Panic Disorder

Overview

Definition

Panic disorder is characterized by chronic recurrent episodes of panic attacks (not triggered) that are associated with significant worry about future attacks, maladaptive behavior, and impaired function for ≥ 1 month.

A panic attack is not a mental disorder. Rather, this disorder is a sudden, spontaneous, time-limited period (minutes to an hour) of heightened anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder or intense fear, often with physical symptoms.

Epidemiology

• Lifetime prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency of panic disorder in the United States is 4.7%.
• Women are twice likely to be affected as men. 
• Usual onset occurs in adolescence to early 30s.
• Close to 40% of those with panic disorder have a lifetime history of major depression.

Pathophysiology

Genetic and environmental factors play a role.

• Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
  • ↑ Rate of panic disorder in those with 1st-degree relatives with the condition
  • Higher concordance in monozygotic twins Monozygotic twins Result from the division of a single zygote; share the same genetic material Multiple Pregnancy
• Structural brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification changes:
  • Involves multiple neural circuits, including the following regions:
    • Prefrontal
    • Temporal
    • Anterior cingulate
    • Insula
    • Amygdala Amygdala Almond-shaped group of basal nuclei anterior to the inferior horn of the lateral ventricle of the temporal lobe. The amygdala is part of the limbic system. Limbic System: Anatomy
    • Hippocampus
    • Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus
  • Alterations in these regions noted in the panic response
  • Also implicates altered GABA-benzodiazepine receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors and serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (↑ fear generalization) 
• Anxious temperament and neuroticism: greater reactivity to stress and poor defense against anxiety-provoking stimuli
• History of physical or sexual abuse Sexual Abuse Sexual abuse and assault are major public health problems that affect many people from all walks of life, including people of all ages and genders, but it is more prevalent in women and girls, with reports of up to 1 in 3 experiencing sexual assault at some time in their life. Sexual Abuse, smoking Smoking Willful or deliberate act of inhaling and exhaling smoke from burning substances or agents held by hand. Interstitial Lung Diseases, and asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma also lead to increased risk of panic disorder.

Clinical Presentation and Diagnosis

Clinical features/criteria

• Panic attack is abrupt in onset and frequently spontaneous, but may arise from excitement, trauma, or physical exertion. 
• Physical and mental symptoms:
  • Palpitations Palpitations Ebstein’s Anomaly, a pounding heart, or increased heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology
  • Sweating
  • Chills Chills The sudden sensation of being cold. It may be accompanied by shivering. Fever or heat Heat Inflammation sensation
  • Trembling or shaking
  • Paresthesias Paresthesias Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. Posterior Cord Syndrome
  • Shortness of breath Shortness of breath Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea 
  • Choking sensation
  • Chest pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways or chest discomfort
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics or abdominal distress
  • Feeling dizzy, unsteady, light-headed, or faint
  • Derealization Derealization Derealization is a persistent subjective sense of detachment or unreality of the surrounding world often described by the patient as unreal, dreamlike, foggy, lifeless, or visually distorted reality. Depersonalization/Derealization Disorder (feelings of unreality) or depersonalization Depersonalization State in which an individual perceives or experiences a sensation of unreality concerning the self or the environment; it is seen in disorders such as schizophrenia, affection disorders, organic mental disorders, and personality disorders. Depersonalization/Derealization Disorder (being detached from one’s own self)
  • Fear of losing control or of going insane/crazy
  • Fear of dying
• Some people develop agoraphobia Agoraphobia Agoraphobia is fear or anxiety in a situation that would be difficult to leave or to obtain help in the event that one develops panic-like symptoms. Situations include being in public or open spaces, lines, crowds, or public transport. Agoraphobia (fear and avoidance of situations or places where it is difficult to leave or escape Escape With constant immune mechanisms holding unstable tumor cells in equilibrium, tumor-cell variants may emerge. These cancer cells may express fewer antigens on their surfaces or lose their MHC class I expression.Variants may also protect themselves from T-cell attack via expression of IC molecules on their surfaces, like normal cells.Creation of an immunosuppressive state in the microenvironment is another way to grow without immunologic interference. Cancer Immunotherapy, especially if panic symptoms were to occur).
• Panic attacks followed by either/both ≥ 1 month of:
  • Continued concern or worry about future panic attacks or their consequences (e.g., heart attack Heart attack Mi is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction or going crazy)
  • Significant maladaptive behavioral change or inappropriate adjustment secondary to the attacks (e.g., avoidance behaviors)

