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must not be ignored. For example, patients with systemic lupus erythematosus (SLE)
may have cerebral vasculitis, production of autoantibodies with cross-affinity for neu-
ral tissue resulting in cerebral inflammation and/or tissue damage, and destruction of
the integrity of the blood-brain barrier. Nevertheless, neuropsychiatric symptoms have
also been reported in disorders not typically associated with direct cerebral involve-
ment (e.g., Sjogren's syndrome), and where other evidence of cerebral involvement is
lacking (e.g., absence of abnormalities seen on EEG or with enhanced neuroimaging
techniques). It is, however, pertinent to note that autoimmune disorders are overrepre-
sented among groups of patients with treatment-resistant depression [63] .
12.4 Cytokines and Affective Disorders
The potential link between immune alterations and affective disorders has been rec-
ognized for many years. Early work in the field of psychoneuroimmunology tended
to concentrate on whether psychological stress or psychiatric disorders such as
depression could result in changes in humoral or cell-mediated immunity, and the
possible mechanisms underlying such occurrences. Indeed, there is significant evi-
dence to suggest that psychological stress or depression can directly stimulate the
production of pro-inflammatory cytokines that influence a range of conditions,
particularly those that are more prevalent during aging, such as cardiovascular dis-
ease, osteoporosis, arthritis, type 2 diabetes, certain types of cancer, and functional
decline. Depression can also down-regulate the cellular immune response; as a
consequence, processes, such as prolonged infection and delayed wound healing,
that fuel sustained production of pro-inflammatory cytokines may be promoted. It
is not surprising, therefore, that antidepressant drugs have been shown to possess
anti-inflammatory effects [64,65] . It has now become accepted that CNS-immune
system interactions are in fact mutual and that the converse also applies: namely,
that disturbances of immune function may play a role in the etiology of psychiat-
ric disease, including depression [66] . For example, a mild, non-sickness-inducing
inflammatory stimulus ( salmonella typhi vaccine) can evoke negative mood changes
in healthy individuals, which are correlated with increases in IL-6 production [67] .
Furthermore, neuropsychiatric symptoms such as psychomotor slowing, subjective
fatigue, and subjective cognitive impairment are common not only in major depres-
sion but also in specific infective and autoimmune disorders, such as lupus, sclero-
derma, and Sjogren's syndrome, thus suggesting that these symptoms may be due
to a common central action of cytokines. Endogenous psychoses also show several
other parallels with autoimmune diseases, including early onset, genetic predisposi-
tion, waxing and waning of symptoms, and (in the case of depression) sex ratio.
12.4.1 Stress and Anxiety
Experimental and epidemiological data have revealed that psychological and physi-
cal stresses are capable of altering the function of immunocompetent cells [68,69] ,
although the precise nature of the alteration depends on the type and severity of the
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