Historical aspects of the neuroendocrine-immune connection
In order to understand the connection between the neuroendocrine and immune system, it is important to discuss the historical aspects of this relationship and the formulation of the concepts of homeostasis and stress. Claude Bernard in the 1860s developed the concept of “the milieu interne” to describe the balance of the internal milieu. In 1927, Cannon defined the fight or flight response to a threat and the concept of homeostasis as the physiological process by which an organism maintains a stable internal environment . Then in 1936, Hans Selye observed that sick patients all had similar nonspecific symptoms: malaise, fever, and loss of appetite . He proposed the general adaptation syndrome that states that when threatened by a threat or infection, the central nervous system (CNS) diverts the organism's energy reserves from nonessential functions (reproduction, growth) to functions that allow the organism to cope with the insult. Selye borrowed the term “stress” from the physical sciences to describe factors that upset homeostasis. He observed that stressed animals developed atrophy of the thymus, spleen, and lymph nodes and enlarged adrenal glands. Eventually, these effects were discovered to be the result of activation of the hypothalamic-pituitary-adrenal axis (HPA). Recently, McEwen has proposed the concept of allostatic load, which describes the cumulative effects of chronic stess that can result in dysregulation of multiple integrated physiological systems .
Abuse of alcohol and illicit drugs is on the increase in many parts of the world and, not surprisingly, people with psychosis participate in this general trend. But do people with schizophrenia abuse substances over and above the frequency of abuse in the general population, and, if so, do they abuse all or only some drugs? Unfortunately, much of the research in this area is subject to a range of methodological biases. First, these studies have commonly been carried out in unrepresentative samples such as inpatients in hospitals for veterans of the armed forces. Second, inadequate attention has often been paid to either the measurement of the substance abuse or the diagnosis of schizophrenia. Third, many samples mix together first-onset, relapsing and chronic patients. Fourth, very few studies are prospective.
Finally, even when the facts are established, they are often obscured by the clamorous debate between those who believe that substance abuse can cause schizophrenia and those who believe that schizophrenia predisposes to increase in abuse of substances. These opposing views are frequently held with a certainty that goes way beyond the evidence. As we shall see, different mechanisms may underlie the association between schizophrenia and substance misuse in different situations, and the way in which comorbidity develops may vary from substance to substance.
From an epidemiological point of view, there are a number of possible explanations for a reported association between a substance of abuse and schizophrenia (Thornicroft, 1990; Blanchard et al., 2000).
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