although the results of these studies have not always coincided, a tendency toward a reduction in the high-frequency component of the spectral power of heart rate variability has been noted in adult patients with panic disorder, indicating a deficit of parasympathetic influence. However, much more often, when studying heart rate variability, signs of an imbalance between the sympathetic and parasympathetic systems with a predominance of sympathetic influence are revealed. Panic disorder is associated with an increase in the ratio of the power of the low- and high-frequency components of heart rate variability. This increased ratio is especially evident in situations where sympathetic activity is enhanced, for example, during an orthostatic test or the administration of yohimbine. Preliminary data indicate that the acceleration of the heart rate during a panic attack is due to a weakening of parasympathetic influences.

However, the significance of these findings is significantly limited by their nonspecificity. Signs of weakening parasympathetic influences in the analysis of heart rate variability are revealed not only in panic disorder, but also in other mental illnesses, such as major depression or generalized anxiety disorder.

The role of the noradrenergic system in panic disorder is also studied using neuroendocrinological methods. The most conclusive results were obtained using clonidine, a selective alpha2-adrenoreceptor agonist. In adult patients with panic disorder, a smoothing of the growth hormone secretion curve was found in response to clonidine administration, indicating a decrease in the sensitivity of hypothalamic alpha1-adrenoreceptors. Since such a response persists despite successful treatment of panic disorder, it can be considered a marker of predisposition to this disease. In patients with panic disorder, an increase in blood pressure and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in response to clonidine is also detected. The data obtained may indicate a dysfunction of the hypothalamic-pituitary-adrenal axis due to a disruption in its interaction (dissociation) with the noradrenergic system. The clonidine test data indicate a dysfunction of the noradrenergic system, more likely of the dysregulation type, rather than of the hyperactivity or hypoactivity type.

In panic disorder, a more chaotic MHPG response to alpha2-adrenergic receptor stimulation is observed, but with successful treatment, a normal response is restored in the form of a decrease in MHPG levels in response to clonidine. Adult patients with panic disorder show an increase in anxiety in response to yohimbine and alpha2-adrenergic receptor agonists that stimulate the locus ceruleus. These data, as well as the results of heart rate variability studies, indicate a possible role for autonomic dysfunction in the pathogenesis of panic disorder.

However, the results presented are also not entirely specific: smoothing of the growth hormone secretion curve in response to clonidine administration is found not only in panic disorder, but also in major depression, generalized anxiety disorder, and social phobia. Moreover, adult patients with posttraumatic stress disorder show an increased anxiety response to yohimbine, while in major depression and generalized anxiety disorder a normal response to yohimbine is found.

Serotonin Theories of Panic Disorder

The most convincing data on the role of serotonin in the pathogenesis of panic disorder have been obtained in pharmacological studies. Individual reports by a number of researchers that patients with panic disorder are predisposed to the development of anxiety at the beginning of treatment with selective reuptake inhibitors were subsequently confirmed in more systematic studies.

Although the results were not always consistent, studies of neuroendocrine reactions in response to the administration of serotonergic drugs such as fenfluramine, isapyrone, and meta-chlorophenylninerazine (mCPP) revealed certain changes in patients with panic disorder. The most striking result was the change in cortisol secretion in response to the administration of fenfluramine and mCPP. Patients with panic disorder also showed changes in the content of platelet serotonin-related protein, although these results were contradictory. A hypothesis was put forward that panic disorder is associated with the production of xerotonin autoantibodies.

Some studies on the role of serotonin in the pathogenesis of panic disorder have emphasized the importance of interactions between the serotonergic and other neurotransmitter systems. In particular, the close relationship between the serotonergic and noradrenergic systems suggests a link between dysfunction of the serotonergic system and impaired autonomic regulation in panic disorder. Thus, selective serotonin reuptake inhibitors may reduce the symptoms of panic disorder indirectly, through their effect on the noradrenergic system. Evidence of this is the fact that fluoxetine, a selective serotonin reuptake inhibitor, is able to normalize the chaotic MHPG response to clonidine administration in patients with panic disorder.

Conditioned reflex theory of panic disorder

The development of a conditioned reflex phobic reaction in experimental animals allows one to create a laboratory model of anxiety. For this purpose, neutral conditioned stimuli (e.g., a flash of light or sound) were given in pairs with negative or unconditioned stimuli, e.g., an electric shock. As a result, the same physiological and behavioral reaction arose in response to the conditioned stimulus as to the unconditioned stimulus. The neuronal circuit associated with the development of this conditioned reflex has been studied. This circuit includes somatosensory pathways that follow from the exteroceptors to the thalamus and the central nucleus of the amygdala. The central nucleus of the amygdala also receives cortical projections that can regulate the functioning of the subcortical circuit, which mainly ensures the development of a conditioned reflex phobic reaction. Projections from the hyphaeocampal region and the prefrontal cortex are of certain importance. It is believed that any anxiety reaction, including a panic attack, occurs as a result of the interaction of the amygdala with the brainstem structures, basal ganglia, hypothalamus and cortical pathways.

