Anxiety Disorders

Background

Anxiety disorders are the most common type of psychiatric disorders. Many patients with anxiety disorders experience physical symptoms related to anxiety and subsequently visit their primary care providers. Despite the high prevalence rates of these anxiety disorders, they often are underrecognized and undertreated clinical problems.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), [1] anxiety disorders include disorders that share features of excessive fear and anxiety and related behavioral disturbances. These disorders include separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder, substance/medication-induced anxiety disorder, and anxiety disorder due to another medical condition. Obsessive-compulsive disorder (included in the obsessive-compulsive and related disorders), acute stress disorder, and posttraumatic stress disorder (included in the trauma and stress-related disorders) are no longer considered anxiety disorders as they were in the previous version of the DSM. However, these disorders are closely related to anxiety disorders and the sequential order of these chapters in the DSM-5 reflects this close relationship.

Anxiety disorders appear to be caused by an interaction of biopsychosocial factors, including genetic vulnerability, which interact with situations, stress, or trauma to produce clinically significant syndromes. (See Pathophysiology and Etiology.)

Symptoms vary depending on the specific anxiety disorder. (See Clinical Presentation.)

Treatment usually consists of a combination of pharmacotherapy (see Medication) and/or psychotherapy. (See Treatment Strategies and Management.)

Anatomy

The brain circuits and regions associated with anxiety disorders are beginning to be understood with the development of functional and structural imaging. The brain amygdala appears key in modulating fear and anxiety. Patients with anxiety disorders often show heightened amygdala response to anxiety cues. The amygdala and other limbic system structures are connected to prefrontal cortex regions. Hyperresponsiveness of the amygdala may relate to reduced activation thresholds when responding to perceived social threat. [2, 3] Prefrontal-limbic activation abnormalities have been shown to reverse with clinical response to psychologic or pharmacologic interventions.

Pathophysiology

In the central nervous system (CNS), the major mediators of the symptoms of anxiety disorders appear to be norepinephrine, serotonin, dopamine, and gamma-aminobutyric acid (GABA). Other neurotransmitters and peptides, such as corticotropin-releasing factor, may be involved. Peripherally, the autonomic nervous system, especially the sympathetic nervous system, mediates many of the symptoms. [4]

Positron emission tomography (PET) scanning has demonstrated increased flow in the right parahippocampal region and reduced serotonin type 1A receptor binding in the anterior and posterior cingulate and raphe of patients with panic disorder. [5]MRI has demonstrated smaller temporal lobe volume despite normal hippocampal volume in these patients. [6] The CSF in studies in humans shows elevated levels of orexin, also known as hypocretin, which is thought to play an important role in the pathogenesis of panic in rat models. [7]

 

Etiology

Anxiety disorders in general

The first consideration is the possibility that anxiety is due to a known or unrecognized medical condition. Substance-induced anxiety disorder (over-the-counter medications, herbal medications, substances of abuse) is a diagnosis that often is missed.

Genetic factors significantly influence risk for many anxiety disorders. Environmental factors such as early childhood trauma can also contribute to risk for later anxiety disorders. The debate whether gene or environment is primary in anxiety disorders has evolved to a better understanding of the important role of the interaction between genes and environment. [13] Some individuals appear resilient to stress, while others are vulnerable to stress, which precipitates an anxiety disorder.

Most presenting anxiety disorders are functional psychiatric disorders. Psychological theories range from explaining anxiety as a displacement of an intrapsychic conflict (psychodynamic models) to conditioning (learned) paradigms (cognitive-behavioral models). Many of these theories capture portions of the disorder.

The psychodynamic theory has explained anxiety as a conflict between the id and ego. Aggressive and impulsive drives may be experienced as unacceptable resulting in repression. These repressed drives may break through repression, producing automatic anxiety. The treatment uses exploration with the goal of understanding the underlying conflict. Cognitive theory has explained anxiety as the tendency to overestimate the potential for danger. Patients with anxiety disorder tend to imagine the worst possible scenario and avoid situations they think are dangerous, such as crowds, heights, or social interaction.

