Biomarkers of inflammation, including inflammatory cytokines and the acute-phase reactant C-reactive protein (CRP), are reliably increased in a subset of patients with depression, anxiety disorders and post-traumatic stress disorder (PTSD). Administration of innate immune stimuli to laboratory subjects and the associated release of inflammatory cytokines has been shown to affect brain regions involved in fear, anxiety and emotional processing such as the amygdala. However, the role of inflammation in altered circuitry involving amygdala and other brain regions and its subsequent contribution to symptom severity in depression, anxiety disorders and PTSD is only beginning to be explored. Herein, medically-stable, currently unmedicated outpatients with a primary diagnosis of major depressive disorder (MDD; n = 48) underwent resting-state functional MRI (rfMRI) to determine whether altered connectivity between the amygdala and whole brain was observed in a subset of patients with high inflammation and symptoms of anxiety. Whole-brain, voxel-wise functional connectivity analysis of the right and left amygdala as a function of inflammation (plasma CRP concentrations) revealed that increased CRP predicted decreased functional connectivity between right amygdala and left ventromedial prefrontal cortex (vmPFC) (corrected p < 0.05). Amygdala-vmPFC connectivity was, in turn, negatively correlated with symptoms of anxiety (r = -0.33, df = 46, p = 0.022). In exploratory analyses, relationships between low amygdala-vmPFC connectivity and high anxiety were only observed in patients with a secondary diagnosis of an anxiety disorder or PTSD (r = -0.54 to -0.87, p < 0.05). More work is needed to understand the role of inflammation and its effects on amygdala-vmPFC circuitry and symptoms of anxiety in MDD patients with comorbid anxiety disorders or PTSD.

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Abstract Trauma exposure is associated with increased inflammatory biomarkers (e.g. C-reactive protein [CRP] and cytokines), and inflammation has been shown to impact corticostriatal reward circuitry and increase anhedonia-related symptoms. We examined resting-state functional MRI in a high-trauma inner-city population of African-American women (n = 56), who reported on average five different types of trauma exposures, to investigate whether inflammation correlated with functional connectivity (FC) in corticostriatal reward circuitry in association with symptoms of anhedonia and PTSD. Plasma CRP negatively correlated with bilateral ventral striatum (VS) to ventromedial prefrontal cortex (vmPFC) FC (P &lt; 0.01). In participants where plasma was available to also measure cytokines and their soluble receptors, left (L)VS-vmPFC FC negatively correlated with an inflammatory composite score (previously shown to be increased in plasma and cerebrospinal fluid of depressed patients with high CRP) only in women with significant PTSD symptoms (n = 14; r = −0.582, P = 0.029) and those who experienced moderate–severe childhood trauma (r = −0.595, P = 0.009). Exploratory analyses indicated that LVS-vmPFC FC correlated with anhedonia-related subscales from the Beck Depression Inventory (r = −0.691, P = 0.004) and PTSD Symptom Scale (avoidance/numbness; r = −0.514, P = 0.042) in participants with an inflammatory score over the median (n = 16). Results suggest that inflammation contributes to compromised reward circuitry and symptoms of anhedonia and PTSD in trauma-exposed women.

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Introduction Depression and diabetes are highly prevalent worldwide and often co-exist, worsening outcomes for each condition. Barriers to diagnosis and treatment are exacerbated in low and middle-income countries with limited health infrastructure and access to mental health treatment. The INtegrating DEPrEssioN and Diabetes treatmENT (INDEPENDENT) study tests the sustained effectiveness and cost-effectiveness of a multi-component care model for individuals with poorly-controlled diabetes and depression in diabetes clinics in India. Materials and Methods Adults with diabetes, depressive symptoms (Patient Health Questionnaire-9 score ≥10), and ≥1 poorly-controlled cardiometabolic indicator (either HbA1c ≥8.0%, SBP ≥140mmHg, and/or LDL ≥130mg/dl) were enrolled and randomized to the intervention or usual care. The intervention combined collaborative care, decision-support, and population health management. The primary outcome is the between-arm difference in the proportion of participants achieving combined depression response (≥50% reduction in Symptom Checklist score from baseline) AND one or more of: ≥0.5% reduction in HbA1c, ≥5 mmHg reduction in SBP, or ≥10 mg/dl reduction in LDL-c at 24 months (12-month intervention; 12-month observational follow-up). Other outcomes include control of individual parameters, patient-centered measures (i.e. treatment satisfaction), and cost-effectiveness. Results The study trained seven care coordinators. Participant recruitment is complete – 940 adults were screened, with 483 eligible, and 404 randomized (196 to intervention; 208 to usual care). Randomization was balanced across clinic sites. Conclusions The INDEPENDENT model aims to increase access to mental health care and improve depression and cardiometabolic disease outcomes among complex patients with diabetes by leveraging the care provided in diabetes clinics in India (clinicaltrials.gov number: NCT02022111).