Interventions for Panic

#### **Chapter 5**

## Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving toward Future Directions

*Behrooz Afshari*

#### **Abstract**

Panic disorder is one of the most debilitating mental disorders. Therefore, it is necessary to apply treatments for this problem to eliminate the disability of patients. Both psychotherapy and medication have been shown to reduce the frequency and severity of panic attacks and panic disorder. In this chapter, we first mentioned cognitive-behavioral therapy as the cornerstone of psychotherapy for panic disorder and then, medication as one of the most common treatments for this disorder. Cognitive-behavioral therapy has been found by numerous studies to be the most important psychotherapy for panic attacks and panic disorder. Medication is another effective treatment because some medications can be very helpful in managing the symptoms of a panic attack as well as anxiety and depression. Finally, emotion regulation therapies for the treatment of panic disorder will be introduced and explained for the first time.

**Keywords:** panic disorder, cognitive-behavioral therapy, medication, emotion regulation therapies

#### **1. Introduction**

A severe acute attack of anxiety with a feeling of imminent harm is called panic disorder. People with panic disorder suffer from multiple panic attacks that are unrelated to specific situations. These attacks are periods of intense fear and physical discomfort; so the sick people feel that they cannot control themselves. The onset of these attacks is sudden and usually reaches its peak in 10 min. For a panic attack to be diagnosed as panic disorder, a person must have certain reactions to these attacks, including constant worry about the recurrence of attacks or worry about the consequences of the attacks, avoiding activities that may cause the physiological feelings associated with panic, or participation in safety-related behaviors, such as carrying a cell phone or medication [1]. Concerns about the consequences of attacks may include fear of having a fatal heart attack or fainting in front of others. Panic disorder is a unique disorder among anxiety disorders whose symptoms and signs are physical

in the first stage. These patients are highly sensitive to unpredictable events, and their symptoms are almost related to one of three systems, including the autonomic nervous system (heart palpitations and sweating), the respiratory system (shortness of breath and chest tightness), and the cognitive system (personalization, fear of loss of control, and fear of death). This disorder is one of the most common disorders in the mental health system, so its prevalence is estimated at 5–9%. This disorder is associated with an increase in cardiovascular complications and mortality [2].

#### **2. Investigating cognitive models of a panic attack**

A panic attack is considered an acquired fear of bodily sensations (heart palpitations, dizziness, nausea, etc.), especially sensations associated with automatic arousal. In simple terms, after having panic attacks, people become over-sensitive to their physical feelings and feel threatened by any slight physical sensation and consider it as the possibility of starting a panic attack. Therefore, those who have panic disorder, after experiencing an unexpected panic attack, become anxious about experiencing such attacks in the future and are always worried about having these attacks again. Therefore, they become very sensitive to the smallest changes in their body to avoid panic attacks [3].

#### **3. Why do we experience panic attacks?**

From an evolutionary point of view, the reaction of fear or panic in the presence of a threatening situation is adaptive. It is assumed that panic occurs in the absence of a threatening stimulus, as a result of the interaction of stressful life events and psychological and biological vulnerabilities. The tendency to experience negative emotions, often labeled as neuroticism, is largely heritable and has been shown to predict panic attacks. This temperament probably acts as a biological vulnerability to experience fear (a rapid alarm response characterized by strong arousal of the nervous system) and experience anxiety (a negative mood state characterized by worry about future events and signs of physical tension) [4].

Environmental factors in childhood can play a key role in the formation of people's confidence and their abilities to control future life events. Such a sense of control or lack of control can act as a psychological vulnerability in the experience of fear and anxiety. Stressful life events, such as a new job or the death of a family member, may combine with biological and psychological vulnerabilities to trigger an emotional fear response or panic attack. Accumulated stressors built up over time by stressful life events can trigger a panic attack, even though the person perceives it as "unexpected" because there is no immediate threatening stimulus [5]. Therefore, three factors play a role in the occurrence of panic: (1) inheritance, (2) family environment in childhood, and (3) environmental factors.

#### **4. After an unexpected panic attack, what causes the attacks to continue?**

General vulnerabilities (heredity, family environment, and environmental factors) may play a key role in determining whether a person develops "anxious fear" about experiencing attacks in the future or not. In addition to general vulnerabilities in experiencing panic and anxiety, it is believed that there are specific vulnerabilities

*Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving… DOI: http://dx.doi.org/10.5772/intechopen.107482*

that contribute to the formation of panic attacks. An example is anxiety sensitivity. According to this belief, anxiety and its symptoms cause harmful physical, social, and psychological consequences beyond the physical discomfort of a panic attack. After a panic attack, a person becomes sensitive to the discovery of his bodily arousal, which leads to vulnerability to subsequent panic attacks [6].

Anxiety about unexpected panic attacks is linked to fear of physical sensations (such as heart racing) that accompany the attacks. At first, the person is anxious about their physical sensations and worries that it will lead to a panic attack. At this time, automatic thoughts such as catastrophizing (e.g., I will be ashamed if I have a panic attack) and over probability (e.g., If I go out I will have a panic attack) cause a person's anxiety to increase and as a result, physical feelings such as heart rate and dizziness increase. The increase in bodily sensations strengthens automatic thoughts and the person becomes more certain of the correctness of his beliefs, and as a result, these thoughts become stronger and cause more anxiety again. This self-perpetuating cycle continues until it results in a panic attack again [7].

#### **5. Conditioning in a panic attack**

Accompanying physical feelings with a panic attack makes a person more conditioned, and consequently becomes more sensitive to physical feelings. Then, physical feelings occur in all people sometimes and are resolved after a while; for a person with panic disorder, it means the beginning of a panic attack. Such anxiety about bodily sensations plays an essential role in the persistence of panic disorder. Physical sensations can be caused by physical activity, chemicals such as caffeine, a frightening environmental stimulus, and anxious images or thoughts. When physical sensations are noticed by a person suffering from panic disorder, they create fear. This fear intensifies bodily sensations and leads to an increase in that fear, and in turn, as a selfperpetuating cycle of fear and bodily sensations, leads to a further increase in bodily sensations, which ultimately leads to a panic attack. Therefore, the fear of experiencing physical sensations of arousal leads to a full-blown panic attack and reinforces the belief that these sensations should be feared [8].

To condition a person, it is sometimes enough to experience physical sensations with a panic attack once, and after that, other factors such as safety seeking and avoidance, which are explained below, cause the panic disorder to continue. People with panic disorder are often not aware that panic attacks can be triggered in this way (by bodily sensations or internal and external stimuli). For people with panic disorder, this means that panic attacks often occur unexpectedly and unpredictably. Because they cannot stop panic attack symptoms once they begin, they consider such attacks uncontrollable. The unpredictability and uncontrollability of a panic attack can fuel chronic anxiety levels, resulting in constant fear of another attack. Higher levels of chronic anxiety can lead to increased physical arousal as well as increased attention to one's bodily sensations. Increasing physical sensations and increasing attention to these sensations lead to an increase in the probability of panic attacks in the future [9].

#### **6. How do avoidance and safety-seeking behaviors perpetuate panic attacks?**

Behavioral responses to panic, especially safety-seeking behaviors (such as walking slowly to avoid elevated heart rate, not going to heights to avoid dizziness, and eating

less food to prevent nausea) and avoidance (not leaving the house for fear of being attacked and avoiding lonely situations) apply as perpetuating factors of the panic disorder. A person with panic disorder mistakenly believes that a panic attack will cause catastrophic physical or mental harm, such as a heart attack, going crazy, passing out, or losing control. Therefore, experiencing panic attacks in which none of these things occur should necessarily undermine these beliefs [10].

However, people with panic disorder engage in certain safety-seeking behaviors that they believe enable them to escape or avoid the consequences of fear. For example, if a person believes they are going to pass out during a panic attack, they may sit or hold an object. Engaging in safety-seeking behaviors prevents a person from realizing that a panic attack does not cause a physical or psychological catastrophe because he believes that if he does not have a disaster, it is because he is sitting on a chair, or walking slowly, and not because a panic attack does not hurt him. Disconfirming false beliefs about panic attacks help to maintain the panic disorder. People may engage in safety-seeking behaviors designed to prevent panic or its feared consequences, such as taking antianxiety medication with them or traveling with people who make them feel safe [10].

Another behavioral response that perpetuates fear is overt avoidance. People tend to avoid certain places or situations that they believe are more likely to trigger a panic attack. Avoidance prevents the disconfirmation of false and catastrophic appraisals and reinforces the belief that these particular situations are dangerous, and increases the likelihood of having a panic attack in those situations in the future. Furthermore, if a person avoids situations in which they experienced an unexpected panic attack in the past, future attacks will inevitably spread to new, previously safe situations. Therefore, the range of safe conditions is limited. So most places become dangerous places where a panic attack is likely to occur. This pattern can increase behavioral avoidance and chronic levels of anxiety perception. Now let us look at useful techniques and therapies for treating panic disorder.

#### **7. Psychological training in the treatment of the panic disorder**

In the method of treating panic through psychoeducation, the therapist provides information to help correct the client's misconceptions about panic attacks and anxiety and to normalize the situation for him, which are effective for treating panic. In the first session of treatment, the therapist explains things about panic attacks so that these attacks become unpredictable and uncontrollable in the person's mind, and the person's misconceptions about panic symptoms, including the idea of going crazy, disappear, such as "When our ancestors were in the forests, they were residents, they were exposed to all kinds of natural disasters." Naturally, if they did not sleep at night with the fear of a lion or leopard attack, they would fall into such a deep sleep that they would not notice the presence of a lion or a leopard and become their prey [11]. Therefore, we are the descendants of ancestors who were worried about the dangers around them and were in a state of alertness.

#### **8. The function of anxiety**

The function of anxiety is to preserve the survival of the generation, and it is used when a person feels threatened. Now this danger can be real or imagined. At this time, *Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving… DOI: http://dx.doi.org/10.5772/intechopen.107482*

anxiety is activated in the person's body and prepares him for fight or flight. That is, where it is possible to attack, attack the cause of fear, and otherwise, escape from the cause of fear. To prepare the body for fight or flight, changes are made in the body. Among other things, increasing the arousal of the autonomic nervous system, which controls many of our bodily processes, such as the cardiovascular and gastrointestinal systems. During anxiety, blood flow to the extremities of the body such as hands, feet, and arms increases, and blood flow to the head and internal organs decreases. Heart rate and breathing speed up and digestion slow down. These changes cause symptoms such as increased heart rate, shortness of breath, dizziness, and feelings of weakness and nausea. These symptoms all mean that the body is ready to face a dangerous factor, but it is not dangerous because they are used for the preservation and survival of the person and not to harm it. The problem arises when this survival protection system becomes overly sensitive, such as an over-sensitive burglar alarm that goes off at unnecessary and unhelpful times [12].

#### **9. Cognitive factors in panic attacks**

Another factor in panic attacks is the cognitive factor. The cognitive factor comes into action in the form of internal conversations: "Oh, what if my heart rate goes up? If I faint, my reputation will go down. I will have an attack at a party. How badly will they judge me if I have a panic attack? I'm going crazy." These negative thoughts intensify physical feelings. That is, they increase heart rate, intensify dizziness, and... The intensification of physical feelings, in turn, makes the person's negative thoughts stronger [13]. Also, he is more sure of the correctness of his belief that the attack will start. And he says to himself, "So I think I'm right that I'm having an attack." These symptoms are due to the negative cycle of physical feelings and negative thoughts that have intensified in the person. Finally, the arousal reaches the point where the person sometimes has an attack. As the number of these attacks increases, the person becomes more conditioned and more sensitive to his physical changes. He also noticed very small changes in his body and assumed it was a sign of the beginning of an attack.

#### **10. Behavioral factors in panic attacks**

Another factor in panic attacks is the behavioral factor. After the panic attack happened, the person adopts two strategies to deal with the risk of its recurrence [14], both of which cause the panic attack cycle to continue in the person: (1) Seeking safety and (2) avoid.

#### **10.1 Seeking safety**

In seeking safety, a person tries to reduce his sense of internal danger by using things that give him a sense of security. For example, wherever he goes, he takes his friend or his parents with him. In the case of each client, it should be investigated what factors he uses as safety so that after identifying its cases, little by little the client will face his imagined danger without them. In some cases, the use of sedatives is also considered a safety measure. Because the person thinks that these drugs have reduced his anxiety. Therefore, it is necessary to make exposure after some time when stopping the drug so that the person feels confident about himself [15].

