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Aims: Substantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants., Methods: In a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method., Results: Compared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12-1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09-1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04-1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02-1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC. Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75-0.77) CONCLUSIONS: Higher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD., Competing Interests: Declaration of Competing Interest KC, HHP, JLF, KM, SS, MFJ, HLK, RFS, CTE, SRO and KMW declare no conflicts of interest. MV discloses within the last three years consultancy fees from Lundbeck and Janssen Cilag. LVK has within the preceding three years been a consultant for Lundbeck and Teva., (Copyright © 2024. Published by Elsevier Inc.)

Electroconvulsive therapy (ECT) is one of the most effective and rapid-acting treatment for severe depression but is associated with cognitive side-effects. Identification of add-on treatments that counteract these side-effects would be very helpful. This randomized, double-blinded, placebo-controlled, parallel-group study investigated the effects of four add-on erythropoietin (EPO; 40,000 IU/ml) or saline (placebo) infusions over 2.5 weeks of ECT (eight ECT sessions) in severely depressed patients with unipolar or bipolar depression. Neuropsychological assessments were conducted pre-ECT, three days after the eighth ECT (week 4), and at a 3-month follow-up. Further, functional magnetic resonance imaging (fMRI) was conducted after the eighth ECT. The primary outcome was change from pre- to post-ECT in a 'speed of complex cognitive processing' composite. Secondary outcomes were verbal and autobiographical memory. Of sixty randomized patients, one dropped out before baseline. Data were thus analysed for 59 patients (EPO, n = 33; saline, n = 26), of whom 28 had fMRI data. No ECT-related decline occurred in the primary global cognition measure (ps≥0.1), and no effect of EPO versus saline was observed on this outcome (ps≥0.3). However post-ECT, EPO-treated patients exhibited faster autobiographical memory recall than saline-treated patients (p = 0.02), which was accompanied by lower memory-related parietal cortex activity. The absence of global cognition changes with ECT and EPO, coupled with the specific impact of EPO on autobiographical memory recall speed and memory-related parietal cortex activity, suggests that assessing autobiographical memory may provide increased sensitivity in evaluating and potentially preventing cognitive side-effects of ECT. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT03339596, EudraCT no.: 2016-002326-36., Competing Interests: Declaration of Competing Interest KWM has received consultancy fees from Lundbeck, Janssen, Angelini Pharma and Gedeon Richter in the past three years. JZP has within the last three years received honoraria from Lundbeck Pharma A/S. MV has within the last three years received consultancy fees from Janssen Cilag and Lundbeck. LVK has within recent three years been a consultant for Lundbeck and Teva. CHK receives honoraria from Cambridge University Press, and fees from UpToDate and Northwell Health. JMAC, KC, IAL, ATYN, MBM, HE, IH, PV, KG, LGH, JLJ, and MBJ report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Although cross-sectional studies show heterogeneity in emotional cognition in bipolar disorder (BD), the temporal course within subgroups is unclear. In this prospective, longitudinal study we assessed the trajectories of emotional cognition subgroups within a 16-month follow-up period in recently diagnosed BD patients compared to healthy controls (HC). Recently diagnosed BD patients and HC underwent comprehensive emotional and non-emotional testing at baseline and again at follow-up. We employed hierarchical cluster analysis at baseline to identify homogenous emotional cognition subgroups of patients, and changes across the subgroups of BD and HC were assessed with linear mixed-model analyses. We found two emotional cognition subgroups: subgroup 1 (65%, n = 179), showing heightened negative emotional reactivity in neutral and negative social scenarios and faster recognition of emotional facial expressions than HC (ps<0.001, n = 190), and subgroup 2 (35%, n = 96) showing blunted reactivity in positive social scenarios, impaired emotion regulation, poorer recognition of positive and slower recognition of all facial expressions than HC (ps≤.03). Subgroup 1 exhibited normalization of the initial emotional cognition abnormalities in follow-up. In contrast, subgroup 2 showed a lack of improvement in reactivity positively-valenced emotional information. Patients in subgroup 2 presented more and longer mixed episodes during the follow-up time and were more often prescribed lithium. One third of patients display blunted emotional reactivity, impaired emotion regulation abilities and facial expression recognition difficulties also show persistent impairments and poorer course of illness. This subgroup may indicate a need for earlier and more targeted therapeutic interventions., Competing Interests: Declaration of Competing Interest MV has received consultancy fees from Angelini, Janssen, aviators, and Lundbeck the past three years. LVK has within the preceding three years been a consultant for Lundbeck and Teva. KWM has received consultancy fees from Lundbeck and Janssen-Cilag in the past three years. The remaining authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Increased oxidative stress generated nucleoside damage seems to play a crucial role in bipolar disorder (BD) pathophysiology. It may contribute to