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Major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia-spectrum disorders (SSD) are heterogeneous psychiatric disorders, which place significant burden on patient's well-being and global health. Disruptions in the gut-microbiome may play a role in these psychiatric disorders. This review presents current data on composition of the human gastrointestinal microbiota, and its interaction mechanisms in the gut–brain axis in MDD, BD and SSD. Diversity metrics and microbial relative abundance differed across studies. More studies reported inconsistent findings (n = 7) or no differences (n = 8) than studies who reported lower α-diversity in these psychiatric disorders (n = 5). The most consistent findings across studies were higher relative abundances of the genera Streptococcus, Lactobacillus, and Eggerthella and lower relative abundance of the butyrate producing Faecalibacterium in patients with psychiatric disorders. All three increased genera were associated with higher symptom severity. Confounders, such as medication use and life style have not been accounted for. So far, the results of probiotics trials have been inconsistent. Most traditional and widely used probiotics (consisting of Bifidobacterium spp. and Lactobacillus spp.) are safe, however, they do not correct potential microbiota disbalances in these disorders. Findings on prebiotics and faecal microbiota transplantation (FMT) are too limited to draw definitive conclusions. Disease-specific pro/prebiotic treatment or even FMT could be auspicious interventions for prevention and therapy for psychiatric disorders and should be investigated in future trials.

Aims: Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under-researched in psychiatry. Methods: We obtained body mass index (BMI) and magnetic resonance imaging-derived regional cortical thickness, surface area from 836 bipolar disorders (BD) and 1600 control individuals from 14 sites within the ENIGMA-BD Working Group. We identified regionally specific profiles of cortical thickness using K-means clustering and studied clinical characteristics associated with individual cortical profiles. Results: We detected two clusters based on similarities among participants in cortical thickness. The lower thickness cluster (46.8% of the sample) showed thinner cortex, especially in the frontal and temporal lobes and was associated with diagnosis of BD, higher BMI, and older age. BD individuals in the low thickness cluster were more likely to have the diagnosis of bipolar disorder I and less likely to be treated with lithium. In contrast, clustering based on similarities in the cortical surface area was unrelated to BD or BMI and only tracked age and sex. Conclusions: We provide evidence that both BD and obesity are associated with similar alterations in cortical thickness, but not surface area. The fact that obesity increased the chance of having low cortical thickness could explain differences in cortical measures among people with BD. The thinner cortex in individuals with higher BMI, which was additive and similar to the BD-associated alterations, may suggest that treating obesity could lower the extent of cortical thinning in BD.

MRI‐derived brain measures offer a link between genes, the environment and behavior and have been widely studied in bipolar disorder (BD). However, many neuroimaging studies of BD have been underpowered, leading to varied results and uncertainty regarding effects. The Enhancing Neuro Imaging Genetics through Meta‐Analysis (ENIGMA) Bipolar Disorder Working Group was formed in 2012 to empower discoveries, generate consensus findings and inform future hypothesis‐driven studies of BD. Through this effort, over 150 researchers from 20 countries and 55 institutions pool data and resources to produce the largest neuroimaging studies of BD ever conducted. The ENIGMA Bipolar Disorder Working Group applies standardized processing and analysis techniques to empower large‐scale meta‐ and mega‐analyses of multimodal brain MRI and improve the replicability of studies relating brain variation to clinical and genetic data. Initial BD Working Group studies reveal widespread patterns of lower cortical thickness, subcortical volume and disrupted white matter integrity associated with BD. Findings also include mapping brain alterations of common medications like lithium, symptom patterns and clinical risk profiles and have provided further insights into the pathophysiological mechanisms of BD. Here we discuss key findings from the BD working group, its ongoing projects and future directions for large‐scale, collaborative studies of mental illness., This review discusses the major challenges facing neuroimaging research of bipolar disorder and highlights the major accomplishments, ongoing challenges and future goals of the ENIGMA Bipolar Disorder Working Group.

