1. Generalized Anxiety Disorder & Panic Disorder
Jeannette Dagam, D.O.
Department of Psychiatry
The Ohio State University
College of Medicine

2. At the end of this module, you will know the following:
Learning Objectives
At the end of this module, you will know the following:
Identify etiological and diagnostic considerations in patients with anxiety disorders: Panic Disorder.
Differential diagnosis
Clinical Workup
DSM 5 criteria
Clinical Features
Epidemiology
Pathophysiology
Course
Treatment
Identify etiological and diagnostic considerations in patients with anxiety disorders: Panic Disorder.
Be able to discuss the differential diagnosis and clinical workup of patients who present with anxiety symptoms
Learn the DSM 5 criteria for generalized anxiety disorder and panic disorder
Be able to discuss the clinical features of these disorders, as well as the course and prognosis
Recognize the epidemiology and significance of generalized anxiety and panic disorders
Understand the neurobiologic and pathophysiologic changes in these anxiety disorders
Comment on treatment for these anxiety disorders

3. Approach to the Patient with a Chief Complaint of Anxiety
History & Physical
Lethality Assessment
Past Psychiatric History
Family Psychiatric History
Medical/Surgical History
Physical
History & Physical
Be sure to include a suicide risk assessment and inquire about suicidal/homicidal ideation, past suicide attempts, family psychiatric history, and history of mood and other psychiatric symptoms
A complete medical history, list of medications (including herbs/supplements), as well as a substance use history are all vital
On physical, examine for indications of other medical problems including signs of endocrine disorders, heart murmurs, neurologic dysfunction, vitamin deficiencies, and infections

4. Mental Status Examination
Appearance
Level of consciousness/alertness
Orientation/memory
Psychomotor abnormalities (agitation or retardation)
Suicidal or homicidal ideation
Hallucinations or delusional thought content
Insight
Judgment
Impulse Control
Elements of the Mental Status Exam that are of particular importance:
Appearance
Level of consciousness/alertness
Orientation/memory
Psychomotor abnormalities (agitation or retardation)
Suicidal or homicidal ideation
Hallucinations or delusional thought content
Insight
Judgment
Impulse Control

5. Laboratory and Diagnostic Testing
Standard workup
Other testing to consider
Standard workup would include:
Complete blood count with differential
Complete metabolic panel (chemistries, liver function tests)
TSH and free T4
Toxicology screen
ECG
Other testing to consider if clinically indicated:
Chest x-ray
Blood gas studies
D-dimer
24 hour urine study for catecholamines and metanephrines
CT scan with pulmonary embolism protocol
Holter monitoring
Head imaging
Pregnancy and sexually transmitted diseases screening

6. Differential Diagnosis of Anxiety / General Medical Conditions
Endocrine
Neurologic
Infections
Cardiopulmonary disease
Cancers
Autoimmune disorders
Endocrine disorders – thyroid, adrenal, parathyroid, diabetes
Neurologic Disorders – strokes, infections, epilepsy, Parkinson’s or Huntington’s disease
Infections – HIV, mononucleosis, encephalitis, hepatitis, neurosyphillis, tuberculosis, pneumonia
Cardiopulmonary disease – angina, cardiomyopathies, valvular dysfunction, asthma/COPD, pulmonary hypertension, pulmonary embolus
Cancers – intracranial (primary or metastatic), endocrine malignancies
Autoimmune disorders – system lupus erythematosus, rheumatoid arthritis, multiple sclerosis

7. Differential Diagnosis of Anxiety – Substance-Induced Disorders
Intoxication
Withdrawal
Surreptitious use medications
Side effects of medications
Intoxication with/use of: anabolic steroids, hallucinogens, inhalants, opioids, phencyclidine, alcohol, amphetamines, cannabis, sedative-hypnotics, cocaine
Withdrawal from: alcohol, amphetamines, sedative-hypnotics, cocaine
Surreptitious use of over the counter or prescription medications: decongestants, thyroid supplementation, corticosteroids
Side effects of medications used for appropriate medical indications: antidepressants, stimulants, anticonvulsants, corticosteroids, antipsychotics, antineoplastic agents, oral contraceptives, interferon-alpha, xanthine compounds (caffeine, aminophylline), insulin, sympathomimetics