#### **10.2 Avoidance**

In avoidance, a person avoids being in places or situations where he believes that the probability of a panic attack is high. This makes him never understand that these situations are not dangerous. Rather, the assumption is strengthened that if he was not attacked, it is because he avoided these situations [16]. The problem is that avoidance does not remain in one area and is constantly expanding. First, the lonely person is afraid of being attacked outside the city. He tells himself that in order not to be attacked, it is better not to go too far from the city. If he does what he thinks and avoids, the internal conversations become more threatening and this time he tells him not to be attacked from somewhere in the city. After some time, his inner dialog tells him again not to have a panic attack at a distance of more than 1 km from home. Finally, he reaches a stage where he cannot leave the house. Because he believed that it was his avoidance and seeking safety that caused him not to have a panic attack. In this case, it should be said that what helps a person treat panic without drugs is facing the issue of anxiety [17].

After being taught the three important components of fear and anxiety—physical symptoms, thoughts (cognitions), and behavior—as well as how they interact to contribute to panic disorder survival, clients are encouraged to list physical symptoms, thoughts, and behaviors related to their most recent episode of panic, and find out how their responses may prolong or exacerbate panic attacks. For example, when Tina realizes that her heart rate is fast, she is overcome with fear and has a panic attack, and faints. This alarming thought leads to a faster heart rate and other physical signs of anxiety, which ultimately increases his fear of having a panic attack. His behavior (rushing home, where it is safe) reinforces his belief that anywhere else is unsafe. Treatment aims to break this negative cycle by addressing the three main components of anxiety: changing self-talk or beliefs, controlling physiological responses, and confronting objects, situations, and places that cause fear [18].

#### **11. Self-monitoring in the treatment of panic attack disease**

In the treatment of panic attacks, the self-monitoring method helps the patients to observe their emotional reactions as an external observer instead of judging them subjectively. Self-monitoring can reduce anxiety, increase awareness of emotional reactions, and increase feelings of control [19]. For example, Tina's mental appraisal "I feel anxious, so there is no way I can go shopping" could be objectively described as "My heart beats faster. I think that if I go to the store, I will have a panic attack and faint." Clients are asked to complete a monitoring form for a recent panic attack that includes the following details: physical sensations, thoughts and behavioral reactions, the situation in which the attack occurred, and the degree of fear.

#### **12. Teaching relaxation techniques in the treatment of panic**

Breathing retraining is introduced as an adaptive skill in stopping physiological overreactions in the treatment of panic. The mechanisms by which breathing retraining is effective and the extent to which it is effective for panic are still under investigation. However, therapists must not use it as a means of avoiding negative emotions. The client is taught diaphragmatic breathing: breathing from the belly instead of the

*Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving… DOI: http://dx.doi.org/10.5772/intechopen.107482*

chest. The client is supposed to focus on his breathing by counting breaths (one) and thinking of the word "relaxation" as he exhales. For the first week of training, the therapist should breathe at a normal rate and speed. After 3–5 min of practice in the session, the client is assigned a breathing retraining task for the next week: 10 minu of practice, twice a day in a comfortable and quiet place [20].

#### **13. Cognitive restructuring in the treatment of panic**

Cognitive restructuring is the process of displacing automatic anxious thoughts or cognitive errors, such as risk overestimation and catastrophizing. In this case, therapists are taught how to identify their automatic anxious thoughts. Then, they are taught how to treat these thoughts as hypotheses and gather evidence to support or disprove them. Finally, they are encouraged to develop alternative hypotheses and gather evidence to support and reject them. Clients are explained that although anxious thoughts can be "automatic" and occur very quickly without full awareness, they can influence feelings and actions. The content of these thoughts is specific and may be different in different situations and times. Subsequently, it is important to identify or predict the specific content that creates anxiety in certain situations [21].

#### **14. The "down arrow" technique for identifying automatic thoughts**

Subjects are taught to use the "down arrow" technique to identify these automatic thoughts. The technique works like this: therapists ask themselves, for example, what they fear in a hypothetical situation. Then, they figure out what those fears would mean and what would happen if they were real. Then, the meaning of the thoughts of the lower layers is examined, and this process continues until the central anxious automatic thought is identified [22].

For example, Tina writes on her monitoring form: While driving, she became frightened when her heart rate increased. So she left the car and her mother sat behind the wheel instead. To uncover her automatic thinking, the therapist should ask her what would happen if her heart continued to beat. The therapist responds to Tina saying, "That is horrible!" she can ask what she imagines is happening that she finds terrifying. Again, in response to Tina saying, "My heart would beat faster, I would start shaking, and I would pass out," the therapist can ask what she thinks would happen if she experienced those feelings. The therapist can continue these questions until she gets to the central belief of her anxiety. The belief is that if she did not move the car, she would faint, have an accident, and kill herself and her mother. It is explained that identifying automatic thought is the first step in cognitive restructuring. And it should be practiced as part of this week's self-assessment assignment [23].

Then, they teach the audience to view their thoughts not as absolute facts, but as hypotheses. The Socratic questioning method is used to help them gather evidence to determine a more realistic possibility. For example, Tina thinks that the probability of losing control of the car and crashing during a panic attack is close to 100%. She is asked if this has happened before. Do you have any proof of its occurrence or nonoccurrence? After arriving at a more realistic possibility, the referent is assisted in generating alternative thoughts. For Tina, the alternative hypothesis might be: I'm just experiencing anxiety, and I'm also able to drive while experiencing anxious thoughts and bodily sensations [23].

#### **15. Exposure in the treatment of panic**

Repeated exposure to fearful physical feelings (physical exposure) and fearful situations (exposure in natural situations) to reject the incorrect cognitive evaluation and turn off conditioned emotional reactions to these feelings and situations is considered one of the main methods of panic treatment [24]. Using breathing retraining and cognitive restructuring to deal with these feelings and situations provides corrective experiences to therapists, which are not achieved by avoiding or running away from these feelings and fearful situations [24].

#### **15.1 Exposure based on emotional arousal**

First, physical exposure is done to increase learning about bodily sensations. Clients are told that their anxiety-provoking physical sensations are stimulated. To learn that these feelings are not harmful and can be tolerated. They remind them of the conditioning of bodily sensations and how minor changes in physiology can trigger anxious thoughts and physiological over-arousal in them due to prior pairing of bodily sensations with a panic attack [25].

Clients are reminded that avoiding changes in physical state or avoiding activities that cause changes in physical state (such as avoiding running because it raises the heart rate and evokes a panic attack) prevents remedial learning. Learning that physical symptoms are not harmful and can be tolerated. It is explained that avoidance perpetuates fear. By facing uncomfortable bodily sensations, they learn not to fear them [26].

Clients are directed to perform activities (e.g., climbing stairs, turning, gasping, etc.) to reexperience the bodily sensations experienced during a panic attack. They should continue the activity for 30 s after they first notice their bodily sensations. Then, record the bodily sensations they had, their level of anxiety, and how similar these sensations were to the bodily sensations experienced during the panic attack. An activity with a moderate degree of fear and little resemblance to the actual feelings of a panic attack is used to practice exposure to physical feelings within sessions and is assigned as a task (to be practiced three times a day) [27].

Clients are taught how to control the exercises by arousing emotions, assessing fear levels, using breathing retraining, and cognitive restructuring of adaptive skills [28]. Clients should answer these questions in each exercise: Did the disaster they feared (e.g., loss of control) happen? Did they survive from being scared? Did their fear subside with repetition?

#### **15.2 Exposure to the natural environment**

The next type of exposure is exposure in the natural environment: exposure in places and situations that clients avoid or fear. For the assignment, therapists must arrange a hierarchy of these situations by rating the intensity of the fear of each situation. A driving hierarchy for Tina (with fear rates in parentheses) might look like this: (1) Sitting in the car, (2) one-mile drive with mother in the car, (3) driving to the local store with mother, (4) five miles driving on the highway with mother, (5) driving to the local store alone, and (6) five miles of highway driving alone [29].

Subsequent sessions are devoted to safety cues, which include specific people and objects that make a person feel safe from anxiety, loss of control, physical injury, or

*Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving… DOI: http://dx.doi.org/10.5772/intechopen.107482*

embarrassment. In Tina's case, her house, her parents, and her inhaler were all signs of safety. Clients were explained that the removal of safety cues would improve the learning effect of the exposure [29]. When faced with situations with safety cues, the client still believes that the situations are dangerous, but the danger is prevented by safety signs. Abandoning safety cues are combined with direct exposure hierarchies [29].

#### **16. Medication in the treatment of panic**

Medication is one of the most popular and effective treatment options for panic disorder, panic attacks, and agoraphobia. Doctors may prescribe medication to reduce the severity of panic attacks, reduce overall feelings of anxiety, and potentially treat co-morbid conditions such as depression. Panic disorder medications usually fall into one of two categories: antidepressants and antianxiety medications.

#### **17. Antidepressants for panic**

Antidepressants are now commonly used to treat many anxiety disorders, including panic disorder and agoraphobia. Antidepressants affect the brain's chemical messengers known as neurotransmitters. It is thought that different types of these chemical messengers communicate between brain cells.

#### **18. Types of antidepressants for panic disorder**

#### **18.1 Selective serotonin reuptake inhibitors**

Selective serotonin reuptake inhibitors (SSRIs) are a popular class of antidepressants prescribed to reduce symptoms of anxiety and depression. Serotonin is a natural neurotransmitter in the brain. Studies have shown the long-term effects of SSRIs. These drugs have also been found to cause limited side effects, making them the prescription drugs of choice for panic disorder.

#### **18.2 Tricyclic antidepressants**

Since the introduction of SSRIs, tricyclic antidepressants (TCAs) have become less popular in the treatment of anxiety and mood disorders. However, TCAs are still an effective treatment option for people with anxiety disorders, including panic disorders. Like SSRIs, TCAs work by blocking the reuptake of the chemical messenger serotonin. In addition, many TCAs inhibit the reuptake of norepinephrine, another neurotransmitter in the brain that is often associated with the fight-or-flight stress response.

#### **18.3 Monoamine oxidase inhibitors**

Monoamine oxidase inhibitors (MAOIs) are one of the first antidepressants developed to effectively treat mood and anxiety disorders. MAOIs work by inhibiting the activity of the enzyme monoamine oxidase. This enzyme is involved in

breaking down neurotransmitters, such as norepinephrine, serotonin, and dopamine. Dopamine helps to regulate many functions, including movement, physical energy levels, and feelings of motivation. Despite their effectiveness, MAOIs are used because of the dietary restrictions necessary and the potential for significant drug interactions that can occur when taking MAOIs with other medications.

#### **18.4 Antianxiety drugs for panic**

Antianxiety medications are prescribed to quickly relieve panic symptoms. These drugs work to calm the central nervous system, which can reduce the severity of panic attacks and make the person feel relaxed. Because of their sedative effect and quick relief, antianxiety drugs are often prescribed to treat panic disorder.

#### **18.5 Benzodiazepines**

Benzodiazepines are the most common class of antianxiety medications prescribed for panic disorder. Known for their sedative effect, these drugs can quickly reduce panic attack symptoms and induce a more relaxed state. By targeting gammaaminobutyric acid (GABA) receptors in the brain, benzodiazepines slow down the central nervous system and induce a sense of relaxation. Despite the potential risks and side effects of these drugs, benzodiazepines provide safe and effective treatment.

#### **18.6 Effective psychotherapies for panic disorder**

#### *18.6.1 Cognitive-behavioral therapy*

Cognitive-behavioral therapy (CBT) in patients with mental disorders was initially developed to provide additional treatments for residual symptoms based on the principles and strategies of intervention previously developed for anxiety and depression. About 1% of psychiatric patients with persistent positive and negative symptoms do not need medication, even if they are compatible with prescription medications. However, despite the introduction of unusual antipsychotics, patient compliance with the drug is still a major problem. Studies have shown that 4% of outpatient and inpatient patients have stopped their treatment [30].

CBT in mental disorders is currently recognized as an effective intervention for mental disorders in clinical guidelines. Despite available evidence that side effects are absent, public access to this treatment in the community remains limited and low [31]. CBT is a goal-based approach to solving the problem of mental illness, especially mental disorders, to change the patterns of thinking or behavior that are behind people's problems and change their feelings. CBT in mental disorders is a common type of speech therapy (psychotherapy). You talk to a psychologist or psychotherapist in a structured way and with a specific number of sessions. This will help you identify the wrong or negative thinking so you can see the challenging situations more clearly and respond more effectively. CBT can be a very useful tool in the treatment of mental disorders, such as schizophrenia, depression, posttraumatic stress disorder, or an eating disorder, but not everyone who benefits from CBT in schizophrenic patients may necessarily have complete mental health. This therapy can be an effective tool to help anyone learn how to manage stressful life situations [32].