Assessment

• Complete medical, social, family, and psychiatric history with physical examination
• Laboratory testing and further workup (e.g., ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG), Holter monitoring, pulmonary function test Pulmonary function test Pulmonary function tests are a group of diagnostic procedures yielding useful, quantifiable information about the rate of the flow of air through the individual’s airways, lung capacity, and the efficiency of gas exchange in relation to time. The most commonly utilized tests include spirometry (before and after bronchodilator use), lung volumes, and quantitation of diffusing capacity for carbon monoxide (CO). The tests can be influenced by the individual’s effort/fatigue, disease state, or anatomical malformation. Pulmonary Function Tests) based on patient’s age, risk, and medical history
• Rule out other psychiatric disorders.
• Rule out substance use or effects of medication(s).
• Panic Disorder Severity Scale Scale Dermatologic Examination ( PDSS PDSS Postpartum Psychiatric Disorders):
  • Instrument uses a severity rating for different behaviors ( scale Scale Dermatologic Examination: 0–4).
  • Information obtained:
    • Attack frequency
    • Attack intensity
    • Anticipatory anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder
    • Phobic avoidance
    • Avoidance of internal bodily sensations
    • Relationship impairment, work impairment

Management

With proper management, most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship show improvement in symptoms of panic disorder.

A choice of treatment can be CBT and/or medication, depending on patient preference, availability, and response.

Cognitive-behavioral therapy Cognitive-behavioral therapy Cognitive-behavioral therapy corrects faulty assumptions and tries to replace maladaptive behavior with healthier alternatives. Psychotherapy

• Goal is to have the patient understand that panic attacks last for a short period and that they are not life-threatening. 
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are taught cognitive and somatic coping skills to recognize panic and replace catastrophic thoughts.
• Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are encouraged to apply these skills during exposure so that they learn to manage the symptoms.
• Used with medications for maintenance therapy if monotherapy alone is not effective

Pharmacotherapy

• Acute attack:
  • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines (BDZs), such as alprazolam Alprazolam A triazolobenzodiazepine compound with antianxiety and sedative-hypnotic actions, that is efficacious in the treatment of panic disorders, with or without agoraphobia, and in generalized anxiety disorders. Benzodiazepines
  • Recommended for short course alongside selective serotonin reuptake inhibitors Selective Serotonin Reuptake Inhibitors Serotonin Reuptake Inhibitors and Similar Antidepressants ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants), such as paroxetine Paroxetine A serotonin uptake inhibitor that is effective in the treatment of depression. Serotonin Reuptake Inhibitors and Similar Antidepressants 
  • Must be used with caution due to side effects and potential for misuse 
• Maintenance therapy:
  • Antidepressants ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants or serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS– norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS reuptake inhibitors ( SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants)) are 1st-line. 
  • SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants include paroxetine Paroxetine A serotonin uptake inhibitor that is effective in the treatment of depression. Serotonin Reuptake Inhibitors and Similar Antidepressants, citalopram Citalopram A furancarbonitrile that is one of the serotonin uptake inhibitors used as an antidepressant. The drug is also effective in reducing ethanol uptake in alcoholics and is used in depressed patients who also suffer from tardive dyskinesia in preference to tricyclic antidepressants, which aggravate dyskinesia. Serotonin Reuptake Inhibitors and Similar Antidepressants, and sertraline Sertraline A selective serotonin uptake inhibitor that is used in the treatment of depression. Serotonin Reuptake Inhibitors and Similar Antidepressants.
  • SNRIs SNRIs Serotonin Reuptake Inhibitors and Similar Antidepressants include venlafaxine Venlafaxine A cyclohexanol and phenylethylamine derivative that functions as a serotonin and noradrenaline reuptake inhibitor (SNRI) and is used as an antidepressant agent. Serotonin Reuptake Inhibitors and Similar Antidepressants and duloxetine Duloxetine A thiophene derivative and selective neurotransmitter uptake inhibitor for serotonin and noradrenaline (SNRI). It is an antidepressant agent and anxiolytic, and is also used for the treatment of pain in patients with diabetes mellitus and fibromyalgia. Serotonin Reuptake Inhibitors and Similar Antidepressants.
  • Need weeks or months to show their effects
  • If maintenance with SSRI fails, tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants or monoamine oxidase Oxidase Neisseria inhibitors may be used.