accelerated ageing and reduced life expectancy in patients with BD., Methods: In the five-year prospective "Bipolar Illness Onset study", we investigated repeated measurements of oxidative stress generated RNA and DNA damage in 357 patients with newly diagnosed/first-episode BD (880 visits), 132 of their unaffected first-degree relatives (236 visits) and 198 healthy age- and sex-matched control persons with no personal or first-degree family history of affective disorder (432 visits). Amongst patients with BD, we further investigated associations of oxidative stress generated RNA- and DNA damage with affective phases and measures of illness load., Results: Patients newly diagnosed with BD and their unaffected relatives had higher levels of oxidative stress generated RNA damage than healthy control individuals and these differences persisted over time, whereas DNA damage was less consistently elevated. Neither illness load nor affective phase impacted the levels in patients with BD., Conclusions: Our findings support elevated oxidative stress generated RNA damage being a trait phenomenon in BD as indicated by persistent increase in RNA damage over time in patients newly diagnosed with BD and in their unaffected first-degree relatives compared with healthy control individuals. We did not detect state alterations in levels of oxidative stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cognitive impairments are evident in remitted patients with bipolar disorder (BD) and their unaffected relatives (UR) compared to healthy controls (HC). However, the temporal course of cognition, and whether cognition is marked by neuroprogressive changes, remain unclear. In a large prospective study of newly diagnosed patients with BD, we assessed patients with BD (n = 266), UR (n = 105) and HC (n = 190) using an extensive cognitive battery of non-emotional and emotional cognition at baseline and 16-months follow-up. Cognitive change across groups was examined with linear mixed-model analyses. Results showed no evidence of trajectory differences between patients with BD, UR, and HC in neurocognition and emotional cognition (ps≥.10). Patients with BD showed stable impairments in global neurocognitive functioning over time, as well as within the domains of 'working memory and executive function' and 'attention and psychomotor speed', compared to HC. Patients who relapsed during the follow-up time were less successful at down-regulating emotions in positive social scenarios compared to HC. Unaffected relatives also displayed stable deficits in 'working memory and executive function' over time, with performance at intermediate levels between BD probands and HC. Finally, poorer neurocognition and positive emotion regulation were associated with more subsyndromal symptoms and functional impairments. In conclusion, we found no evidence of a neuroprogressive origin of cognitive impairments in the newly diagnosed BD or in their UR. Patients' and UR's impairments in working memory and executive function may reflect a stable cognitive trait-marker of familial risk. Difficulties with positive emotion regulation may be associated with illness progression in BD., Competing Interests: Declaration of Conflicts Interest MV has received consultancy fees from Lundbeck and Janssen Cilag the past three years. LVK has within the preceding three years been a consultant for Lundbeck and Teva. KWM has received consultancy fees from Lundbeck and Janssen-Cilag in the past three years. The remaining authors declare no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Oxidative stress generated nucleoside damage seems to represent key pathophysiological mechanisms of bipolar disorder (BD). Likewise, mood and activity are core features of BD and can be reliably monitored using smartphone-based applications. The aim was to investigate whether oxidative stress generated nucleoside damage could reflect psychopathology in BD using easily available and non-invasive patient-reported smartphone-based symptoms. We included 223 patients newly diagnosed with BD and employed linear mixed-effect regression models to associate baseline measurements of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels with patient-reported smartphone measures of mood, activity, anxiety, stress and sleep duration monitored three days prior to and 30 days after the baseline visit in the longitudinal Bipolar Illness Onset Study. In patients newly diagnosed with BD higher 8-oxoGuo levels were inversely associated with the patient-reported activity level (B = 0.953, 95%CI = 0.909;0.99, p = 0.043) and positively associated with patient-reported anxiety (B = 1.104, 95%CI = 1.022;1.161, p=0.012), perceived stress (B = 1.092, 95%CI = 1.009;1.183, p = 0.014) and sleep duration (B = 1.000, 95%CI = 1.000;1.001, p = 0.001), respectively, in analyses, adjusted for sex and age. The associations between 8-oxoGuo levels and anxiety, perceived stress and sleep duration, respectively, withstood adjustment for sex, age, smoking, BMI and alcohol intake. No associations between 8-oxodG levels and patient-reported smartphone-based data were found and mood was not associated with 8-oxoGuo. Oxidative stress was associated with patient-reported smartphone-based data on activity, anxiety, stress and sleep duration pointing towards that oxidative stress generated nucleoside damage may reflect ongoing psychopathology in BD., Competing Interests: Declaration of Competing Interest MV discloses within the last three years consultancy fees from Lundbeck, Sunovion and Janssen-Cilag. LVK has within the preceding three years been a consultant for Lundbeck and Teva and KC and SS has within the preceding three years been a consultant for Lundbeck. MFJ declares no conflicts of interests. HEP declares no conflict of interest., (Copyright © 2022. Published by Elsevier B.V.)