#### **18.7 The benefits of CBT in mental disorders**

CBT in mental disorders patients can also be effective in treating some mental health problems, but may not be effective for everyone. Some of the benefits of CBT in mental disorders include [32]:


The stages of CBT in mental disorders [33] usually include the following:


#### *18.7.1 Treatment duration*

CBT in mental disorders is generally a short-term therapy requiring approximately two to four sessions. You and your therapist can talk about the number of sessions that are right for you. Factors affecting the number of treatment sessions are as follows:


In general, CBT in mental disorders is of low risk. As this treatment usually relieves the patient's painful feelings and experiences, in some cases the person may feel unwell. You may be upset, crying, angry, or maybe physically weak during a challenging meeting. Some types of cognitive-behavioral therapy in mental disorders, such as the exposure phase, may put you in a situation where you have always wanted to escape. For example, if you are afraid of flying, you may be asked to board a plane. This situation can lead to temporary stress or anxiety. However, working with a skilled expert minimizes any risks. The coping skills you learn can help you manage and overcome negative emotions and fears [33].

Studies have shown that the results of short-term CBT continue for a long time after treatment. The effectiveness of cognitive therapies has been proven for most anxiety disorders. All kinds of psychological treatments are suggested to effectively deal with this disorder and also to deal with the problems caused by medication, but what should be considered is the difference between these interventions in terms of ease of implementation and continuity of treatment results. The treatment of muscle relaxation plays an important role in the new treatments of anxiety disorders. In research, Conrad and Ruth showed the effectiveness of relaxation therapy for anxiety disorders (generalized anxiety disorder and panic disorder). CBT is one of the basic treatments for panic disorder. In a study by Salkovskis and Warwick [34], the effectiveness of CBT on panic disorder was investigated. The results of this study showed that this treatment is very effective and the rate of recurrence of attacks after the implementation of this treatment method is insignificant.

#### **18.8 Dialectal behavior therapy**

Dialectical behavioral therapy (DBT) is a form of cognitive-behavioral therapy (CBT) that consists of a set of different techniques and treatments. These two treatments are technically different. DBT uses different languages, in addition to acceptance and mindfulness techniques. DBT considers judgment beyond CBT and is a way for clients to think, but it is not intended to change the way they think. Instead, the DBT acknowledges that there is a problem with how clients think, but the therapist first encourages clients to accept it instead of judging it and then helps them to do what they want. They can change, and look to make their thinking more balanced [35].

Although DBT was primarily designed to treat BPD, research has shown that it is helpful for other disorders [36–39]. We now know that this type of treatment is helpful for people who have difficulty adjusting their emotions, even if the cause is not related to a mental disorder. Due to the success of DBT in helping people learn to manage their emotions more effectively, today this treatment is increasingly being pursued by mental health professionals. Given the number of people seeking this form of treatment to help with their problems, there are unfortunately very few therapists who have been prominently trained in DBT.

*Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving… DOI: http://dx.doi.org/10.5772/intechopen.107482*

#### **18.9 DBT patterns**

As mentioned earlier, the DBT model is made up of four components. Although DBT can be effectively presented to clients without these components, most research on BDT for BPD focuses on the whole pattern, which includes group skills training, individual therapy, telephone counseling, and counseling.

#### **18.10 Group treatment**

Group skills training is a structured and psychological group form of training designed to grow and increase clients' abilities. The group is formed once a week and is divided into four patterns: basic mindfulness skills, interpersonal effectiveness skills, emotion regulation skills, and distress tolerance skills.

#### *18.10.1 Mindfulness skills*

Linehan et al. [40] divided mindfulness skills into smaller sections to make it easier for clients to understand and integrate with their lives. The goal of mindfulness in treating disorders is to increase self-awareness. Increasing self-awareness helps clients become aware of their thoughts, motivations, and emotions and gradually learn to control them in more effective ways. Through mindfulness, clients also learn to tolerate thoughts, emotions, and motivations that they cannot tolerate and that they do not need to disclose their inner experiences, but can easily accept. Until these experiences gradually disappear.

#### *18.10.2 Interpersonal effectiveness skills*

The goal of these skills is to help clients reduce the interpersonal turmoil that often occurs in their lives and is basically about how to be more determined. Clients are taught to think about something that will allow them to make an acceptable interaction, and then they will learn techniques that will make them more likely to achieve this goal.

#### *18.10.3 Emotion regulation skills*

The goal of these skills is to reduce mood instability. Clients are taught general information about emotions, such as why we need them, and why we do not want to get rid of them even when they are completely painful. Clients learn the connection between their thoughts, feelings, and behaviors, and that changing one can affect the other. Self-validation through other techniques helps clients manage their emotions more effectively.

#### *18.10.4 Disturbance tolerance skills*

These skills are also known as "crisis survival" skills and aim to help clients without resorting to problematic behaviors, such as suicide attempts, self-harm, and substance abuse, to make something worse, to survive the crisis. These skills help clients stay calm and distract themselves from problems.

Group skills training as opposed to individual therapy for a variety of reasons: First, clients with problems with emotion regulation often go from one crisis to

another, and when clients seek help because of this crisis, techniques training in an individual meeting is very difficult. In addition, an important aspect of any group meeting is credibility, for example, clients gain the experience of being in a group where others have a similar problem. Another advantage of the group is that the learning experience can be richer, such as when each client learns to follow the experience of other members. Finally, because interpersonal issues often arise in a group, this can be a great way to practice the techniques learned, as well as allow clients to learn how the technique works, use them more effectively, and get guidance [41].

#### **18.11 Individual treatment**

Clients usually attend one-on-one sessions with a DBT therapist once a week. The purpose of individual sessions is to help clients apply the skills learned in the group to reduce harmful behaviors, such as suicide, self-harm, drug use, and more. Like group meetings, individual meetings have a very clear shape and structure that will be discussed in detail in the following sections.

#### **18.12 Telephone consultation**

Telephone counseling is done to guide clients to use their skills. Telephone counseling means a brief interaction to help clients identify which techniques may be more helpful in the situation they are facing. It helps them overcome the barriers to using these skills and act more effectively.

#### **18.13 Counseling team**

According to Linehan et al. [40], DBT is meaningless without a counseling team. The structure of the DBT counseling team will vary depending on the therapist's environment. The team usually includes all DBT therapists in the clinic, such as social workers, psychologists, psychiatrists, and anyone working in individual therapy and skills training groups with DBT clients. For therapists who work privately, this is a little more complicated. Because teamwork is important in pursuing practice, private therapists may want to create a team that includes other private DBT therapists in their environment or even online, provided they adhere to it in secret. It does not have to be a big team. Depending on your situation, the team is used in two ways: First, to provide support to therapists and help them continue to develop techniques for working with clients using the DBT model, and second, to discuss the case. During the case study, the team assists the therapist to ensure that DBT techniques and strategies are adhered to. The team also feels exhausted and ineffective. In counseling sessions, the team uses DBT techniques such as taking a dialectical and nonjudgmental stance to prevent team members from engaging in power struggles and other dynamics that can disrupt the team and the healing process.

#### **19. Effects of DBT on psychiatric disorders**

Much research has been done on the use of DBT to treat other disorders besides BPD. Due to the large volume of research, only a summary of them is provided here, which is given below:

*Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving… DOI: http://dx.doi.org/10.5772/intechopen.107482*


Many specialists today are using DBT to treat illnesses and problems unrelated to the axis of a mental disorder. For example, Evershed et al. [50] used DBT to treat anger in male court patients and found that DBT had more benefits than patients who received conventional treatment. Sakdalan, Shaw, and Collier [51] found that DBT reduced the risk of suicidal ideation in patients with mental disabilities, and Drossell et al. [52] found that DBT First-degree caregivers of dementia patients helped to increase their search for appropriate behaviors, improved their psychosocial adjustment, increased their ability to cope, improved their emotional well-being, and reduced caregiver fatigue.

#### **19.1 Stages of treatment**

Linehan et al. [40] proposed a set of steps by which clients progress toward recovery: The direction of commitment and commitment (before treatment), the achievement of basic capacities (step 1), the reduction of post-traumatic stress (step 2), and increasing self-esteem and achievable goals (Step 3). In the rest of this section, we will summarize all the steps of Linehan.

#### **19.2 Emotion regulation therapy**

Emotion regulation therapy (ERT) is a manualized treatment that integrates components of cognitive-behavioral therapy, acceptance and commitment therapy, dialectical behavior therapy, mindfulness-based stress reduction, and emotionfocused treatments using a mechanistic framework drawn from basic and translational findings [37].

The goals of ERT are as follows:


These skills are taught in the first half of the treatment and are then utilized by patients in an exposure/behavioral activation phase in the second half of the treatment.

#### **19.3 Mindfulness-based cognitive therapy**

Mindfulness-based cognitive therapy (MBCT) is a treatment protocol comprising meditation practices and cognitive behavior therapy skills. This treatment, which was formulated for unipolar depression, was later adapted for other psychiatric disorders [53].

Kabat-Zinn [54] argues that by adding mindfulness to the cognitive approach, it is easier to accept what has happened to the individual. The goal of mindfulness is to equip patients with ways to respond to life's stresses so that they can get rid of the psychological reactions that often exacerbate stress and interfere with effective problemsolving methods. Mindfulness therapy progressed rapidly to reduce stress. In this method, patients were taught to monitor their thoughts with a broader perspective and to have a decentralized relationship with their mental content. In the mindfulness method, what matters is how you feel free to understand that most thoughts are just thoughts and not objects or realities [55]. The simple act of recognizing thoughts as it can free the patient from the distorted reality often gives the patient more insight and a greater sense of control over life. Sometime later, the mindfulness model emerged based on the initial view of Kabat-Zinn [54] on treatment.

Mindfulness-based cognitive therapy is a new promise in explaining the cognitivebehavioral therapy approach. Mindfulness training requires metacognitive learning and new behavioral strategies to focus on attention, prevent mental ruminants, tend to worry, and expand new thoughts and reduce unpleasant emotions.

Mindfulness-based cognitive therapy (MBCT) is a combination of meditation, yoga, and cognitive therapy exercises developed by Segal et al. [53] to alleviate and treat human suffering, especially the emotional suffering of people. Expands to prepare for depression.

Mindfulness-based cognitive therapy is based on the Kabat-Zinn Mindfulness Stress Reduction Model, and the principles of cognitive therapy are added to it. This type of cognitive therapy includes various meditations, stretching yoga, basic training on depression, body review exercises, and several cognitive therapy exercises that show the relationship between mood, thoughts, feelings, and physical sensations. All

#### *Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving… DOI: http://dx.doi.org/10.5772/intechopen.107482*

of these exercises provide some sort of attention to physical and surrounding situations in the "present moment" and reduce automatic depressurization processes.

Mindfulness-based cognitive therapy is mind-based therapy and is one of the third-wave therapies [56]. In this style, the principles of cognitive therapy integrate with the mindset of mindfulness to improve emotional well-being and mental health.

#### **19.4 Mindfulness-based stress reduction**

According to the mindfulness-based stress reduction (MBSR) developed by John Kabat-Zinn, the main goal of the MBSR is to help people to improve their relationships with their thoughts, feelings, and physical feelings [57].

The MBSR was first practiced at the University of Massachusetts by John Kabat Zinn. In his stress-relieving clinic, participants were taught to practice mental relaxation with mindfulness. These efforts led to the formation of a mindfulness model based on stress reduction.

Currently, the most common method of mindfulness is MBSR, formerly known as the stress reduction program as well as relaxation. This method was designed in the structure of behavioral medicine and for a wide range of people with stress-related disorders and chronic pain. The program runs as an 8–10-week program for groups of more than 30 participants. In addition, meetings are held weekly and each session lasts about 2 h. Meeting instructions include practicing meditation skills, discussing stress, coping techniques, and homework.

Body examination, for example, is an exercise in which participants lie on the floor with their eyes closed for about 45 min, focusing their attention on different parts of their body, and carefully observing the emotions associated with each area of their body [58].

How mindfulness can act so markedly on resilience is still being studied, but it is now evident that the practice of mindfulness, if well learned, trains certain critical skills and changes the neurophysiology of the brain.

Furthermore, the MBSR is a practice-based, interactive learning program. Research shows the MBSR to be an effective complement to a wide variety of medical and psychological conditions. These include anxiety, asthma, cancer, chronic pain, depression, diabetes, fibromyalgia, gastrointestinal disorders, heart disease, hypertension, mood disorders, sleep disturbances, and stress disorders.

Mindfulness is the practice of *present-moment awareness.* It promotes personal well-being and enables us to experience life more fully by developing the ability to return with kindness to the present moment rather than being lost in repetitive thoughts and worries about the past or the future. In this way, we can make wise choices, rather than react unconsciously.

