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When evaluating the anxious patient, the clinician must first determine whether the anxiety antedates or postdates a medical illness or is due to a medication side effect. Approximately one-third of patients presenting with anxiety have a medical etiology for their psychiatric symptoms, but an anxiety disorder can also present with somatic symptoms in the absence of a diagnosable medical condition.

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. 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 ; allelic polymorphism of the catechol-O-methyltransferase (COMT) gene; increased adenosine receptor function; increased cortisol ; diminished benzodiazepine receptor function; and disturbances in serotonin, serotonin transporter (5-HTTLPR) and promoter (SLC6A4) genes, norepinephrine, dopamine, cholecystokinin, and interleukin-1-beta. Some theorize that panic disorder may represent a state of chronic hyperventilation and carbon dioxide receptor hypersensitivity. 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.

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)
• Use of stimulants, such as caffeine, decongestants, cocaine, and sympathomimetics (eg, amphetamine, MDMA ["ecstasy"])
• Certain settings, such as stores and public transportation (especially in patients with agoraphobia)
• Sertraline can induce panic in previously asymptomatic patients.
• 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, cholecystokinin, isoproterenol, flumazenil, or naltrexone. The carbon dioxide inhalation challenge is especially provocative of panic symptoms in smokers.

Social phobia (social anxiety disorder)

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.

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 (simple) 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. In addition, specific phobia can be acquired by conditioning, modeling, or traumatic experience.

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.

Obsessive-compulsive disorder

The cause of OCD is not known; however, genetic factors, infections, other neurologic conditions, stress, and interpersonal relationships have all been shown to be relevant.

Twin studies have supported strong heritability for OCD, with a genetic influence of 45-65% in studies in children, and 27-47% in adults. Monozygotic twins may be strikingly concordant for OCD (80-87%), compared with 47-50% concordance in dizygotic twins. Several genetic studies have supported linkages to a variety of serotonergic, dopaminergic, and glutamatergic genes. Other genes putatively linked to OCD have included those coding for catechol-O-methyltransferase (COMT), monoamine oxidase-A (MAO-A), brain-derived neurotrophic factor (BDNF), myelin oligodendrocyte glycoprotein (MOG), GABA-type B-receptor 1, and the mu opioid receptor, but these must be considered provisional associations at this time. In some cohorts, OCD, attention deficit hyperactivity disorder (ADHD), and Tourette disorder/tic disorders co-vary in an autosomal dominant fashion with variable penetrance.

Case reports have been published of OCD with and without tics arising in children and young adults following acute group A streptococcal infections. Fewer reports cite herpes simplex virus as the apparent precipitating infectious event. It has been hypothesized that these infections trigger a CNS autoimmune response that results in neuropsychiatric symptoms (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections [PANDAS]). A number of the poststreptococcal cases have reportedly improved following treatment with antibiotics.

Rare reports exist of OCD presenting as a manifestation of neurologic insults such as brain trauma, stimulant abuse, and carbon monoxide poisoning.

OCD symptoms can worsen with stress; however, stress does not appear to be an etiologic factor. OCD symptoms can interact negatively with interpersonal relationships, and families can become involved with the illness in a counterproductive way (eg, a patient with severe doubting obsessions may constantly ask reassurance for irrational fears from family members or significant others; constantly providing this can inhibit the patient from making attempts to work on their behavioral disturbances). Parenting style or upbringing does not appear to be a causative factor in OCD.

Posttraumatic stress disorder

PTSD is caused by experiencing, witnessing, or being confronted with an event involving serious injury, death, or threat to the physical integrity of an individual, along with a response involving helplessness and/or intense fear or horror. The more severe the trauma and the more intense the acute stress symptoms, the higher the risk for PTSD. When these events involve an individual with a physiologic vulnerability based on genetic (inherited) contributions and other personal characteristics, PTSD results.

Researchers have identified factors that interact to influence vulnerability to developing PTSD. These factors include the following:

• The characteristics of the trauma exposure itself, such as proximity to, severity of, and duration of exposure to the trauma
• The characteristics of the individual, such as prior exposure to trauma, childhood adversity (eg, separation from parents), preexisting anxiety or depression, and sex (women are at greatest risk for many of the most common assertive traumas)
• Posttrauma factors, such as availability of social support, emergence of avoidance or numbing, hyperarousal, and reexperiencing symptoms (for reexperiencing symptoms specifically, a pilot monozygotal twin study shows that patients with PTSD have impaired extinction of novel conditioned fear stimuli )

Symptoms

Symptoms vary depending on the type of anxiety disorder, but general symptoms include:

• Feelings of panic, fear, and uneasiness
• Problems sleeping
• Cold or sweaty hands and/or feet
• Shortness of breath
• Heart palpitations
• An inability to be still and calm
• Dry mouth
• Numbness or tingling in the hands or feet
• Nausea
• Muscle tension
• Dizziness

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.

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. 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. 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.