Genetic determinants of micronucleus formation in vivo.

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

BDNF and BMI effects on brain structures of bipolar offspring: results from the global mood and brain science initiative.

OBJECTIVE: To compare brain-derived neurotrophic factor (BDNF) levels between offspring of individuals with bipolar disorders (BD) and healthy controls (HCs) and investigate the effects of BDNF levels and body mass index (BMI) on brain structures. METHOD: Sixty-seven bipolar offspring and 45 HCs were included (ages 8-28). Structural images were acquired using 3.0 Tesla magnetic resonance imaging. Serum BDNF levels were measured using enzyme-linked immunosorbent assay. Multivariate and univariate analyses of covariance were conducted. RESULTS: Significantly higher BDNF levels were observed among bipolar offspring, relative to HCs (P > 0.025). Offspring status moderated the association between BDNF and BMI (F1 =4.636, P = 0.034). After adjustment for relevant covariates, there was a trend for a significant interaction of group and BDNF on neuroimaging parameters (Wilks'λ F56,94 =1.463, P = 0.052), with significant effects on cerebellar white matter and superior and middle frontal regions. Brain volume and BDNF were positively correlated among HCs and negatively correlated among bipolar offspring. Interactions between BDNF and BMI on brain volumes were non-significant among HCs (Wilks'λ F28,2 =2.229, P = 0.357), but significant among bipolar offspring (Wilks'λ F28,12 =2.899, P = 0.028). CONCLUSION: Offspring status and BMI moderate the association between BDNF levels and brain structures among bipolar offspring, underscoring BDNF regulation and overweight/obesity as key moderators of BD pathogenesis.

The Effects of Vortioxetine on Cognitive Function in Patients with Major Depressive Disorder: A Meta-Analysis of Three Randomized Controlled Trials.

BACKGROUND: Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD. METHODS: Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5-20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen's d ) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). RESULTS: Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25-0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial ( p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). CONCLUSIONS: Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.

Are medical comorbid conditions of bipolar disorder due to immune dysfunction?

OBJECTIVE: Epidemiological data have shown a clear association between bipolar disorder (BD) and medical comorbidities. The aim of this article was to assess the evidence of immune dysfunction as a key mediator of this observed association. METHOD: For this narrative clinical overview, the MEDLINE/PubMed, EMBASE, Google Scholar, and ClinicalTrials.gov databases were searched for relevant articles. RESULTS: Bipolar disorder has been shown to have an increased prevalence in patients with autoimmune disorders, cardiovascular disease, and metabolic dysfunction. Further, an elevation in proinflammatory cytokines in BD has been repeatedly demonstrated. Several mechanisms have been proposed to explain the effect of immune dysfunction on mood and cognition. Anti-inflammatory agents including TNF-α inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), minocycline and omega-3 polyunsaturated fatty acids (O3PUFA) are being investigated for their use as novel treatment of BD in patients with immune dysfunction. CONCLUSION: Immune dysfunction appears to be an important mediator of the association observed between BD and medical comorbidities. It therefore serves as a potential novel target for treatment of BD. Further, the observed bidirectional interaction merits screening for psychiatric disorders in patients with immune dysfunction and vice versa to allow for early detection and treatment of this at risk population.

Increased body mass index makes an impact on brain white-matter integrity in adults with remitted first-episode mania.

BACKGROUND: Obesity is increasingly prevalent in bipolar disorder (BD) but data about the impact of elevated body mass index (BMI) on brain white-matter integrity in BD are sparse. Based on extant literature largely from structural magnetic resonance imaging (MRI) studies, we hypothesize that increased BMI is associated with decreased fractional anisotropy (FA) in the frontal, temporal, parietal and occipital brain regions early in the course of BD. METHOD: A total of 26 euthymic adults (12 normal weight and 14 overweight/obese) with remitted first-episode mania (FEM) and 28 controls (13 normal weight and 15 overweight/obese) matched for age, handedness and years of education underwent structural MRI and diffusion tensor imaging scans. RESULTS: There are significant effects of diagnosis by BMI interactions observed especially in the right parietal lobe (adjusted F(1,48) = 5.02, p = 0.030), occipital lobe (adjusted F(1,48) = 10.30, p = 0.002) and temporal lobe (adjusted F(1,48) = 7.92, p = 0.007). Specifically, decreased FA is found in the right parietal (F(1,48) = 5.864, p = 0.023) and occipital lobes (F(1,48) = 4.397, p = 0.047) within overweight/obese patients compared with normal-weight patients with FEM. Compared with overweight/obese controls, decreased FA is observed in right parietal (F(1,48) = 6.708, p = 0.015), temporal (F(1,48) = 10.751, p = 0.003) and occipital (F(1,48) = 9.531, p = 0.005) regions in overweight/obese patients with FEM. CONCLUSIONS: Our findings suggest that increased BMI affects temporo-parietal-occipital brain white-matter integrity in FEM. This highlights the need to further elucidate the relationship between obesity and other neural substrates (including subcortical changes) in BD which may clarify brain circuits subserving the association between obesity and clinical outcomes in BD.

