Depression is one of the leading causes of mortality, disability, and loss of productivity. The World Health Organization (WHO) ranks depressive disorders as the eleventh cause of disability and mortality (1, 2). The worldwide lifetime prevalence of depression is around 12% (3). In spite of the considerable burden of depression both in terms of prevalence and public health impact, the search for more effective treatments for depression is still ongoing. Emerging evidence suggests that personalizing treatments based on individuals’ biosignature could be the “way forward” (4).

The search for brain morphology findings that could explain behavioral disorders has gone through a long path in the history of psychiatry. With the advance of brain imaging technology, studies have been able to identify brain morphology and neural circuits associated with the pathophysiology of mental illnesses, such as bipolar disorders (BD). Promising results have also shown the potential of neuroimaging findings in the identification of outcome predictors and response to treatment among patients with BD. In this chapter, we present brain imaging structural and functional findings associated with BD, as well as their hypothesized relationship with the pathophysiological aspects of that condition and their potential clinical applications.

BACKGROUND:Depression research historically uses both self- and clinician ratings of symptoms with significant and substantial correlations. It is often assumed that manic patients lack insight and cannot accurately report their symptoms. This delayed the development of self-rating scales for mania, but several scales now exist and are used in research. Our objective is to systematically review the literature to identify existing self-ratings of symptoms of (hypo)mania and to evaluate their psychometric properties.METHODS:PubMed, Web of Knowledge, and Ovid were searched up until June 2018 using the keywords: "(hypo)mania," "self-report," and "mood disorder" to identify papers which included data on the validity and reliability of self-rating scales for (hypo)mania in samples including patients with bipolar disorder.RESULTS:We identified 55 papers reporting on 16 different self-rating scales claiming to assess (hypo)manic symptoms or states. This included single item scales, but also some with over 40 items. Three of the scales, the Internal State Scale (ISS), Altman Self-Rating Mania Scale (ASRM), and Self-Report Manic Inventory (SRMI), provided data about reliability and/or validity in more than three independent studies. Validity was mostly assessed by comparing group means from individuals in different mood states and sometimes by correlation to clinician ratings of mania.CONCLUSIONS:ASRM, ISS, and SRMI are promising self-rating tools for (hypo)mania to be used in clinical contexts. Future studies are, however, needed to further validate these measures; for example, their associations between each other and sensitivity to change, especially if they are meant to be outcome measures in studies.

Few investigations have assessed brain structural development in children and adolescents who develop bipolar disorder. The literature mostly comprises cross-sectional data comparing different age groups. Studies of bipolar offspring have allowed a more targeted approach to this important topic.

Increasing rates of antimicrobial-resistant infections and the dwindling pipeline of new agents necessitate judicious, evidence-based antimicrobial prescribing. Clinical trials represent a vital resource for establishing evidence of safety and efficacy, which are crucial to guiding antimicrobial treatment decisions. The objective of this study was to comprehensively evaluate the characteristics of antimicrobial research studies registered in ClinicalTrials.gov. Primary outcome measures, funding sources, inclusion criteria and the reporting of study results were evaluated for 16 055 antimicrobial studies registered in ClinicalTrials.gov as of mid 2012. Interventional studies accounted for 93% of registered antimicrobial studies. Clinical trials of drugs (82%) and biologics (9%) were most common. Antibacterial, antiviral and antifungal studies accounted for 43%, 41% and 16% of drug trials, respectively. Among interventional drug trials, 73% featured randomised allocation to study arms and 71% included measures of safety and/or efficacy as primary endpoints. Children were eligible for enrolment in 26% of studies. Among the studies, 60% were sponsored primarily by non-profit organisations, 30% by industry and 10% by the federal government. Only 7% of studies reported results; however, 71% of these were sponsored primarily by industry. Antimicrobial studies commonly incorporated elements of high-quality trial design, including randomisation and safety/efficacy endpoints. Publication of study results and updating of ClinicalTrials.gov should be encouraged for all studies, with particular attention paid to research sponsored by non-profit organisations and governmental agencies. Leveraging the application of these data to guide the careful selection of antimicrobial agents will be essential to preserve their utility for years to come.

Evidence suggests accelerated aging mechanisms in bipolar disorder (BD), including DNA methylation (DNAm) aging in blood. However, it is unknown whether such mechanisms are also evident in the brain, in particular in association with other biological clocks. To investigate this, we interrogated genome‐wide DNAm in postmortem hippocampus from 32 BD‐I patients and 32 non‐psychiatric controls group‐matched for age and sex from the NIMH Human Brain Collection Core.