8. Differential Diagnosis of Anxiety / Other Psychiatric Disorders
Major Depressive Disorder
Schizoaffective Disorder or Schizophrenia
Delusional disorder or Paranoid Personality Disorder
Delirium
Adjustment Disorders with anxious or mixed features
Social Phobia
Obsessive Compulsive Disorder
Major Depressive Disorder
Anxiety is often co-morbid with and can be fueled by depression
Schizoaffective Disorder or Schizophrenia
Anxiety can manifest from delusional content or distress about hallucinations
Delusional disorder or Paranoid Personality Disorder
Anxieties revolving around certain themes or pervasive mistrust towards others and their intentions
Delirium
Watch for clouding of consciousness
Adjustment Disorders with anxious or mixed features
Emotional or behavioral symptoms in response to an identifiable stressor(s) occurring within 3 months of the stressor(s)
Social Phobia
Specific worry related to being evaluated, embarrassed or humiliated in front of others
Obsessive Compulsive Disorder
Obsessive thoughts that are focused on exaggerated or unrealistic expectations +/- mental rituals or compulsions

9. DSM 5 Criteria Generalized Anxiety Disorder
A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance).
B. The person finds it difficult to control the worry.
C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms present for more days than not for the past 6 months).
Note: Only one item is required in children.
(1) restlessness or feeling keyed up or on edge
(2) being easily fatigued
(3) difficulty concentrating or mind going blank
(4)irritability
(5)muscle tension
(6) sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep)

10. DSM 5 Criteria Generalized Anxiety Disorder
D. The focus of the anxiety and worry is not confined to features of an Axis I Disorder, e.g., the anxiety or worry is not about having a panic attack (as in panic disorder), being in embarrassed in public (as in social phobia), being contaminated (as in obsessive-compulsive disorder), being away from home or close relatives (as in separation anxiety disorder), gaining weight (as in anorexia nervosa), having multiple physical complaints (as in somatization disorder), or having a serious illness (as in hypochondriasis), and the anxiety and worry do not occur exclusively during posttraumatic stress disorder.
E. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
F. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism) and does not occur exclusively during a mood disorder, a psychotic disorder, or a pervasive developmental disorder.

11. DSM 5 Criteria Panic Disorder
A. Recurrent unexpected panic attacks. A panic attack is an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, and during which time four (or more) of the following symptoms occur:
Note: The abrupt surge can occur from a calm state or an anxious state.
1) Palpitations, pounding heart, or accelerated heart rate
2) Sweating
3) Trembling or shaking
4) Sensations of shortness of breath or smothering
5) Feelings of choking
6) Chest pain or discomfort
7) Nausea or abdominal discomfort
8) Feeling dizzy, unsteady, light-headed, or faint
9) Chills or heat sensations
10) Paresthesias (numbness or tingling sensations)
11) Derealization (feelings of unreality) or depersonalization (being detached from oneself)
12) Fear of losing control or ‘going crazy’
13) Fear of dying

12. DSM 5 Criteria Panic Disorder
Note: Culture-specific symptoms (e.g., tinnitus, neck soreness, headache, uncontrollable screaming or crying) may be seen. Such symptoms should not count as one of the four required symptoms. B. At least one of the attacks has been followed by 1 month (or more) of one or both of the following: 1. Persistent concern or worry about additional panic attacks or their consequences (.e.g., losing control, having a heart attack, or ‘going crazy’) 2. A significant maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks, such as avoidance of exercise or unfamiliar situations) C. The disturbance is not attributable to the physiologic effects of a substance (e.g., a drug of abuse, a medications) or another medical condition (e.g., hyperthyroidism, cardiopulmonary disorders) D. The disturbance is not better explained by another mental disorder (e.g., the panic attacks do not occur only in response to feared social situations, as in social anxiety disorder; in response to circumscribed phobic objects or situations, as in specific phobia; in response to obsessions, as in OCD; in response to reminders of traumatic events, as in PTSD; or in response to separation from attachment figures, as in separation anxiety disorder ).