Becoming more aware of our thoughts, feelings, and sensations, in a way that suspends judgment and self-criticism, can have surprising results. Many people report finding inner strengths and resources that help them make wiser decisions about their health and life in general.

Most of us find ourselves "swept away" at times by a current of thoughts, feelings, worries, pressures, and responsibilities. We want things to be different from how they are right now. Feeling stuck in this way can be draining. Mindfulness can help us work directly with the struggle we sometimes have in relating to life's experiences. In doing so, we can greatly improve the quality of our life.

The MBSR is now taught in every state in the U.S. and in more than 30 countries. MBSR classes include instruction in mindfulness meditation, mindful movement, and other mindfulness practices, all guided by a skilled tutor.

For the program to be effective, your commitment to 45 minu of daily practice and active participation in all classes as well as the daylong retreat is important. The 8-week course meets for 2.5 h weekly. The all-day silent retreat provides an opportunity for participants to experience more deeply the mindfulness techniques learned in class.

Mindfulness means paying attention on purpose, nonjudgmentally, to what is happening in the present moment, both internally (physical sensations, thoughts, and emotions) and externally (sounds, sights, and smells). Mindfulness enables us to be in the present moment and aware of our experiences. This allows us to make more purposeful and wise choices, instead of reacting automatically (often with adverse consequences) to things we cannot control. Mindfulness also involves an intention to reduce or relieve suffering through the cultivation of kindness and compassion for oneself and others [59].

MBSR is appropriate for people with a wide variety of conditions, needs, and goals, including:


MBSR provides systematic training in both formal and informal ways to bring mindfulness into daily life. Formal practices, taught in class, include:


Participants will also learn about the physiology of stress and how to use mindfulness skills in diverse contexts, including relationships, work, daily self-care, and managing physical symptoms. A central feature of this course is that participants are asked to engage in 45 minu of daily home practice, using recordings available on the web, as well as informal practice assignments, bringing mindfulness to daily activities they are already doing.

#### **19.5 Acceptance and commitment therapy**

Acceptance and commitment therapy (ACT) was established by Hayes et al. [60]. This method is part of the third wave of behavioral therapies and followed by the second wave of these therapies such as cognitive-behavioral therapy. The ACT is affiliated with a research program called Communication System Theory. This approach accepts the change of thoughts and feelings instead of their transformation, content, or abundance [61]. This treatment is one of the most recently developed models whose key therapeutic processes are different from cognitivebehavioral therapy.

Its underlying principles include:


The ACT is a model derived from the third wave of therapeutic behavior. The main goal of this model is to perform an effective action, an action that is conscious with full presence of mind and is value-oriented [61]. This model differs from traditional cognitive-behavioral therapy, which seeks to teach people almost how to control thoughts, feelings, memories, and other events, so it helps therapists with a sublime sense of self (spectator self). In general, in the third wave of therapeutic therapy, the main emphasis is on awareness of emotions and thoughts. In the ACT, the goal of the therapist is to increase psychological flexibility in clients. Accordingly, psychological flexibility means being able to go back to the present moment, be aware of and observe one's thoughts and emotions, distance oneself from rigid beliefs, and do what is important, despite unpleasant events [63].

The ACT derives its name from its two main messages: acceptance of what is beyond your control and commitment to an action that improves your living conditions and purpose. It is to maximize man's potential for a rich, fulfilling, and meaningful life. This is based on three main methods, which are as follows:

• Be present.

Consider yourself here and now, so you can react to life instantly and effectively.

• Welcome.

You will learn to change your relationship with these painful experiences, without drowning in them and instead of trying in vain to control them.

• Commit to important activities.

Identify what matters to you (we do not value it) and then use that knowledge to guide, inspire, and motivate you to change and improve your life [64].

Acceptance and occupational therapy also look at people in a health-oriented manner, so they are opposed to clinical diagnoses and base their work on a case-bycase *formulation*. In other words, the ACT refers to the two hexagons of psychological flexibility and nonpsychological flexibility. According to this model, those attending counseling or psychotherapy sessions are trapped in a hexagonal psychological inflexibility hexagon and suffer from an unreasonable conflict. Instead of communicating with the present, these people become captivated by mental rumination (past) and anxiety (future). In this case, the person experiences an avoidance (doing something to get rid of painful internal experiences that reduce a person's quality of life), intermingling (clinging to thoughts, judgments, or emotions), self-conceptualized attachment (effect verbal meaning that a person has created for himself or others), persistent inactivity (performing impulsive or passive behaviors or insisting on avoiding an experience that does not lead to a step in the direction of one's values), and not specifying values (lack of awareness of central values self or noncontact with them). Therefore, the main goal of the ACT is to live rich and valuable. The six aspects of psychological flexibility included: (1) contact with the present moment, (2) acceptance, (3) fault, (4) communication, (5) the definition of values, and (6) the committed action [65].

#### **19.6 Metacognitive therapy**

In the field of newer psychological treatments, metacognitive therapy was first introduced by Adrienne Wells. The term metacognition refers to cognitive processes that play a role in controlling different aspects of cognition. Although, based on many kinds of research, it can be concluded that psychological treatments have longer-term therapeutic effects than drug therapy alone on patients suffering from phobias, more efficient, shorter, and more accessible types of psychological treatments should be used as well. Metacognitive therapy was invented to improve the results of cognitive therapies. The effectiveness of behavioral-metacognitive therapy on mental disorders has also been confirmed. Wells and King [66] have proven the effectiveness of this treatment on generalized anxiety disorder, obsessive–compulsive disorder, and post-traumatic stress disorder, respectively. Studies show that anxiety disorders, including generalized anxiety disorder, respond to cognitivebehavioral therapy, but Wells, as the main creator of metacognitive therapies, believes that anxiety disorders, including generalized anxiety disorder, respond only to a certain extent to cognitive-behavioral therapy. What is emphasized in metacognitive therapy are factors that control thinking and change the state of mind, not challenges with thoughts and cognitive errors or long-term and repeated exposure to beliefs about trauma or physical symptoms [33].

#### **20. Conclusion**

This chapter outlined the most effective evidence-based psychotherapies for panic disorder, namely medication, cognitive behavior therapy, dialectical behavior therapy, mindfulness-based cognitive therapy, mindfulness-based stress reduction, acceptance and commitment therapy, and metacognitive therapy. Evidence suggests that medication may have an effect on the reduction of physical sensations associated with anxiety. However, cognitive behavior therapy is the common psychotherapy that addresses dysfunctional thinking and behavior in order to alleviate psychological *Psychotherapy of Panic Disorder: Revisiting Past and Present Research and Moving… DOI: http://dx.doi.org/10.5772/intechopen.107482*

problems in panic. The main technique in psychotherapy of panic disorder is exposure, which is significantly effective in treating panic. Other psychotherapies are not effective than cognitive behavior therapy and exposure.

### **Author details**

Behrooz Afshari Department of Clinical Psychology, Kashan University of Medical Sciences and Health Services, Kashan, Iran

\*Address all correspondence to: behrooz.afshari71@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 6**

## The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children, Adolescents and Early Adulthoods: A Meta-Analysis

*Lin Wang and Yihao Liu*

#### **Abstract**

Physical activity is believed to promote mental health. However, research has not yet reached a consensus on whether physical activity declines panic and anxiety symptoms in children, adolescents, and early adulthoods. The current chapter carried out a meta-analysis to investigate the association between physical activity and panic/anxiety based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Search is conducted on 22nd April 2022, which follow databases: MEDLINE (Ovid), EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and SPORTDiscus. Fifteen articles (N = 994) were identified and included, where four studies reported measurement in panic symptoms and fourteen studies reported measurement in anxiety symptoms. The meta-analysis among the pooled effect sizes demonstrated a small significant effect of physical activity intervention reducing panic disorder (d = −. 45, SE = .12, Z = −3.65, p < .001) and a middle effect reducing anxiety (d = −.51, SE = .15, Z = −3.38, p < .001) in children, adolescents and early adulthoods. Age or gender ratio was not found to be significant in predicting the effect sizes. More evidence is required to produce a solid conclusion.

**Keywords:** panic disorder, anxiety disorder, physical activity intervention, children and adolescents, systematic review

#### **1. Introduction**

Physical activity (PA) is one of the most accessible interventions for anxiety disorders for the public, whereas few systematic research has been done to examine its efficacy. PA is defined as a movement that causes an increase in energy expenditure in the movement of people [1], including walking, running, doing housework, jogging, or other sports that are defined as PA behaviour [2, 3]. Dollman et al. (2015) have classified PA intensity with metabolic equivalent (MET) as light PA (MET: 0–2.99),

moderate-to-vigorous PA (MET:3–5.99), and vigorous PA (MET: ≥6) through a scale of energy expenditure [4–6]. PA intervention aims to promote the health of people through exercise training, sports and habit of PA [7, 8]. A PA intervention study should specify the processing target (e.g., children, adolescents, or some clinic population), PA type (e.g., aerobic exercise, resistance exercise, or yoga), PA intensity (e.g., light, moderator, moderator-to-vigorous), PA frequency (e.g., three sessions per week, 60 minutes per session), PA duration (e.g., three months, 1 years), and outcome measurement [9]. The PA intervention research is easier to quantify and more accessible to the generalised population. It is also found to benefit mental health. Therefore, research is also focused on the effect of PA intervention on panic disorder.

For example, Ensari, Petruzzello [10] conducted an RCT experiment to deliver a 40-minute yoga programme for eighteen participants with high-anxious. The result suggested a significant main effect of the task on panic and respiratory measures (p < .05). When collapsed over inhibition task and condition, there was a small reduction in cognitive anxiety from baseline to immediately post and 1-h post-condition (p < .05) [10]. Similarly, Naderi, Naderi [11] investigated the effect of physical exercise on anxiety among victims of child abuse and reported a significant reduction in anxiety (p < .001). Accordingly, the author argued that such improvement is comparable to empirically supported treatments for panic and GAD. However, such effects of PA intervention on panic disorder used a variety of PA types, intensity levels, or frequency and, therefore, produced isolated effects. The effect of PA could vary regarding individual differences, such as age and gender [12]. A most recent systematic review in 2022 tended to examine the effect of regular exercise interventions on the panic disorder in adults. They only retrieved eight studies in this field and demonstrated no clear evidence suggesting whether regular exercise programs (at least two 20-minute sessions per week for at least six weeks) reduce panic-related symptoms. The study argued for more RCT studies to support more robust and clear evidence for better understanding [11].

Moreover, there were even fewer studies focused on the effect of PA intervention on the panic disorder or general anxiety disorder (GAD) in children and adolescents, respectively. This may be because it is difficult to categorise different anxiety disorders among children. Furthermore, there is a lack of tools to measure child panic in laboratory settings. For example, there is the anxiety scale for children with autism spectrum disorder, revised children's manifest anxiety scale and social anxiety scale for children to measure anxiety disorder in children and adolescents [9, 13, 14], whereas the panic disorder is measured based on the sensitivity of anxiety scales in children and adolescents [15]. These unclear concepts may increase the research difficulty, which supports the evidence for PA intervention on panic disorder in children and adolescents. Therefore, this chapter aims to carry out a quantitative review to clarify and explore the evidence in this area. Moreover, the secondary objective is to investigate the effect of PA intervention on anxiety disorder in children and adolescents.

The previous Machado, Telles [11] review obtained a similar outcome measurement to examine the effect of PA on anxiety disorder. Their target sample did not limit the population age, which means there is no evidence that physical activities affect panic and anxiety disorder in children and adolescents. Consequently, the current analysis aims 1) to summarise and explain the potential impact of PA interventions on panic symptoms and critically comment on the research that exists and 2) to analyse the effect of PA intervention on panic and anxiety symptoms in children, adolescents and early adulthood, through meta-analysis, which provides reference evidence for further research.

*The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*

#### **2. Method**

#### **2.1 Materials and methods protocol and registration**

The study is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A protocol for this review was registered with PROSPERO (CRD42022334054).

#### **2.2 Search strategy and databases**

Search is conducted on 22nd April 2022, which follow databases: MEDLINE (Ovid), EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and SPORTDiscus. Search terms based on the PICO format (participants/population, intervention/exposure, comparison, outcome) were divided, and adjusted according to the respective databases' Thesaurus and Medical Subject Headings (MeSH) terms (Bramer et al., 2018) through Ovid. Articles must be available in English, there will be no restriction on the publication period. The full list of search terms is provided in Supplementary Material 1.

