Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.

No abstract

Summary Aims:  The objectives of the present review were to summarise the key findings from the clinical literature regarding the neurobiology of major depressive disorder (MDD) and their implications for maximising treatment outcomes. Several neuroanatomical structures in the prefrontal and limbic areas of the brain are involved in affective regulation. In patients with MDD, alterations in the dynamic patterns of activity among these structures have profound implications for the pathogenesis of this illness. Discussion:  The present work reviews the evidence for the progressive nature of MDD along with associated changes in neuroanatomical structure and function, especially for the hippocampus. The role of glucocorticoids, inflammatory cytokines and brain‐derived growth factors are discussed as mediators of these pathological alterations. From this integrated model, the role of antidepressant therapy in restoring normative processes is examined along with additional treatment guidelines. Conclusion:  Major depressive disorder is an illness with significant neurobiological consequences involving structural, functional and molecular alterations in several areas of the brain. Antidepressant pharmacotherapy is associated with restoration of the underlying physiology. Clinicians are advised to intervene with MDD using an early, comprehensive treatment approach that has remission as the goal.

This article synthesizes recent data suggesting that the high rates of comorbidity observed between major depression, fibromyalgia and neuropathic pain likely result from the fact that these disorders share multiple biological and environmental underpinnings. This perspective suggests that these biologically complex conditions result from similar genetic vulnerabilities interacting with environmental adversity. Shared genetic determinants include poorly functional alleles regulating monoaminergic, glutamatergic, neurotrophic, opioid and inflammatory cytokine signaling. Chief among environmental risk factors are psychosocial stress and illness, both of which promote, in vulnerable individuals, relative resistance to glucocorticoids, increased sympathetic/decreased parasympathetic activity and increased production and release of proinflamnmatory mediators. Dysregulation of stress/inflammatory pathways promotes alterations in brain circuitry that modulates mood, pain and the stress response. Over time, these functional changes likely promote disruptions in neurotrophic support and disturbances of glia-neuronal communication. These changes, in turn, have been associated with the related processes of central sensitization in pain disorders and "kindling" in depression, both of which may account for the progressive and self-perpetuating nature of these disorders, especially when inadequately treated.

From a neurobiological perspective there is no such thing as bipolar disorder. Rather, it is almost certainly the case that many somewhat similar, but subtly different, pathological conditions produce a disease state that we currently diagnose as bipolarity. This heterogeneity – reflected in the lack of synergy between our current diagnostic schema and our rapidly advancing scientific understanding of the condition – limits attempts to articulate an integrated perspective on bipolar disorder. However, despite these challenges, scientific findings in recent years are beginning to offer a provisional “unified field theory” of the disease. This theory sees bipolar disorder as a suite of related neurodevelopmental conditions with interconnected functional abnormalities that often appear early in life and worsen over time. In addition to accelerated loss of volume in brain areas known to be essential for mood regulation and cognitive function, consistent findings have emerged at a cellular level, providing evidence that bipolar disorder is reliably associated with dysregulation of glial–neuronal interactions. Among these glial elements are microglia – the brain’s primary immune elements, which appear to be overactive in the context of bipolarity. Multiple studies now indicate that inflammation is also increased in the periphery of the body in both the depressive and manic phases of the illness, with at least some return to normality in the euthymic state. These findings are consistent with changes in the hypothalamic–pituitary–adrenal axis, which are known to drive inflammatory activation. In summary, the very fact that no single gene, pathway, or brain abnormality is likely to ever account for the condition is itself an extremely important first step in better articulating an integrated perspective on both its ontological status and pathogenesis. Whether this perspective will translate into the discovery of innumerable more homogeneous forms of bipolarity is one of the great questions facing the field and one that is likely to have profound treatment implications, given that fact that such a discovery would greatly increase our ability to individualize – and by extension, enhance – treatment.