13. DSM 5 Criteria Panic Attack
Note: Symptoms are presented for the purpose of identifying a panic attack; however panic attack is not a mental disorder and cannot be coded. Panic attacks can occur in the context of any anxiety disorder as well as other mental disorder (e.g., depressive disorders, PTSD, substance use disorders) and some medical conditions (e.g., cardiac, respiratory, vestibular, gastrointestinal). When the presence of a panic attack is identified, it should be noted as a specifier (e.g., “posttraumatic stress disorder with panic attacks”).
For panic disorder, the presence of panic attack is contained within the criteria for the disorder and panic attack is not used as a specifier.
An abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, and during which time four (or more) of the following symptoms occur:
Note: the abrupt surge can occur from a calm state or an anxious state.

14. DSM 5 Criteria Panic Attack
1) Palpitations, pounding heart, or accelerated heart rate
2) Sweating
3) Trembling or shaking
4) Sensations of shortness of breath or smothering
5) Feelings of choking
6) Chest pain or discomfort
7) Nausea or abdominal discomfort
8) Feeling dizzy, unsteady, light-headed, or faint
9) Chills or heat sensations
10) Paresthesias (numbness or tingling sensations)
11) Derealization (feelings of unreality) or depersonalization (being detached from oneself)
12) Fear of losing control or ‘going crazy’
13) Fear of dying
Note: Culture-specific symptoms (e.g., tinnitus, neck soreness, headache, uncontrollable screaming or crying) may be seen. Such symptoms should not count as one of the four required symptoms.

15. DSM 5 Criteria Agoraphobia
Marked fear or anxiety about two (or more) of the following five situations:
1. Using public transportation (e.g., automobiles, buses, trains, ships, planes).
2. Being in open spaces (e.g., parking lots, marketplaces, bridges).
3. Being in enclosed places (e.g., shops, theaters, cinemas).
4. Standing in line or being in a crowd.
5. Being outside of the home alone.
The individual fears or avoids these situations because of thoughts escape might be difficult or help might not be available in the event of developing panic-like symptoms or other incapacitating or embarrassing symptoms (e.g., fear of falling in the elderly; fear of incontinence).
The agoraphobic situations almost always provoke fear or anxiety.
The agoraphobic situations are actively avoided, require the presence of a companion, or are endured with intense fear or anxiety.
The fear or anxiety is out of proportion to the actual danger posed by the agoraphobic situations and the sociocultural context.
The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.

16. DSM-5 Criteria Agoraphobia
G. The fear, anxiety, or avoidance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
H. If another medical condition (e.g., inflammatory bowel disease, Parkinson’s disease) is present, the fear, anxiety, or avoidance is clearly excessive.
I. The fear, anxiety, or avoidance is not better explained by the symptoms of another mental disorder – for example, the symptoms are not confined to specific phobia, situational type; do not involve only social situations (as in social anxiety disorder); and are not related exclusively to obsessions (as in obsessive-compulsive disorder), perceived defects or flaws in physical appearance (as in body dysmorphic disorder), reminders of traumatic events (as in posttraumatic stress disorder), or fear of separation (as in separation anxiety disorder).
Note: Agoraphobia is diagnosed irrespective of the presence of panic disorder. If an individual’s presentation meets criteria for panic disorder and agoraphobia, both diagnoses should be assigned.