Objectives Societal restrictions imposed to prevent transmission of COVID-19 may challenge circadian-driven lifestyle behaviours, particularly amongst those vulnerable to mood disorders. The overarching aim of the present study was to investigate the hypothesis that, in the routine-disrupted environment of the COVID-19, amongst a sample of people living with mood disorders, greater social rhythm disruption would be associated with more severe mood symptoms. Methods We conducted a two-wave, multinational survey of 997 participants [Formula: see text] who self-reported a mood disorder diagnosis (i.e., major depressive disorder or bipolar disorder). Respondents completed questionnaires assessing demographics, social rhythmicity (The Brief Social Rhythm Scale), depression symptoms (Patient Health Questionnaire-9), sleep quality and diurnal preference (The Sleep, Circadian Rhythms and Mood questionnaire) and stressful life events during the COVID-19 pandemic (The Social Readjustment Rating Scale). Results The majority of participants indicated COVID-19-related social disruption had affected the regularity of their daily routines to at least some extent ( n = 788, 79.1%). As hypothesised, lower social rhythmicity was associated with greater depressive symptoms when tested cross-sectionally (standardised β = −.25, t = −7.94, P = 0.000) and when tested using a 2-level hierarchical linear model across two time points ( b = −0.14, t = −3.46, df = 264, P ≤ 0.001). Conclusions These results are consistent with the social zeitgeber hypothesis proposing that mood disorders are sensitive to life events that disrupt social rhythms.

Depression is associated with general medical conditions (GMCs), but it is not known if treatment-resistant depression (TRD) affects GMC risk and vice versa. We estimated bidirec-tional associations between TRD and GMCs (prior and subsequent). All individuals aged 18-69 years, born and living in Denmark, with a first-time prescription for an antidepressant between 2005 and 2012 were identified in the Danish Prescription Registry ( N = 154,513). TRD was de -fined as at least two shifts in treatment regimes. For prior GMCs, we estimated odds ratios (ORs) using conditional logistic regression comparing TRD patients with matched non-TRD controls adjusted for other GMCs and number of other GMCs. For subsequent GMCs, we used Cox regression to calculate hazard ratios (HRs) in TRD vs. non-TRD patients adjusted for age at first prescription, calendar time, other GMCs and number of other GMCs. Patients with TRD had higher prevalence of prior GMCs related to the immune or neurological systems; musculoskeletal disorders (women aOR: 1.35, 95% CI: 1.26-1.46, men aOR: 1.30, 95% CI: 1.19-1.42) and migraine (women aOR: 1.22, 95% CI: 1.09-1.36, men aOR: 1.25, 95% CI: 1.00-1.56). Subsequent GMCs were related to a broader spectrum; cardiovascular (women aHR: 1.43, 95% CI: 1.32-1.54, men aHR: 1.31, 95% CI: 1.19-1.43), endocrine (women aHR: 1.52, 95% CI: 1.37-1.67, men aHR: 1.24, 95% CI: 1.07-1.44), and neurological disorders (women aHR: 1.24, 95% CI: 1.13-1.35, men aHR: 1.19, 95% CI: 1.07-1.34). Our study presents a broad overview of comorbid medical conditions in patients with TRD and further studies are needed to explore the associations in detail. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

The prenatal and early postnatal stages represent a critical time window for human brain development. Interestingly, this window partly overlaps with the maturation of the intestinal flora (microbiota) that play a critical role in the bidirectional communication between the central and the enteric nervous systems (microbiota-gut-brain axis). The microbial composition has important influences on general health and the development of several organ systems, such as the gastrointestinal tract, the immune system, and also the brain. Clinical studies have shown that microbiota alterations are associated with a wide range of neuropsychiatric disorders including autism spectrum disorder, attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. In this review, we dissect the link between these neuropsychiatric disorders and the intestinal microbiota by focusing on their effect on synaptic pruning, a vital process in the maturation and establishing efficient functioning of the brain. We discuss in detail how synaptic pruning is dysregulated differently in the aforementioned neuropsychiatric disorders and how it can be influenced by dysbiosis and/or changes in the intestinal microbiota composition. We also review that the improvement in the intestinal microbiota composition by a change in diet, probiotics, prebiotics, or fecal microbiota transplantation may play a role in improving neuropsychiatric functioning, which can be at least partly explained via the optimization of synaptic pruning and neuronal connections. Altogether, the demonstration of the microbiota's influence on brain function via microglial-induced synaptic pruning addresses the possibility that the manipulation of microbiota-immune crosstalk represents a promising strategy for treating neuropsychiatric disorders.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD., The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder.In the largest study of hippocampal subfields in bipolar disorder to date, from 23 sites worldwide, we report widespread reductions in nine of 12 subfields.The lack of differences between lithium users and healthy controls supports a possible protective role of lithium in bipolar disorder.