Testing awareness of heart disease among West Australian women.

Cardiovascular disease [CVD] is the top cause of death in Australian women. Large studies in the US and Europe have shown that the majority of women do not consider CVD as their greatest health threat. Australian women's awareness has not previously been investigated. The aim of this cross-sectional survey [TAWDAH] was to assess Australian women's awareness of CVD their leading causes of death [LCD].

Correlation between improved leptin signaling and cognitive function post bariatric surgery.

Determining whether changes in leptin signaling plays a role in the improvement of cognitive function post-bariatric surgery may aid in the understanding and development of novel therapeutic approaches targeting cognitive dysfunction through the greater understanding of processes connecting obesity and brain health. Several studies have explored the effects of cognition post bariatric surgery, and others have studied leptin and its changes post surgery. However the amalgamation of the effects of leptin signaling in relation to cognition post bariatric surgery have yet to be considered as key tools in the understanding of cognitive dysfunction in obese subjects with leptin resistance or insensitivity. This review serves to highlight the potential correlations, to further elucidate the effect of improved leptin signaling on cognition post bariatric surgery, and to propose a direct cause for the improvement of cognitive function via the amelioration of the leptin Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathway as a result of the reversal of inflammatory processes involved in diseased individuals.

The impact of COVID-19 on subthreshold depressive symptoms: a longitudinal study.

AIMS: The coronavirus disease 2019 (COVID-19) pandemic represents an unprecedented threat to mental health. Herein, we assessed the impact of COVID-19 on subthreshold depressive symptoms and identified potential mitigating factors. METHODS: Participants were from Depression Cohort in China (ChiCTR registry number 1900022145). Adults (n = 1722) with subthreshold depressive symptoms were enrolled between March and October 2019 in a 6-month, community-based interventional study that aimed to prevent clinical depression using psychoeducation. A total of 1506 participants completed the study in Shenzhen, China: 726 participants, who completed the study between March 2019 and January 2020 (i.e. before COVID-19), comprised the 'wave 1' group; 780 participants, who were enrolled before COVID-19 and completed the 6-month endpoint assessment during COVID-19, comprised 'wave 2'. Symptoms of depression, anxiety and insomnia were assessed at baseline and endpoint (i.e. 6-month follow-up) using the Patient Health Questionnaire-9 (PHQ-9), Generalised Anxiety Disorder-7 (GAD-7) and Insomnia Severity Index (ISI), respectively. Measures of resilience and regular exercise were assessed at baseline. We compared the mental health outcomes between wave 1 and wave 2 groups. We additionally investigated how mental health outcomes changed across disparate stages of the COVID-19 pandemic in China, i.e. peak (7-13 February), post-peak (14-27 February), remission plateau (28 February-present). RESULTS: COVID-19 increased the risk for three mental outcomes: (1) depression (odds ratio [OR] = 1.30, 95% confidence interval [CI]: 1.04-1.62); (2) anxiety (OR = 1.47, 95% CI: 1.16-1.88) and (3) insomnia (OR = 1.37, 95% CI: 1.07-1.77). The highest proportion of probable depression and anxiety was observed post-peak, with 52.9% and 41.4%, respectively. Greater baseline resilience scores had a protective effect on the three main outcomes (depression: OR = 0.26, 95% CI: 0.19-0.37; anxiety: OR = 1.22, 95% CI: 0.14-0.33 and insomnia: OR = 0.18, 95% CI: 0.11-0.28). Furthermore, regular physical activity mitigated the risk for depression (OR = 0.79, 95% CI: 0.79-0.99). CONCLUSIONS: The COVID-19 pandemic exerted a highly significant and negative impact on symptoms of depression, anxiety and insomnia. Mental health outcomes fluctuated as a function of the duration of the pandemic and were alleviated to some extent with the observed decline in community-based transmission. Augmenting resiliency and regular exercise provide an opportunity to mitigate the risk for mental health symptoms during this severe public health crisis.

