Sapolsky

"In this article, I review the brain bases of anxiety and depression (although both words describe everyday transient states that can trouble all of us, throughout I am referring to the medical diagnoses of anxiety disorders and major depression, diseases that incapacitate their sufferers chronically)''. 

"In contrast to anxiety, which can feel like desperate hyperactivity, major depression is characterized by helplessness, despair, an exhausted sense of being too overwhelmed to do anything (psychomotor retardation) and a loss of feelings of pleasure. Accordingly, depression has a different biology and requires some different strategies for treatment. But it, too, can be related to stress, and there is ample evidence of this association. First of all, psychological stress entails feeling a loss of control and predictability—an accurate description of depression. Second, major stressful events seem to precede depressive episodes early in the course of the disease."

"Imagine a rat trained to press a lever to avoid a mild, occasional shock—a task readily mastered. The rat is placed into a cage with the lever, and the anticipatory sense of mastery might well activate the pleasurable dopaminergic projections to the frontal cortex. When the increase in glucocorticoid secretion is moderate and transient—as would likely be the case here—the hormone enhances dopamine release. Suppose that in this circumstance, however, the lever has been disconnected; pressing it no longer prevents shocks. Initially this alteration produces a wildly hypervigilant state in the rat as it seeks a new coping response to stop the shocks. The animal presses the lever repeatedly, frantically trying to regain control. This is the essence of anxiety and of the multiple, disorganized attempts at coping. Physiologically, this state is characterized by massive activation of the sympathetic nervous system by epinephrine and of the norepinephrine projection from the locus coeruleus, as well as moderately increased glucocorticoid secretion".

"In the 1950s and 1960s pioneers such as John Mason, Seymour Levine and Jay Weiss—then at the Walter Reed Army Medical Center, Stanford University and the Rockefeller University, respectively— began to identify key facets of psychological stress. They found that such stress is exacerbated if there is no outlet for frustration, no sense of control, no social support and no impression that something better will follow. Thus, a rat will be less likely to develop an ulcer in response to a series of electric shocks if it can gnaw on a bar of wood throughout, because it has an outlet for frustration. A baboon will secrete fewer stress hormones in response to frequent fighting if the aggression results in a rise, rather than a fall, in the dominance hierarchy; he has a perception that life is improving. A person will become less hypertensive when exposed to painfully loud noise if she believes she can press a button at any time to lower the volume; she has a sense of control. But suppose such buffers are not available and the stress is chronic. Repeated challenges may demand repeated bursts of vigilance. At some point, this vigilance may become overgeneralized, leading an individual to conclude that he must always be on guard—even in the absence of the stress. And thus the realm of anxiety is entered. Alternatively, the chronic stress may be insurmountable, giving rise to feelings of helplessness. Again this response may become overgeneralized: a person may begin to feel she is always at a loss, even in circumstances that she can actually master. Depression is upon her".  

Sapolsky