Panic disorder
Synonyms and keywords: Fit of terror, spasm, anxiety disorder

# Overview
Panic disorder is an anxiety condition characterized by recurring panic attacks with significant behavioral change or at least a month of ongoing worry about having another attack. Panic disorder patients have a series of episodic severe anxiety, known as panic attacks.  These attacks typically last 10 minutes, however, they can be of shorter duration. They may vary in intensity and symptoms over a period of time. Symptoms of panic disorder commonly present in the form of rapid heart beat, perspiration, dizziness, dyspnea, tremors, uncontrollable fear or feeling of impending doom.  The panic attacks often result in embarrassment and social stigma, ultimately resulting in social isolation. Therefore, most of the individuals with panic disorder also develop agoraphobia. If not treated, somatic symptoms like insomnia and/or anorexia develop, which may eventually result in clinical depression and suicide. So, early, efficient, and affordable treatment options should be encouraged.

# Historical Perspective
- Panic disorder has a long history, dating back to folklores.
- Greek mythology includes one of the examples. The term 'Panic' originated from the Greek god, pan who was responsible for anxiety.
- In Greek myths, 'pan' was a man with horns and legs of a goat. His mere appearance was so frightening that it developed irrational fear in people, without any apparent reason. This came to be known as panic attacks or terrors. 
- Fear of meeting pan once more stopped the travelers from going to the market. In Greek, agora stands for market and this led to the development of a new term 'agoraphobia'. It stands for the fear of public places or large open spaces.
- In 1621, Burton described different varieties of pathological anxiety. He related the anxiety to delirium, depersonalization, hypochondria, hyperventilation, and phobias.
- In 1812, Benjamin Rush (father of American psychiatry), described the relation between somatic causes and phobias in his book. He established an association between depression and hypochondriasis. 
- In 1879, Henry Maudsley used the term panic for the first time in psychiatry, and also explained melancholic panic.
- Sigmund Freud, in the year 1925, described anxiety neurosis. He separated it from neurasthenia and further elaborated anxiety neurosis with a particular clinical presentation.
- In 1964, Klein proposed three types of panic attacks:  situational (related to agoraphobia), spontaneous, and in response to a stimulus (like height, animals, etc.). 

# Classification
- In 1980, panic disorder was first described in DSM-III, based on Klein's description of panic attacks. 
- In 1987, after consistent work on DSM for the next seven years, DSM-III-R described agoraphobia as a consequence of panic disorder. So, agoraphobia was divided into 'panic disorder with and without agoraphobia'.
- In 1992, DSM-IV described panic attacks related to other conditions. The criteria for panic disorder was not required to be fulfilled here.
- The criteria for panic disorder remained the same in the revised version of DSM-IV (DSM-IV-TR), published in 2000.
- DSM-5 has unlinked panic disorder and agoraphobia. 
- The tenth edition of International Classification of Diseases (ICD-10) describes agoraphobia as a distinct condition that may not occur with panic attacks.

# Pathophysiology
- Multiple factors are associated with the pathophysiology of panic disorder.
- Imbalance of neurobiological, neuroanatomic, and neurochemical factors lead to the production of this condition.
- Pathogenesis of Panic Disorder is related to the amygdala, the center for fear processing. MRI studies have further substantiated this finding by showing lesser left and right-sided amygdalar volumes in panic disorder patients as compared to controls. 
- There is dysregulation of the prefrontal cortex as well as the subcortical components.
- The patients with panic disorder have more noradrenergic neuronal activity than controls. 
- Another neurochemical theory proposes that these patients have deficient serotonergic inhibition of neurons in the dorsal periaqueductal gray matter of the midbrain and the rostral ventrolateral medulla. 
- The endogenous opioids buffer the panic attacks in normal subjects and their deficit results in the development of the panic disorder. 
- Panic disorder patients have also been found to have lower occipital cortex GABA levels. Other studies suggest dysfunction of GABA(A) receptors in the pathophysiology of panic disorder. This is further supported by improvement in symptoms by treatment focused on GABA binding site of the GABA(A) and benzodiazepine receptor complex. 

# Differential Diagnosis
There are some medical and psychiatric conditions with symptoms mimicking panic disorder: 
- Anxiety disorder due to other medical condition
- Pheochromocytoma
- Hyperthyroidism
- Hyperparathyroidism
- Vestibular abnormalities
- Seizure disorders
- Sleep apnea
- Cardiopulmonary conditions
- Arrhythmias
- Asthma
- Supraventricular tachycardia
- Chronic obstructive pulmonary disease
- Other mental disorders with panic attacks
- Psychotic disorders
- Other anxiety disorders
- Other specified or unspecified anxiety disorder
- Substance-induced anxiety disorder
- Cocaine
- Amphetamines
- Caffeine
- Cannabis
- Medication-induced anxiety disorder
- Withdrawal from CNS depressants like alcohol, barbiturates

# Epidemiology and Demographics

## Prevalence
- The prevalence of the panic disorder is 2,000-3,000 / 100,000 (2%-3%) of the overall population.
- 2.7-7.1% of the general population suffers from a lifetime prevalence of panic disorder.  

