Influenza Challenge in Mood Disorders

Psychological stress has been shown to impair the efficacy of the influenza vaccine, particularly in older individuals (> 60 years). However, the effect of depression (as opposed to stress per se) on vaccine response has not been measured, especially in younger people. One possible cause of this putative impaired vaccine response is suppression of the immune system in a subgroup of individuals with depression. Major depressive disorder (MDD) has been associated with a decline in total numbers of circulating B-cells, T-cells, and natural killer cells (NKC), a reduction in the proliferative responses of NKC and T-cells in vitro that is ameliorated by administration of selective serotonin reuptake inhibitors (SSRIs), increased susceptibility to various viral infections, and a decline in the efficacy of the herpes zoster vaccine in the elderly (1, 2). On the other hand, MDD appears also to be characterized by immunological abnormalities that manifest both as low-grade inflammation, including over-activity of the innate immune system (3). Whether inflammation and immune suppression are two different manifestations of the same underlying abnormality (unitary model) or whether inflammation and immune suppression are distinct phenomena occurring in different MDD subtypes (independent model) is not known.

MDD is also characterized by neurophysiological abnormalities of striatal, cortical midline, and limbic brain structures that regulate hormonal, autonomic, and emotional responses to reward and stress (4-6). Yet, it remains unclear how immune function relates to these depression-associated functional neuroimaging abnormalities. Studies of healthy volunteers (HCs) administered endotoxin or the typhoid vaccine have reported inflammation-associated increases in negative affect along with neurophysiological changes in brain regions comprising the affective and reward circuitry (7-8). However, because these studies were limited to HCs, it is possible that the observed inflammation-induced neurophysiological changes were adaptive and therefore not applicable to MDD populations. That is, it remains unclear whether any experimentally-induced immune abnormalities in MDD are correlated and therefore potentially causally-related to the neuroimaging abnormalities observed in MDD.

In order to address these questions, we use a parallel group, placebo-controlled influenza vaccine challenge to induce transient inflammation that peaks 2-days post vaccination in MDD subjects and HCs. Subjects may complete a pre-and-post vaccination MRI scan, the latter during the peak inflammatory response.

Aim 1: To examine whether influenza vaccine effectiveness is compromised in a young-to-middle-aged sample (18-55 years of age) of individuals with MDD.

Hypothesis 1.1. Compared with HCs (n=40), individuals with MDD (n=40) will display reduced vaccine titers and reduced influenza virus-induced CD4+ memory T-cell proliferation four weeks post vaccination (T2).

Hypothesis 1.2. A greater number of MDD subjects than HCs will fail to show a four-fold increase in antibody titer, the conventional standard for determining a clinically significant response to a viral vaccine.

Aim 2: To test the competing models of immune dysfunction in MDD.

Hypothesis 2.1. At T0 and T1, stimulated and unstimulated monocytes from MDD subjects will show increased interleukin 6 (IL-6) and tumor necrosis factor (TNF) production compared with HCs. The effect will be most salient at T1 in individuals receiving vaccine.

Hypothesis 2.2. Consistent with the unitary model, monocyte IL-6 and/or TNF production at T0 and T1 will be inversely correlated with antibody titers at T2 in the MDD group.

Aim 3: To test for neurophysiological differences between MDD patients and HCs in resting state cerebral blood flow (with arterial spin labeling), resting EEG activity, and BOLD response to monetary rewards and interoceptive stimuli (with fMRI) at T0 and T1, and to correlate depression-associated perfusion, EEG activity, reward response, and interoceptive function with immune function at T0 and T1.

Hypothesis 3.1: Compared with HCs, the MDD subjects will display reduced perfusion of the subgenual anterior cingulate cortex (sgACC) and/or pregenual ACC (pgACC), hemispheric asymmetry in the alpha (8-13 Hz) power band (left prefrontal cortex hypoactivation), as well as reduced hemodynamic response to anticipatory reward in the ventral striatum. These differences will be most salient at T1 in the MDD group receiving vaccine versus the HCs receiving vaccine.

Hypothesis 3.2: The functional imaging abnormalities in the MDD group at T0 and/or T1 will be correlated with the abnormalities in monocyte activation in the MDD group at T0 and/or T1.