#### **2.3 Eligibility criteria**

The inclusion criteria of the current analysis were: 1) Population: studies included participants who primarily exhibited panic or anxiety symptoms or were diagnosed with panic or anxiety disorders in children, adolescents (5–19 years) and early adulthoods (19– 22 years). Participants may present secondary comorbid other illnesses, such as diabetes; 2) Intervention: studies applied regular PA intervention (i.e. walk, jog, aerobic, strength, or multimodal training), which is prescribed to reduce panic disorder or GAD, social anxiety disorder, obsessive–compulsive disorder, post-traumatic stress disorder, and agoraphobia. PA interventions can be combined with other treatment procedures were also included; 3) Comparators: studies included a control group as a comparator, which is not received the PA intervention delivery; 4) Outcomes: studies that took panic symptoms or panic disorder as the primary outcome. And the second outcome was anxiety symptoms, GAD, social anxiety disorder, obsessive–compulsive disorder, post-traumatic stress disorder, or agoraphobia; 5) Study Design: studies carried out in randomised trials (RCT) comparing an intervention(s) encompassing PA with a group(s) without PA intervention or encompassing PA at the baseline with post PA intervention.

The exclusion criteria were: 1) studies reported in non-English language; 2) studies reported insufficient information to estimate effect size or other essential data.

#### **2.4 Article selection and data extraction**

Study selection: Data will be formatted in RIS format and will be managed using the endnote software. PRISMA 2020 guidelines will be applied for reporting the screening process [16]. Two researchers will undertake the removal process through an independent screen. Firstly, all duplicate articles will be removed before reviewing titles and abstracts. Those not fitting the inclusion criteria will be removed. Then, full-text versions will be collected when the articles meet the screening criteria. Discussions with a third reviewer will resolve discrepancies between the two independent reviewers.

Data extraction: Two independent reviewers will extract the following four data dimensions. Including fundamental characteristics (e.g., author, public year, country, population, sample, age, sex, weight status), intervention characteristics (e.g., PA intensity/frequency/duration, intervention program), methodology (e.g., data analysis method), and effect size.

#### **2.5 Risk-of-bias (quality) assessment**

Two reviewers will independently score the studies according to the National Institutes of Health study quality assessment tool for Quality Assessment of Controlled Intervention Studies from the National Heart, Lung, and Blood Institute (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools). The quality assessment focused on the specification of eligibility criteria, generalisability, intervention description, outcome assessment and incomplete data [17]. There were 14 items assessed in the quality assessment, as shown in Appendix S1. The tool does not assign numeric values or definite judgements of the quality of the studies, although it has good, fair, and poor results. Good quality studies have less bias risk and are more valid. A fair study is prone to some bias but insufficient to invalidate its findings. A poor study has a high-risk of bias and is considered invalid [18]. The results of quality assessment are presented in **Table 1**.

#### **2.6 Effect size estimation**

The studies we aimed to include in the current analysis were RCTs with both between-subject, within-subject and mixed designs. Consequently, a combined effect size of standard mean difference (Cohen's d) was calculated for each study to produce a pooled effect size based on the improved method provided in Morris [19]. Firstly, the effect size of studies reported only median and interquartile range was estimated based on the improved formula [20, 21], where d refers to Cohen's d; q1 refers to the first quartile; q3 refers to the third quartile:

$$\mathbf{d} = \frac{\mathbf{q}\_{3-} \mathbf{q}\_{1}}{1.35}$$

Moreover, studies reported pre-calculated Cohen's d without providing the mean or standard deviation was estimated standard error using the 95% confidence interval for meta-analysis weighting [22], where SE refers to standard error, CLup and CLlow refer to the upper and the lower bound of the confidence interval, respectively:

$$\text{SE} = \frac{\text{CL}\_{up-}\text{CL}\_{low}}{3.92}$$

The effect sizes were from between-subject design, within-subject design and mixed design studies were extracted, converted and matched to Cohen's d with an online converter tool 'Psychometrica' (https://www.psychometrica.de/effect\_size. html), which follows the method proposed in Morris [19] and Lakens [23].

#### **2.7 Statistical data analysis**

The statistical analysis was carried out in STATA v.17. The estimated effect sizes of adolescent panic and anxiety were pooled in a quantitative meta-analysis in a random *The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*


**Table 1.**

*Summary of quality of included studies.*

effect model and Cohen's d to determine the overall effect among the studies. A significant result of this analysis indicates that there was a significant effect of physical activities/exercise on adolescent panic or anxiety across the studies. The effect size is considered small when SMD is between 0.2 and 0.5, medium when it is between 0.5 and 0.8, and large when it is above 0.8 [24].

Then, a heterogeneity test of the available data was carried out with the random effect model. A non-significant result in the heterogeneity test would mean that the effect sizes were homogenous and measured a consistent effect on the same side. The heterogeneity I 2 is considered moderate when I2 > 50%, and it is considered high when I2 > 75% [21]. Egger's regression-based tests were then used to assess the publication bias. A significant result in this test would suggest potential publication bias in the current analysis.

Finally, exploratory meta-regression analyses were performed on the available characteristic data, including age, gender and intervention duration, to determine potential predictors of the current effect. The research method would be entered into subgroup analysis to determine whether the study design made a difference in the overall effect.

#### **3. Results**

#### **3.1 Data acquisition**

As shown in Appendix 2, keywords searching in MEDLINE (Ovid), EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and SportDiscus resulted in 1691 articles. After reviewing, based on inclusion criteria, twelve studies were identified, and four studies were excluded based on exclusion criteria, leaving eight studies for the meta-analysis. The included 11 studies were all RCTs in different designs (within-subject, between-subject and mixed design).

#### **3.2 Characteristics of included literature**

As shown in **Table 2**, 15 RCT studies with sufficient data were included. Among these studies, 14 obtained anxiety measurements, including social anxiety disorder [14, 25, 26] and GAD [10, 13, 27–32], and 4 studies obtained panic measurements [10, 31–33]. There were 994 participants included in total, and 478 and 354 participants were allocated in the intervention and control groups, respectively. The mean age of the participants was 13.21 ± 4.16 years old, ranging from 8 to 24 years old. Physical activity intervention duration was from a minimum of 2 weeks to 8 months, and frequency was 2 or 3 sessions per week, with two studies performing a onesession intervention [10, 34]. Two studies also provided discussion and reflection sessions after the physical activity sessions [34, 35] and two studies were conducted on the school campus [14, 28].

IG = intervention group; CG = control group; Pre-I: pre-intervention; Post-I: post-intervention; s/w = sessions per week; NR = not reported; NA = not applicable; ASC-ASD: Anxiety Scale for Children–Autism Spectrum Disorder RCMAS = Revised Children's Manifest Anxiety Scale; SAQ-C24 = Social Anxiety Scale for Children; SAS-A = Social Anxiety Scale for Adolescents; STAI = State–Trait Anxiety Inventory; SAI = State Anxiety Inventory; SPAS = Social Physique Anxiety Scale; RCADS = Anxiety and Depression Scale in Children-Revised; API = Acute Panic Inventory; ASI-R = Anxiety Sensitivity Index-Revised. The sports type are labelled in bold.


*The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*


*The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*




**Table 2.**

*Characteristics of included studies.*

*The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*

NA: not applicable, NR: not reported, CD: cannot determine, overall of Good: more than 10Y (NA = Y), Fair 8 to 10Y, Poor: Below 8.

#### **3.3 Risk-of-bias (quality) assessment**

Overall, three reports showed good quality, whereas most studies were fair. We can find that in terms of random methods, most of the studies do not report the process of random sampling and there are basically no studies that apply computer random sampling methods. In addition, the information reported on the sample power is relatively lacking.

#### **3.4 Effect of PA intervention on panic**

*Main effect.* As shown in **Figure 1**, the pooled effect size revealed a significant overall effect of physical activity on panic symptoms from four studies (Random effects; *d* = −. 45, SE = .12, Z = −3.65, *p* < .001). Estimation of the homogeneity suggested that the chance of inconsistent distribution of the effect sizes was not significant, Q(3) = 1.36, *p* = .715. Sensitivity analysis revealed small-to-no heterogeneity across the effect sizes of the studies, I2 = 0.00%. These results mean that the effect sizes across four studies suggested a significant small effect of physical activity in reducing panic symptoms among children, adolescents and early adulthood compared to the controls.

*Publication bias.* As shown in **Figure 2**, Egger's regression-based tests suggested no estimated publication bias, β = .57, SE = .1,06 t = .54, *p* = .644. One study with small sample size (N = 24) reported high standard error [32].

*Exploratory meta-regression.* Age and gender ratios were entered into meta-regression analysis to determine potential predictors for the combined effect sizes. As summarised in **Table 3**, meta-regression analysis suggested no significant predictor for the combined effect sizes of current studies, R2 = .00, Qw(2) = 1.35, *p* = .508. This means that age or gender ratios were not significant predictors of the current pooled effect sizes.

#### **3.5 Effect of PA intervention on anxiety**

*Main effect.* As shown in **Figure 3**, the pooled effect size revealed a significant overall effect of physical activity on anxiety from 14 studies (Random effects;


#### **Figure 1.**

*The forest plot of the effect size of physical activity on panic in children, adolescents and early adulthood.*

*The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*

#### **Figure 2.**

*Funnel plot of the effect size estimates of physical activity on the panic symptoms in children and adolescents.*


#### **Table 3.**

*Meta-regression analysis on age and gender predicting pooled effect sizes of PA intervention reducing panic disorder.*

*d* = −.51, SE = .15, Z = −3.38, *p* < .001). Estimation of the homogeneity suggested that the chance of inconsistent distribution of the effect sizes was not significant, Q(13) = 20.83, *p* = .076. Sensitivity analysis revealed moderate-to-small heterogeneity across the effect sizes of the studies, I2 = 47.52%. These results mean that the effect sizes across 14 studies suggested a significant medium effect of physical activity in reducing anxiety among children and adolescents compared to the controls.

*Publication bias.* As shown in **Figure 4**, Egger's regression-based tests suggested no estimated publication bias, β = −.58, SE = .63, t = −.92, *p* = .377. One study was outside of the funnel [10], of which the recorded main effect was a three-way interaction (pre vs. post & PA vs. Control & inhalation task 1 vs. task 2 vs. task 3). Such a small sample size (N = 18) and physiological measurement design (inhalation task) reported a greater effect size and small standard error comparing to other self-report questionnaires. It only counted 8.34% of the weight, which was not considered producing bias to the overall result. And another study reported high standard error because the sample size was very small (N = 23) [30].

*Exploratory meta-regression and subgroup analysis.* Age and gender ratios were entered into meta-regression analysis to determine potential predictors for the


#### **Figure 3.**

*The forest plot of the effect size of physical activity on anxiety disorder in children and adolescents.*

#### **Figure 4.**

*Funnel plot of the effect size estimates of physical activity on anxiety disorder in children and adolescents.*

*The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*

combined effect sizes. Meta-regression analysis suggested no significant predictor for the combined effect sizes of current studies, R2 = .00, Qw(2) = .29, *p* = .865. This means that age or gender ratios were not significant predictors of the current pooled effect sizes.

The research method (mixed-design vs. between-subject & within-subject design) was entered into subgroup analysis to determine whether the main effect changed between the two interactive groups. No significant group difference in homogeneity was identified in either research method, Qb(1) = 1.26, *p* = .26.

#### **4. Discussion**

The current chapter carried out a meta-analysis on 15 reports to investigate the pooled effect sizes of PA intervention on panic and anxiety symptoms among children, adolescents and early adulthood. Compared to the controls, we reported a small effect of PA on reducing panic symptoms and a middle effect on reducing anxiety symptoms. To our knowledge, this is the first study to summarise the effect of PA on panic and anxiety symptoms in children, adolescents and early adulthood with meta-analysis.

The primary finding of the current meta-analysis is that the pooled effect sizes from 4 reports yielded a significant small effect (*d* = −.45) of PA intervention in reducing panic symptoms. This means PA obtains such potential to be used in therapeutic intervention for panic in children, adolescents and early adulthoods. The mechanism of PA affecting panic symptoms was suggested to be related to the metabolism of CO2 and lactate. Accordingly, CO2 and lactate hydrolysed into HCO3- were found to moderate the blood pH level and influence brain acidosis [35]. Specifically, such change in pH level and brain acidosis is related to the activation of the amygdala and, furthermore, regulates the reaction of fear [36, 37]. Here, we would not discuss the biochemical pathology further but highlight the importance of CO2 and lactate. Empirical evidence suggested that patients with panic disorder were found to have chronically low end-tidal CO2 [38] and, vice versa, CO2 inhalation reduces panic symptoms [39]. Similarly, early literature reported an increased lactate level among panic patients [40, 41]. As a result, regulating the brain acidosis condition is believed to attenuate panic symptoms. Apart from direct CO2 inhalation, appropriate physical activity also regulates CO2 inhalation and lactate levels, eventually balancing the blood pH and brain acidosis, which is potentially the mechanism of how PA intervention works.