Panic disorder

Panic disorder appears to be a genetically inherited neurochemical dysfunction that may involve autonomic imbalance; decreased GABA-ergic tone [14] ; allelic polymorphism of the catechol-O-methyltransferase (COMT) gene; increased adenosine receptor function; increased cortisol [15] ; diminished benzodiazepine receptor function; and disturbances in serotonin, [16] serotonin transporter (5-HTTLPR) [17] and promoter (SLC6A4) genes, [18] norepinephrine, dopamine, cholecystokinin, and interleukin-1-beta. [19] Some theorize that panic disorder may represent a state of chronic hyperventilation and carbon dioxide receptor hypersensitivity. [8] Some epileptic patients have panic as a manifestation of their seizures. Genetic studies suggest that the chromosomal regions 13q, 14q, 22q, 4q31-q34, and probably 9q31 may be associated with the heritability of panic disorder phenotype. [20]

The cognitive theory regarding panic is that patients with panic disorder have a heightened sensitivity to internal autonomic cues (eg, tachycardia). Triggers of panic can include the following:

  • Injury (eg, accidents, surgery)
  • Illness
  • Interpersonal conflict or loss
  • Use of cannabis (can be associated with panic attacks, perhaps because of breath-holding) [21]
  • Use of stimulants, such as caffeine, decongestants, cocaine, and sympathomimetics (eg, amphetamine, MDMA [“ecstasy”]) [22]
  • Certain settings, such as stores and public transportation (especially in patients with agoraphobia)
  • Sertraline can induce panic in previously asymptomatic patients. [23]
  • The SSRI discontinuation syndrome can induce symptoms similar to those experienced by panic patients.

In experimental settings, symptoms can be elicited in people with panic disorder by hyperventilation, inhalation of carbon dioxide, caffeine consumption, or intravenous infusions of hypertonic sodium lactate or hypertonic saline, [24] cholecystokinin, isoproterenol, flumazenil, [25] or naltrexone. [26] The carbon dioxide inhalation challenge is especially provocative of panic symptoms in smokers. [27]

Social anxiety disorder (social phobia)

Genetic factors seem to play a role in social phobia. Based on family and twin studies, the risk for social phobia appears to be moderately heritable. [28, 29]

Social phobia can be initiated by traumatic social experience (eg, embarrassment) or by social skills deficits that produce recurring negative experiences. A hypersensitivity to rejection, perhaps related to serotonergic or dopaminergic dysfunction, is present. Current thought is that social phobia appears to be an interaction between biological and genetic factors and environmental events.

A psychoanalyst would likely conceptualize social anxiety as a symptom of a deeper conflict-for instance, low self-esteem or unresolved conflicts with internal objects. A behaviorist would see phobia as a learned, conditioned response resulting from a past association with a situation with negative emotional valence at the time of association (eg, social situations are avoided because intense anxiety was originally experienced in that setting). Even if no danger is posed in most social encounters, an avoidance response has been linked to these situations. Treatment from this perspective aims to weaken and eventually separate the specific response from the stimulus.

Specific phobia

Genetic factors seem to play a role in specific phobia as well (eg, in blood-injury phobia), and the risk for such phobias also seems to be moderately heritable. [28] In addition, specific phobia can be acquired by conditioning, modeling, or traumatic experience.

Agoraphobia

Agoraphobia may be the result of repeat, unexpected panic attacks, which, in turn, may be linked to cognitive distortions, conditioned responses, and/or abnormalities in noradrenergic, serotonergic, or GABA-related neurotransmission.

 

Epidemiology

United States statistics

Anxiety disorders are the most common type of psychiatric disorders in the United States. The lifetime prevalence of anxiety disorders among American adults is 28.8%. [42]

Social anxiety disorder (social phobia) is the most common anxiety disorder; it has an early age of onset—by age 11 years in about 50% and by age 20 years in about 80% of individuals that have the diagnosis—and it is a risk factor for subsequent depressive illness and substance abuse. [40]  The 12-month prevalence estimate of social anxiety disorder for the United States is approximately 7%. [1]

According to two major studies in the United States—the Epidemiological Catchment Area (ECA) study [41] and the National Comorbidity Survey (NCS) study[42] —in conjunction with other studies, the estimated lifetime prevalence rates for individual anxiety disorders are 2.3-2.7% for panic disorder, 4.1-6.6% for generalized anxiety disorder, and 2.6-13.3% for social phobia.

Further, the NCS reported the following lifetime (and 30-day) prevalence estimates: 6.7% (and 2.3%) for agoraphobia, 11.3% (and 5.5%) for simple (ie, specific) phobia, and 13.3% (and 4.5%) for social phobia. [43, 44]

International statistics

The prevalence of specific anxiety disorders appears to vary between countries and cultures. A cross-national study of the prevalence of panic disorder found lifetime prevalence rates ranging from 0.4% in Taiwan to 2.9% in Italy. The median prevalence of social anxiety disorder in Europe is 2.3%. [1]

In some Far East cultures, individuals with social anxiety disorder may develop fears of being offensive to others rather than fears of being embarrassed. In Japan and Korea, this syndrome is referred to as taijin kyofusho. [1]

Prevalence of anxiety disorders by race

The ECA study found no difference in rates of panic disorder among white, African American, or Hispanic populations in the United States.

