Biology Reference
In-Depth Information
expression of antinuclear and antiphospholipid autoantibodies may indicate an auto-
immune response. The main findings that indicate activation of cell-mediated immu-
nity are those that show an increased number of T helper cells (CD4), T memory
cells (CD4 CD45RO-), activated T cells (i.e., CD25 T and HLA-DR T cells),
and B cell subsets, as well as an increased ability of monocytes and lymphocytes to
produce cytokines such as IL-1, IL-2, IL-6, IFN-, and TNF-, all of which have
been noted in patients with depression
[92-98]
.
Although it has been suggested that the increase in pro-inflammatory cytokines
in patients with major depression correlates with illness severity and indices of HPA
hyperactivity
[99,100]
, these observations have not always been replicated by oth-
ers
[101,102]
. Furthermore, some authors consider the possible association between
cytokines and depression to be highly speculative
[103]
. Most authors have, how-
ever, confirmed that there are increases in the plasma concentrations of acute phase
proteins
[104]
. This observation, along with reports of mild leukocytosis, neutro-
philia, and elevated C-reactive protein and components of the complement system
[105]
, suggests the presence of a mild inflammatory response in depression, possi-
bly initiated by cytokines. Functional markers of cellular immunity have been stud-
ied in patients with major depression (MD), with or without melancholic features.
Patients who had MD with melancholia produced significantly less IL-2 than did
MD patients without melancholia; the latter did not differ from normal subjects.
Melancholia patients also showed reduced IFN- and IL-10 production. IL-12 levels
of both groups with MD were higher than the control group, and decreased signifi-
cantly after 8 weeks of antidepressant treatment
[106]
. IFN- is produced in larger
amounts by lymphocytes of patients with MD than by those of healthy subjects.
The higher plasma IFN- concentrations in such patients are accompanied by lower
plasma tryptophan availability
[97]
. This occurs because IFN- is capable of induc-
ing the enzyme indoleamine 2,3-dioxygenase, which converts tryptophan to kynure-
nine. The reduced plasma tryptophan concentrations will ultimately lead to reduced
synthesis of 5HT in the CNS. Pro-inflammatory cytokines also up-regulate the 5HT
transporter, causing a reduction in extracellular 5HT concentrations. These effects on
central 5HT, coupled with effects on noradrenergic and HPA function, could underlie
the depressogenic actions of the pro-inflammatory cytokines. Conversely, the anti-
inflammatory cytokine IL-4 reduces 5HT uptake.
12.4.1.2 Effects of Antidepressants on Immune Function
If cytokines are involved in the etiology of depression, then cytokine antagonists
should have antidepressant actions. Similarly, the antidepressant drugs that are used
clinically should be able to modify the production and/or actions of cytokines. The
former possibility has not been tested extensively, but it is known that centrally
administered IL-1 antagonists can block learned helplessness
[91]
and can reduce
cytokine-induced decreases in social exploration
[107]
.
The effects of antidepressant drugs on immune function have been studied in
more detail. These have been shown to have an inhibitory effect on the release of pro-
inflammatory cytokines from activated monocytes and macrophages, and to enhance