Other Anxiety Disorders

Differential Diagnosis

• Pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma: catecholamine-secreting tumor Tumor Inflammation derived from chromaffin cells Chromaffin cells Cells that store epinephrine secretory vesicles. During times of stress, the nervous system signals the vesicles to secrete their hormonal content. Their name derives from their ability to stain a brownish color with chromic salts. Characteristically, they are located in the adrenal medulla and paraganglia of the sympathetic nervous system. Adrenal Hormones. The majority of pheochromocytomas originate in the adrenal medulla Adrenal Medulla The inner portion of the adrenal gland. Derived from ectoderm, adrenal medulla consists mainly of chromaffin cells that produces and stores a number of neurotransmitters, mainly adrenaline (epinephrine) and norepinephrine. The activity of the adrenal medulla is regulated by the sympathetic nervous system. Adrenal Glands: Anatomy, but they can also arise from sympathetic ganglia (also referred to as paragangliomas). Symptoms are associated with excessive catecholamine production and commonly include hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, pallor, tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies, and sweating. The clinical features of pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma are very similar to those of panic disorder, but there is no severe hypertension Severe hypertension A confirmed blood pressure ≥ 180 mm Hg systolic and/or ≥ 120 mm Hg diastolic. Uncontrolled Hypertension in panic disorder. 
• PTSD PTSD Posttraumatic stress disorder is a psychiatric illness characterized by overwhelming stress and anxiety experienced after exposure to a life-threatening event. Symptoms last more than 1 month and involve re-experiencing the event as flashbacks or nightmares, avoiding reminders of the event, irritability, hyperarousal, and poor memory and concentration. Posttraumatic Stress Disorder (PTSD): seen after experiencing a life-threatening event. Symptoms last > 1 month and involve reexperiencing the event as flashbacks or nightmares, avoiding reminders, irritability, hyperarousal and poor memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment and concentration. Panic attacks are a hallmark of PTSD PTSD Posttraumatic stress disorder is a psychiatric illness characterized by overwhelming stress and anxiety experienced after exposure to a life-threatening event. Symptoms last more than 1 month and involve re-experiencing the event as flashbacks or nightmares, avoiding reminders of the event, irritability, hyperarousal, and poor memory and concentration. Posttraumatic Stress Disorder (PTSD) but the diagnosis of PTSD PTSD Posttraumatic stress disorder is a psychiatric illness characterized by overwhelming stress and anxiety experienced after exposure to a life-threatening event. Symptoms last more than 1 month and involve re-experiencing the event as flashbacks or nightmares, avoiding reminders of the event, irritability, hyperarousal, and poor memory and concentration. Posttraumatic Stress Disorder (PTSD) must also meet other criteria, such as history of life-threatening events or presence of intrusion symptoms or negative mood changes, that are not commonly found in those with panic disorder. 
• Generalized anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder disorder: common mental condition defined by excessive, uncontrollable worrying that causes distress and occurs frequently for ≥ 6 months. Clinical presentation includes fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, low concentration, restlessness, irritability, and sleep Sleep A readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility. Physiology of Sleep disturbance. If patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have symptoms of anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder without reporting experiencing panic attacks (as defined above), they do not meet the criteria for the diagnosis of panic disorder. 
• Withdrawal (from alcohol or benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines): patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder or anxiolytic use disorder are at increased risk of withdrawal if they discontinue their substance use abruptly. Symptoms include worsening of initial anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia, psychosis, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Withdrawal from alcohol and anxiolytics are distinguished from panic disorder by history, physical exam, and urine toxicology screen.