However, it is very important to bear in mind that this result is very primal and exploratory because it was summarised from four reports with limited sample sizes, of which one study targeted children (N = 28) [33], two studies targeted adolescents (N = 92; N = 24, respectively) [31, 32] and one study targeted early adulthoods (N = 18; age mean = 22.1) [10]. There is, to date, indeed a shortage of evidence in this field. A most recent 2022 systematic review only identified eight studies testing PA intervention's effect on panic disorder among adults [11] and argued for more evidence. On the one hand, it is difficult to recruit children with panic symptoms or diagnosed with panic disorder and deliver interventions for them. Unlike general anxiety symptoms, panic disorder is often clinically diagnosed and needs to be treated with extra caution. On the other hand, the tool to measure panic symptoms are limited among children. The experiments included in the current analysis used measurements, including API, RCAD and ASI-R [10, 31–33]. Among these scales, RCAD and

ASI-R are developed for anxiety and only address panic symptoms in their subscales, which were not specifically developed for panic disorder. API was developed for panic symptoms but not aimed at children. It is important to evaluate the assessment tool because the panic among children and adolescents could differ between ages [42]. In comparison, another scale developed after 2014 to measure panic symptoms, namely the Panic Disorder Severity Scale for Children, adapted for adolescents from 11 to 17 years old [43], and used in some studies testing the effect of CBT on panic disorder. Future studies could consider testing the effect of PA on children's panic with suitable assessments.

The secondary finding of the current analysis is that PA intervention had a middle effect (*d* = −.51) in reducing anxiety among children and adolescents. The mechanism of PA reducing anxiety symptoms could be similar to panic symptoms, as mentioned earlier. However, it is noticeable that only four isolated effects were found significant among the included reports in which Kenis-Coskun, Aksoy [33] applied repeated rehabilitation exercises, Nazari, Shabani [13] applied continuous aerobic & resistance exercise intervention, Mücke, Ludyga [34] applied only one session of aerobic exercise at moderate intensity on the bicycle ergometer., and Ensari, Petruzzello [10] applied one Yoga session. A possible reason is that most of these experiments were conducted using a mixed design, with comparisons between experiment and control groups and within the experiment groups. Studies may have reported isolated pronounced effects between the experiment and control group or within the experiment groups, whereas the interaction was not significant [28] or not reported [9, 13, 25, 26, 29, 30]. Only one study reported no effect at all [27]. The data extracted from these studies reflected more combined effects than isolated between-group or within-group effects [19]. Subgroup analysis was also carried out to determine the potential difference between mixed-design and non-mixed design studies (only between-subject or within-subject designs), and no difference was identified between the effect sizes. Consequently, this result should be considered to reflect the actual effects of PA intervention on reducing anxiety.

Knowing that PA intervention reduces panic and anxiety symptoms across the empirical evidence, the next question is what type of exercise produces an optimal effect. The current meta-analysis could not perform the proper subgroup analysis to determine the best PA type due to insufficient data inclusion. Among the 15 studies, three studies applied resistance training, including push up [33], weight-lifting [13] and treadmill exercises [31], whereas others applied aerobic exercise in groups or individually. Among which, the push up and weight-lifting seems to produced the large and significant effect sizes reducing anxiety symptoms (d = −1.72, p < .001; d = −1.07, p = .002, respectively) [13, 33]. The effect of resistance training seemed somewhat contradictive to the mechanism in which the high lactate level could induce panic and anxiety symptoms when such anaerobic exercise produces lactate. There are two possible reasons to explain this. One possible reason is that only lactate in the brain induces the change in brain acidosis that leads to panic and anxiety symptoms [44], whereas muscle lactate produced by anaerobic exercise is independent of that in the brain [45]. It is the blood lactate which influences brain acidosis. The second reason is that the participants were measured almost immediately after the PA intervention cooled down, where the blood lactate level remained still. Hiscock, Dawson [46] tested 4 different types of weight-lifting technic to investigate the difference in muscle activation and blood lactate. The blood lactate was measured immediately after the exercise and no change in blood lactate was detected with a significant difference in muscle

#### *The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*

activation. Consequently, blood lactate was not influenced by different exercise intensities if measured immdiately after the intervention. Hypothetically, it is the regulation of CO2 during PA that potentially attenuates panic and anxiety symptoms. Future studies could compare, first, the effect of breathing practice from CBT and PA intervention with controlled blood lactate levels. Second, future studies could investigate the long-term effect of resistance training on blood lactate and panic & anxiety symptoms.

The last point to make is that the current meta-regression analysis did not suggest evidence of whether individual differences predicted the pooled effect sizes. Although it was argued in other literature that gender or age could moderate the effect of PA [12]. Previous literature reported gender differences in PA index as age grows [47], and more mature adolescents have more autonomy in PA than children [48], such that they can initiate behaviours that enhance the positive effects of PA on anxiety. As a result, the benefits of PA on depression and anxiety may increase with age. However, the current meta-regression analysis failed to demonstrate such effects on gender or age. One possible reason is that there were only 15 experiments identified in this study, which obtained limited power to detect any individual difference. Thirteen studies reported their gender ratio, and 12 reported the distribution of age. More studies are required to investigate individual differences' role in the effect of PA intervention on anxiety and panic symptoms.

This meta-analysis has several limitations. Firstly, we used Cohen's d rather than Hedges' g to estimate the SMD, which the results might be biased in small sample studies. The reason to pick Cohen's d was that some studies already reported precalculated Cohen's d and did not provide sufficient information (N, mean, SD) to carry out transformation or bias correction. With limited numbers of the study identified, it would be impossible to exclude them from the analysis, and this could only be solved by including more studies with sufficient data. Secondly, the current study did not control the comorbidity among children and adolescents, which could affect the outcome of physical activities on panic and anxiety symptoms. As a result, the current results were very primal and exploratory, which should be considered cautiously.

#### **Conclusions**

The current meta-analysis reported a small effect of PA intervention on reducing panic symptoms and a middle effect on reducing anxiety symptoms in children, adolescents and early adulthood. Meta-regression analysis did not support age or gender predictors of the pooled effect size. More studies in this field are required to produce a more solid conclusion.

#### **Acknowledgements**

We thank all of the staff who contributed their time to our research.

#### **Funding**

China Scholarship Council and University of Exeter PhD Scholarship.

### **Appendices and nomenclature**

Appendix 1 Search strategy of systematic review.

Appendix 2 Flow chart of studies retrieved and screened according to the PRISMA.

Appendix 3 Characteristics of included studies.docx. Appendix 4 Summary of quality of included studies. Appendix 5 Meta-analysis of raw data.

### **Author details**

Lin Wang1,2\* † and Yihao Liu3†

1 Sports Department, Guilin University of Electronic Technology, China

2 Sport and Health Science Department, University of Exeter, UK

3 Psychology Department, University of Exeter, UK

\*Address all correspondence to: lw679@exeter.ac.uk

† Both authors contributed equally to the chapter.

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*The Effect of Physical Activity Intervention on Panic and Anxiety Symptoms in Children… DOI: http://dx.doi.org/10.5772/intechopen.106049*

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[34] Mücke M et al. The influence of an acute exercise bout on adolescents' stress reactivity, interference control, and brain oxygenation under stress. Frontiers in Psychology. 2020;**11**:3091

[35] Wemmie JA. Neurobiology of panic and pH chemosensation in the brain. Dialogues in Clinical Neuroscience. 2022;**13**:475-483

[36] Coryell MW et al. Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit. Biological Psychiatry. 2007;**62**(10):1140-1148

[37] Wemmie JA et al. Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning. Journal of Neuroscience. 2003;**23**(13):5496-5502

[38] Papp LA et al. Respiratory psychophysiology of panic disorder: Three respiratory challenges in 98 subjects. American Journal of Psychiatry. 1997;**154**(11):1557-1565

[39] Griez E, van Den Hout MA. CO2 inhalation in the treatment of panic attacks. Behaviour Research and Therapy. 1986;**24**(2):145-150

[40] Stewart PA. Independent and dependent variables of acid-base control. Respiration Physiology. 1978;**33**(1):9-26

[41] Maddock RJ et al. Elevated brain lactate responses to neural activation in panic disorder: A dynamic

1H-MRS study. Molecular Psychiatry. 2009;**14**(5):537-545

[42] Sheikh JI et al. Aging and panic disorder: Phenomenology, comorbidity, and risk factors. The American Journal of Geriatric Psychiatry. 2004;**12**(1):102-109

[43] Elkins RM, Pincus DB, Comer JS. A psychometric evaluation of the panic disorder severity scale for children and adolescents. Psychological Assessment. 2014;**26**(2):609

[44] Riske L et al. Lactate in the brain: An update on its relevance to brain energy, neurons, glia and panic disorder. Therapeutic advances in psychopharmacology. 2017;**7**(2):85-89

[45] Martinsen EW et al. Tolerance to intensive exercise and high levels of lactate in panic disorder. Journal of Anxiety Disorders. 1998;**12**(4):333-342

[46] Hiscock DJ et al. Muscle activation, blood lactate, and perceived exertion responses to changing resistance training programming variables. European Journal of Sport Science. 2016;**16**(5):536-544

[47] Teixeira e Seabra AF et al. Age and sex differences in physical activity of Portuguese adolescents. Medicine and Science in Sports and Exercise. 2008;**40**(1):65-70

[48] Courtney JB et al. Autonomous motivation and action planning are longitudinally associated with physical activity during adolescence and early adulthood. Psychology of Sport and Exercise. 2021;**56**:101974

#### **Chapter 7**

## Evidence-Based Pharmacotherapies for Panic Disorder

*Seth Davin Norrholm*

#### **Abstract**

This chapter presents a review of the primary psychopharmacological interventions for panic disorder and the empirically derived evidence supporting their continued use. Key factors such as dosing, contraindications, safety, tolerability, and polypharmacy are discussed. The chapter will include a currently supported tier structure for pharmacological treatment planning as well as means for how best to tailor regimens to specific patient needs. Comorbidities and practical applications are addressed as well. Lastly, the chapter closes with some emerging pharmacotherapies that show promise but for which empirical evidence supporting their use remains in its infancy.

**Keywords:** anxiety, pharmacology, antidepressants, benzodiazepines, treatment planning

#### **1. Introduction**

#### **1.1 Panic disorder**

In large part because this current text has an overall focus on panic disorder, a review of the signs and symptoms of the clinical presentation of panic disorder will not be provided here (please refer to relevant chapters in this book). Rather, the salient features of panic that represent potential pharmacological treatment targets will be highlighted as this chapter proceeds to review drug treatments for this disorder and its subtypes, common comorbidities, and disability. Panic disorder, per DSM-5 criteria, consists of recurrent panic attacks accompanied by at least a 1-month period in which one of the following occurs: (1) persistent concern about having additional attacks or their consequences, or (2) a significant maladaptive change in behavior due to the attacks [1]. Many panic patients display significant fear and avoidance of places and situations in which a panic attack has previously occurred or may occur in the future [termed agoraphobia]. As has been reviewed in several places throughout this text, panic disorder is common (approximately 3.8% prevalence per Western surveys) [2–4], often chronic, and can have a substantial effect on patient level of function and quality of life [5]. In fact, an estimated 15–20% of panic patients treated pharmacologically with leading effective drugs such as tricyclic antidepressants (TCAs), serotonin selective reuptake inhibitors (SSRIs), or benzodiazepines still meet for panic diagnostic criteria or have experienced symptom relapse as measured 6–12 months after treatment [6]. For these reasons, there continues to be compelling rationale for pursuing more effective treatments for this debilitating disorder.

At the time of clinical intake and initial symptom considerations, therapists should be mindful of other existing conditions that may include the presence of panic attacks or panic-like manifestations but are not true panic attacks in the DSM-5 diagnostic sense. Panic-like attacks, and more generalized anxiety, can accompany clinical presentations of depression, bipolar disorder, and substance use or substance withdrawal [1]. In addition, panic- and anxiety-like reactions can be initiated by exposure to stressors and cues related to tangible, "real-life" situations such as occupational, academic, interpersonal, or social difficulties and obstacles; these events would not be considered panic attacks in the diagnostic sense as: (1) they do not occur spontaneously, (2) may be better accounted for by situational aspects or presence of another disorder, or (3) can be considered reasonably predictable or provoked [1].