BACKGROUND: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD). METHODS: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters. RESULTS: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation. CONCLUSIONS: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging. ispartof: PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY vol:111 ispartof: location:England status: published

The brain-gut axis is increasingly recognized as an important contributing factor in the onset and progression of severe mental illnesses such as schizophrenia spectrum disorders and bipolar disorder. This study investigates associations between levels of faecal metabolites identified using 1H-NMR, clinical parameters, and dietary components of forty-two individuals diagnosed in a transdiagnostic approach to have severe mental illness. Faecal levels of the amino acids; alanine, leucine, and valine showed a significant positive correlation with psychiatric symptom severity as well as with dairy intake. Overall, this study proposes a diet-induced link between the brain-gut axis and the severity of psychiatric symptoms, which could be valuable in the design of novel dietary or therapeutic interventions to improve psychiatric symptoms.

Social distancing/lockdown policies during the coronavirus (COVID-19) pandemic may alter social rhythms of people through imposition of restrictions on normal daily activities. This may in turn challenge circadian function, particularly in people with mood disorders. Although objective data describing the relationship between circadian disturbances and mood disorders exist, data regarding the subjective experience of circadian challenge is sparse, and its association with mood symptoms is unclear. The present qualitative study was one component of a mixed-methods multi-national project, which took advantage of widespread disruption to daily routines due to Government COVID-related lockdowns during 2020. The Behavior Emotion and Timing during COVID-19 (BEATCOVID) survey study included three open questions generating qualitative data on participants' subjective experience of social disruption due to social distancing/lockdown policies, two of which asked about the barriers and opportunities for stabilizing routines. Responses were coded and analyzed using Thematic Analysis. A total of N = 997 participants responded to at least one of the free-text questions. Four themes were identified: 1) loss of daily timed activities, 2) role of social interaction, 3) altered time perception and 4) disruption to motivation and associated psychological effects. Themes were organized into a provisional heuristic map, generating hypotheses for future research centered on the new concept of 'psychological drift.'

OBJECTIVES: The International Society for Bipolar Disorders Big Data Task Force assembled leading researchers in the field of bipolar disorder (BD), machine learning, and big data with extensive experience to evaluate the rationale of machine learning and big data analytics strategies for BD.METHOD: A task force was convened to examine and integrate findings from the scientific literature related to machine learning and big data based studies to clarify terminology and to describe challenges and potential applications in the field of BD. We also systematically searched PubMed, Embase, and Web of Science for articles published up to January 2019 that used machine learning in BD.RESULTS: The results suggested that big data analytics has the potential to provide risk calculators to aid in treatment decisions and predict clinical prognosis, including suicidality, for individual patients. This approach can advance diagnosis by enabling discovery of more relevant data-driven phenotypes, as well as by predicting transition to the disorder in high-risk unaffected subjects. We also discuss the most frequent challenges that big data analytics applications can face, such as heterogeneity, lack of external validation and replication of some studies, cost and non-stationary distribution of the data, and lack of appropriate funding.CONCLUSION: Machine learning-based studies, including atheoretical data-driven big data approaches, provide an opportunity to more accurately detect those who are at risk, parse-relevant phenotypes as well as inform treatment selection and prognosis. However, several methodological challenges need to be addressed in order to translate research findings to clinical settings.

