Current Molecular Medicine - Volume 16, Issue 2, 2016

Bipolar disorder (BD) is a debilitating psychiatric disorder and a growing global public health issue. Notwithstanding BD has been conceptualized as a neuroprogressive illness, there are some evidences to suggest a role for neurodevelopmental pathways in the patho-etiology of this disorder. Evidences on the associations between perinatal infections and risk for bipolar disorder have been inconsistent across studies. Here, we performed a systematic review of observational studies on the relationship between exposure to perinatal pathogens and bipolar disorder. A computerized literature search of the PubMed, Embase, and PsyINFO databases till January 31st, 2015 was performed. Twenty-three studies ultimately met inclusion criteria. Studies investigated exposure to several pathogens namely Cytomegalovirus (CMV), Epstein–Barr Virus (EBV), Herpes simplex virus-1 (HSV-1), Herpes simplex virus-2 (HSV-2), Human herpesvirus 6 (HHV-6), Toxoplasma gondii, Influenza, and Varicella zoster virus (VZV). Overall, studies provided mixed evidences. Thus, contrary to schizophrenia, the role of perinatal infections as risk factors for BD remain inconclusive. Larger studies with a prospective design would be necessary to elucidate the role of previous exposure to infectious agents as a potential risk factor for BD.

Fibromyalgia (FM) is a prevalent disorder defined by the presence of chronic widespread pain in association with fatigue, sleep disturbances and cognitive dysfunction. Recent studies indicate that bipolar spectrum disorders frequently co-occur in individuals with FM. Furthermore, shared pathophysiological mechanisms anticipate remarkable phenomenological similarities between FM and BD. A comprehensive search of the English literature was carried out in the Pubmed/MEDLINE database through May 10th, 2015 to identify unique references pertaining to the epidemiology and shared pathophysiology between FM and bipolar disorder (BD). Overlapping neural circuits may underpin parallel clinical manifestations of both disorders. Fibromyalgia and BD are both characterized by functional abnormalities in the hypothalamic-pituitary-adrenal axis, higher levels of inflammatory mediators, oxidative and nitrosative stress as well as mitochondrial dysfunction. An over-activation of the kynurenine pathway in both illnesses drives tryptophan away from the production of serotonin and melatonin, leading to affective symptoms, circadian rhythm disturbances and abnormalities in pain processing. In addition, both disorders are associated with impaired neuroplasticity (e.g., altered brain-derived neurotrophic factor signaling). The recognition of the symptomatic and pathophysiological overlaping between FM and bipolar spectrum disorders has relevant etiological, clinical and therapeutic implications that deserve future research consideration.

Depression, the most common mood disorder, is a leading contributor to the global burden of disease affecting more than 120 million individuals worldwide. Various pathophysiological processes underlie depression; this complexity renders it difficult to identify clinically useful diagnostic and prognostic markers, as well as treatment options. The current state of knowledge driving the management and treatment of depression remains incomplete, which underscores the need for further insight into pathways relevant to depression. Exploring co-morbid conditions, such as coronary artery disease, may be useful to further elucidate the etiopathology of depression. The present review therefore systematically identifies and critically evaluates relevant markers of depression as assessed in a high-risk population, namely patients with coronary artery disease. Biomarkers related to hypothalamicpituitary- adrenal axis dysregulation, inflammation, endothelial dysfunction, platelet activation and aggregation, serotonin activity, sympathetic nervous system activation, thyroid function, structural and morphological brain abnormalities, genetic variation, lipid metabolism, one-carbon metabolism, endocannabinoid signalling irregularities, and vitamin D deficiency are reviewed. Markers exhibiting the most consistent associations with depression include tumour necrosis factor-α, flow-mediated dilation, endothelin-1, endothelial progenitor cells, brain-derived neurotrophic factor, and docosahexaenoic acid. Further investigating the mechanisms underlying those markers and exploring novel pathways, such as oxidative stress, will extend the current state of knowledge and potentially lead to the identification of novel therapeutic targets.

