Rene Love, Rose Vick Anxiety disorders are the most commonly occurring class of mental disorders per lifetime prevalence data.1 Within anxiety disorders, specific phobias are the most common, with social phobias being the next most common. The least common of the anxiety disorders are obsessive-compulsive disorder (OCD) and agoraphobia without a history of panic disorder.2 The development of anxiety disorders depends on several variables that affect the way the body responds to fear and anxiety, such as gender, age, culture, environment, qualities of the stressor, and genetics. In general, anxiety disorders typically begin much earlier than other mental disorders, and women are at higher risk than men.2 More specifically, the onset of tic disorders and specific phobias begins in childhood with social phobias and OCD beginning in adolescence or early adulthood. The onset of post-traumatic stress disorder (PTSD) can vary; the disorder results from trauma exposure, which may occur at any point in life. Panic disorder, generalized anxiety disorder (GAD), and agoraphobia are the only anxiety disorders that have adult onset. Fear can be healthy in our lives. Healthy fear warns us to get out of harm’s way or motivates a person to take action. However, if a person’s stress level becomes persistent, excessive, overwhelming, and disabling, then an anxiety disorder should be considered. There are several factors to take into account, such as culture, genetics, environment, and psychosocial issues, when diagnosing anxiety disorders. In looking at the burden of anxiety disorders, women were found to miss more days from work as a result of anxiety disorders,3 although both men and women with anxiety disorders were frequent users of all types of health care services, including emergency rooms. On the other hand, men but not women were more likely to visit a professional for either an emotional or substance use issue in the past year if they had an anxiety disorder. In considering cultural impact, European-American women were high health care users.3 With regard to specific phobias, Asians and Latinos reported significantly lower rates than non-Latino whites.4 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) identifies the following anxiety disorders: Separation Anxiety Disorder; Selective Mutism; Specific Phobia; Social Anxiety Disorder (Social Phobia); Panic Disorder; Agoraphobia; Substance/Medication-Induced Anxiety Disorder; Anxiety Disorder Due to Another General Medical Condition; and Generalized Anxiety Disorder.4 Also included are Posttraumatic Stress Disorder (PTSD) and Acute Stress Disorder (ASD).4 The following definitions of the more common anxiety disorders are adapted from the DSM-5. Separation anxiety disorder is developmentally excessive and inappropriate anxiety and distress regarding separating from attachment figures. Selective mutism is consistently failing to speak in situations in which the person is expected to speak, even though the person will speak in other situations, thereby interfering with the person’s education and occupation. A specific phobia is extreme fear and distress about a specific object or situation such as snakes or heights. A social anxiety disorder is extreme fear and distress about social situations in which the individual is exposed to possible scrutiny by other people, which may cause the person to avoid social situations altogether. Panic disorder is characterized by recurring and unanticipated panic attacks. GAD is excessive anxiety that occurs more days than not about a wide variety of events or activities. PTSD occurs when a person is exposed to a trauma that causes intense psychological distress when he or she is exposed to either internal or external cues.4 Fear is a normal response that promotes survival in the face of an actual environmental threat. For example, it is adaptive and beneficial to experience a fight-or-flight response via the sympathetic nervous system (SNS) when confronted by dangerous stimuli. Anxiety, on the other hand, is an unhealthy, exaggerated fear response that often occurs in the absence of a true environmental threat.5 Physiologically, the body does not differentiate between anxiety and fear. Simply stated, blood flow is increased to the large muscle groups in preparation to flee or fight; the heart and legs are ready to take action, and the digestive system slows. However, the fear response is a complex process involving multiple organ systems, and therefore anxiety has many associated physical and psychological consequences. Subcortical (amygdala, hippocampus, brainstem, and hypothalamus) and cortical regions (insular cortex, orbitofrontal cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) of the brain are involved in anxiety disorders.6 The amygdala and hypothalamic-pituitary-adrenal (HPA) axis are two primary areas implicated in the neuropathology of anxiety. The amygdala is part of the limbic system and processes emotionally salient stimuli and initiates the appropriate behavioral response. The HPA axis functions as a hormonal feedback system and includes the hypothalamus, pituitary gland, and adrenal gland. Harmful stimuli undergo sensory processing, and information is relayed to the hypothalamus. The hypothalamus initiates the HPA axis by releasing corticotropin-releasing factor (CRF), which triggers the release of adrenocorticotropic hormone (ACTH) from the pituitary, which then triggers the release of glucocorticoids (including