The risk of anxiety disorder symptom onset has been associated with moderate genetic, psychological, and biological system alterations.3 Family, twin, and adoptive family studies have consistently shown a strong genetic liability for these disorders. However, experts now speculate that the etiology question is no longer nature versus nurture. Current models seek to explain the interactions of nature and nurture that can create susceptibility to anxiety. Brain regions that underpin the experiences of fear, anxiety, and stress are thought of as circuits that can be shaped and altered by a wide range of forces. Neurobiological conditioning is one force shown to impact such circuits and thus is of particular importance to understanding the development of anxiety disorders.

Brain serotonin activity has been revealed to interact with both genes and environment, and these interactions contribute to what has come to be referred to as synaptic plasticity.³ In this way, genes are linked with brain cell neurochemistry and psychological characteristics such as temperament. More specifically, evidence of genetic variability in negative emotions, such as anxiety, has been found in studies of serotonin transporter cells. In this research, gene variability is in gene allele length. For example, family studies have shown that siblings with serotonin transporter cells with the short-form gene allele had higher neuroticism scores than their siblings with the long-form gene allele. Research aimed at gene typing mental disorders clearly is in its infancy and findings such as these are inconclusive, but they demonstrate the possibility of genetics-based neurobiological models of anxiety.

Susceptible persons who breathe air with high levels of carbon dioxide will experience an acute onset of panic anxiety symptoms.⁴ A small study of persons with panic anxiety disorder, using an infusion of doxapram (respiratory stimulant) to cause profound hyperventilation, examined the effectiveness of cognitive interventions to reduce respiratory anxiety symptoms.⁵ Cognitive interventions were designed to minimize misinterpretation of drug-induced hyperventilation as a sign of danger and thereby reduce the odds of the respiratory stimulant triggering panic anxiety. Breath-by-breath analyses of the patients and healthy controls were performed. The researchers⁵ hypothesized that if the respiration anxiety symptoms were the result of dysregulation within the brain respiratory control center, cognitive interventions would not be particularly effective. They found that less fearful thinking did reduce panic, but some respiratory anxiety symptoms persisted despite less fearful thinking. In other words, respiratory anxiety symptoms appeared to result both from anticipatory anxiety and from dysregulation within the brain respiratory center.

Surges of physiologic activation and physiologic instability are thought to be the hallmark neurobiological processes underlying panic anxiety disorder.⁶ Multiple organ systems, including the cardiovascular and respiratory systems, are thought to be involved. Observations such as these help to explain why, for example, caffeine triggers panic anxiety symptoms in susceptible individuals. Physiologic instability may prove to be the key to identifying a genetics-based marker for susceptibility to panic. However, the biopsychological marker for the disorder is likely to be the overinterpretation of physical anxiety symptoms (e.g., sudden increase in heart rate) as life threatening. This thinking, referred to as learned panic, is thought to result from inordinately high levels of life stress in early childhood.

Overwhelming life stress can increase the level of circulating glucocorticoids (stress hormones) and stimulate the release of glutamate (which inhibits neurogenesis).⁷ Early-childhood life stress, specifically abuse and neglect, has been studied as a possible predictor of various adult-onset anxiety disorders. These models are based on altered serotonin, norepinephrine, and dopamine neurotransmission; glutamate release; and physiologic instability. Repeated and prolonged childhood exposure to overwhelming stress is thought to create adult susceptibility to anxiety disorders. The leading theory is that early life stress leads to an overspecialized or excessive stress response.

Early life stress is thought to produce adult susceptibility to anxiety by altering critical neuron structures and functioning during this critical stage of human growth and development. Brain regions most vulnerable to alteration as a result of early life stress include the hippocampus (glucocorticoid receptors), amygdala (γ-aminobutyric acid [GABA] and benzodiazepine receptors), corpus callosum (glial cells critical to myelination), cerebellar vermis (glucocorticoid receptors), and the prefrontal cortex (glucocorticoid receptors, dopamine projections, and inhibition of hypothalamic-pituitary-adrenal [HPA] axis activation).^7,8 When the developing brain of a young child is exposed to overwhelming life stress, the stress response system appears to adapt by overbuilding or building additional brain stress response pathways. Later, under less stressful adult circumstances, this overbuilt stress response system becomes maladaptive. Like a very large overpowered car on a small, winding road, the overbuilt stress response system could become the source of physiologic instability that has come to be associated with panic anxiety.⁹