Panic attacks themselves, by nature, are foundationally physiological and largely driven by a surging activation of the autonomic nervous system (ANS) and, as such, proceed with about a 10-minute or less duration that coincides with arousing activation of the sympathetic division of the ANS followed by subsequent recruitment of the calming parasympathetic division of the ANS. It is this physiological aspect of panic attacks that is highly responsive to acute drug treatments such as a benzodiazepine. Of note, it is also this physiological aspect that leads many panic sufferers to seek primary care providers or urgent/emergent care for acute treatment [7]. The principally psychological elements of concern and worry about future attacks or their consequences, including avoidance of contexts or cues in which an attack may occur, are targeted by psychotherapeutic approaches such as cognitive behavioral therapy. That is not to say that pharmacological solutions cannot influence the clinical impact of psychological interventions [8]. This will be discussed in further detail later in this chapter.

#### **2. Current pharmacological treatment practices for panic disorder**

It has been well established that the most effective treatments for panic disorder include psychotherapies that capitalize on cognitive-behavioral methodologies [9]. That being said, it is also well known in psychiatry that pharmacological interventions, whether in tandem with psychotherapy or as a monotherapy, can provide these patients and clients with clinical benefits as well [10]. The heterogeneity of panic disorder, with possible variations in etiology, symptom profile, and underlying neural mechanisms, has resulted in a wide-ranging pharmacological treatment approach spanning multiple drug classes and several putative central nervous system targets and mechanisms of action [11–13]. In general, pharmacotherapies for panic disorder can be classified into first-, second-, and third-line agents with other drug classes often recruited for refractory cases (**Figure 1**). Not surprisingly, first-line treatments include the selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines [14]. The second-line drug interventions for panic include alternative classes of antidepressants including serotonin/norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, newer serotonin "multimodal" agents, mirtazapine, and to some extent, some antipsychotics and anticonvulsants [14]. Third-line agents are generally represented by beta blockers, buspirone, and hydroxyzine.

#### **Figure 1.**

*Schematic illustration of the first-, second-, and third-line pharmacological treatments for panic disorder. Dashed lines indicate an approximation of the division between each drug tier based on the available literature discussed in this chapter. As the drug treatments progress from first- to third-line, there is a general increase in the potential side effects experienced by patients as well as a decrease in the overall empirical data available, either by number of studies performed and/or impact of reported studies. BZD: benzodiazepine; SSRI: serotonin selective reuptake inhibitor; CBT: cognitive behavioral therapy; TCA: tricyclic antidepressant; SNRI: serotonin-norepinephrine reuptake inhibitor; and MAOI: monoamine oxidase inhibitor. Created with BioRender.com.*

#### **2.1 First-line pharmacotherapies for panic disorder**

#### *2.1.1 Serotonin selective reuptake inhibitors (SSRIs)*

Selective serotonin reuptake inhibitors (SSRIs) are a safe and effective pharmacological choice for the treatment of a wide range of mood and anxiety disorders with a large body of empirical evidence supporting their administration [15]; this indication is present for treating panic disorder as well [16–19]. A recent systematic review and meta-analysis by Chawla et al. [14] identified SSRIs as most closely associated with high remission and low risk of adverse events when the most common pharmacotherapies for panic were evaluated with sertraline (trade name Zoloft) and escitalopram (trade name Lexapro) showing clearest clinical benefit [14]. Relatedly, a network analysis by Du et al. [20] of 42 clinical trials encompassing almost 6000 panic disorder patients showed the SSRIs paroxetine, sertraline, fluoxetine, citalopram, and escitalopram to be more efficacious than placebo with the latter drug displaying the most robust efficacy [20].

#### *2.1.2 Benzodiazepines*

It is clear from the available empirical literature and clinical guidelines that benzodiazepines are effective in treating many signs and symptoms of panic disorders [16, 21–23] which as described above can include several physiological, stressor- and

fear-related features (e.g., tachycardia, rapid breathing, increased perspiration, acute sense of dread, dizziness). In addition, there is effectiveness and safety data supporting the concurrent prescription of benzodiazepines and an antidepressant such as those already mentioned [23]. This may be particularly important during the initial stages of SSRI administration during which time there can be slow onset of SSRI-related benefits and acute increase in panic symptoms [6]. What is not so clear even after decades of research and clinical practice is: (1) the duration for which to prescribe benzodiazepines both short- and long-term, (2) the optimal dosages to use for the available short- and long-acting benzodiazepines, (3) whether or not chronic regimens or as-needed [PRN] indications are more beneficial as compared to the other, (4) the degree to which benzodiazepines may exceed antidepressants for treating panic disorder, or (5) the hierarchical structure for benzodiazepines as organized by clinical benefits [21] .

There is a degree of hesitancy in psychiatry to use benzodiazepines with some patients. This is primarily due to the potential for these drugs to be misused as a result of inherent factors a such as tolerance, dependence, and withdrawal (with its associated potential for rebound effects and symptom relapse). Additionally, there are significant adverse effects to be wary of as clinicians, including but not limited to, sedation, increased risk of falling, impaired memory, and cognitive slowing [17, 22, 24]. As a result, it is important for providers to consider panic disorder patients on a case-by-case basis when selecting antidepressants, benzodiazepines, or a combination of these.

As with many anxiety disorders, panic disorder is associated with incomplete remission and relapse even with first-line pharmacotherapies [14] [and possibly, concomitant psychotherapies]. As such, it is important for treating clinicians to generate a treatment algorithm that accounts for lack of remission, comorbidity, and combined treatment approaches. With regard to transitioning from first-line pharmacological options to a second-line agent, there are some suggestions for how to do so in the available literature. According to Ziffra [16], there are two potential strategies for changing the treatment of a panic patient who has been prescribed monotherapy with an SSRI for a reasonable amount of time with no significant change in symptoms. The first option is to add a second medication to the current SSRI such as a benzodiazepine or another antidepressant. The second alternative is to move to the second-line possibilities, most notably if the patient had little to no improvement with the SSRI alone or could not tolerate the side effects.

#### **2.2 Second-line pharmacotherapies for panic disorder**

#### *2.2.1 Serotonin-norepinephrine reuptake inhibitors (SNRIs)*

As of this writing, the only FDA-approved serotonin-norepinephrine reuptake inhibitor (SNRI) approved for panic disorder treatment is venlafaxine (trade name Effexor) [25–27]. A number of studies published in the mid-2000s identified superiority of venlafaxine over placebo in reducing panic symptoms in randomized, placebo-controlled, double-blind studies [25, 27–30]. That being said, additional drugs in this class have FDA-approval for treatment of major depressive disorder (MDD) including desvenlafaxine (trade name Pristiq) and duloxetine (trade name Cymbalta) [16]. In addition, despite not having FDA approvals for use with panic disorder patients, there is some open-label evidence available that supports prescribing duloxetine for this clinical population [31] as well as FDA approval for this drug for treating generalized anxiety disorder (GAD) [16].

*Evidence-Based Pharmacotherapies for Panic Disorder DOI: http://dx.doi.org/10.5772/intechopen.106205*

#### *2.2.2 Tricyclic antidepressants (TCAs)*

There is some debate in the field as to whether or not to consider the older tricyclic antidepressants (TCAs) as first- or second-line treatments for panic disorder. In short, the reported efficacy of these drugs, as compared to the SSRIs for example, suggests that they should be treated as first-line agents. However, the side effect profile (e.g., sedation, anticholinergic and cardiac adverse possibilities, weight gain) and potential drug interactions, including with benzodiazepines [14], associated with TCAs provide support for a secondary role within the pharmacological armamentarium available for panic disorder [32].

#### *2.2.3 Monoamine oxidase inhibitors (MAOIs)*

While widely considered to be an older antidepressant pharmacotherapy, monoamine oxidase inhibitors (MAOIs; e.g., phenelzine, trade name Nardil) can be considered second- [or possibly third-line] treatments for panic disorder treatment as they have similar side effect concerns and potential medical interactions as TCAs [18]. These potential adverse effects include the need for a low tyramine diet and hypertension monitoring as examples [33]. Yet, there remains strong provider support for keeping this class of drugs as a viable option despite the possible patient adjustments they may require.

#### *2.2.4 "Multimodal" serotonin agents*

There are also newer antidepressant drugs that, similar to SSRIs, are FDAapproved for the treatment of MDD and inhibit the reuptake of synaptic serotonin, namely, vilazodone (trade name Viibryd) and vortioxetine (trade names Trintellix/ Brintellix). In addition to acting as serotonin reuptake inhibitors, these drugs act at several other classes of serotonin receptors [34] (vortioxetine) including as an agonist at 5-HT1a receptors (vilazodone) [35]. Empirical evidence suggests that these newer antidepressants may be effective for the treatment of panic disorder because of their shared similarity with SSRIs and their enhanced pharmacological profile [36–39].

#### *2.2.5 Mirtazepine*

Mirtazapine is one drug for which there is some evidence for use with panic disorder [40] but the available literature is small and, similar to other drugs within this second-line, there are possible adverse effects such as sedation and weight gain to consider [41]. It should be noted here that most of the support for mirtazapine comes from work done over a decade ago and there has been little advancement in recent years.

#### *2.2.6 Anticonvulsants*

Clinical evidence supporting the use of anticonvulsants with panic disorder patients comes from the success of these drugs in treating bipolar disorder [42–45] and, as such, the list of candidate agents includes topiramate, lamotrigine, carbamazepine, oxcarbazepine, valproic acid, gabapentin, and pregabalin. The most compelling empirical and clinical arguments, albeit somewhat limited, for using anticonvulsants with panic disorder are available for the latter three drugs. Valproic acid [trade name Depakote] acts at the primary inhibitory GABAergic transmitter

systems in the brain and, as such, may help attenuate panic symptoms. Valproic acid is used for mood stabilization in bipolar disorder including in the presence of co-morbid panic [45]. However, as with most of its prescribing practices, valproic acid pharmacotherapy requires close monitoring due to its side effects profile and potential to alter some metabolic functions [46]. The evidence for prescribing gabapentin and pregabalin for panic disorder is scant and consists primarily of a few individual patient cases and open-label trials [47–49]. In addition, there is no FDA approval for the use of these two drugs in anxiety disorders nor is there enough evidence to formulate a treatment algorithm encompassing dosage level, frequency of dosage, or single versus in-tandem, multidrug administration [16]. As such, gabapentin and pregabalin are listed here by drug classification only and not in line with a treatment algorithm. There is simply insufficient evidence to describe them as even a third-line option.

#### **2.3 Third-line pharmacotherapies for panic disorder**

#### *2.3.1 Antipsychotics*

Selecting an antipsychotic pharmacotherapy for panic disorder likely represents an option when all others have been exhausted. In terms of first-generation (e.g., haloperidol, trade name Haldol) or second-generation antipsychotics (e.g., quetiapine, trade name Seroquel), there exists no available literature supporting their use or very little empirical evidence, respectively, with regard to with panic disorder [50]. In fact, a systematic review of the use of second-generation antipsychotics for anxiety disorders as a whole yielded no positive results [51]. As of this writing, there is a glimmer of support for prescribing quetiapine for GAD but nothing to suggest a use for panic disorder [16]. Lastly and understandably so, there exists no FDA approval for treating panic disorder with antipsychotics [16, 50].

#### *2.3.2 Beta blockers*

As mentioned in the Introduction, panic attacks by nature have a psychophysiological component to them as they mirror activation of the sympathetic nervous system complete with tachycardia and perception of impending threat. For this reason, there is compelling rationale to use beta blockers to stem many of these physiological effects; an approach consistent with the acute use of beta blockers to prevent hyper-arousals stemming from performance-based tasks like public speaking [52]. However, the potential clinical advantage of using beta blockers to prevent panicrelated somatic manifestations and distress is surprisingly weak [11, 53] and thus relegates these drugs to the third-line tier at best.

### *2.3.3 Buspirone*

The 5-HT1a partial agonist, buspirone, can be considered a third-line treatment option for panic disorder but that standing is somewhat tenuous given that: (1) there is only a small body of literature supporting its use here, (2) the best evidence appears to be its administration with a concomitant antidepressant, (3) the available literature reveals notable adverse effects and a high dropout rate [14], and (4) its FDA approval for treatment of anxiety disorders is limited to generalized anxiety disorder (GAD) [16, 54].

#### *2.3.4 Hydroxyzine*

An antihistamine with sedative properties, there is some small support of its use for anxiety, including panic disorder [55]. Despite having FDA approval for use with GAD, empirical evidence of hydroxyzine effectiveness for GAD is mixed [56–58]. Thus, one can consider administering hydroxyzine for panic disorder symptoms as a tertiary strategy [16].