cortisol) from the adrenal gland.5 When the system is functioning properly, it operates on a negative feedback loop: the binding of glucocorticoids to glucocorticoid receptors inhibits further release of CRF and ACTH.5 However, abnormalities in the HPA axis are implicated in individuals with anxiety disorders.7 It is well known that anxiety disorders have a strong familial link, and it is also understood that environmental factors contribute significantly to the development of anxiety disorders. Gene-environment (G × E) interactions related to anxiety have been demonstrated quite eloquently in rat studies, highlighting the significance of genetic and environmental influences as well as the concept of epigenetics.8 During recent years, the serotonin transporter gene-linked polymorphic region (5-HTTLPR) has received a lot of attention in the literature owing to its association with increased vulnerability to psychiatric illness when combined with environmental stressors or adversity. There is evidence suggesting that individuals who are carriers of at least one short (S) allele and a history of adverse life events are at an increased risk for depression.9 Experimental studies aimed at investigating the relationship between the 5-HTTLPR genotype and HPA axis reactivity in healthy individuals have produced inconsistent results. However, a recent meta-analysis demonstrated a small but significant association between the 5-HTTLPR genotype and HPA axis reactivity: specifically, individuals with the S/S genotype displayed increased cortisol reactivity compared with the S/L and L/L genotypes.7 Neurotransmitters including serotonin, norepinephrine, dopamine and γ-aminobutyric acid (GABA) have been well studied and are implicated in the pathophysiology of anxiety disorders. The involvement of these multiple neurotransmitter systems is complex and cannot be oversimplified as the presence of too much or not enough of a particular neurotransmitter. For example, serotonin pathways are involved in regulating mood states including anxiety and are also involved in the modulation of dopaminergic and noradrenergic pathways. Dopamine, serotonin, norepinephrine, and GABA have been linked to anxiety states and treatment for many years. Recent studies have investigated the role of glutamate, specifically the N-methyl-D-aspartate (NMDA) receptor, in the development and treatment of mood disorders and have led to efforts to develop novel psychopharmacologic treatments.10 Clinical trials that expand our understanding of the role of glutamate in anxiety could change the way we treat anxiety disorders in the future. There remains much to learn about the development and management of anxiety disorders, but it is safe to stay that they involve complex interplay among genes, environment, culture, personality, and psychoneuroimmunologic factors. Individuals with anxiety disorders often first are seen for treatment in primary care clinics and emergency departments. In addition to complaints of worry, anxiety, or fear, these individuals may also have numerous physical complaints. Anxiety disorders are highly comorbid with one another and other psychiatric illnesses including depression and substance use disorders. Anxiety, by definition, is the anticipation of a future threat and is often associated with preparation for potential danger and/or avoidant behaviors.4 Anxiety disorders differ from developmentally or situationally appropriate fears in that they are persistent (typically lasting 6 months or longer) and cause significant impairments in functioning.4 GAD is characterized by excessive anxiety and worry about a number of events or activities. The anxiety and worry are associated with three or more of the following six symptoms: (1) restlessness or feeling on edge, (2) easy fatigability, (3) difficulty concentrating, (4) irritability, (5) muscle tension, (6) sleep disturbance.4 GAD is a chronic condition in which full remission rates are very low.4 Children and adolescents tend to experience performance-focused worry and anxiety, whereas adults report more worry about their physical health or the well-being of their family.4 In addition to worry, these individuals may also experience a variety of physical symptoms including tachycardia, shortness of breath, muscle tension and aches, trembling, twitching, sweating, dizziness, nausea, and diarrhea. Headaches and irritable bowel syndrome are two medical conditions frequently associated with GAD. In the United States, GAD causes significant functional impairment and disability and accounts for 110 million disability days per annum.4 Specific phobias are characterized by marked fear or anxiety about a specific object or situation. The phobic object or situation almost always provokes immediate fear, and the object or situation is either avoided or endured with intense fear or anxiety.4 Specific phobias are coded based on the phobic stimulus (animal, natural environment, blood-injection-injury, situational, or other). Most people with specific phobias have more than one phobic stimulus, and functional impairment increases with the number of phobic stimuli. Blood-injection-injury phobias may cause individuals to neglect their physical health because of the anxiety associated with provider appointments. Fear of falling in the geriatric population can lead to reduced mobility and impairments in physical health and social functioning.4 Social anxiety disorder or social phobia involves clinically