Possible association between social cognition and metabolic dysfunctions in Bipolar Disorder and Schizophrenia: Preliminary results.

BACKGROUND: Social cognition (SC) and Theory of Mind (ToM) are compromised in patients with Schizophrenia (SKZ) and Bipolar Disorder (BD) and an increased frequency of metabolic abnormalities is reported in both disorders. Obesity seems associated with cognitive impairments The aim of our study is thus to assess the relationship between obesity and ToM in SKZ and BD. METHODS: 36 stabilized outpatients (18 SKZ and 18 BD) were recruited and completed Reading the Mind in the Eyes Test, Italian version and Faux Pas Recognition Test, adult version. BMI was calculated from self-reported height and weight. Two different Generalized Linear Models were created including performance in Eyes test and in Faux Pas test as outcomes and BMI as covariate. RESULTS: After stratifying for sex, we found a significant relationship between BMI and Faux Pas performance for male patients (p = 0.017), without significant interactions between sex and diagnosis. These results suggest a BMI effect on both affective and cognitive ToM in male patients. LIMITATIONS: Major confounders need to be considered: the greater number of subjects with SKZ in male subsample, a possible influence of neurocognitive performance, small sample size and self-reported BMI. CONCLUSIONS: There could be a relationship between ToM and metabolic dysfunctions, at least in male patients. The exact nature of this relationship has yet to be determined; an interesting theoretical framework is based on a combination of increased brain energy request and inefficient peripheral compensatory mechanisms, resulting in inefficient energy allocation to the brain.

MeV photoelectron spectrometer for ultraintense laser interactions with atoms and molecules.

Traditional laser-matter spectroscopy techniques fail to accurately analyze photoelectrons and ions from ultrahigh intensity studies with terawatt and petawatt laser systems. We present a magnetic deflection, photoelectron spectrometer for ultrahigh intensity laser interactions with atoms and molecules in the single atom/molecule limit. Spectrometer fabrication and calibration, and noise background are presented as well as example photoelectron spectra for argon and chloromethane over an energy range from 20 keV to 2 MeV.

The effect of bipolar I disorder and major depressive disorder on workforce function.

This investigation was undertaken to explore and compare the effect of bipolar I disorder (BD) and major depressive disorder (MDD) on workforce function. The data for this analysis were procured from the Canadian Community Health Survey (CCHS 1.2). The sample consisted of 20,747 individuals (>or=18 years or older and currently working); the proportions screening positive for lifetime BD and MDD were 2.4% and 11.2%, respectively. Individuals with BD or MDD had a significantly lower mean annual income, compared to people without these disorders. Individuals with BD had a significantly lower annual income when compared to MDD (p < 0.05). Results from a multiple logistic regression also indicate that employed individuals with BD had greater odds of reporting one or more mental health disability days in the past two weeks, compared with those with MDD (OR = 1.6; 95% CI = 1.0 to 2.6). Currently employed individuals with BD had lower odds of "good job security" relative to those with MDD (OR = 0.6 95% CI = 0.5 to 0.9). The data herein underscore the pernicious effect of BD on workforce function, and suggest that opportunistic screening for BD in all individuals utilizing employment assistance programs for depression might be warranted.

Targeting cytokines in reduction of depressive symptoms: A comprehensive review.

Heterogeneity in response to conventional antidepressants is a well-recognized limitation of evidence-based pharmacological treatments of major depressive disorder (MDD). Abnormal activation of inflammatory pathways is postulated as one likely mechanism contributing to treatment resistance in MDD. In a subset of depressed patients, the balance between pro- and anti-inflammatory cytokines is thought to be altered, causing mood symptoms due to inflammation, as seen in co-morbid depression associated with inflammatory conditions (e.g. psoriasis, hepatitis C, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis). The objectives of the current narrative review are to critically evaluate the literature about the effects of cytokine blockers on clinical outcomes in MDD and in the reduction of depressive symptom severity in individuals using these medications primarily to treat inflammatory conditions. A small number of clinical trials assessing the effects of cytokine blockers for depression and depressive symptoms have been completed. These trials suggest that in individuals with immune dysfunction (e.g. elevated pro-inflammatory cytokine levels), cytokine blockers may allow for improved clinical outcomes in MDD that would not be achievable with current conventional antidepressants alone. Additional well-designed clinical trials to assess the clinical utility of anti-inflammatory medications for the treatment of depression and depressive symptoms are merited. Further, the use of anti-inflammatories show promise for disease modifying effects that may alter illness trajectory, rather than solely ameliorating current mood symptoms.