Major depressive disorder (MDD) is a pervasive chronic condition that contributes substantially to the global burden of disease and disability. Adding to the complexity of this disorder are numerous associated medical comorbidities with a bidirectional impact on morbidity and mortality. In recent years, osteoporosis has been increasingly identified as a significant comorbidity of MDD. This narrative review examines the literature to summarize key epidemiological studies and discuss postulated mechanisms of interaction. Epidemiological studies have repeatedly shown an increased co-prevalence of fractures and decreased bone mineral density (BMD) in MDD. The pathophysiological mechanism underlying this interaction is undoubtedly complex and multifactorial, and proposed pathways have varying levels of evidence from preclinical and clinical models. Conceptually, the mechanisms by which depression might influence bone metabolism can be categorized into biological, behavioral, iatrogenic, and comorbidity-related factors. Biological factors include the inflammatory-mood pathway, hypothalamic-pituitary-adrenal (HPA) axis dysregulation, metabolic dysfunction, and serotonin’s direct and indirect effects on bone cells. Behavioral factors incorporate lifestyle choices typical in depressed patients, such as increased tobacco use or limited exercise. The prominent iatrogenic factor is the independent effects of anti-depressants on bone metabolism. Psychiatric and medical comorbidities common to both osteoporosis and MDD are also important to consider. Physical activity promotion, vitamin D supplementation, and routine BMD screening of MDD patients are simple interventions that might lead to improved outcomes for both conditions. An improved understanding of the underlying mechanisms may yield insights into novel prevention and treatment strategies to target osteoporosis and fractures in the MDD population.

Comorbid migraine in the course of bipolar disorder has been reported as highly prevalent and associated with increased morbidity. Patients with bipolar disorder and comorbid migraine tend to present with higher rates of rapid cycling, increased number of depressive episodes, more severe depression, and increased suicidality when compared to subjects with bipolar disorder alone. Both conditions display similar clinical features, such as relapsing-recovering presentation, and vulnerability to psychological and physical stress. Clinical implications of this association have been well established, however the biological underpinnings involved in both conditions remain poorly understood. Inflammation and oxidative and nitrosative stress seem to play a role as mediators in the cross-sensitization between bipolar disorder and migraine. Therefore, the present study aims to review the role of inflammation, oxidative and nitrosative stress as underlying mechanisms in the natural history of bipolar disorder comorbid with migraine.

Several biological systems are implicated in the neuroprogression of bipolar disorder including but not limited to cytokine levels, oxidative stress markers, monoamine levels, tryptophan catabolite and glutamate-mediated excitotoxicity, microglial activation as well as structural and functional changes. The high rate of smoking behaviour in individuals with bipolar disorder provides the impetus for exploring shared and discrete pathogenetic mechanisms. In addition to contributing to increased mortality, smoking activates several neurobiological effector systems implicated in the progression of bipolar disorder. Here, a narrative review provides evidence and putative mechanisms of comorbid effects of BD, cigarette use, and nicotine dependence, and discusses the clinical implications of these interactions.

Major depressive disorder (MDD) is a multi-factorial and heterogeneous disease. Robust evidence suggests that inflammation is involved in the pathogenesis of MDD for a subpopulation of individuals. However, it remains unclear what traits and/or states precede the onset of inflammation in this subpopulation of individuals with MDD. Several recent studies have implicated nitric oxide (NO) as a critical regulator of neuroinflammation, thus suggesting a possible role in the pathophysiology of MDD. The aim of this review is to evaluate the evidentiary base supporting the hypothesis that the increased hazard for developing MDD in certain subpopulations may be mediated, in part, by inflammogenic trait and/or state variations in NO signaling pathways. We conducted a non-systematic literature search for English language studies via PubMed and Google Scholar, from 1985 to October 2014. Replicated evidence suggests that NO has contrasting effects in the central nervous system (CNS). Low concentrations of NO are neuroprotective and mediate physiological signaling whereas higher concentrations mediate neuroinflammatory actions and are neurotoxic. Certain polymorphisms in the neuronal nitric oxide synthase gene (NOS1) are associated MDD. Furthermore, state variations (e.g. decreased levels of essential co-factor, 5,6,7,8-tetrahydrobiopterin [BH4], enhanced microglial cell activity) in the NO signaling pathway are associated with an increased risk of developing MDD. Increased concentrations of NO enhance the production of reactive nitrogen species (RNS) and reactive oxygen species (ROS), which are associated with an increase in pro-inflammatory cytokines. Taken together, evidences suggest that abnormalities in NO signaling may constitute a trait-marker related to MDD pathophysiology, which could be explored for novel therapeutic targets.