Fear is a complex physiological, behavioral, cognitive, and, in humans, subjective response to a threaten-ing stimulus. It evolved as an adaptive response to real threats and is usually transient. Anxiety is a longer-lasting response to danger signals that can arise either from immediate circumstances that signal well-defined danger or from vague indications of ill-defined events that are thought to have adverse consequences.
Anxiety can be highly adaptive; arousal, vigilance, and physical preparedness increase the likelihood of survival in dangerous situations. However, because many situations lack clear signs of safety, anxiety can persist. When anxiety persists beyond genuine risk, or when it produces a response out of proportion to the possible threat, the result can be distressing and disabling. Anxiety is the core symptom in several common psychiatric disorders. In the United States 28.5% of the population suffer from one or more anxiety disorders over the course of their lifetimes.
Anxiety disorders are distinguished from each other by the nature, intensity, and time course of symptoms, patterns of familial transmission, precipitating factors, the role of external cues in triggering episodes, and the constellation of associated symptoms. In some situations anxiety is not produced by a single eliciting stimulus but by an accumulation of cues. The currently recognized anxiety disorders are panic disorder, post-traumatic stress disorder, generalized anxiety disorder, social anxiety disorder (also called social phobia), simple phobias, and obsessive-compulsive disorder.
Panic disorder. The cardinal symptom of panic disorder is the unexpected panic attack consisting of a discrete period of intense fear accompanied by somatic symptoms such as palpitations, shortness of breath, sweating, paresthesias, and dizziness, and by a powerful fear of losing control or of dying (Table 63–5). Panic disorder is diagnosed when panic attacks recur and give rise to anticipatory anxiety about future attacks. People with panic disorder might restrict their lives progressively to avoid situations or places in which attacks occur or from which they might not be able escape should they experience an attack. It is common for patients to avoid crowds, bridges, and elevators; some individuals eventually stop leaving home altogether. A generalized phobic avoidance is called agoraphobia.
Table 63–5Symptoms of a Panic Attack ||Download (.pdf) Table 63–5 Symptoms of a Panic Attack
|A discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: |
|Palpitations, pounding heart, or accelerated heart rate |
|Trembling or shaking |
|Sensations of shortness of breath or smothering |
|Feeling of choking |
|Chest pain or discomfort |
|Nausea or abdominal distress |
|Feeling dizzy, unsteady, lightheaded, or faint |
|Derealization (feelings or unreality) or depersonalization (being detached from oneself) |
|Fear of losing control or going crazy |
|Fear of dying |
|Paresthesias (numbness or tingling sensations) |
|Chills or hot flushes |
Post-traumatic stress disorder. Post-traumatic stress disorder (PTSD) follows an experience of severe danger or injury. First recognized in soldiers during World War I after combat trauma, it also occurs after civilian traumas such as violent assaults or serious accidents. It is characterized by emotional numbness to ordinary stimuli, punctuated by painful reliving of the traumatic episode, often initiated by sounds, images, or odors that trigger highly charged memories of the circumstances in which the trauma occurred. For example, a Vietnam War veteran with PTSD might experience intense symptoms after hearing a traffic helicopter pass overhead (recalling the heavy use of assault helicopters in that war). It is also characterized by disturbed sleep that can include nightmares, and by hyperarousal, such as an exaggerated startle response.
Generalized anxiety disorder. This disorder is characterized by chronic (months-long) worry and vigilance that is not warranted by circumstances. This worry is accompanied by physiological disturbances such as heightened sympathetic nervous system arousal (evidenced by an increase in heart rate) and by motor tension.
Social anxiety disorder. This disorder is characterized by a persistent fear of social situations or performance situations that expose a person to the scrutiny of others. The patient has an intense fear of acting in a way that will prove humiliating. Stage fright is a form of social anxiety that is limited to special circumstances, such as public speaking. Generalized social anxiety, as its name implies, involves adverse responses to most social situations and can therefore prove quite disabling.
Simple phobias consist of intense, excessive fear of specific stimuli, such as snakes, spiders, or height.
Obsessive-compulsive disorder. Obsessive-compulsive disorder (OCD) is characterized by obsessions (intrusive, unwanted thoughts) and compulsions (performance of highly ritualized behaviors intended to neutralize the negative thoughts and emotions resulting from the obsessions). The person experiences the obsessions as foreign and unwanted. Attempts to resist the urge to perform the compulsive acts result in high levels of anxiety. Typical symptom patterns are repetitive hand washing to neutralize fears of contamination (sometimes hours a day to the point of skin damage), or repeatedly checking the front door to see that it is locked.
