The Scientific Journals

By : Esther M. Sternberg and Philip W. Gold

Although the role of the stress response in inflammatory disease in humans is more difficult to prove, there is a growing amount of evidence that a wide variety of such diseases are associated with impairment of the HPA axis and lower levels of CRH secretion, which ultimately results in a hyperactive immune system.  Furthermore, patients with a mood disorder called atypical depression also have a blunted stress response and impaired CRH function, which leads to lethargy, fatigue, increased sleep and increased feeding that often produces weight gain.

Patients with other illnesses characterized by lethargy and fatigue, such as chronic fatigue syndrome, fibromyalgia and seasonal affective disorder (SAD), exhibit features of both depression and a hyperactive immune system. A person with chronic fatigue syndrome classically manifests debilitating lethargy or fatigue lasting six months or longer with no demonstrable medical cause, as well as feverishness, aches in joints and muscles, allergic symptoms and higher levels of antibodies to a variety of viral antigens (including Epstein-Barr virus).

Patients with fibromyalgia suffer from muscle aches, joint pains and sleep abnormalities, symptoms similar to  early, mild rheumatoid arthritis. Both these illnesses are associated with a profound fatigue like that in atypical depression. SAD, which usually occurs in winter, is typified by lethargy, fatigue, increased food intake and  increased sleep. Many of its symptoms are similar to those of atypical depression.

CRH, the Locus Ceruleus and Sympathetic Nervous System HYPOTHALAMIC CRH produces changes important to stress and inflammation adaptation in ways other than inducing cortisol release from the adrenal glands. Pathways from CRH-secreting neurons in the hypothalamus extend to the locus ceruleus in the brain stem. Separate pathways from other hypothalamic neurons to the brain stem influence sympathetic nervous system activity, which modulates inflammatory responses as well as regulating metabolic and cardiovascular activities. Stimulation by CRH of the locus ceruleus produces protective behaviors such as arousal and fear (red indicates stimulation, blue inhibition). The locus ceruleus, in turn, provides feedback to the hypothalamus for continued production of CRH and also acts on the sympathetic nervous system. Self-inhibitory feedback keeps the activities of CRH and the locus ceruleus under control.

A deficiency of CRH could contribute to lethargy in patients with chronic fatigue syndrome. Injection of CRH into patients with fatigue syndrome causes a delayed and blunted ACTH secretion by the HPA axis. That same response is also seen in patients whose hypothalamus has been injured or who have a tumor. Also, fatigue and hyperactivity of the immune response are associated with cortisol deficiency, which occurs when CRH secretion decreases. The hormone levels and responses in patients with fatigue syndromes suggest— but do not prove—that their HPA-axis functions are impaired, resulting in a decrease in CRH and cortisol secretion and an increase in immune system activity. Together these findings suggest that human illness  characterized by fatigue and hyperimmunity could possibly be treated by drugs that mimic CRH actions in the brain.

In contrast, the classic form of depression, melancholia, actually is not a state of inactivation and suppression of thought and feeling; rather it presents as an organized state of anxiety. The anxiety of melancholia is chiefly about the self. Melancholic patients feel impoverished and defective and often express hopelessness about the prospects for their unworthy selves in either love or work. The anxious hyperarousal of melancholic patients also manifests as a pervasive sense of vulnerability, and melancholic patients often interpret relatively neutral cues as harbingers of abandonment or embarrassment.

Melancholic patients also show behavioral alterations suggestive of physiological hyperarousal. They characteristically suffer from insomnia (usually early-morning awakening) and experience inhibition of eating,  sexual activity and menstruation. One of the most widely found biological abnormalities in patients with melancholia is that of sustained hypersecretion of cortisol.

Many studies have been conducted on patients  with major depression to determine whether the excessive level of cortisol associated with depression correlates with suppressed immune responses. Some have found  a correlation between hypercortisolism and immunosuppression; others have not. Because depression can have a variety of mental and biochemical causes only some depressed patients may be immunosuppressed.

The excessive secretion of cortisol in melancholic patients is the result predominantly of hypersecretion of  CRH, caused by a defect in or above the hypothalamus. Thus, the clinical and biochemical manifestations of  melancholia reflect a generalized stress response that has escaped the usual counterregulation, remaining, as it were, stuck in the “on” position.

The effects of tricyclic antidepressant drugs on components of the stress response support the concept that melancholia is associated with a chronic stress response. In rats, regular, but not acute, administration of the  tricyclic antidepressant imipramine significantly lowers the levels of CRH precursors in the hypothalamus. Imipramine given for two months to healthy persons with normal cortisol levels causes a gradual and sustained decrease in CRH secretion and other HPA-axis functions, indicating that down-regulation of important components of the stress response is an intrinsic effect of imipramine.

Depression is also associated with inflammatory disease. About 20 percent of patients with rheumatoid arthritis develop clinical depression at some point during the course of their arthritic disease. A questionnaire commonly used by clinicians to diagnose depression contains about a dozen questions that are almost always  answered affirmatively by patients with arthritis.

Next : Stress and Illness