Sex ratio for anxiety disorders

The female-to-male ratio for any lifetime anxiety disorder is 3:2 (see the image below).

Anxiety. Chart showing the female-to-male sex ratiAnxiety. Chart showing the female-to-male sex ratio for anxiety disorders. Adapted from Kessler et al, 1994.

Age distribution for anxiety disorders

Most anxiety disorders begin in childhood, adolescence, and early adulthood (see the image below). Separation anxiety is an anxiety disorder that commonly begins in childhood and often includes anxiety related to going to school. This disorder may be a precursor for adult anxiety disorders, most commonly panic disorder. According to the DSM-5, separation anxiety disorder can begin in adulthood.

Anxiety. Age of onset for anxiety disorders based Anxiety. Age of onset for anxiety disorders based on specific anxiety disorder type.

Panic disorder demonstrates a bimodal age of onset in the NCS study in the age groups of 15-24 years and 45-54 years. The age of onset for OCD appears to be in the mid 20s to early 30s.

Most social phobias begin before age 20 years (median age at illness onset, 16 years [43] ).

Agoraphobia usually begins in late adolescence to early adulthood (median age at illness onset, 29 years [43] ).

In general, specific phobia appears earlier than social phobia or agoraphobia. The age of onset depends on the particular phobia. For example, animal phobia is most common at the elementary school level and appears at a mean age of 7 years; blood phobia appears at a mean age of 9 years; dental phobia appears at a mean age of 12 years; and claustrophobia appears at a mean age of 20 years. Most simple (specific) phobias develop during childhood (median age at illness onset, 15 years). [43] and eventually disappear. Those that persist into adulthood rarely go away without treatment.

New-onset anxiety symptoms in older adults should prompt a search for an unrecognized general medical condition, a substance abuse disorder, or major depression with secondary anxiety symptoms.

Prognosis

Anxiety disorders have high rates of comorbidity with major depression and alcohol and drug abuse. Some of the increased morbidity and mortality associated with anxiety disorders may be related to this high rate of comorbidity. Anxiety disorders may contribute to morbidity and mortality through neuroendocrine and neuroimmune mechanisms or by direct neural stimulation, (eg, hypertension or cardiac arrhythmia). Chronic anxiety may be associated with increased risk for cardiovascular morbidity and mortality.

Considerable evidence shows that social phobia (social anxiety disorder) results in significant functional impairment and decreased quality of life. [45, 46]

Severe anxiety disorders may be complicated by suicide, with or without secondary mood disorders (eg, depression). The Epidemiological Catchment Area study found that panic disorder was associated with suicide attempts (odds ratio = 18 compared with populations without psychiatric disorders). How much of the association of panic disorder with suicide is mediated through the association of panic disorder with mood and substance abuse disorders is unclear. Acute stress may play a role in producing suicidal behavior. The presence of any anxiety disorder, phobias included, in combination with a mood disorder appears to increase likelihood of suicide attempts compared with a mood disorder alone. [47] Suicide attempts can be precipitated by adverse life events such as divorce or financial disaster. The effects of acute stress in producing suicidal behavior are increased in those with underlying mood, anxiety, and substance abuse problems.

Phobias are highly comorbid. Most comorbid simple (specific) and social phobias are temporally primary, while most comorbid agoraphobia is temporally secondary. Comorbid phobias are generally more severe than pure phobias. Social phobia is also frequently comorbid with major depressive disorder and atypical depression, which results in increased disability. [46, 48] Despite evidence of impairment, only a minority of individuals with simple (specific) phobia ever seek professional treatment.

Interestingly, in clinical samples, over 95% of the patients reporting agoraphobia also present with panic disorder, while in epidemiologic samples, simple agoraphobia appears to be more prevalent than panic disorder with agoraphobia.[49]

Patient Education

Education can be obtained through books, newsletters, support groups, and the Internet. Some useful Web sites are as follows:

Family members should receive information about the effect of anxiety disorders on mood, behavior, and relationships. Family members can assist in care by reinforcing the need for medical treatment and supervision. Family members may also assist by providing a collaborative resource for monitoring the severity of the patient’s anxiety symptoms and response to treatment interventions.

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