Background and AimsCognitive impairments are primary hallmarks symptoms of bipolar disorder (BD). Whether these deficits are markers of vulnerability or symptoms of the disease is still unclear. This study used a component-wise gradient (CGB) machine learning algorithm to identify cognitive measures that could accurately differentiate pediatric BD, unaffected offspring of BD parents, and healthy controls.Methods59 healthy controls (HC; 11.19 ± 3.15 yo; 30 girls), 119 children and adolescents with BD (13.31 ± 3.02 yo, 52 girls) and 49 unaffected offspring of BD parents (UO; 9.36 ± 3.18 yo; 22 girls) completed the CANTAB cognitive battery.ResultsCGB achieved accuracy of 73.2% and an AUROC of 0.785 in classifying individuals as either BD or non-BD on a dataset held out for validation for testing. The strongest cognitive predictors of BD were measures of processing speed and affective processing. Measures of cognition did not differentiate between UO and HC.ConclusionsAlterations in processing speed and affective processing are markers of BD in pediatric populations. Longitudinal studies should determine whether UO with a cognitive profile similar to that of HC are at less or equal risk for mood disorders. Future studies should include relevant measures for BD such as verbal memory and genetic risk scores.

Executive dysfunctions are recognized in pediatric bipolar spectrum disorder (PBSD). Previous studies suggest that deficits in executive functions in PBSD are related to difficulties in academic functioning. The aim of this study was to compare the performance on the Stockings of Cambridge (SOC) computerized task, which is a measure of executive function (spatial planning) between youths with PBSD and healthy control (HC) subjects.

A significant amount of literature has highlighted that patients with schizophrenia (Sz)-spectrum disorders, and to a lesser extent bipolar disorder (BD), are characterized by deficits in social cognition. At present, it is unclear whether the behaviorally measured social cognitive deficits evident in Sz-spectrum disorders are the same as those evident in BD. In this chapter, we provide a brief overview of the current state of the social cognitive literature on these disorders, with an aim to discuss overlaps and differences in behavioral deficit characterization, their clinical correlates, and their possible contributing factors.

Objectives: Reward sensitivity is suggested to be an influence on the onset and reoccurrence of bipolar disorder (BD) in observational longitudinal studies. The current study examined whether reward sensitivity predicted the recurrence of mood episodes in a treatment seeking sample. We also explored if reward sensitivity moderated treatment outcomes of psychosocial treatment. Methods: Seventy-six euthymic adult patients with BD were randomly assigned to either Cognitive Behavioral Therapy (CBT) or Supportive Therapy (ST) and followed up for 2 years after completing therapy (Meyer and Hautzinger, 2012). The primary outcome measure was recurrence of mood episodes. The final multivariate Cox regression models included potential covariates, therapy conditions, BAS reward sensitivity, and the interaction between BAS and therapy conditions. Results: BAS emerged as the only significant predictor of time till recurrence of mania, but not depression, but the overall model did not reach significance. There was no interaction between treatment and BAS reward sensitivity. Interestingly, a diagnosis of BD II predicted time till recurrence of depression. Conclusion: The main result regarding BAS partially confirms prior studies linking BAS and mania, but power and the specific sample seeking psychosocial treatment might have reduced the effect.

Magnetic resonance imaging (MRI) studies have identified neural structures implicated in the pathophysiology of mood disorders, especially bipolar disorder (BD) and major depressive disorder (MDD). However, the role of genetic and environmental influences on such brain deficits is still unclear. In this context, the present review summarizes the current evidence from structural MRI and Diffusion Tensor Imaging (DTI) studies on twin samples concordant or discordant for BD or MDD, with the aim of clarifying the role of genetic and environmental risk factors on brain alterations. Although the results showed a complex interplay between gene and environment in affective disorders, the evidence seem to underline that both genetic and environmental risk factors have an impact on brain areas and vulnerability to MDD and BD. However, the precise mechanism of action and the interaction between these factors still needs to be unveiled. Therefore, future larger studies on concordant or discordant twins should be encouraged, because this population provides a unique opportunity to probe separately genetic and environmental markers of disease vulnerability.

OBJECTIVES:Cognitive dysfunction affects a significant proportion of people with bipolar disorder (BD), but the cause, trajectory and correlates of such dysfunction remains unclear. Increased understanding of these factors is required to progress treatment development for this symptom dimension.METHODS:This paper provides a critical overview of the literature concerning the trajectories and emerging correlates of cognitive functioning in BD. It is a narrative review in which we provide a qualitative synthesis of current evidence concerning clinical, molecular, neural and lifestyle correlates of cognitive impairment in BD across the lifespan (in premorbid, prodromal, early onset, post-onset, elderly cohorts).RESULTS:There is emerging evidence of empirical links between cognitive impairment and an increased inflammatory state, brain structural abnormalities and reduced neuroprotection in BD. However, evidence regarding the progressive nature of cognitive impairment is mixed, since consensus between different cross-sectional data is lacking and does not align to the outcomes of the limited longitudinal studies available. Increased recognition of cognitive heterogeneity in BD may help to explain some inconsistencies in the extant literature.CONCLUSIONS:Large, longitudinally focussed studies of cognition and its covariation alongside biological and lifestyle factors are required to better define cognitive trajectories in BD, and eventually pave the way for the application of a precision medicine approach for individual patients in clinical practice.