With panic disorder, no single experience consistently triggers symptom onset, although the first attack(s) frequently occur(s) during a life-threatening illness or accident, loss of a close interpersonal relationship, or separation from family. After that, they can occur during any routine activity, from reading to driving. When patients experience their first few panic attacks they frequently think they are either having a heart attack or losing their mind and it is common to seek emergency medical treatment.2 Physical symptoms are most prominent and emphasized, and include respiratory distress, heart palpitations, tachycardia, pounding heart, chest pain, smothering or choking sensation, dizziness, lightheadedness, faintness, sweating, trembling, shaking, hot flushes, chills, numbness, tingling, nausea, abdominal distress, and urinary frequency.² Psychological and cognitive symptoms include expressed fears of dying, fear of cardiac arrest, fear of losing control, fear of nervous breakdown, derealization, depersonalization, and perceptual distortions. Behavioral symptoms include hyperkinesis, pressured speech, and exaggerated startle response. The attacks usually last between 5 and 20 minutes, although they can last as long as an hour. They can happen in a wavelike manner, so that they occur successively, or as described earlier, as part of another clinical disorder. Some people experience such severe anticipatory anxiety that it is hard to separate when the attack starts and ends, so that the panic attack is experienced as continuous.

Panic disorder is characterized by two important psychological symptoms: anticipatory anxiety and avoidance anxiety. Anticipatory anxiety refers to fearful expectation of panic anxiety onset. People with the disorder tend to develop a morbid dread of events or experiences that they come to believe might trigger panic anxiety. Avoidance anxiety refers to personal strategies used to increase feelings of control and thereby decrease the risk of panic anxiety. Persons with panic disorder strive to avoid situations and circumstances they associate with their symptoms. This helps to explain why panic disorder and agoraphobia (the phobic avoidance of public spaces beyond personal control, e.g., airports and shopping malls) often coexist.

Panic anxiety disorder can be effectively managed with cognitive-behavioral therapy aimed at reducing fearful thinking and desensitization of cognitive and physical stress responses. When panic symptoms are disabling, medication for symptom management is recommended.2 Long-acting benzodiazepines, such as clonazepam, are the sedatives of choice when short-term calming and symptom relief are mandatory. Tolerance to benzodiazepines develops with continuous use regardless of dosage. Misuse of benzodiazepines represents a serious health hazard. Although these drugs are useful in blocking the panic attack, they do not always decrease the anticipatory anxiety and avoidance, especially when drug regimens are initially undertaken. Many atypical psychiatric medications that can target serotonin, dopamine, or norepinephrine receptors have been clinically tested and shown to be effective treatment for anxiety symptoms. Examples of such medications found to be helpful include paroxetine, sertraline, citalopram, and fluoxetine. Unless contraindicated, β-blocker medications that dampen physical anxiety symptoms may also be helpful.

GAD10 differs from other anxiety disorders in that the cognitive, psychological, and behavioral symptoms are relatively constant. Psychoanalysts developed most of the original etiologic theories concerning persistent worry. What now is referred to as persistent worry was then described as anxious expectation. Even at that early stage of discovery, it was apparent that generalized anxiety rarely occurred without comorbid conditions such as depression. This psychodynamic view of generalized anxiety prevailed until the late 1980s and early 1990s. More recently, cognitive theorists view GAD as having its origins in early attachment to the primary caretaker. Conceptually, worry is seen as an avoidance strategy for negative affect; as a distraction from realistic and proximal threats that need immediate solutions; and as a coping method to “prevent” the feared outcome, such as occurs with magical thinking. Unlike panic disorder, where the worry is more typically about physical catastrophes, in GAD, worries are more about interpersonal confrontation, competence, and acceptance. Technologically advanced research methods have now made it possible to precisely define GAD symptoms in terms of their actual qualities, intensity, and duration, but physical GAD symptoms continue to be viewed as somatic expressions of psychological problems.¹⁰

Unlike other anxiety disorders, GAD onset typically is gradual with symptom duration measured in years. As has been observed with other anxiety disorders, vulnerability to GAD likely is inherited. Twin and family study findings indicate a 30% increase in risk of GAD among the relatives of persons with the disorder.² Efforts to describe the neurobiological basis of GAD will no doubt be greatly advanced by theoretical models of inherited vulnerability as well as improved understanding of GAD symptoms. The most important unanswered question likely will have to do with the fact that the alterations in brain structure and functioning shown to be associated with GAD also are consistent with alterations observed with other disorders.

