Analysis of causes of anxiety disorders. Some, like panic disorder, have a genetic basis. Others may be reactions to stressful life events.

The underlying causes of most anxiety disorders, although not fully understood, has come into sharper focus in the last decade. In broad terms, the likelihood of developing anxiety involves a combination of life experiences, psychological traits, and/or genetic factors. The anxiety disorders are so heterogeneous that the relative roles of these factors are likely to differ. Some anxiety disorders, like panic disorder, appear to have a stronger genetic basis than others (National Institute of Mental Health [NIMH], 1998), although actual genes have not been identified. Other anxiety disorders are more rooted in stressful life events.

It is not clear why females have higher rates than males of most anxiety disorders, although some theories have suggested a role for the gonadal steroids. Other research on women's responses to stress also suggests that women experience a wider range of life events (e.g., those happening to friends) as stressful as compared with men who react to a more limited range of stressful events, specifically those affecting themselves or close family members (Maciejewski et al., 1999).

What the myriad of anxiety disorders have in common is a state of increased arousal or fear (Barbee, 1998). Anxiety disorders often are conceptualized as an abnormal or exaggerated version of arousal. Much is known about arousal because of decades of study in animals² and humans of the so-called "fight-or-flight response," which also is referred to as the acute stress response. The acute stress response is critical to understanding the normal response to stressors and has galvanized research, but its limitations for understanding anxiety have come to the forefront in recent years, as this section later explains.

In common language, the term "stress" refers either to the external stressor, which can be physical or psychosocial in nature, as well as to the internal response to the stressor. Yet researchers distinguish the two, calling the stressor the stimulus and the body's reaction the stress response. This is an important distinction because in many anxiety states there is no immediate external stressor. The following paragraphs describe the biology of the acute stress response, as well as its limitations, in understanding human anxiety. Emerging views about the neurobiology of anxiety attempt to integrate and understand psychosocial views of anxiety and behavior in relation to the structure and function of the central and peripheral nervous system.

Acute Stress Response

When a fearful or threatening event is perceived, humans react innately to survive: they either are ready for battle or run away (hence the term "fight-or-flight response"). The nature of the acute stress response is all too familiar. Its hallmarks are an almost instantaneous surge in heart rate, blood pressure, sweating, breathing, and metabolism, and a tensing of muscles. Enhanced cardiac output and accelerated metabolism are essential for mobilizing fast action. The host of physiological changes activated by a stressful event are unleashed in part by activation of a nucleus in the brain stem called the locus ceruleus. This nucleus is the origin of most norepinephrine pathways in the brain. Neurons using norepinephrine as their neurotransmitter project bilaterally from the locus ceruleus along distinct pathways to the cerebral cortex, limbic system, and the spinal cord, among other projections.

Normally, when someone is in a serene, unstimulated state, the firing of neurons in the locus ceruleus is minimal. A novel stimulus, once perceived, is relayed from the sensory cortex of the brain through the thalamus to the brain stem. That route of signaling increases the rate of noradrenergic activity in the locus ceruleus, and the person becomes alert and attentive to the environment. If the stimulus is perceived as a threat, a more intense and prolonged discharge of the locus ceruleus activates the sympathetic division of the autonomic nervous system (Thase & Howland, 1995). The activation of the sympathetic nervous system leads to the release of norepinephrine from nerve endings acting on the heart, blood vessels, respiratory centers, and other sites. The ensuing physiological changes constitute a major part of the acute stress response. The other major player in the acute stress response is the hypothalamic-pituitary-adrenal axis, which is discussed in the next section.

In the 1980s, the prevailing view was that excess discharge of the locus ceruleus with the acute stress response was a major contributor to the etiology of anxiety (Coplan & Lydiard, 1998). Yet over the past decade, the limitations of the acute stress response as a model for understanding anxiety have become more apparent. The first and most obvious limitation is that the acute stress response relates to arousal rather than anxiety. Anxiety differs from arousal in several ways (Barlow, 1988; Nutt et al., 1998). First, with anxiety, the concern about the stressor is out of proportion to the realistic threat. Second, anxiety is often associated with elaborate mental and behavioral activities designed to avoid the unpleasant symptoms of a full-blown anxiety or panic attack. Third, anxiety is usually longer lived than arousal. Fourth, anxiety can occur without exposure to an external stressor.

Other limitations of this model became evident from a lack of support from clinical and basic research (Coplan & Lydiard, 1998). Furthermore, with its emphasis on the neurotransmitter norepinephrine, the model could not explain why medications that acted on the neurotransmitter serotonin (the selective serotonin reuptake inhibitors, or SSRIs) helped to alleviate anxiety symptoms. In fact, these medications are becoming the first-line treatment for anxiety disorders (Kent et al., 1998). To probe the etiology of anxiety, researchers began to devote their energies to the study of other brain circuits and the neurotransmitters on which they rely. The locus ceruleus still participates in anxiety but is understood to play a lesser role.