Norepinephrine (NE) is recognized as having a key role in the pathophysiology of major depressive disorder (MDD) and schizophrenia, although its distinct actions via α-adrenergic receptors (α-ARs) are not well defined. We performed a systematic review examining the roles of NE and α-ARs in MDD and schizophrenia. PubMed and ProQuest database searches were performed to identify English language papers published between 2008 and 2015. In total, 2,427 publications (PubMed, n = 669; ProQuest, n = 1,758) were identified. Duplicates, articles deemed not relevant, case studies, reviews, meta-analyses, preclinical reports, or articles on non-target indications were excluded. To limit the review to the most recent data representative of the literature, the review further focused on publications from 2010 to 2015, which were screened independently by all authors. A total of 16 research reports were identified: six clinical trial reports, six genetic studies, two biomarker studies, and two receptor studies. Overall, the studies provided indirect evidence that α-AR activity may play an important role in aberrant regulation of cognition, arousal, and valence systems associated with MDD and schizophrenia. Characterization of the NE pathway in patients may provide clinicians with information for more personalized therapy of these heterogeneous diseases. Current clinical studies do not provide direct evidence to support the role of NE α-ARs in the pathophysiology of MDD and schizophrenia and in the treatment response of patients with these diseases, in particular with relation to specific valence systems. Clinical studies that attempt to define associations between specific receptor binding profiles of psychotropics and particular clinical outcomes are needed.

Background: Viloxazine was historically described as a norepinephrine reuptake inhibitor (NRI). Since NRIs have previously demonstrated efficacy in attention deficit/hyperactivity disorder (ADHD), viloxazine underwent contemporary investigation in the treatment of ADHD. Its clinical and safety profile, however, was found to be distinct from other ADHD medications targeting norepinephrine reuptake. Considering the complexity of neuropsychiatric disorders, understanding the mechanism of action (MoA) is an important differentiating point between viloxazine and other ADHD medications and provides pharmacology-based rationale for physicians prescribing appropriate therapy. Methods: Viloxazine was evaluated in a series of in vitro binding and functional assays. Its effect on neurotransmitter levels in the brain was evaluated using microdialysis in freely moving rats. Results: We report the effects of viloxazine on serotoninergic (5-HT) system. In vitro, viloxazine demonstrated antagonistic activity at 5-HT 2B and agonistic activity at 5-HT 2C receptors, along with predicted high receptor occupancy at clinical doses. In vivo, viloxazine increased extracellular 5-HT levels in the prefrontal cortex (PFC), a brain area implicated in ADHD. Viloxazine also exhibited moderate inhibitory effects on the norepinephrine transporter (NET) in vitro and in vivo, and elicited moderate activity at noradrenergic and dopaminergic systems. Conclusion: Viloxazine's ability to increase 5-HT levels in the PFC and its agonistic and antagonistic effects on certain 5-HT receptor subtypes, which were previously shown to suppress hyperlocomotion in animals, indicate that 5-HT modulating activity of viloxazine is an important (if not the predominant) component of its MoA, complemented by moderate NET inhibition. Supported by clinical data, these findings suggest the updated psychopharmacological profile of viloxazine can be best explained by its action as a serotonin norepinephrine modulating agent (SNMA).

A wealth of information exists regarding the plight of patients suffering with diabetic peripheral neuropathic pain (DPNP). Although physical pain is certainly a primary challenge in the management of this condition, disorders associated with emotional pain-especially depression and anxiety-also greatly complicate the clinician's efforts to attain optimal outcomes for DPNP patients. This article reviews the high rate of comorbidity between DPNP and depression/anxiety with a focus on why this pattern of comorbidity exists and what can be done about it. To accomplish this, the many physiologic similarities between neuropathic pain and depression/anxiety are reviewed as a basis for better understanding how, and why, optimal treatment strategies use behavioral and pharmacologic modalities known to improve both physical pain and symptoms of depression and anxiety. We conclude by highlighting that screening, diagnosing, and optimally treating comorbid depression/anxiety not only improves quality of life, these but also positively impacts DPNP pain.