The conditioned fear theory was proposed in relation to panic disorder by LeDoux (1996). According to this theory, internal stimuli (e.g., increased blood pressure or changes in breathing) are considered conditioned stimuli that can trigger a panic attack. Thus, a panic attack may result from activation of neural pathways that mediate the conditioned phobic response in response to normal fluctuations in physiological functions. Clinical studies indicate that the brain structures that mediate the conditioned phobic response in experimental animals may also be involved in humans. This theory has been supported by neuroimaging data, which have revealed dysfunction of structures projecting to the amygdala, particularly the prefrontal cortex and hippocampus, in patients with panic disorder. The fact that a conditioned reflex can be developed based on the respiratory and physiological response to carbon dioxide inhalation also supports this model. Agoraphobia can also be considered as a form of conditioned reflex phobic reaction, with panic attacks playing the role of an unconditioned stimulus in the formation of fear. To study the mechanisms of panic attack development, a model of affectively enhanced startle reflex was proposed, but the results of the study were ambiguous.

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Cognitive Theories of Panic Disorder

Most experts acknowledge that there is a strong biological component to panic attacks, but they disagree on what causes the condition. Some believe that cognitive factors may be the cause.

It is assumed that a number of cognitive factors influence the development of panic attacks. It has been noted that patients with panic disorder are characterized by increased anxiety sensitivity and a reduced threshold for perceiving signals from internal organs. This theory is supported by the fact that people with anxiety sensitivity report a greater number of symptoms when anxiety is provoked by physical exertion. At the same time, this theory has not received significant confirmation in experiments with biofeedback, when subjects were able to control their physiological indicators, such as heart rate.

Another theory, related to the one mentioned above, suggests that people with panic disorder tend to “catastrophize” (think catastrophically), especially in situations they cannot fully control. This theory is supported by research showing that learning to control a situation affects sensitivity to stimuli that trigger panic attacks.

Some theories suggest that separation anxiety, particularly in childhood, predisposes the development of panic disorder. These theories are supported by a number of studies, although the results have not always been replicated. One recent study found that separation from a person who symbolized safety influenced the occurrence of panic attacks in response to carbon dioxide inhalation. Thus, there is a trend toward integrating modern versions of cognitive theories with the biological theories described above.

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The course of panic disorder with or without agoraphobia

Panic disorder usually begins in adolescence or young adulthood, although cases with onset in childhood and adulthood have been described. Only rough data on the course of panic disorder are available. More reliable data can be obtained only through prospective epidemiological studies, while retrospective and clinical studies often provide imprecise data that are difficult to interpret. Data obtained from retrospective and clinical studies indicate that panic disorder has a fluctuating course with a variable outcome. About one-third to one-half of patients are mentally healthy at follow-up, and most lead relatively normal lives despite fluctuations in the severity of symptoms or the presence of relapses. Chronic disorders typically involve alternating exacerbations and remissions, rather than a constant level of symptoms. Clinicians most often see patients at the onset of the disorder or during periods of exacerbation. Therefore, when examining a patient with panic attacks, it is especially important to obtain a detailed anamnestic information about the preceding symptoms. It is necessary to find out about the results of the examinations carried out, calls to the ambulance or emergency hospitalizations due to unexplained somatic symptoms, as well as about medications or narcotic substances that the patient may have used.

Diagnostic criteria for panic attack

A clearly defined period of intense fear or discomfort, accompanied by at least four of the following symptoms, that begin suddenly and reach a peak within 10 minutes

1. Palpitations, a feeling of heart pounding, or increased heart rate
2. Sweating
3. Trembling or chills
4. Feeling short of breath or short of breath
5. Feeling of suffocation
6. Pain or discomfort in the chest
7. Nausea or discomfort in the abdomen
8. Feeling dizzy and unsteady
9. Derealization (feeling of unreality of what is happening) or depersonalization (alienation from oneself)
10. Fear of losing control or going crazy
11. Fear of dying
12. Paresthesia
13. Heat or cold waves

Note: Panic attack does not have a specific code; the disorder in which panic attacks occur is coded (e.g. 200.21 - panic disorder without agoraphobia).

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Diagnostic criteria for agoraphobia

• Anxiety about being in places or situations from which it may be difficult (or inconvenient) to escape or where help cannot be provided if an unexpected or situational panic attack or panic-like symptoms occur. Fears in agoraphobia are usually associated with specific groups of situations, including being alone outside the home, being in a crowd, standing in line, being on a bridge, or riding a bus, train, or car.

If the patient avoids only one or several specific situations, then a specific phobia should be diagnosed; if avoidance is limited to communication situations only, then social phobia is diagnosed.