Although current classifications of psychiatric disorders, including DSM-IV, place OCD among the anxiety disorders, family studies and imaging studies suggest that the disorder may share risk factors and dysfunction of striatal circuits with Tourette disorder, which is characterized by motor tics (involuntary, rapid movements) as well as vocal tics—grunts, noises, obscenities—and is often accompanied by obsessive-compulsive symptoms. Additional evidence for primary problems in striatal circuits, rather than the amygdala circuits implicated in other anxiety disorders, comes from the study of Sydenham chorea, a movement disorder that can result from acute rheumatic fever. Interestingly, many patients with Sydenham chorea experience transient OCD-like symptoms. Sydenham chorea results from antibodies developed in response to a streptococcal infection, and the antibodies have been shown to bind to neurons in the striatum. OCD can be treated with high doses of selective serotonin reuptake inhibitor and by psychotherapy aimed at stopping intrusive thoughts and compulsive rituals.
Anxiety Disorders Have a Genetic Component
Panic disorder, generalized anxiety disorder, phobias, and OCD all run in families. First-degree relatives of individuals with panic disorder have a significantly greater risk of panic disorder than the general population or the first-degree relatives of unaffected control subjects.
Twin studies have concluded that panic disorder, generalized anxiety disorder, and probably phobias are explained to a large extent by genes. Twin studies also suggest overlapping genetic risk factors for depression and generalized anxiety disorder, which helps explain the observation that these two disorders often occur together.
In post-traumatic stress disorder genes appear to act in two important ways. They influence (1) the risk of developing the disorder after exposure to traumatic events and (2) the likelihood of individuals exposing themselves to dangerous situations.
Animal Models of Fear May Shed Light on Human Anxiety Disorders
Because many responses to fearful stimuli are conserved across mammalian species, animal models are potentially relevant to human disorders. In addition, because stimuli that elicit fear and anxiety can be readily produced in the laboratory, animal models are amenable to study. Studies using animal models have focused on two general classes of fear: innate fear and learned fear.
Studies of innate or instinctual fear exploit the natural tendencies of rats and mice to avoid open spaces or other situations that expose them to predators (Figure 63–10). Studies of learned or conditioned fear exploit the ability of rodents and other animals to form powerful associations between previously neutral cues and temporally linked danger. As described in Chapter 48, studies using these animal models have led to the outline of an amygdala-based fear circuitry that mediates defensive behaviors and appropriate physiologic responses to danger. They have been useful in designing noninvasive studies of human subjects with anxiety disorders, and as screens for anxiety-reducing drugs and genetic mutations that influence fear.
The effects of anxiety-reducing drugs can be tested on rodents in the elevated plus maze.
The apparatus has two intersecting arms, one enclosed and the other open. A rat or mouse is placed at the intersection and the time spent on the open or enclosed arms is measured. Rodents normally prefer the closed arm. Rodents given benzodiazepine drugs, such as diazepam, which reduce anxiety in humans, spend more time in the open arm. Rodents given the benzodiazepine inverse agonist β-carboline (β-CCE), which strongly induces anxiety in humans, spend less time in the open arm. (Reproduced, with permission, from Nestler, Hyman, and Malenka 2009.)
Our growing understanding of fear circuitry has generated testable hypotheses about the pathophysiology of human anxiety disorders such as post-traumatic stress disorder. For example, fear conditioning occurs normally in humans and is usually adaptive. By learning cues that signify danger and developing efficient responses, an individual minimizes future risk of harm. The central abnormality in post-traumatic stress disorder appears to be fear conditioning that is excessive, such that later minor cues are able to elicit fear responses. This dysregulated fear response alters other cognitive, emotional, and physiological responses. By mechanisms that are not yet well understood, it may alter basal levels of arousal, leading to exaggerated startle responses and disordered sleep. Other aspects of post-traumatic stress disorder, such as emotional numbing, are more difficult to model in experimental animals.
The unexpected panic attack—the hallmark of panic disorder—may represent a "false alarm" in which the fear circuitry is activated in the absence of a threat. Whether such abnormal activation originates from the fear circuitry itself or elsewhere in the nervous system is not known. Panic attacks can be produced in susceptible people by increasing partial pressure of carbon dioxide (PCO2) in their blood or administering caffeine or drugs, which increase sympathetic outflow. Although these observations suggest a low threshold for activating the fear circuitry in persons with panic disorder, we do not yet understand the neurophysiologic mechanisms that trigger spontaneous panic attacks.
Panic attacks can be a source of fear conditioning. Initially, panic attacks are usually spontaneous, with no obvious relationship to the immediate context or environmental stimuli. However, environmental cues experienced in conjunction with a panic attack can become fear-associated stimuli. Later, these cues can trigger severe anticipatory anxiety or even a full panic attack.
With simple phobias and social anxiety the fear circuitry may be activated by cues that ordinarily signal very limited, if any, danger, such as risk of embarrassment. The experience can lead to avoidance of the cues. A person with a phobia of air travel might limit travel to surface transportation, and a person with stage fright might alter career plans to avoid public speaking.