U-shaped relationship between depression and body mass index in the Korean adults.

BACKGROUND: Although a number of studies have examined the relationship between depression and obesity, it is still insufficient to establish the specific pattern of relationship between depression and body mass index (BMI) categories. Thus, this study was aimed to investigate the relationship between depression and BMI categories. METHODS: A cross-sectional study was conducted for a cohort of 159,390 Korean based on Kangbuk Samsung Health Study (KSHS). Study participants were classified into 5 groups by Asian-specific cut-off of BMI (18.5, 23, 25 and 30kg/m2). The presence of depression was determined by Center for Epidemiologic Studies-Depression scales (CES-D)≥16 and≥25. The adjusted odd ratios (ORs) for depression were evaluated by multiple logistic regression analysis, in which independent variable was 5 categories of BMI and dependent variable was depression. Subgroup analysis was conducted by gender and age. RESULTS: When normal group was set as a reference, the adjusted ORs for depression formed U-shaped pattern of relationship with BMI categories [underweight: 1.31 (1.14-1.50), overweight: 0.94 (0.85-1.04), obese group: 1.01 (0.91-1.12), severe obese group: 1.28 (1.05-1.54)]. This pattern of relationship was more prominent in female and young age group than male and elderly subgroup. BMI level with the lowest likelihood of depression was 18.5kg/m2 to 25kg/m2 in women and 23kg/m2 to 25kg/m2 in men. CONCLUSIONS: There was a U-shaped relationship between depression and BMI categories. This finding suggests that both underweight and severe obesity are associated with the increased risk for depression.

Epstein-Barr virus in an American patient with Burkitt's lymphoma: detection of viral genome in tumor tissue and establishment of a tumor-derived cell line (NAB).

Epstein-Barr virus (EBV) DNA (17.7 genome equivalents/cell) was found in tumor tissue from an American patient with Burkitt's lymphoma who had never traveled outside the United States. A lymphoid cell line (NAB) containing the EBV genome was established from tumor tissue from this patient; characteristics of this cell line were described. Previous Burkitt's tumors found in Americans and examined by molecular hybridization were negative for EBV DNA. Our results suggested that EBV is associated with at least some American Burkitt's tumors.

Monoclonal antibodies to human melanoma-associated antigens: an amplified enzyme-linked immunosorbent assay for the detection of antigen, antibody, and immune complexes.

An amplified, indirect biotin-avidin micro-enzyme-linked immunosorbent assay was developed for the measurement of human melanoma-associated antigens, either free or circulating with associated immunoglobulin in patient sera. Parameters and specificity of detection were assessed using monoclonal antibody to human melanoma-associated antigens. The main advantages of the assay are its flexibility, through the use of indirect detection and a variety of formats, and its sensitivity, with a lower limit of antibody detection at 100 pg/well and a lower limit of soluble antigen detection at 10 pg/well. The assay was applied to cell surface antigen detection with monoclonal antibody 9.2.27 to a melanoma-associated antigen against a panel of glutaraldehyde-fixed cells, and gave similar binding specificity as assessed by a previous 125I-Protein A assay. Utilizing a unique "sandwich" format, aMr 100,000 melanoma-carcinoma-associated antigen was quantitated in melanoma patient sera and found highly elevated in Stage IV disease. The same sandwich format was also used to detect and determine the class of human immunoglobulin associated with circulating Mr 100,000 human melanoma-associated antigens in normal donor sera. Thus, the sensitivity and flexibility of this enzyme-linked immunosorbent assay system make it particularly suitable for numerous applications in the study of monoclonal antibody-defined tumor-associated antigens.

Nitric Oxide and Major Depressive Disorder: Pathophysiology and Treatment Implications.

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.

Depression and Disturbed Bone Metabolism: A Narrative Review of the Epidemiological Findings and Postulated Mechanisms.

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.

Fibromyalgia and Bipolar Disorder: Emerging Epidemiological Associations and Shared Pathophysiology.

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 overlapping between FM and bipolar spectrum disorders has relevant etiological, clinical and therapeutic implications that deserve future research consideration.