Biology Reference
In-Depth Information
in depression. Fluoxetine has also been shown to suppress IFN- production in
human whole blood. Clinical studies suggest that all classes of antidepressants can
exert immunosuppressant effects, as they reduce the production of pro-inflammatory
cytokines such as IL-1, TNF-, and IFN-, and stimulate the production of negative
immunoregulators such as IL-10 and IL-1ra.
However, in some animal models only the tricyclic antidepressants, and not the
SSRIs or venlafaxine, normalize changes in immune function by an action on TNF.
These differences may be due to the limitations of the animal models of psychiat-
ric disorders. Nevertheless, chronic antidepressant treatment abolished LPS-induced
anhedonia in rats
[87]
, an effect believed to be due to a reduction in the capacity of
monocytes and macrophages to produce pro-inflammatory cytokines.
More recently, it has been shown that IL-6 is necessary for the antidepressant action
of
Hypericum perforatum
(HP; St. John's wort), and that activation of CNS 5HT
metabolism following HP treatment may be attributed to increased IL-6. HP extract
reduced immobility in a model of depression (forced swim test) in wild-type, but not
IL-6 knockout, mice. It also induced significantly higher levels of 5HT and 5HIAA in
the diencephalon of wild-type mice compared with IL-6 knockout mice
[125]
.
Thus, evidence obtained with a wide range of antidepressant drugs and from
depressed subjects, as well as from healthy volunteers, supports the contention that
antidepressant drugs are able to affect cytokine production and that altered cytokine
concentrations may be related to depressive illness. However, there is a paucity of
data relating to predepression cytokine concentrations in patients, and it is difficult
to determine which came first, the depression or the elevated concentrations of pro-
inflammatory cytokines. Studies involving the use of cytokines in immunotherapy
appear to lend support to the idea of a role for cytokines in the etiology of depres-
sion. However, the doses used for immunotherapy are high and in excess of concen-
trations that may be achieved endogenously. Furthermore, such patients are already
seriously ill, and the effects of severe stress caused by the presence of the illness can-
not be ruled out. It is known that stressors can influence pro-inflammatory cytokine
function, and it is therefore possible that the altered cytokine activity observed in
depression may be secondary to an increase in stress or stress perception.
Indeed, all subtypes of depression are associated with an increase in stress and/
or stress perception, as well as excessive emotionality, reduced efficiency of coping
strategies, diminished quality of life, anhedonia, reduced interpersonal skills, and
reduced social buffering. Thus, cytokine changes may be secondary to the real or
perceived stress associated with the disease. Additionally, comorbid features (e.g.,
anxiety, personality disturbances, and self-neglect
[126]
) are often present in depres-
sion, which could influence cytokine concentrations. At present, the correlative rela-
tionship between cytokines and depression requires further investigation, but it is
possible that the elevated cytokine concentrations contribute to symptoms such as
somnolence, muscle fatigue, and reduced food intake that are noted in this condi-
tion. There is a consensus of opinion that depression is characterized by changes in
neuroendocrine and immune system function. Novel antidepressants that affect the
central corticotropin system and HPA activity, the CRH-R1 antagonists, are already
undergoing clinical trials. It seems worthwhile, too, to develop antagonists of pro-