Neuro-imaging Implicates Amygdala-Based Circuits in Human Fear and Anxiety
The understanding of the neural circuitry underlying fear and anxiety in animal models has guided neuro-imaging studies of humans. In healthy subjects the amygdala is activated in response to stimuli that reliably induce fear, such as faces portraying fear, as well as during fear conditioning.
In a functional magnetic resonance imaging (fMRI) study of normal volunteers the presentation of a face portraying fear activated the dorsal subregion of the amygdala; this region contains what is thought to be the amygdala's main output nucleus, the central nucleus. When the same faces were shown only briefly to these subjects, followed by a neutral face (referred to as backward masking), the subjects did not report awareness of having seen the fearful face. Yet they exhibited physiological signs of fear (activation of the sympathetic nervous system). This test paradigm activates the basolateral subregion of the amygdala (which contains inputs from the thalamus and cerebral cortex) in healthy subjects similar to that of subjects with anxiety disorders (Figure 63–11).
Amygdala activation in response to a masked presentation of a fearful stimulus.
A human subject observes projected images while being scanned by magnetic resonance imaging. When a fearful face is presented for a very brief time followed by presentation of a neutral face (a protocol called backward masking), the subject is not consciously aware of the fearful face. Under these conditions the basolateral region of the amygdala predicts individual differences in trait anxiety in healthy subjects similar to those found in patients with anxiety disorders. (Reproduced, with permission, from Etkin et al. 2004.)
Functional neuroimaging has also revealed heightened activity in the amygdala in specific anxiety disorders, including social anxiety disorder and post-traumatic stress disorder. In individuals with social anxiety disorder the increase in activity is induced by images of fearful faces; in individuals with post-traumatic stress disorder it is induced by narratives that are reminiscent of their trauma.
Structural imaging has also been used to study anxiety disorders. The most often replicated structural finding is diminished hippocampal volume in individuals with depression or post-traumatic stress disorder. Until longitudinal studies are performed, it is not clear whether a small hippocampus is a risk factor for post-traumatic stress disorder or a result of the disorder.
Anxiety Disorders Can Be Treated Effectively with Medications and Psychotherapy
Cognitive-behavioral therapies designed for specific anxiety disorders have proved as effective as medication in the treatment of anxiety disorders. For example, a person with cue-elicited anxiety, whether a simple phobia, phobic avoidance resulting from panic disorder, or social anxiety disorder, is coached to confront the phobic stimulus with adequate support and a new cognitive schema for coping with the fear. For many patients a combination of medication and cognitive-behavioral therapy may prove necessary.
Among the medications used for various anxiety disorders, drugs that were initially developed as antidepressants have proven highly efficacious and are the drugs of choice. The selective serotonin reuptake inhibitors are most widely used because they are easily tolerated. Simple phobias are best treated with cognitive-behavioral therapy rather than medication. The response of obsessive-compulsive disorder to treatment differs from those anxiety disorders in which amygdala-based fear circuitry is thought to be the primary abnormality. Obsessive-compulsive disorder responds only to serotonin selective drugs at higher doses. Medications are generally combined with cognitive-behavioral therapy specially designed to inhibit compulsive behaviors.
Another class of drugs, the benzodiazepines, are occasionally used for generalized anxiety disorder, whereas higher doses are used for panic disorder. However, existing benzodiazepines can cause sedation; indeed, they are also used as hypnotics, and can degrade cognitive function. Moreover, benzodiazepines can cause dependence (as evidenced by worsened, so-called rebound anxiety) and insomnia when drugs are discontinued. In some individuals they can produce addiction (see Chapter 49). An advantage of the benzodiazepines is they react rapidly following a single dose, in contrast to the antidepressants, which can take weeks to become effective. Overall, they are second-line treatments to the selective serotonin reuptake inhibitors and other antidepressants, often used temporarily until the response to antidepressants takes effect.
The benzodiazepines produce their therapeutic effect by enhancing the inhibitory action of GABA at GABAA receptors. This receptor is ionotropic and selective for Cl–. It is a pentamer, organized like barrel staves around an aqueous pore (Figure 63–12). Allosteric binding of benzodiazepine modifies the receptor complex, increasing the affinity of the GABA binding site for GABA. As a result, GABA-activated Cl− channels open more frequently, enhancing the hyperpolarizing effect of GABA on the neuron. The sedative barbiturate drugs also bind the GABAA receptor complex, but at a site near the Cl– channel. Barbiturates increase not only the affinity of the receptor for GABA but also channel open time, creating a greater risk of excessive central nervous system depression than is seen with benzodiazepines.
The GABAA receptor complex.
The GABAA (γ-aminobutyric acid A) receptor is a pentamer arranged to form a Cl– channel. In addition to the neurotransmitter GABA, the receptor binds several important drugs, including benzodiazepines and barbiturates, at physically separate sites.