Neuroimaging studies of bipolar disorder (BD) generally involve comparison with healthy controls (HC), which may mask neurobiological variability within the disorder. This study aims to assess the neural underpinnings of potential subgroups of BD patients based on functional activity in the emotion regulation network and its relation to illness characteristics and relapse risk. Eighty-seven remitted patients with recently diagnosed BD and 66 HC underwent functional magnetic resonance imaging (fMRI) while performing an emotion regulation task. Patients were re-assessed with clinical interviews after 16 (±5) months. Data-driven hierarchical cluster analysis was employed to investigate 'neuronal subgroups' of patients based on their neuronal activity in a pre-defined emotion regulation network. Relations between neuronal subgroups and illness characteristics and relapse rates were examined. Patients were allocated into two subgroups. Subgroup 1 (n=62, 75%) was characterized by exaggerated bilateral amygdala reactivity but normal prefrontal and temporo-parietal activation. Subgroup 2 (n= 22, 25%) showed widespread hypo-activity within all emotion regulation regions. Both subgroups were less successful at down-regulating their emotions than HC (F(2,146)=5.33, p=.006, η p 2 =.07). Patients in subgroup 2 had a history of more and longer mixed episodes (ps≤.01). Importantly, heightened amygdala activity across all patients was associated with increased risk of relapse during a 16-month follow-up period (β=3.36, 95% CI [1.49;550.35], N=60, p=.03). The identified neuronal subgroups of patients with either amygdala hyper-activity or broad network hypo-activity during emotion regulation points to neurobiological heterogeneity among remitted patients with BD. Heightened amygdala reactivity may be a neuronal target for personalized treatments to prevent relapse., Competing Interests: Declaration of Competing Interest MV has received consultancy fees from Lundbeck, Sunovion and Janssen Cilag in the past three years. LVK has within the preceding three years been a consultant for Lundbeck and Teva. GMK has received honoraria as speaker and consultant for Sage Therapeutics/Biogen and from Sanos. JM has received honoraria as speaker for Lundbeck for the last three years. KWM has received consultancy fees from Lundbeck and and Janssen-Cilag in the past three years. The remaining authors declare no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome., Objective: To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome., Data Sources: Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists., Study Selection: Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected., Data Extraction & Synthesis: Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model., Main Outcomes & Measures: The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome., Results: The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p < 0.001; n = 25,268; I 2  = 99.1%). The proportion of individuals exhibiting cognitive impairment was 0.22 (95% CI, 0.17, 0.28; p < 0.001; n = 13,232; I 2  = 98.0). Moreover, narrative synthesis revealed elevations in proinflammatory markers and considerable functional impairment in a subset of individuals., Conclusions & Relevance: A significant proportion of individuals experience persistent fatigue and/or cognitive impairment following resolution of acute COVID-19. The frequency and debilitating nature of the foregoing symptoms provides the impetus to characterize the underlying neurobiological substrates and how to best treat these phenomena., Study Registration: PROSPERO (CRD42021256965)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Patients with mood disorders show heterogeneity in non-emotional cognition. However, it is unclear whether emotional cognition (EC) is characterised by similar heterogeneity. We aimed to investigate the heterogeneity in EC among remitted patients with mood disorders and explore its association with familial risk. Data from 269 partially or fully remitted patients with mood disorders, 87 of their unaffected relatives (UR) and 203 healthy controls (HC) were pooled from two cohort studies. Hierarchical cluster analysis was conducted using the EC data from patients. UR were categorised into groups consistent with their affected relatives' cluster assignment. Clusters were compared to HC on EC, non-emotional cognition, clinical characteristics and functioning.  We identified three clusters: an 'emotionally preserved' (57%), an 'emotionally blunted' (26%) and an 'emotionally volatile' cluster (17%). 