Biology Reference
In-Depth Information
The therapeutic use of cytokines has been associated with a range of dose-
dependent neuropsychiatric symptoms, including symptoms similar to those noted
in depressive disorders: fatigue, altered sleep patterns, irritability, loss of appetite,
weight loss, low mood, anhedonia, apathy, and mental retardation
[84,85]
. These
symptoms are most common in patients treated with IFN-, occurring in up to 36%
of cases, and are often of sufficient severity to necessitate discontinuation of therapy
or the co-administration of antidepressant drugs. In rarer cases, IFN- may cause
psychosis, delirium, and persistent manic-depressive illness, the recurrence of post-
traumatic stress disorder (PTSD) or suicidal behavior. The severity of the observed
effects tends to be related to the dose and duration of treatment, as well as to indi-
vidual differences between patients, including previous psychiatric history. Although
it is possible that those patients who became depressed during the course of cytokine
therapy were predisposed to this condition, the neuropsychiatric symptoms disap-
peared upon cessation of treatment. In animals, cytokines also evoke anhedonia,
anorexia, a decrease in social behavior, psychomotor retardation, altered sleep pat-
terns, and impaired cognitive function. Some of these alterations in behavior are
associated with HPA overactivity and glucocorticoid resistance.
These changes are similar to those noted during chronic immune activation, and
it has been difficult to distinguish what is due to “sickness” from what may be due
to specific psychiatric effects. However, this distinction has been achieved for two of
the symptoms, namely anhedonia and helplessness.
Anhedonia
(the inability to expe-
rience pleasure) is one of the essential features noted in major depressive episodes
with melancholia. It can be demonstrated experimentally in animals by attenuated
responses to rewarding intracranial self-stimulation (ICSS), a reduced preference
for sweet solutions, and an impairment of sexual behavior. Interleukin-1, TNF-,
and IL-2 can all cause anhedonia in rats and mice
[86,87]
. In experimental animals,
LPS administration, which induces production of pro-inflammatory cytokines and
IL-6, also induces anhedonia, as evidenced by disrupted sexual behavior in female
rats, decreased response to rewarding lateral hypothalamic self-stimulation, and a
decreased consumption of saccharine
[88]
. The latter effect could be attenuated by
chronic imipramine treatment
[89]
. It is also pertinent that the nonsteroidal anti-
inflammatory drug diclofenac attenuates LPS-induced reductions in reward behav-
ior, as we know that cytokines can induce prostaglandin synthesis
[90]
. Helplessness,
another key symptom of depression, can be studied in animals by using a “learned
helplessness” behavioral model. This relates to learning the lack of contingency
between behavior and its consequences and occurs, for example, when animals are
exposed to a situation from which they cannot escape. Both LPS and IL-1 have been
found to increase immobility time in two such models, the forced swim test and
during exposure to inescapable electric shocks. The effects of IL-1 in the latter test
are abolished by administration of IL-1ra, thus emphasizing the importance of this
cytokine in mediating these behavioral effects
[91]
.
The activation of inflammatory, autoimmune, and cell-mediated immune
responses may accompany depression. Increased plasma concentrations of posi-
tive acute phase proteins, and a reduction in the levels of negative acute phase pro-
teins, have been noted. As well as the presence of an acute phase response, enhanced