## Gender
- Women are twice as likely as men to develop panic disorder. 
- For both men and women, panic disorder has similar age of onset. Preceding premorbidity was found to be different for men and women.
- Men had higher rates of body dysmorphic disorder, cyclothymia, and depersonalization preceding panic disorder. Whereas, women had higher rates of bulimia nervosa. Life stressors played a significant precipitating factor for women. 

## Age
- Anticipation is characterized by the decrease in age at onset and/or the increase in severity of a disorder in successive generations. It helps in exploring the genetic basis of some diseases.
- Anticipation is responsible for the familial aggregation of panic disorder. 
- There is an increased risk of disease in the relatives of panic disorder patients with age of onset 20 years or less. The age of onset is useful in determining the familial subtypes. 

## Race
- Various studies presented with mixed results.
- A study comparing the White, African American, Asian, and Latino groups found that the Whites had higher rates of panic disorder, as compared to the African American, Latino, and Asian groups.

# Risk Factors
Several factors can increase the chances of Panic Disorder: 
- Asthma
- Childhood sexual and physical abuse
- Genetic predisposition
- History of "fearful spells"
- Identifiable stressors
- Interpersonal stressors
- Stressors related to physical well-being
- Negative experiences with illicit or prescription drugs
- Disease
- Death in the family
- Negative affect (neuroticism)
- Offsprings of parents with anxiety, depression, or bipolar disorders
- Separation anxiety in childhood
- Smoking

# Natural History, Complications, and Prognosis
- Anxiousness in people with panic disorder begins in childhood due to traumatic life events or distressing family conditions.
- Family history and genetics play a very important role in the development of panic disorder.
- Poor prognostic factors are:
- Female gender
- Comorbid agoraphobia
- Comorbid depression
- Comorbid personality disorder
- Higher oxidative stress index and higher ceruloplasmin level
- Catastrophic agoraphobic cognitions
- Panic disorder patients with non-suppression on Dexamethasone Suppression Test (DST)

# Diagnostic Criteria

## DSM-5 Diagnostic Criteria for Panic Disorder
- A. Recurrent unexpected panic attacks. A panic attack is an abrupt surge of intense fear or discomfort that reaches a peak within minutes, and associated with at least four of these symptoms:
Note: The abrupt surge can occur from a calm state or an anxious state.
- 1. Palpitations
- 2. Sweating
- 3. Trembling
- 4. Shortness of breath
- 5. Feeling of choking
- 6. Chest pain or discomfort
- 7. Nausea or abdominal distress
- 8. Feeling dizzy, or unsteady
- 9. Chills or sensation of heat
- 10. Paresthesias (numbness or tingling sensations)
- 11. Derealization (feelings of unreality) or depersonalization (being detached from oneself)
- 12. Fear of losing control
- 13. Fear of dying
Note: Culture-specific symptoms (e.g., tinnitus, neck soreness, headache, uncontrollable screaming or crying) may occur. Such symptoms should not be included as one of the four required symptoms.
AND
- B. At least one of the attacks has been followed by a minimum of 1 month of the following:
- 1. Persistent worries about having another panic attack or the consequences (like losing control).
- 2. A major maladaptive behavioral change in relation to the attacks (behaviors to avoid having panic attacks).
AND
- C. The disturbance is not due to the effects of a substance or another medical condition.
AND
- D. The disturbance is not better explained by another mental disorder or due to separation from attachment figures.