Current available maintenance pharmacotherapy for bipolar disorder (BD) leaves ample room for improvement. Up to 50% of patients with BD do not respond adequately to available treatments and still suffer from manic and/or depressive episodes. In this perspective article, we will give an overview of the neuropharmacodynamics of (low-dose) aspirin, reflect on the published clinical studies and argue that aspirin is a promising, yet understudied option for recurrence prevention This article is protected by copyright. All rights reserved.

IntroductionFor patients with bipolar disorder, early recognition of impending mood episodes is crucial to enable timely intervention. Longitudinal digital mood monitoring using ecological momentary assessment (EMA) enable prospective study of early warning signals (EWS) in momentary affective estates prior to symptom transitions.ObjectivesThe present study examined in a unique longitudinal EMA data set whether EWS prospectively signal transitions to manic or depressive episodes.MethodsTwenty bipolar type I/II patients completed EMA questionnaires five times a day for four months (average 491 observations per person), as well as weekly symptom questionnaires concerning depressive (Quick Inventory for Depressive Symptomatology) and manic (Altman Self-Rating Mania Scale) symptoms. Weekly data was used to determine transitions (i.e., abrupt increase in symptoms). Prior to these transitions, EWS (autocorrelation at lag-1 and standard deviation) were calculated in moving windows over 17 affective EMA states. Kendall’s tau was calculated to detect significant rises in the EWS indicator prior to the transition.ResultsEleven patients reported one or two transitions to a mood episode. All transitions were preceded by at least one EWS. Average sensitivity for detecting EWS was slightly higher for manic episodes (36%) than for depressive episodes (25%). For manic episodes, EWS in thoughts racing, being full of ideas, and feeling agitated showed the highest sensitivity and specificity, whereas for depression, only feeling tired showed high sensitivity and specify.ConclusionsEWS show promise in anticipating transitions to mood episodes in bipolar disorder. Further investigation is warranted.DisclosureNo significant relationships.

Aims To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. Methods PRISMA-based systematic review of the literature. Results The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. Conclusions The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered.

Background: In the current DTI study we compared euthymic bipolar I disorder (BD-I) patients and healthy controls (HC). We subsequently divided the total patient group into lithium-users and non-lithium-users and estimated differences across the three groups.Methods: Twenty-one euthymic BD-I patients and twenty-two HC participants were included in psychiatric interviews and MRI image acquisition (diffusion-weighted (DW) and T1-weighted scans). Fractional anisotropy (FA), radial, mean and axial diffusivity (RD, MD, AD) were estimated from the DW data, using DTI. These measures were then compared between groups using FSL Tract Based Spatial Statistics (TBSS). Correlations with age at onset, number of episodes and depression score were analyzed.Results: A difference in FA, MD, RD and AD between the whole sample of euthymic BD-I patients and healthy controls could not be detected. Amongst others, lithium-using patients demonstrated a higher FA and lower RD when compared to non-lithium-using BD-I patients in the corpus callosum and left anterior corona radiata. Widespread clusters demonstrated negative FA associations and positive RD and MD associations with minor depressive symptoms.Limitations: Patients were naturalistically treated. Although the sample size is comparable to several other DTI studies, a larger sample size would have been benificial. TBSS and DTI have their own limitations.Conclusion: Our findings support the theory that previously described DTI-based microstructural differences between HC and BD patients could be less pronounced in euthymic BD patients. Differences in FA between patients using and not using lithium suggest a counteracting effect of lithium on white matter microstructural disturbances. (C) 2016 Elsevier B.V. All rights reserved.