'Emotionally blunted' and 'emotionally volatile' patients also presented more deficits in non-emotional cognition (global cognition read z=-0.3 and -0.5 respectively). Relatives of 'emotionally preserved' patients were more successful at dampening negative emotions (p=.01, d=0.39, 95% CI [-0.76,-0.09]), whereas UR of 'emotionally impaired' patients underperformed in verbal fluency (p=.03, d=0.46, 95% CI [.03, 0.68]) compared to HC. The existence of impaired EC groups in remitted mood disorder highlights a need to screen for and treat EC in mood disorders. Improved ability to dampen emotions in UR of 'emotionally preserved' patients may reflect a resilience marker while impaired verbal fluency in UR of 'emotionally impaired' patients may reflect distinct genetic risk profiles in these EC subgroups., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Pregnancy and childbirth are among the strongest risk factors for depression but the neurocognitive mechanisms underlying this enhanced risk are unknown. This study investigated emotional and non-emotional cognition in 57 pregnant women with or without an affective disorder during their third trimester, and the association between cognitive biases and subsequent postpartum depression (PPD). Of the pregnant women, 22 had a diagnosis of unipolar disorder (UD) and seven of bipolar disorder (BD) in full or partial remission, while 28 had no history of affective disorder. We included a control group of 29 healthy non-pregnant women. First, participants were interviewed, completed non-emotional and emotional cognitive tests and lastly filled out questionnaires. The participants were assessed two times after birth: at a home visit shortly after birth, and with a telephone interview to assess PPD in the first six months after birth. Healthy pregnant women rated infant cries less negatively than non-pregnant women, possibly reflecting preparation for motherhood. Pregnant women with UD exhibited a negative bias in ratings of infant cries, whereas pregnant women with BD showed a positive bias in ratings of infant happy faces and recognition of adult facial expressions. Across all pregnant women, more negative ratings of infant cries were associated with enhanced risk of PPD. Negatively biased perception of infant cries during pregnancy may thus signal vulnerability toward PPD., (Copyright © 2020. Published by Elsevier B.V.)

Bipolar disorders are a complex group of severe and chronic disorders that includes bipolar I disorder, defined by the presence of a syndromal, manic episode, and bipolar II disorder, defined by the presence of a syndromal, hypomanic episode and a major depressive episode. Bipolar disorders substantially reduce psychosocial functioning and are associated with a loss of approximately 10-20 potential years of life. The mortality gap between populations with bipolar disorders and the general population is principally a result of excess deaths from cardiovascular disease and suicide. Bipolar disorder has a high heritability (approximately 70%). Bipolar disorders share genetic risk alleles with other mental and medical disorders. Bipolar I has a closer genetic association with schizophrenia relative to bipolar II, which has a closer genetic association with major depressive disorder. Although the pathogenesis of bipolar disorders is unknown, implicated processes include disturbances in neuronal-glial plasticity, monoaminergic signalling, inflammatory homoeostasis, cellular metabolic pathways, and mitochondrial function. The high prevalence of childhood maltreatment in people with bipolar disorders and the association between childhood maltreatment and a more complex presentation of bipolar disorder (eg, one including suicidality) highlight the role of adverse environmental exposures on the presentation of bipolar disorders. Although mania defines bipolar I disorder, depressive episodes and symptoms dominate the longitudinal course of, and disproportionately account for morbidity and mortality in, bipolar disorders. Lithium is the gold standard mood-stabilising agent for the treatment of people with bipolar disorders, and has antimanic, antidepressant, and anti-suicide effects. Although antipsychotics are effective in treating mania, few antipsychotics have proven to be effective in bipolar depression. Divalproex and carbamazepine are effective in the treatment of acute mania and lamotrigine is effective at treating and preventing bipolar depression. Antidepressants are widely prescribed for bipolar disorders despite a paucity of compelling evidence for their short-term or long-term efficacy. Moreover, antidepressant prescription in bipolar disorder is associated, in many cases, with mood destabilisation, especially during maintenance treatment. Unfortunately, effective pharmacological treatments for bipolar disorders are not universally available, particularly in low-income and middle-income countries. Targeting medical and psychiatric comorbidity, integrating adjunctive psychosocial treatments, and involving caregivers have been shown to improve health outcomes for people with bipolar disorders. The aim of this Seminar, which is intended mainly for primary care physicians, is to provide an overview of diagnostic, pathogenetic, and treatment considerations in bipolar disorders. Towards the foregoing aim, we review and synthesise evidence on the epidemiology, mechanisms, screening, and treatment of bipolar disorders., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