• The patient avoids certain situations (for example, limits walking routes), or when entering them experiences severe discomfort or anxious concerns about the possible development of a panic attack or panic-like symptoms, or insists on being accompanied by another person
• Anxiety or phobic avoidance is not better explained by the presence of other mental disorders, such as social phobia (if the patient avoids only social situations and fears being embarrassed), specific phobias (if the patient avoids only one specific situation, such as riding in an elevator), obsessive-compulsive disorder (for example, if the avoidance is due to obsessive fears of contamination or contamination), post-traumatic stress disorder (if stimuli associated with severe psychological trauma are avoided), or separation anxiety disorder (if possible separation from home or relatives is avoided).

Note: Agoraphobia does not have a specific code; the disorder that causes agoraphobia is coded (e.g. 300.21 - panic disorder with agoraphobia or 200.22 - agoraphobia without panic disorder).

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Differential diagnosis of panic disorder

Diagnosis begins with a thorough identification of the symptoms described above. It is also necessary to consider the possibility of other diseases that can cause similar symptoms. Like other anxiety disorders, panic disorder is often combined not only with agoraphobia, but also with other mental disorders of an anxious and depressive nature. Comorbid conditions include specific and social phobias, generalized anxiety disorder, major depression, drug addiction, bipolar disorder, and suicidal behavior. The high degree of comorbidity between anxiety and depressive disorders can apparently be partially explained by the characteristics of the contingent of patients referred to specialists, but comorbidity between these conditions is also revealed in epidemiological studies.

Panic disorder with or without agoraphobia should be differentiated from these comorbid conditions. First of all, it is necessary to establish whether the attacks are spontaneous or are provoked by a certain situation that the patient fears. Patients describe spontaneous panic attacks as occurring "in the midst of perfect health" or "like a bolt from the blue." At the same time, a patient with social phobia may have a panic attack before a public speech, a patient with post-traumatic stress disorder may have an attack provoked by painful memories, and a patient with a specific phobia may have an attack provoked by a certain situation that causes him fear.

Having established the spontaneous nature of panic attacks, their frequency and severity should be clarified. Single spontaneous panic attacks are common in adults, but the diagnosis of panic disorder is made only in the presence of multiple recurring panic attacks. The diagnosis is confirmed by the presence of obvious anxiety that the patient experiences in connection with the attacks, while he or she should either have anxious concerns about a possible recurrence of attacks, or should exhibit restrictive behavior aimed at reducing the possible adverse effect of attacks. Differential diagnosis with generalized anxiety disorder can also be difficult. A classic panic attack is characterized by a rapid onset and a short duration (usually no more than 10-15 minutes) - this is the main difference from generalized anxiety disorder, in which anxiety increases and decreases more slowly.

However, this distinction is not always easy to make, since a panic attack is sometimes followed by diffuse anxiety, which may regress slowly. Severe anxiety can be observed in many mental illnesses, including psychoses and affective disorders, but it can be quite difficult to differentiate panic disorder from other psychopathological conditions. The main thing in differential diagnosis is the analysis of the course of psychopathological symptoms. If recurring panic attacks occur only against the background of another mental disorder, then treatment should be aimed primarily at the underlying disease. But at the same time, drugs should be selected in such a way that they are also effective for panic disorder. For example, panic attacks can occur during episodes of major depression, for which tricyclic antidepressants, monoamine oxidase inhibitors, or selective serotonin reuptake inhibitors are prescribed; all of these drugs are also effective for panic disorder. As a rule, panic disorder should be diagnosed only when recurring panic attacks cannot be attributed to another mental disorder that the patient has.

Panic disorder (with or without agoraphobia) should also be differentiated from somatic diseases that may present with similar symptoms. Panic attacks may occur with a number of endocrine diseases, including hypothyroidism, thyrotoxicosis, hyperparathyroidism, and pheochromocytoma. Episodes of hypoglycemia with insulinoma are also accompanied by panic-like symptoms and other signs of nervous system damage. In such patients, a thorough physical examination of systems and organs, biochemical blood tests, and endocrinological tests usually reveal signs of endocrine dysfunction. Although these conditions can cause almost the same symptoms as idiopathic panic disorder, endocrine dysfunction is extremely rare without other somatic manifestations. Symptoms of panic disorder may also occur with organic pathology of the central nervous system, including epilepsy, vestibulopathy, tumors, as well as under the influence of drugs or narcotics. A thorough examination may reveal signs of a neurological disease. Electroencephalography (EEG) and neuroimaging (computed tomography or magnetic resonance imaging) are not indicated in all cases, but if a neurological disease is suspected, these methods, as well as a consultation with a neurologist, should be included in the examination complex. Thus, if a panic attack is preceded by an aura, and confusion persists after it, a thorough neurological examination and EEG are necessary. In case of newly discovered neuropsychological disorders or focal neurological symptoms, a consultation with a neurologist is required. Heart and lung diseases, including heart rhythm disorders, obstructive bronchopulmonary diseases, bronchial asthma, can cause vegetative symptoms and increasing anxiety, which can be difficult to distinguish from the manifestations of panic disorder. In these cases, signs of somatic disease help to make the correct diagnosis.

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