Background Recent studies have pointed to the gut-brain axis as a new venue for treatment of psychiatric disorders, with increased inflammation stemming from increased intestinal permeability to further affect brain functioning in a significant subset of patients. Yet, this line of research is still in its infancy, with multiple studies showing increased intestinal permeability in schizophrenia and bipolar disorders, demonstrated as translocation of food and bacterial antigens, as well as intestinal microbiome disturbances. Methods Therefore, we measured intestinal permeability markers soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) in schizophrenia patients and healthy controls. Intestinal permeability markers were compared to several sociodemographic, including age, gender and BMI, and physical health variables, including CRP, glucose, cholesterol, triglycerides, HDL, LDL and non-HDL, and Positive and Negative Syndrome Scale (PANSS) scores. Of the control group (n = 43), 76.7% was male, with a mean age of 25.1 years. Of the schizophrenia group (n = 105) 75.2 % was male, with a mean age of 27.4 years and an average PANSS score of 57.2. Results Levels of LBP and sCD14 were not significantly different between schizophrenia patients and controls. LBP and sCD14 levels were neither correlated in the control group, nor in the schizophrenia group. In the control group Females had elevated LBP levels compared to males (p < 0.01), but not in the schizophrenia group. Quantitative levels of LBP, but not sCD14, correlated with triglycerides in the schizophrenia group (R2 = 0.049, p < 0.05). Furthermore, quantitative levels of sCD14, but not LBP, correlated with CRP in the schizophrenia group (R2 = 0.078, p < 0.05). Finally, LBP levels in patients correlated with PANSS negative scores (R2 = 0.055, p < 0.05). Neither a correlation of LBP and sCD14 with age, nor with BMI was observed in both the control and the schizophrenia group. Discussion In conclusion, these intestinal permeability markers showed few differences between the schizophrenia and the control group. We found weak, yet significant correlations with triglycerides, CRP and severity of negative symptoms, which may be caused by poor eating habits or metabolic syndrome leading to leaky gut in the more severely affected patients. These results are not in line with results of Severance et al. (2013), who performed a similar analysis and found differences in intestinal permeability markers between a control group and a schizophrenia group. Furthermore, they did observe a positive correlation between sCD14 and LBP in both the control and the schizophrenia group. The difference between that study and our current findings may stem from the different patients samples, as we assessed patients in their first five years after diagnosis, when metabolic syndrome was less abundant.

BACKGROUND: The combination of sleep deprivation and light therapy, called combined chronotherapy, may yield positive short- and long-term results, even in patients with treatment resistant depression (TRD). The implementation of combined chronotherapy in daily clinical practice is rare. This study describes the implementation and the effectiveness in a clinical setting.METHODS: Twenty six depressed patients with unipolar or bipolar depression received combined chronotherapy consisting of three nights of sleep deprivation with alternating recovery nights, light therapy, and continuation of antidepressant medication. Inventory of Depressive Symptoms C (IDS-C) scores were determined before chronotherapy and at week 1, 2, and 4. Paired t-tests were used to compare the IDS-C scores over time.RESULTS: The mean pre-treatment IDS-C score was 39.3 ± 9.6, the mean score in week 2 was 28.4 ± 10.2, and 28.6 ± 14.0 in week 4. A subsample of patients with psychiatric co-morbidities showed a reduction in depression severity from a mean score of 42.9 ± 11.0 to a mean score of 34.9 ± 13.0 after 4 weeks. The overall response rate was 34.6%, the remission rate 19.2%.LIMITATIONS: This open label case series has a relative small sample size and no control group CONCLUSION: In a clinical setting patients with major depressive disorder or bipolar disorder benefited significantly from combined chronotherapy. This chronotherapeutic intervention appears to have a rapid effect that lasts for at least several weeks, even in patients with psychiatric comorbidity or TRD. Indicating that chronotherapy can be a valuable treatment addition for depressed patients.

Introduction: Clinical differentiation between bipolar disorder (BD) and major depressive disorder (MDD) is difficult. Research has therefore focused on discriminatory biological markers. Previous studies in MDD reported T cell deficits, while the limited studies in BD reported T cell activation. Studies directly comparing circulating numbers of T cells and T cell subsets between BD and MDD are lacking. The studies in the MOODINFLAME consortium make such a comparison possible.Methods: The number of circulating leukocyte populations (lymphocytes, monocytes, NK cells, B cells, T cells, CD3+CD8+ T cytotoxic cells, CD3+CD4+ T helper cells, Th1, Th2, Th17 and T regulatory cells) was determined using FACS technology in a cohort of 83 euthymic BD patients, 8 BD patients with a current mood episode and 165 healthy controls (HC). Data were compared to those of 34 moderately and 56 severely depressed MDD patients.Results: Compared to MDD patients, BD patients showed significantly increased levels of Th17, Th2, Th1 and T regulatory cells (all p Conclusion: This study shows CD4+ T helper cell deficits in MDD patients, while normal or even raised levels of these cells were found in BD patients. The differences in CD4+ T helper cell differentiation was most outspoken for Th17 cells.