17. Epidemiology Generalized Anxiety Disorder (GAD)
Common in primary care settings
Higher prevalence in women
High comorbidity with other psychiatric disorders including substance abuse disorders
GAD is the most common anxiety disorder in primary care settings
GAD is approximately twice as common in females as in males
In a community sample, the 1-year prevalence rate was approximately 3% and the lifetime prevalence was 5%
Up to 90% of patients who meet criteria for GAD also meet criteria for another Axis I condition
Patients with GAD have a 10 to 12 fold increase in risk for mood and personality disorders
They also have a greatly increased risk for substance use disorders

18. Heritability Generalized Anxiety Disorder
Familial
Genetic loading
Anxiety as a trait has a familial association
Earlier studies produced inconsistent findings regarding familial patterns for GAD but more recent twin studies suggest a genetic contribution to the development of this disorder
Genetic factors influencing risk of GAD may be closely related to those for Major Depressive Disorder

19. Pathophysiology Generalized Anxiety Disorder
Biologically heterogeneous
Knowledge about the disorder derived indirectly
GABA, serotonin and norepinephrine neurotransmitters interplaying within the limbic system
Among the DSM-IV Anxiety Disorders, GAD is the most biologically heterogeneous condition – relatively little has been established about its pathophysiology but it also seems that no abnormalities exist that are both sensitive and specific for GAD
This body of knowledge has been largely derived from pharmacologic studies of anti-anxiety drugs (benzodiazepines, buspirone) and the anxiogenic or anxiolytic effects of various agents
Neuroanatomic localization is believed to involve the limbic system and the neurotransmitters believed to be involved are GABA, serotonin and norepinephrine

20. Epidemiology Panic Disorder
More common in women
Average onset in the 3rd decade of life
Various medical settings demonstrate prevalence rates
Panic disorder is more commonly diagnosed in women than in men with a 3:1 ratio in patients with agoraphobia and 2:1 ratio in patients without agoraphobia
On average, the onset of panic disorder is in the third decade and although the onset may be spontaneous, many individuals identify a life stressor occurring prior to the onset of panic symptoms
Lifetime prevalence rates of panic disorder are 1-2%
In general medical settings, prevalence rates vary from 10 to 30% in vestibular, respiratory, and neurology clinics to as high as 60% in cardiology clinics

21. Heritability of Panic Disorder
First degree relatives at high risk
Earlier age of onset confers a higher risk
Twin studies
First-degree relatives of individuals with Panic Disorder are up to 8 times more likely to develop Panic Disorder
If the age of onset of the Panic Disorder is before 20, first-degree relatives have been found to be up to 20 times more likely to have Panic Disorder
Twin studies find an average concordance rate for Panic Disorder of 30% to 40% in monozygotic twin pairs, but only about 4% to 5% in dizygotic pairs

22. Biopsychosocial Correlates Panic Disorder
Decreased exercise tolerance, with increased oxygen consumption and increased production of lactic acid
Increased prevalence of Irritable Bowel Syndrome
Increased prevalence of Peptic Ulcer
Decreased resting pCO2
Increased sensitivity to anxiogenic effects of stimulants (e.g., caffeine)
Increased frequency of history of childhood Separation Anxiety Disorder
Increased frequency of asymptomatic mitral valve prolapse (MVP)

23. Mitral Valve Prolapse and Panic Disorder
Historically tagged as the culprit
Absence of significant differentiation between patient groups
Does not confer increased risk
Once hypothesized to be the cause of Panic Attacks, mitral valve prolapse (MVP; abnormal displacement of the mitral valve leaflets into the left atrium during systole) is now known to occur in about 5% of the population as an asymptomatic condition
Up to 50% of patients with panic disorder have MVP, but there are no consistent differences between panic disorder patients with MVP and those without on other variables such as clinical features, physiologic parameters, clinical course or response to pharmacologic challenge or any form of treatment
Also, compared to controls without MVP, patients with MVP do not have increased risk for Panic or other anxiety disorders

24. Physiologic Challenge Studies Panic Disorder
Panic Disorder patients have an increased sensitivity to the anxiogenic effects of caffeine; however large doses of caffeine can induce panic attacks in anyone
Panic Disorder patients have an increased sensitivity to the physiologic effects of hyperventilation (which decreases pCO2 concentration) and often have Panic Attacks during voluntary over-breathing of room air. Hyperventilation, however, does not produce Panic Attacks in persons who do not have Panic Disorder
Panic Attacks are easily induced in many patients with Panic Disorder, but not in controls who do not have Panic Disorder, in response to:
Injection of sodium lactate
Breathing air in which CO2 is elevated
Injection of isoproterenol, a beta-receptor agonist
Injection of yohimbine, an alpha 2 – receptor antagonist
Injection of cholecystokinin tetrapeptide
Injection of flumazenil, a benzodiazepine receptor antagonist