Preliminary positron emission tomography (PET) studies measuring brain glucose metabolism rates in GAD have shown higher than normal rates in patients at rest.¹² With GAD, apparently some brain regions undergo both increases and decreases in glucose metabolism rates. This mixed response is most apparent in the frontal and cingulate areas of the cortex, the brain region associated with worry and hypervigilance. Findings such as these lend support to the basic GAD explanatory hypothesis of anxiety symptoms as manifestations of hyperactive brain circuits. Just the opposite condition (hypoactive brain circuits) is thought to be the fundamental basis of depressive disorders.¹²

Neurotransmitter findings with GAD, as with other disorders that produce mood, thinking, and behavior symptoms, point to alterations in GABA receptors, benzodiazepine receptors, norepinephrine systems, serotonin systems, HPA axis activation, and plasma cortisol levels. Thus far, no specific alterations that can consistently explain GAD symptoms have been identified.¹² Nevertheless, one interesting observation shows considerable promise. At rest, no obvious alterations in neurotransmission are noted in GAD patients. Only when subjected to laboratory activities designed to induce stress responses is significant neurotransmitter overactivity observed. Evidence of norepinephrine receptor down-regulation lends additional support to this stress response model. Attempting to modulate overactive responses, receptor down-regulation is thought to occur automatically when subjected to prolonged, recurrent, excessive, or hyperactive neurotransmitter activity.

Whereas norepinephrine activity is thought to be associated with physical symptoms of GAD, anticipatory and avoidance symptoms are thought to be associated with activity along a key serotonin pathway linking the amygdala and frontal cortex. As might be expected, insufficient serotonin activity in specific brain regions is thought to be associated with GAD. Given the obvious symptom overlap between stress and anxiety, hyperactivity within the HPA axis and high plasma cortisol levels continue to be leading models in GAD research. Much of the difficulty in defining the neurobiological basis of GAD has to do with significant individual variations in GAD symptomatology. Uncontrollable worry (frontal cortex) is the only symptom likely to show meaningful consistency over time and from individual to individual. A second major research difficulty has to do with the frequency with which GAD symptoms co-occur with depression symptoms—so much so that some experts now view mixed depression-anxiety as a specific disorder.²

Effective psychological and drug treatments for GAD can be relatively complex. When alcohol is comorbid, it may limit the effectiveness of treatment and/or delay the onset of benefits. Delayed onset of benefits from treatment is likely to be seen when GAD symptoms are long-standing and highly disabling. Lastly, neurobiological research findings indicate that effective drug treatment is likely to require one or more medications that are reliable modulators of multiple neurotransmission systems across multiple brain regions. Medications shown to relieve and in some cases remit GAD symptoms include long-acting benzodiazepines (e.g., clonazepam), partial serotonin (i.e., 5-hydroxytryptamine, 5-HT_1A) agonists (e.g., buspirone), tricyclic antidepressants (e.g., imipramine), selective serotonin reuptake inhibitors (e.g., sertraline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), and long-acting β-blockers (e.g., propranolol).13

Cognitive-behavioral therapy combined with relaxation training appears to be more effective than nondirective and supportive therapy for the treatment of GAD. In addition, cognitive-behavioral therapy is also superior to behavioral therapy alone.2

Neurobiological research findings indicate that there is a strong genetic or inherited risk of OCD.2 Twin and family studies show a greater degree of concordance for OCD among monozygotic twins compared to dizygotic twins. Once an adult family member has been diagnosed with the disorder, child relatives are more likely to be diagnosed. Depression, anorexia, and Tourette syndrome are common OCD comorbid disorders. Close links between OCD and the hereditary neurologic disorder Tourette syndrome have been reported, but it is not clear whether this link represents an increased risk of OCD or whether Tourette syndrome and OCD are related in some other way.

OCD studies using PET brain scans have shown significant increases in glucose metabolism rates in the frontal lobes, caudate nucleus, and cingulate gyrus regions of the brain (Figure 49-1). These brain regions are directly associated with response to strong emotions. However, several OCD models of altered brain functioning have been hypothesized. One model proposes that a causal pathway for OCD exists between the frontal cortex region and basal ganglia region of the brain. This model draws on the observation that similar illnesses with well-defined etiologic factors have been shown to involve both cognitive and motor brain regions. Predictably, serotonin activity dysregulation and dysfunction also represent possible OCD models.

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