This is a parallel group, double-blinded, placebo-controlled study. Participants with MDD (n=90) and HC (n=90) will be randomly assigned (2:1) to receive either lipopolysaccharide (LPS) (0.8ng/kg of body weight) or placebo (same volume of 0.9% saline) administered as an intravenous bolus. This will yield the following groups: MDD-LPS (n=60), MDD-Placebo (n=30), HC-LPS (n=60), HC-placebo (n=30).
There are three main aims: to identify immune pathways and neural circuits that respond differently to LPS in MDD vs. HC subjects; (2) to test whether the strength of inflammatory changes induced by LPS is associated with degree of change in anhedonic symptoms and neural circuits in the MDD group, and (3) to identify a biotype of MDD that shows a differential immunological and neurophysiological response to LPS. The main outcome variables are symptoms of anhedonia measured with the Snaith-Hamilton Pleasure Scale (SHAPS), cytokines (Il-6, IL-8, IL-10, and TNF), and BOLD signal change in the neural circuitry mediating interoceptive processing, i.e. the insula and cingulate cortex. The exploratory aim is to determine whether the acute inflammatory response to LPS can predict the clinical course of depression over a period of six months. The main outcome of this component of the study is self-reported depressive symptoms assessed with the QIDS-SR.
None
Pregnancy
A history of fainting during blood draws will be evaluated by the clinical team and may be deemed exclusionary.
Moderate to severe traumatic brain injury (>30 min. loss of consciousness or >24 hours posttraumatic amnesia) or other neurocognitive disorder with evidence of neurological deficits.
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.
Parallel
LPS
Biological/VaccineLipopolysaccharide (LPS) (0.8ng/kg of body weight; E. coli group O:113)
Saline
Biological/Vaccine0.9% saline administered as an intravenous bolus
Inflammatory response
Serum interleukin 6 (IL-6) (pg/mL)
Symptoms of anhedonia
Snaith-Hamilton Pleasure Scale Score (score range 14-56; higher scores more anhedonia)
Depressive Symptoms
Change in Depressive Symptoms measures with the Montgomery-Asberg Depression Rating Scale (MADRS). Score range 0-60. Higher scores = more depression.
Neural response to anticipation of monetary reward
BOLD Signal Change in the ventral striatum measured using MRI
Neural response to interoceptive vs exteroceptive stimuli (interoceptive awareness task)
BOLD Signal Change in the Insula and Posterior Cingulate Cortex measured using MRI
Temperature
Body temperature
Inflammatory response
Serum tumor necrosis factor (TNF) (pg/mL)
Course of Illness
Depressive symptoms at 6 month follow-up measured with the Quick Inventory of Depressive Symptoms (QIDS). Score range 0-27. Higher scores = greater depression.
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