62,63 The harmful effects posed by substance use disorder in bipolar populations have been documented in many studies.5,64 Taken together, alcohol and substance

use disorder are associated with high rates of treatment nonadherence, low rates of recovery, greater risk of aggression and violence, increased rate of attempted and completed suicide, as well as a less favorable response to conventional treatment.65 Comorbidity research in bipolar disorder: Inhibitors,research,lifescience,medical future vistas Medical comorbidity and substance use disorders are prevalent and hazardous conditions in the bipolar population. Future research vistas should attempt to parse out neurobiological mediators that subserve medical comorbidity as well as temporality of onset. Such efforts may inform mechanistic models Inhibitors,research,lifescience,medical as well as individualized treatment planning. Biological mediators of “stress-sensitive” medical disorders Glucose-insulin homeostasis The differential occurrence of “stress-sensitive” medical disorders in the bipolar population suggests that interacting effectors mediating stress are a point of pathophysiological Inhibitors,research,lifescience,medical commonality. In keeping with this view, a testable hypothesis is that some features of bipolar disorder are affected by SN-38 in vivo disturbances in metabolic networks. For example, it, is documented that neurocognitive deficits are

a prevalent and enduring trait abnormality associated with impairment, in psychosocial functioning and reduced quality Inhibitors,research,lifescience,medical of life in bipolar disorder.66-75 Moreover, reports of disparate neurocognitive deficits (eg, nonverbal

and verbal intelligence, information processing, visuospatial ability, attention, executive function, Inhibitors,research,lifescience,medical learning, and memory) have been documented in diabetic populations for several decades (ie, diabetic encephalopathy).76 Taken together, these separate lines of evidence indicate glucose-insulin homeostatic network disturbances are critical mediators of abnormal central nervous system structure and function in mood disorders.75,77-84 Inflammatory networks A growing body of literature indicates that cytokinemediated inflammatory processes are implicated in the pathophysiology of numerous medical and neurological conditions.85 Cytokines are nonantibody proteins that act, as mediators of physiological and pathophysiological cellular processes. For example, elevated proinflammatory cytokines 17-DMAG (Alvespimycin) HCl (eg, interleukin [IL]-1, tumor necrosis factor [TNF]-) have been associated with an accumulation of amyloid-β, the pathophysiological hallmark of Alzheimer’s disease.86-88 Peripherally and centrally-derived cytokines traverse the blood-brain barrier at circumvcntricular organs.89,90 Furthermore, cytokines play a key role in the activation of the hypothalamic-pituitary-adrenal (HPA) axis and peripheral glucocorticoid signaling.