Inflammation-Induced Depressed Mood: The Role of Social Neurocognitive Mechanisms
Inflammation-Induced Depressed Mood: The Role of Social Neurocognitive Mechanisms
Depressive disorders occur at a high rate in patients with inflammatory disorders, with a
 point prevalence of 15-29%, which is two to three times greater than that observed in the
 general population. Substantial evidence has shown that inflammation and increases in
 proinflammatory cytokine activity play a critical role in the onset and perpetuation of
 depression and depressive symptoms (e.g. insomnia, fatigue) in those who are co-morbid for
 inflammatory disorders. Consistent with this, experimental work has shown that an
 inflammatory challenge can increase depressed mood in an otherwise healthy sample. Based on
 these findings, there has been a growing interest in whether inflammatory processes can
 contribute to depression in a causal manner and how these effects might occur.

 Given the observation that inflammatory processes trigger social withdrawal, coupled with
 evidence that feelings of 'social disconnection' play a critical role in the onset and
 perpetuation of (non-inflammatory forms of) depression, it is surprising that the social
 psychological consequences of inflammation and their contribution to depression have not been
 more fully explored. Here, we suggest that inflammation may increase feelings of social
 disconnection and that these social psychological changes may be an important contributor to
 inflammation-associated depression. Indeed, preliminary data demonstrated that an
 experimentally-induced inflammatory challenge (endotoxin) led to increases in self-reported
 feelings of social disconnection (e.g., "I feel disconnected from others") in addition to
 increases in depressed mood. Aside from these findings, however, there are no studies that
 have explored the effect of inflammatory processes on social experience in humans. The
 over-arching objective of this proposal is to explore the experiential and neural correlates
 of inflammatory-induced changes in social experience (e.g., feelings of social
 disconnection), which may provide a critical missing link in understanding the relationship
 between inflammation and depression.

 Participants (n=100) will be randomly assigned to receive either endotoxin or placebo and
 will then be monitored for the next six hours. Blood draws to assess cytokine levels as well
 as self-reported feelings of social disconnection and depressed mood will be collected
 hourly. In addition, at the time of peak cytokine response, participants will complete a
 neuroimaging session to examine the effect of inflammatory challenge on neural sensitivity to
 social rejection and social acceptance. It is hypothesized that endotoxin will increase
 feelings of social disconnection over time, and that the underlying neural sensitivities that
 give rise to these feelings (e.g., increased neural sensitivity to social rejection;
 decreased neural sensitivity to social acceptance) will contribute to inflammatory-induced
 depressed mood.
Inclusion Criteria:

 -  Participants will be required to be in good general health (as evaluated during the
 phone and in-person screening sessions described below), and to be between 18-50 years
 of age. All participants will be required to be fluent in English and to be
 right-handed.

 Exclusion Criteria:

 -  Following a structured telephone interview, prospective participants with the
 following conditions will not advance to the in-person screening session:
 claustrophobia or presence of metal in their body (relevant for the neuroimaging
 component of the study), pregnant or planning to become pregnant in the next 6 months,
 presence of chronic mental or physical illness, history of allergies, autoimmune,
 liver, or other severe chronic diseases, current and regular use of prescription
 medications, nightshift work or time zone shifts (> 3hrs) within the previous 6 weeks,
 or previous history of fainting during blood draws.

 Furthermore, the absence of significant health problems or medication use history will be
 confirmed by an in-person screening session. Any participant who has any of the following
 conditions will be ineligible for the study: Medical conditions. (1) presence of co-morbid
 medical conditions not limited to but including cardiovascular (e.g., history of acute
 coronary event, stroke) and neurological diseases (e.g., Parkinson's disease), as well as
 pain disorders; (2) presence of co-morbid inflammatory disorders such as rheumatoid
 arthritis or other autoimmune disorders; (3) presence of an uncontrolled medical condition
 that is deemed by the investigators to interfere with the proposed study procedures, or to
 put the study participant at undue risk; (4) presence of chronic infection, which may
 elevate proinflammatory cytokines; (5) presence of an acute infectious illness in the two
 weeks prior to an experimental session. Psychiatric Disorders. (6) current and/or lifetime
 history of a major Depressive Disorder or other DSM-IV psychiatric disorder (e.g. substance
 dependence) due to the known effects of major depression and/or substance dependence on
 inflammation. (Absence of a psychiatric diagnosis will be based on a structured psychiatric
 interview (Structured Clinical Interview for DSM-IV Diagnosis: SCID; First et al., 1996).)
 Medication and substance use. (7) current and/or past regular use of hormone-containing
 medications including steroids; (8) current and/or past regular use of non-steroid
 anti-inflammatory drugs; (9) current and/or past regular use of immune modifying drugs that
 target specific immune responses such as TNF antagonists; (10) current and/or past regular
 use of analgesics such as opioids; (11) current and/or past regular use of psychotropic
 medications, including selective serotinergic reuptake inhibitors, antidepressants,
 anxiolytics, hypnotics, sedatives and barbiturates. Health factors. (12) current smokers or
 excessive caffeine users (>600 mg/day) because of known effects on proinflammatory cytokine
 levels; (13) body mass index (BMI) greater than 35, (14) shows evidence of drug use from a
 positive urine test, (15) has a positive pregnancy test, if female, or (16) shows any
 abnormalities on screening laboratory tests.