There is evidence that corticosteroids and corticotropin- releasing hormone (CRH) have a role in the genesis of anxiety. A systemic release of corticosteroid accompanies all states of stress, and the administration of corticosteroids may give rise to anxiety and panic in some patients and to depression in others, suggesting a linkage between steroid stimulation of the limbic system activities that generate these states. In animal models, stress elicited by predators or electric shock as well as by withdrawal of alcohol and other drugs precipitates activity in CRH pathways (amygdala to hypothalamus, raphe nuclei, nucleus ceruleus, and other regions of the brainstem); blocking such activity by drugs or by destruction of the amygdala eliminates anxiety and fear-like behavior. Admittedly, the concepts of fear, stress, and anxiety are used interchangeably in these models, but repeated stimuli that produce fear and stress may eventually induce a state akin to anxiety, and the amygdala appears to be involved in the perpetuation of this anxiety state. The meaning of these effects, that is, whether they are primary or secondary, is not certain, but it is evident that prolonged and diffuse anxiety is associated with certain biochemical abnormalities of the blood and probably of the brain.
In addition to the role of the amygdala, animal studies have related acute anxiety to a disturbance of function of the locus ceruleus and the septal and hippocampal areas, the principal norepinephrine-containing nuclei. The locus ceruleus is involved in rapid eye movement (REM) sleep and drugs such as the tricyclic antidepressants and monoamine oxidase inhibitors, which suppress REM sleep, also decrease anxiety. Certain of the serotonin receptors in the brain, different from those implicated in depression, have been related to anxiety. Other parts of the brain must also be involved; bifrontal orbital leukotomy diminishes anxiety, possibly by interrupting the medial forebrain connections with the limbic parts of the brain. Positron emission tomography (PET) studies in subjects who anticipate an electric shock show enhanced activity in the temporal lobes and insula, implicating these regions in the experience of acute anxiety (see also “Physiology of the Limbic System” in Chap. 25). Other credible studies have demonstrated a role for the anterior cingulate gyrus in eliciting many of the autonomic features (particularly increased heart rate) of excessive arousal and anxiety.
Several other alterations in neurotransmitter function have been implicated in the anxious state. The finding that a small proportion of the inherited personality trait of anxiety can be accounted for by one polymorphism of the serotonin transporter gene is provocative (Lesch et al) but requires confirmation.
DEPRESSIVE REACTIONS (SEE ALSO CHAP. 48)
There are few persons who do not at some time experience periods of severe discouragement and despair. As with nervousness, irritability, and anxiety, depression of mood that is appropriate to a given situation in life (e.g., grief reaction) is seldom the basis of medical concern. People in these situations tend to seek help only when their grief or unhappiness is persistent and beyond control. However, there are numerous instances in which the symptoms of depression assert themselves for reasons that are not apparent. Often the symptoms are interpreted as a medical illness, bringing the patient first to the internist or neurologist. Sometimes another disease is found (such as cancer, chronic hepatitis, or other infection or postinfectious asthenia) in which chronic fatigue is confused with depression; more often the opposite pertains, that is, an endogenous depression is the essential problem even when there has been evidence earlier of a viral or bacterial infection.