Late-life depression is a major public health burden due to its high prevalence and associated morbidity, suicide risk, functional decline, and mortality. Unfortunately, current antidepressant therapies have limited effectiveness; hence, biologically plausible models for new treatments are being pursued. Systemic inflammation is hypothesized to play an important role on the onset and perpetuation of depression, especially in older women. Aging processes involve a heightened inflammatory state, and both inflammatory disorders and depression are more prevalent in women than men. However, increased systemic inflammation does not necessarily lead to depression in all women. Even when robust systemic inflammation is experimentally induced (e.g. endotoxin administration), largely variable increases in depressive symptoms are found. Defining the factors that account for this variability may identify individuals at risk of developing depression when exposed to heightened inflammatory states such as aging, obesity, and chronic disease, and informs future translational studies of depression prevention. In particular, the role of sleep disturbance in explaining this variability requires further attention because it is an independent risk factor for depression and heightens systemic inflammation by increasing the production of proinflammatory cytokines. The investigators have also discovered that women, but not men, who report sleep disturbance including short sleep duration experience significantly more depressive symptoms in response to an inflammatory challenge than women without sleep disturbance. Thus, it is hypothesized that sleep loss is a vulnerability factor for inflammation-induced depressive symptoms in women. However, to date, no experimental approach has been used to evaluate the role of sleep loss on inflammation-induced depressive symptoms. This proposal aims to examine this hypothesis by partial sleep deprivation (PSD) followed by endotoxin challenge in older women. It also aims to explore genomic and socio- emotional mechanisms underlying the association between sleep loss and depressive symptoms. In a randomized controlled factorial design, 80 healthy female volunteers aged 60 to 80 will be randomly assigned to one of 4 arms: 1) uninterrupted sleep followed by placebo; 2) uninterrupted sleep followed by endotoxin; 3) PSD followed by placebo; or 4) PSD followed by endotoxin. Subjects will be administered placebo or endotoxin in the morning after PSD or uninterrupted sleep. Depressive symptoms will be repeatedly assessed over 6 hours after placebo or endotoxin administration.

Inclusion Criteria:

• to be in good general health
• to be female
• to be aged 60 to 80 years

Exclusion Criteria:

• presence of chronic mental or physical illnesses
• history of allergies, auto-immune, liver, or other chronic diseases
• current use of prescription medications such as steroids, non-steroid anti-inflammatory drugs, immune modifying drugs, opioid analgesics, and psychotropic medications
• current sleep disorders such as insomnia or sleep apnea
• nightshift work or time zone shifts (> 3 hours) within the previous 6 weeks
• an Axis I psychiatric disorder as determined by the Research Version of the Structured Clinical Interview for DSM-5 (SCID-5-RV) including a current or within 1 year prior-to-study history of major depressive disorder (a history of depression 1 or more years prior to the study is not an exclusion criterion, which will be considered for a pre-planned sensitivity analysis, however, any prior depressive episode severe enough to have involved suicidal ideation or required an inpatient psychiatric admission is an exclusion criterion)
• prior or current suicidal ideation assessed by the Columbia Suicide Severity Rating Scale (C-SSRS)
• current depressive symptoms assessed by the Patient Health Questionnaire (PHQ-9) (≥ 5)
• sleep disorders identified by the SCID and the Duke Structured Interview for Sleep Disorders (DSISD)
• sleep disturbance defined by the Pittsburgh Sleep Quality Index (PSQI) (≥ 5)
• a positive screen for sleep apnea using the Berlin Sleep Apnea Questionnaire
• excessive caffeine use (>600 mg/day)
• BMI > 35 due to the effects of obesity on cytokine activity and risk for sleep disordered breathing
• evidence of recreational drug use from urine test
• any abnormalities on screening laboratory tests.