Disruption of the biological rhythm in patients with bipolar disorder is a known risk factor for a switch in mood. This case study describes how modern techniques using ambulatory assessment of sleep parameters can help in signalling a mood switch and start early treatment. We studied a 40-year-old woman with bipolar disorder experiencing a life event while wearing an actigraph to measure sleep-wake parameters. The night after the life event the woman had sleep later and shorter sleep duration. Adequate response of both the woman and the treating psychiatrist resulted in two normal nights with the use of 1 mg lorazepam, possibly preventing further mood disturbances. Ambulatory assessment of the biological rhythm can function as an add-on to regular signalling plans for prevention of episodes in patients with bipolar disorder. More research should be conducted to validate clinical applicability, proper protocols and to understand underlying mechanisms.

Background: The "monocyte-T-cell theory of mood disorders" regards neuroinflammation, i.e. marked activation of microglia, as a driving force in bipolar disorder. Microglia activation can be visualized in vivo using [C-11]-(R)-PK11195 PET. Indirect evidence suggests the hippocampus as a potential focus of neuroinflammation in bipolar disorder. We aim to determine if there is increased [C-11]-(R)-PK11195binding to activated microglia in the hippocampus of patients with bipolar I disorder when compared to healthy controls.Material and methods: Fourteen patients with bipolar I disorder and eleven healthy controls were included in the analyses. Dynamic 60-min PET scans were acquired after the injection of [C-11]-(R)-PK11195. All subjects underwent psychiatric interviews as well as an MRI scan, which was used for anatomic co-registration in the data analysis. The data from the PET scans was analyzed with a twotissue-compartment model to calculate the binding potential, using the metabolite-corrected plasma and blood curve as input.: A significantly increased [C-11]-(R)-PK11195 binding potential, which is indicative of neuroinflammation, was found in the right hippocampus of the patients when compared to the healthy controls (1.66 (CI 1.45-1.91) versus 1.33 (Cl 1.16-1.53); p = 0.033, respectively). Although the same trend was observed in the left hippocampus, this difference was not statistically significant.Conclusion: This study is the first to demonstrate the presence of focal neuroinflammation in the right hippocampus in bipolar I disorder. (C) 2014 Elsevier Inc. All rights reserved.

BACKGROUND: Are people who are extraordinarily creative more likely to be mentally ill? Are all mentally ill people more creative? These are questions that have been asked for a very long time by scientists and philosophers. The link between creativity and mental illnesses has been hypothesized in varied ways. However, this link has not been properly established yet. Research from the last two decades has proposed that the problems in establishing such link or relationship is that it may only be present in certain specific mental illnesses, namely those with a psychotic component (e.g. bipolar disorder, schizotypal personality disorder) (Thys, Sabbe, & De Hert, 2014; Barrantes Vidal, 2004). We study this link using musical hallucinations (MH) as these are often being believed to be experienced as less disturbing than other types of hallucinations (e.g. auditory verbal, visual) (Shakenraad et al., 2006; Evers, 2006). Using MH in this study allowed to investigate the creativity-”madness” link in a more positive light. METHODS: 76 participants were measured from a student population, who completed a series of tasks. We introduced a novel approach of measuring creativity (defined as the propensity to detect imaginary music), through a musical Signal Detection Task (SDT). During this SDT, bursts of audible pink noise were being played, sometimes mixed with music, and sometimes without. The participants also completed two questionnaires, related to hallucination proneness (LSHS-R) and schizotypy personality traits (SPQ-BR). Furthermore, the participants performed a series of computer tasks related to different ways of measuring creativity: two classical measures of creativity, namely a biographical questionnaire and an Alternate Uses Task (AUT; Guilford, Dunham, & Hoepfner, 1967). We hypothesized that hearing music when none was being played (false alarm) could be considered to be a form of creativity and that this would positively correlate with proneness to hallucinate. Moreover, we also hypothesized that the included classical creativity measures would be positively associated with SPQ-BR. RESULTS: Correlation and regression analyses showed that in the musical SDT, contrary to our hypothesis, false alarms were negatively correlated to the LSHS-R scores: participants that were more prone to hallucinate reported less false alarms (p=0.040) than those who scored lower on the LSHS-R. Furthermore, more prone individuals reported higher sensitivity scores: they were better able to distinguish noise from music (p=0.004). Additionally, no significant correlation was observed between the classical creativity measures and the musical SDT or with the SPQ-BR scores. DISCUSSION: Further analysis of the sensitivity measures of the SDT revealed that scores of only three subjects could be driving this found correlation, thus caution is needed considering this relatively small, non-clinical, sample. Furthermore, the lack of correlation between the classical creativity measures and the SPQ-BR could be suggesting that there is either no relationship between creativity and schizotypy, or that perhaps, these two classical measures of creativity are measuring a different type of creativity than the one linked to schizotypy in former research. The continuation of this study includes an improved musical SDT and a musical creativity task. In this new experiment, the sample will come from a patient population with psychotic features. By learning more about the relationship of mental illnesses and creativity, and implementing this knowledge, existent treatments can be improved, and new ones may be developed to truly benefit this particular patient population.

