Role of Translocator Protein Density, a Marker of Neuroinflammation, in the Brain During Major Depressive Episodes

118

124

A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

Section: Immunological Mechanismsmentioning

confidence: 56%

Section: Enrich For Patients Based On Peripheral Immune Markersmentioning

confidence: 99%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

118

124

“…Recently, in vivo activation of microglia in the brains of patients with mood disorders has been imaged using positron emission tomography and a radiolabeled tracer for the translocator protein (TSPO), which is overexpressed in these cells upon activation. Using this ligand in patients with major depressive disorder, one study found increased microglial activation (Setiawan et al, 2015), whereas another did not (Hannestad et al, 2013), a discrepancy that may be related to the severity of depression, medication status, and other demographic features. Nevertheless, TSPO ligand binding reliably labeled activated glial cells following endotoxin administration in healthy human subjects (Sandiego et al, 2015).…”

Section: Alternative Activation and Acquired Deactivation Statesmentioning

confidence: 98%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

412

299

Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

“…Furthermore, animal models enabled researchers to use invasive measures to investigate the links between early-life stress and neuroinflammation (ie, the inflammation of the CNS), an area of investigation that is only starting to be applied to clinical populations (Bloomfield et al, 2016;Setiawan et al, 2015). Despite these two crucial advantages, the use of proxy models of human experiences and of brain functioning or behavior have important limitations (Clancy et al, 2007;van der Worp et al, 2010).…”

Section: Observational Studies In Humansmentioning

confidence: 99%

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

Danese

Lewis

2016

305

191

The brain and the immune system are not fully formed at birth, but rather continue to mature in response to the postnatal environment. The two-way interaction between the brain and the immune system makes it possible for childhood psychosocial stressors to affect immune system development, which in turn can affect brain development and its long-term functioning. Drawing from experimental animal models and observational human studies, we propose that the psychoneuroimmunology of early-life stress can offer an innovative framework to understand and treat psychopathology linked to childhood trauma. Earlylife stress predicts later inflammation, and there are striking analogies between the neurobiological correlates of early-life stress and of inflammation. Furthermore, there are overlapping trans-diagnostic patterns of association of childhood trauma and inflammation with clinical outcomes. These findings suggest new strategies to remediate the effect of childhood trauma before the onset of clinical symptoms, such as anti-inflammatory interventions and potentiation of adaptive immunity. Similar strategies might be used to ameliorate the unfavorable treatment response described in psychiatric patients with a history of childhood trauma.