#### **3. Treatment planning**

#### **3.1 Assessment of comorbidities**

A critical step in treatment planning for clients with possible panic disorder is the assessment of other psychological comorbidities, general medical conditions, or substance related elevations in arousal (e.g., caffeine, cannabis) that may mimic signs and symptoms of panic. With regard to the first factor, it is generally well established that anxiety disorders tend to cluster with one another from a symptomatologic and etiological standpoint [59]. As such, it is imperative for the treating clinician to address any barriers to treatment or exacerbation of symptoms presented by comorbidity. Common psychiatric comorbidities [and potential risk factors for developing panic disorder] include, but are not limited to, depression, substance use, disordered personality, and other anxiety disorders [16, 60–63]. In consideration of the second factor, client and therapist should rule out any potential conditions that could be subjectively reported as panic attacks, including but not limited to, hyperthyroidism, epilepsy, hypoglycemia, cardiac issues, asthma or respiratory ailments, or dizziness/ vertigo [16]. Regarding substance intake, clinicians should perform some type of timeline follow-back query to assess the client's use of food, drink, consumables, or recreational drugs known to increase psychophysiological arousal. Relatedly, assessment of substance-induced anxiety disorder should occur as well.

#### **3.2 Course of treatment: how much of which drug and for how long?**

A critical question for which clinicians are still seeking answers is the type and duration of pharmacological interventions for panic disorder. There is still considerable debate regarding several key questions including, but not limited to: (1) for how long should patients take anti-panic medications to best ensure relapse is minimal and gains are maintained, (2) if medications are to be taken long-term, should maintenance doses be reduced or held at short-term therapeutic levels, (3) of the medications reviewed here, are there some that outperform others when length of treatment becomes the issue, (4) what are the persistent, or newly emerging, side effects of which to be wary, and (5) are there identifiable clinical or individual predictors of short- and long-term treatment outcome and relapse suppression? There have been a small number of clinical studies that have sought to answer these questions.

Two randomized trials conducted in the last decade investigated the long-term efficacy of two supported pharmacotherapies for panic disorder, SSRIs and clonazepam, administered in tandem with another type of treatment (CBT) or as compared to an alternative drug regimen [paroxetine], respectively. Nardi et al. [64] compared long-term (34 months) treatment with paroxetine or clonazepam in a study

extended from an ongoing short-term investigation of the medications [64, 65]. In the earlier short-term study, both paroxetine and clonazepam displayed similar reductions in the patient-reported number of panic attacks and in overall level of anxiety as assessed with Hamilton Anxiety and Clinical Global Impression-Severity scores [65]. Patients reported a faster onset of drug effects and fewer adverse events with clonazepam as compared to paroxetine in the short-term. These effects on panic attack reduction and diminished anxiety held true for the long-term extension as did the fewer number of adverse events regarding clonazepam over paroxetine. Not surprisingly, the adverse events reported with clonazepam use were drowsiness and fatigue as well as impairments in memory and concentration while with long-term paroxetine, patients reported change in appetite and weight gain as well as diarrhea, constipation, and dry mouth.

A second long-term study of note directly compared the parallel combination of CBT and SSRIs with each treatment arm alone [66]. When assed over a 1-year treatment period, CBT + SSRI, CBT alone, and SSRI alone all resulted in a significant reduction in panic attack frequency. Of note, patients who received CBT alone reported a slower decline in panic attacks over time and more spontaneous panic attacks during the past year. The authors of this long-term study also highlight that patient symptoms improved at a faster rate with combined CBT and SSRIs particularly in those patients with co-occurring agoraphobia [66]. As will be discussed in the next section, there is certainly evidence for drug monotherapies for panic disorder but the most significant clinical gains may arise from the combination of pharmacotherapy with psychotherapy. In addition, most of the emerging data from this area suggest maintenance therapy of up to a year or more after an initial course of pharmacological treatment and symptom reduction [6].

#### **3.3 Co-administration of pharmacotherapies with psychotherapy**

The primary focus of this chapter is on the use of pharmacological agents to treat the signs and symptoms of panic disorder. However, this chapter would be incomplete if it did not highlight the importance of psychotherapy—namely cognitive behavioral therapy (CBT) for the effective treatment of panic disorder. The most effective interventions for anxiety disorders are CBT-based (for review see Otto and Deveney [67]) and, as such, therapists should seek out ways in which CBT and pharmacotherapy can mutually benefit one another [23, 67]. In addition, as alluded to earlier in this chapter, benzodiazepines are intended for short-term usage for management of panic symptoms and should be tapered when clinically indicated. This weaning can produce a withdrawal process that can acutely exacerbate panic and it is often recommended that a program such as Panic Control Treatment for Benzodiazepine (BZ) discontinuation be incorporated into treatment plans [68–72].

#### **4. Future directions and exploratory pharmacotherapies**

In order to address the shortcomings of the currently available pharmacotherapies for panic disorder, there has been a renewed interest in psychiatry in exploring additional alternative drug therapies. The search for new and innovative medications, for mood and anxiety disorders more broadly, has included psychedelics such as 3,4-methylenedioxymethamphetamine (MDMA), increasingly legal and available cannabinoids, orexinergic compounds, glutamatergic agents (e.g., D-Cycloserine, esketamine), and anesthetics

(e.g., Xenon gas). As of this writing, scant empirical evidence exists to support the use of MDMA nor cannabinoids for panic disorder and there are, in fact, studies that suggest that the use of the latter class of drugs could be problematic [73, 74]. There are, as will be seen below, encouraging emerging findings supporting the use of compounds that act on orexin systems as well as the anesthetic, xenon.

#### **4.1 Orexinergic pathways as a drug target for treating panic disorder**

The orexin system is of particular interest as a pharmacological target for treating panic disorder due to the putative role of this neuropeptide in the underlying pathophysiology of panic including its regulatory functions related to chemo-, cardio-, and behavioral responses to fluctuations in CO2 and H+ [13, 75]. For example, activity within orexinergic hypothalamic neurons and along brainstem cardiorespiratory pathways is increased by CO2 or NaLac challenge [76, 77]. In addition, expression of orexin-1 receptors is rich in areas shown to mediate defensive, emotional, arousal and panic-like behaviors such as the noradrenergic locus coeruleus, serotonergic raphe nucleus, brainstem cardiorespiratory maintenance nuclei, the extended limbic system, and the periaqueductal gray [78, 79]. Consistent with this expression of orexin-1 receptors, selective antagonists can block panic behaviors and cardiovascular responses induced by CO2 challenge, at least when administered directly into the raphe [80].

A recent systematic review by Caldirola et al. [13] examined the empirical, translational evidence supporting the use of orexin receptor antagonists to treat panic disorder. The work reviewed by this group assessed compounds at iterative stages of drug development including preclinical animal studies and Phase I trials with psychiatrically healthy human participants. In the preclinical animal studies, investigators employed commonly used paradigms to produce panic-like behaviors in rodents including external (e.g., cage exchange between housed animal groups) and internal (e.g., sodium lactate, NaLac, injection or 20% CO2 inhalation) stressors. Systematic review by Caldirola's team identified three orexin-1 receptor selective antagonists, compound 56, JNJ-54717793, and JNJ-61393215, that displayed an ability to block panic behaviors and cardiovascular responses induced by the aforementioned paradigms. Notably, there were some differences in effectiveness between tested compounds and as compared to benzodiazepine controls but each appeared to be effective without sedative effects or significant effects on sleep-wake cycles [13, 81–83]. Lastly, selective orexin-2 receptor antagonists did not show any significant capacity to block panic-related behaviors and responses.

The animal studies alluded to above were then subsequently followed by Phase I human trials with healthy participants. For example, Salvadore et al. [83] found that the selective orexin-1 receptor selective antagonist, JNJ-61393215, possessed a good tolerability and safety profile, showed no drowsiness or cardiovascular effects, and significantly reduced panic symptoms induced by a 35% CO2 inhalation challenge when assessed in healthy males. Complementary work by Kaufmann et al. [84] suggested that the selective orexin-1 receptor antagonist, ACT-539313, was generally safe and well tolerated with some reports of somnolence. Yet, the anxiolytic potential of this compound requires further exploration as early evidence suggests it may reduce anxiety associated with a 7.5% CO2 challenge but not necessarily test-elicited panic symptoms [84]. It is clear as of this writing that there remains much translational work to be done before the orexin-1 receptor antagonist class of drugs can be considered for panic disorder treatment.

#### **4.2 Glutamatergic pathways as a drug target for treating panic disorder**

In terms of glutamatergic agents acting as potential anti-panic medications, there is compelling data from the treatment of other anxiety and mood disorders that warrant further investigation. The antibiotic and partial NMDA receptor agonist, D-Cylcoserine (DCS), for example, has a recent history of potential use as a cognitive enhancer that may facilitate cognitive behavioral therapies (CBTs) for anxiety disorders such as specific phobias under specific therapeutic conditions [85]. The use of DCS as an adjunctive treatment for panic-related CBT was recently examined by Reinecke et al. [86] who showed that while DCS reduced bias for threatening faces and associated amygdala activity, it did not differ from placebo on clinical measures of panic-related signs and symptoms [86].

As of this writing, the anti-panic properties of esketamine have not been fully explored and the strongest data available support the use of ketamines as a rapidonset pharmacotherapy for treatment resistant depression [87], but not yet for anxiety disorders.

The inhalation of the anesthetic, xenon, has been studied recently as a potential pharmacotherapy for panic disorder [88], in part because of the gas' ability to decrease excitatory neurotransmission via interactions at glutamatergic NMDA and AMPA, serotonergic 5HT-3, and cholinergic nicotinic receptors [11, 89]. Dobrovolsky et al. [88] administered 6–7 inhalations of xenon at a sub-anesthetic dose for 2.4–4 minutes to a study sample consisting of panic disorder patients with and without psychiatric comorbidity. Symptom ratings, as measured by the Hospital Anxiety and Depression Scale and Zung Self-rating, global impression ratings, and frequency of panic attackers were all reduced following the xenon inhalations, with many patients reporting benefits after only 3 treatments. The authors reported xenon to be well tolerated, however, provided no putative mechanism of action. Continuing work with greater rigor and replicability than the existing studies should provide further insight into this unconventional, yet cautiously promising, delivery of panic disorder treatment.

#### **5. Conclusions**

The available empirical and clinical evidence suggests that first-line pharmacotherapies for panic disorder include selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines with the former best accompanied by cognitive behavioral therapy (CBT) and the latter used for short-term management of panic symptoms (**Figure 1**). In refractory cases, there are second- and third-line pharmacological agents available, however, their use has mixed results and support, possesses less clear treatment regimens and algorithms, and comes with increasing possibility of side effects and adverse interactions. Emerging clinical data from the study of mood disorders, including MDD, suggest that serotonin multimodal drugs and faster acting medications like esketamine may show promise moving forward. One can imagine that the next decade of drug development in the area of panic disorder will represent an amalgam of evidence gleaned from the pharmacological treatment of disorders with which panic is co-morbid, serendipitous findings from the clinic that continue to shed light on new innovations, and a maintenance of the psycho/pharmacotherapy regimen that has shown efficacy for the better part of the past 25 years.

*Evidence-Based Pharmacotherapies for Panic Disorder DOI: http://dx.doi.org/10.5772/intechopen.106205*

#### **Conflict of interest**

The author declares no conflict of interest.

### **Author details**

Seth Davin Norrholm1,2

1 Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan, USA

2 Department of Behavioral Sciences and Leadership, United States Air Force Academy, Colorado, USA

\*Address all correspondence to: snorrholm@wayne.edu

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Edited by Robert W. Motta*

Panic disorder is often confused with elevations of anxiety and what is often described as "anxiety attacks." However, panic is qualitatively different from these phenomena. Panic disorders or panic attacks are intense and usually brief episodes that have often come upon the sufferer as an extreme dread and fear of annihilation. Panic attacks are startling and often produce a sense of impending doom and fear of imminent disaster. They are associated with heart palpitations, dizziness, tingling of extremities, disorientation, and the urge to flee the present environment. During a panic attack, it is not unusual for the sufferer to act in ways that seem completely irrational and beyond the realm of sanity. Imagine sitting quietly in a darkened room and being intensely engrossed in a book that you cannot put down. Suddenly you feel someone's hands grasp your neck and begin choking you. That level of startled and life-threatening fear is like what many report during a panic attack. It is difficult to know what causes this disorder. In many cases, sufferers report having endured traumatic experiences, especially in childhood. However, in an equal percentage of cases, there is no prior trauma history, and the origins of the panic disorder are unknown, although they do tend to run in families. This book elucidates the nature of panic, the factors that contribute to the disorder, and describes psychological, physiological, and medical interventions that have been useful in ameliorating the suffering brought on by panic attacks.

Published in London, UK © 2023 IntechOpen © Marc Andreu / iStock

The Psychology of Panic

The Psychology of Panic

*Edited by Robert W. Motta*