Background The association between inflammation and the course of mood disorders is receiving increased attention. This study aims to investigate whether a sub-group of patients with BD can be identified for which a higher CRP (C-reactive protein) level at baseline is associated with an unfavorable prognosis. Methods This is a historic cohort study using CRP at baseline, with 15-month follow-up of mood status and medication. Cross-sectional analyses include boxplots, one-way ANOVA, receiver operating characteristics (ROC) curve and Chi square test, and the longitudinal analysis using multivariate Cox-regression. Results Eighty-four bipolar disorder patients were included in the analyses. Cross-sectionally, no statistically significant difference was found in CRP distribution across mood states (p = 0.372) or rapid cycling state (p = 0.656). Also, no CRP cut-off level was distinguished between euthymic and non-euthymic patients according to the ROC curve (p = 0.449, AUC = 0.452, 95 % CI 0.327, 0.576), and a literature-derived cut-off value (3 mg/L) again demonstrated no difference (p = 0.530). Longitudinally, no association was found between CRP and prognosis of disease neither in euthymic [−2 log likelihood = 120.460; CRP: p = 0.866, B = −0.011, OR = 0.989 (95 % CI 0.874–1.120)] nor non-euthymic patients [(−2 log likelihood = 275.028; CRP: p = 0.802, B = 0.010, OR = 1.010 (95 % CI 0.937–1.088)]. Medication use did not affect these associations. Conclusions We found no statistically significant association between CRP and a more unfavorable BD prognosis, suggesting that the application of CRP as a practical biomarker to predict outcome in a naturalistic outpatient care setting is not as straightforward as it may seem. Electronic supplementary material The online version of this article (doi:10.1186/s40345-016-0055-3) contains supplementary material, which is available to authorized users.

While retrieving additional information from patients’ medical files for another study, it became clear that one patient who was actually using valproate and levetiracetam, was previously processed as a lithium user. Below you will find the corrected version of the subjects’ characteristics Table 1, as well as corrected results of the explorative analyses of this study where lithium use was involved and an updated version of Fig. 7, summarizing the explorative analysis results of the left hippocampus. The altered text of the concerned paragraphs are set in boldface. The cited references are as in the original report.

Background: The hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning.Materials and methods: Twenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [C-11]-(R)PK11195 neuroinflammation positron emission tomography scan.Results: In contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA) + N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr) + phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA + NAAG concentration, between alcohol use and NM + NAAG concentration, between microglial activation and the depression score and a negative relation between Cr + PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally.Conclusion: Compared to HCs, the decreased NAA + NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis. (C) 2015 Elsevier Inc. All rights reserved.