significant anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others (e.g., social interactions, eating, speaking in public).4 Panic disorder is characterized by recurrent unexpected panic attacks. A panic attack is defined as “an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes”4 and includes four or more of the symptoms listed in Box 247-1. Panic attacks can occur within the context of any other psychiatric disorder, and to reflect this the condition was added as a specifier in the DSM-5. OCD consists of the presence of obsessions, compulsions, or both. Obsessions are defined as recurrent thoughts, urges, or images that are intrusive and unwanted. Compulsions are repetitive behaviors or acts (e.g., checking, counting, praying) that the individual feels driven to perform and are aimed at reducing anxiety or a dreaded situation. Rates of OCD are higher in individuals with body dysmorphic disorder, trichotillomania, excoriation disorder, schizophrenia, schizoaffective disorder, bipolar disorder, eating disorders, and Tourette disorder.4 Impairment is related to severity of symptoms and can affect interpersonal relationships, occupational and academic performance, physical health, and even successful treatment of the disorder.4 The DSM-5 was released in May 2013 and presents a new organizational system for some of the anxiety disorders. OCD is now located in the chapter Obsessive-Compulsive and Related Disorders, which includes OCD, Body Dysmorphic Disorder, Hoarding Disorder, Trichotillomania, and Excoriation Disorder. PTSD is now included with the Trauma- and Stressor-Related Disorders along with Acute Stress Disorder and Adjustment Disorder, among others. Separation Anxiety Disorder was previously included in Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence but is now applicable to adults and is included with the Anxiety Disorders. Another change to the DSM-5 is that individuals older than 18 with Agoraphobia, Specific Phobia, and Social Anxiety Disorder need not recognize that their anxiety is excessive or unreasonable, but the anxiety must be out of proportion to the actual threat.4 It is not surprising that individuals with anxiety disorders often fear an underlying medical disorder, given the frequency of associated physical symptoms. Many of the physical symptoms of anxiety (chest pain, shortness of breath, dizziness, and gastrointestinal symptoms) could signal a serious medical illness. Therefore, medical causes must be explored and ruled out before a diagnosis of an anxiety disorder is made. As with any physical examination, a thorough history is required. Some symptoms of anxiety disorders are preceded by recent events of interpersonal violence, accident, or natural disaster. The potential physical injuries that follow exposure to these events could include damage to any body system; thus a full physical examination is necessary. It is also important to inquire about psychosocial stressors and a remote history of traumas or abuse because these experiences increase risk for anxiety disorders. In a large study of women ages 65 and older, nearly 14% reported a lifetime history of physical assault, sexual assault, or both, and assaults were typically repeated events.11 Women who had experienced a history of interpersonal violence were more likely to meet criteria for PTSD and other anxiety disorders than those who had not experienced interpersonal violence.11 Providers need to ask specific questions regarding trauma history and be prepared to refer the individual for trauma-informed care.11 There is no laboratory test, imaging modality, or physical examination finding that can definitively diagnosis an anxiety disorder. Like all mental health diagnoses, the symptoms must meet the criteria in the DSM-5, with the symptoms being at a moderate to severe level and affecting hygiene, relationships, employment, or education. Urine toxicologies are helpful to determine substance use that may contribute to the symptoms described by the patient. It is equally important to rule out other medical conditions through a physical examination and blood work to assess for infection, anemia, electrolyte imbalance, liver or kidney dysfunction, thyroid disease, hyperparathyroidism, and glucose intolerance. The importance of ruling out exposure to the anxiety-producing effects of caffeine is often missed, but caffeine may play a critical role in anxiety. Electrocardiograms may be obtained to rule out cardiac problems with a person experiencing panic attacks. The screening tool recommended for GAD in primary care settings for anxiety disorders is the GAD 7-item instrument (GAD-7).12 The screening tool recommended for PTSD is the Primary Care PTSD Screen (PC-PTSD).13 The Social Phobia Inventory (SPIN) Mini-SPIN Screening Tool has three items to assess for social phobias.14 These scales will facilitate identification of patients who require additional assessment for a psychiatric disorder. Side effects from medications and the physiologic effects of intoxication or withdrawal from substances should be taken into account when the symptoms of anxiety disorders are reviewed. Medications, other medical conditions, and other psychiatric conditions that mimic symptoms with anxiety disorders are included in the differential diagnosis box. Differential Diagnosis Anxiety Disorders
Anxiety Disorders
Definition and Epidemiology
Pathophysiology
Clinical Presentation
Physical Examination
Diagnostics
Anxiety Disorders
Chapter 247