25. Neuroanatomic correlates Panic Disorder
Clinical features, imaging studies, and drug effects suggest that acute panic attacks originate in the brainstem, probably in the locus ceruleus of the pons. The latter is the major noradrenergic nucleus of the brain.
Anticipatory anxiety between attacks reflects increased activity in the limbic system and may induce kindling (change in diathesis, making new panic attacks increasingly likely)
Avoidance behavior is an adaptive effort by the prefrontal cortex, motivated by the increased limbic activity associated with anticipatory anxiety, and reinforced by diminution of the latter (negative reinforcement), thus promoting a vicious cycle.

26. Neurotransmitter/Neuromodulator Abnormalities in Panic Disorder
Norepinephrine in the locus ceruleus
Serotonin in midbrain neurons
GABA in the limbic system
Adenosine or Cholecystokinin at CNS sites not yet identified
Based largely on indirect evidence such as observed effects of various medications which induce, prevent, or do not prevent panic attacks, several neurotransmitters or neuroregulatory abnormalities have been proposed.
Panic Disorder may involve abnormalities in functioning of:
Norepinephrine in the locus ceruleus
Serotonin in midbrain neurons
GABA in the limbic system
Adenosine or Cholecystokinin at CNS sites not yet identified

27. Course Generalized Anxiety Disorder
The majority of individuals with GAD report that they have felt anxious and nervous all their lives
Over half of those presenting for treatment report onset in childhood or adolescence, onset occurring after age 20 years is not uncommon
The course is chronic but fluctuating and often worsens during times of stress

28. Age of onset Usual course Onset of agoraphobia Course Panic Disorder
Age of onset for Panic Disorder varies considerably but is most typically between late adolescence and the mid-30s
Retrospective descriptions by individuals seen in clinical settings suggest that the usual course is chronic but waxing and waning; some individuals may have episodic outbreaks with years of remission in between, and others may have continuous severe symptomatology
Limited symptom attacks may come to be experienced with greater frequency if the course of the Panic Disorder is chronic
Although agoraphobia may develop at any point, its onset is usually within the first year of occurrence of recurrent Panic Attacks

29. Agoraphobia Naturalistic studies Course Panic Disorder
Agoraphobia may become chronic regardless of the presence or absence of Panic Attacks
Naturalistic follow-up studies of individuals treated in tertiary care settings (which may select for a poor prognosis group) suggest that, at 6-10 years post treatment, about 30% of individuals are well, 40%-50% are improved but symptomatic, and the remaining 20-30% have symptoms that are the same or slightly worse

30. Treatment Antidepressants Benzodiazepines Other Agents Psychotherapy
SSRIs, SNRIs, TCAs, MAOIs
Antidepressants
Lorazepam, clonazepam, diazepam, etc.
Benzodiazepines
Buspirone
Hydroxyzine
Other Agents
Cognitive Behavioral Therapy
Relaxation exercises
Psychotherapy

31. References ISP Module for Psychiatry / OSU Dept. of Psychiatry
Clinical Manual of Anxiety Disorders, edited by Dan J. Stein, MD, PhD; American Psychiatric Publishing, Inc. 2004
DSM 5, American Psychiatric Association, 2013

32. GAD and Panic Disorder Quiz

33. In Summary
Anxiety and panic are common features within many psychiatric conditions, but the focus, scope and intensity of one’s worry is important in determining whether an independent anxiety or panic disorder exists.
Anxiety as a trait has a familial association – panic disorder develops up to 8 times more often in first degree relatives.
Among the anxiety disorders, generalized anxiety disorder is the most biologically heterogeneous condition.
Effective management of anxiety disorders often involves both pharmacologic and psychological interventions.

34. Thank you for completing this module
Questions?