## Diagnosis in practice
Brief, screening and diagnostic surveys have been reviewed by the United States Preventive Services Task Force (USPSTF).
The draft USPSTF guideline recommends screening.
1. The Brief Panic Disorder Severity ScaleSelf-Report (Brief PDSS-SR) can also be used for diagnosis:
- Two items (questions 2 and 4 from the Panic Disorder Severity Scale - Self Report (PDSS-SR)
2. Distress during panic: "If you had any panic attacks during the past week, how distressing (uncomfortable, frightening) were they while they were happening? (If you had more than one, give an average rating. If you didn't have any panic attacks but did have limited symptom attacks, answer for the limited symptom attacks.)
4. Avoidance, agoraphobic: "During the past week were there any places or situations (e.g., public transportation, movie theaters, crowds, bridges, tunnels, shopping malls, being alone) you avoided, or felt afraid of (uncomfortable in, wanted to avoid or leave), because of fear of having a panic attack? Are there any other situations that you would have avoided or been afraid of if they had come up during the week, for the same reason? If yes to either question, please rate your level of fear and avoidance this past week."
- 2. Distress during panic: "If you had any panic attacks during the past week, how distressing (uncomfortable, frightening) were they while they were happening? (If you had more than one, give an average rating. If you didn't have any panic attacks but did have limited symptom attacks, answer for the limited symptom attacks.)
- 4. Avoidance, agoraphobic: "During the past week were there any places or situations (e.g., public transportation, movie theaters, crowds, bridges, tunnels, shopping malls, being alone) you avoided, or felt afraid of (uncomfortable in, wanted to avoid or leave), because of fear of having a panic attack? Are there any other situations that you would have avoided or been afraid of if they had come up during the week, for the same reason? If yes to either question, please rate your level of fear and avoidance this past week."
- Sum of 3 or more points:
Sensitivity of 0.85
Specificity of 0.66
 Gain in certainty (Sensitivy + specifity) 1.5 (0.85 + 0.66)
- Sensitivity of 0.85
- Specificity of 0.66
- Gain in certainty (Sensitivy + specifity) 1.5 (0.85 + 0.66)
2. Panic Disorder Severity ScaleSelf-Report (PDSS-SR):
- Cutoff cutoff 9:
Sensitivity of 67% to 83%
Specificity of 64% to 96%
 Gain in certainty (Sensitivy + specifity) 1.5 (0.75 + 0.79)
- Sensitivity of 67% to 83%
- Specificity of 64% to 96%
- Gain in certainty (Sensitivy + specifity) 1.5 (0.75 + 0.79)
3. PHQ-PD:
- Criteria: questions #3a-d are all YES and 4 or more of #4a-k are YES:
Sensitivity of 81%
Specificity of 99%
 Gain in certainty (Sensitivy + specifity) 1.8
- Sensitivity of 81%
- Specificity of 99%
- Gain in certainty (Sensitivy + specifity) 1.8
4. GAD-7
- Sensitivity: 61%-89%
- Specificity: 82%-88%
 Gain in certainty (Sensitivy + specifity) 1.6 (0.75 + 0.85)
- Gain in certainty (Sensitivy + specifity) 1.6 (0.75 + 0.85)

# Treatment
- Panic Disorder is a potentially disabling condition but can be successfully treated.
- Due to the disturbing symptoms that accompany the panic disorder, it can be mistaken for a life-threatening physical illness.
- Thorough investigation to rule out the suspected medical condition and early initiation of treatment should be the ultimate goal of managing the panic disorder.
- Panic disorder can be treated by medications, psychotherapy, or both.
- A skilled treating team of psychiatrists, psychologists, and social workers is required for this purpose.

## Medications
- Antidepressants (SSRIs, MAOIs, Tricyclic Antidepressants (TCAs), etc.)
- SSRIs such as paroxetine, escitalopram, and citalopram, are used for maintenance therapy. 
- MAOIs are usually avoided because of the life-threatening side effects such as serotonin syndrome, hypertensive crisis, and other drug interactions.
- TCAs are associated with anticholinergic side effects, so avoided in the elderly.
- Both SSRIs and TCAs are effective for the treatment but SSRIs are preferred because of a better tolerability profile.
- Anti-anxiety drugs (benzodiazepines such as Alprazolam, Clonazepam )
- These are used for a short duration to control the acute phase of illness or given until the SSRIs have achieved therapeutic action.
- Long-term use is not advisable because of the high chances of developing dependence and drug-seeking behavior.

## Psychotherapy
- There are multiple treatment options available such as exposure to somatic cues, cognitive behavior therapy (CBT), and relaxation therapy for panic disorder. When combined, these management options provide the best results.
- Exposure to somatic cues and CBT, when combined result in nearly 85% response rate. 
- Relaxation techniques produce greater reduction in the associated anxiety but are related to higher drop-out rates. 
- CBT can also be administered in the form of group therapy. It is found to be equally effective as pharmacotherapy in some studies.
- CBT comprises of: 
- Education and corrective information
- Cognitive therapy
- Training in diaphragmatic breathing
- Interoceptive exposure

## Other treatment modalities
- Regular aerobic exercise alone has been associated with clinical improvement in patients with panic disorder but is lesser effective than pharmacotherapy. 
- When properly used, Internet-based self-help programs with minimal therapist contact can be equally efficacious as traditional individual CBT. 
- Virtual Reality Exposure (VRE) has been found to be effective for both short and long-term management of panic disorder.

# Monitoring response to therapy
1. Panic Disorder Severity ScaleSelf-Report (PDSS-SR).
- Panic frequency
- Distress during panic
- Anticipatory anxiety
- Avoidance, agoraphobic
- Avoidance, physical
- Work Impairment
- Social Impairment
2. The Brief Panic Disorder Severity ScaleSelf-Report can also be used for diagnosis. Two items from the PDSS-SR:
- Distress during panic
- Avoidance, agoraphobic
Cutoffs to define meaningful change are not clear.