There is an increasing interest in the putative role of glucagon-like peptide 1 receptor (GLP-1R) agonists as novel therapeutic agents for mental disorders. Herein, we investigated the expressions of GLP-1R and GLP-2R genes, and its relationship with body mass index (BMI), in the post-mortem brain tissue of patients with mood (MD) and psychotic disorders. Brain samples were localized to the dorsolateral prefrontal cortex (dlPFC) (n = 459) and hippocampus (n = 378). After adjustment for age, sex, ethnicity, post-mortem interval (PMI) and BMI, we observed significant differences, between healthy controls and MD subjects, in GLP-1R and GLP-2R gene expression in the dlPFC (β = 1.504, p = 0.004; and β = 1.305, p = 0.011, respectively); whereas in the hippocampus, only GLP-1R expression was significantly associated with MD (β = -1.28, p = 0.029). No significant differences were found in relation to schizophrenia. In addition, we observed a moderating effect of MD diagnosis on the associations between BMI, GLP-1R and GLP-2R expression values in the dlPFC (β = -0.05, p = 0.003; and β = -0.04, p = 0.004, respectively). There was a similar moderating effect for GLP-1R in the hippocampus (β = 0.043, 95% CI 0.003; 0.08 p = 0.03), but in an opposite direction than observed in the dlPFC. This is the first evidence of abnormal gene expression of GLP-1R and GLP-2R in postmortem brain of individuals with MD, providing a rationale for further inquiry and proof of principle interventional studies., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

Objective: An aberrant gut microbiota may be associated with a broad spectrum of diseases including mental illness. The gut microbiota is scarcely studied in bipolar disorder (BD). We examined the gut microbiota composition in patients with newly diagnosed BD, their unaffected first-degree relatives and healthy individuals., Methods: Stool samples were collected from 113 patients with BD, 39 unaffected first-degree relatives and 77 healthy individuals and the microbiota was profiled using 16S rRNA gene amplicon sequencing., Results: The gut microbiota community membership of patients with BD differed from that of healthy individuals (R 2  = 1.0%, P = 0.008), whereas the community membership of unaffected first-degree relatives did not. Flavonifractor was present in 61% of patients with BD, 42% of their unaffected relatives and 39% of healthy individuals. Presence of Flavonifractor was associated with an odds ratio of 2.9 (95%CI: 1.6-5.2, P = 5.8 × 10 -4 , Q = 0.036) for having BD. When excluding smokers, presence of Flavonifractor was associated with an odds ratio of 2.3 (95%CI: 1.1-5.3, P = 0.019) for having BD. However, when considering the subsample of non-smokers only, BD and presence of Flavonifractor were no longer associated when adjusted for all possible tests at genus level (Q = 0.6). Presence of Flavonifractor in patients with BD was associated with smoking and female sex, but not with age, waist circumference, exercise level, high-sensitive C-reactive protein, current affective state, subtype of BD, illness duration or psychotropic medication, respectively., Conclusion: Flavonifractor, a bacterial genus that may induce oxidative stress and inflammation in its host, was associated with BD. Higher prevalence of smoking among patients with BD contributed to our findings, and it cannot be excluded that findings are influenced by residual confounding., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: We investigated the neural correlates of emotion regulation and -reactivity in adult unaffected monozygotic twins with a co-twin history of unipolar or bipolar disorder (high-risk), remitted or partially remitted twins with a personal history of unipolar or bipolar disorder (affected) and twins with no personal or first-degree family history of unipolar or bipolar disorder (low-risk)., Methods: We assessed 37 high-risk, 56 affected and 28 low-risk participants. Participants viewed unpleasant and neutral pictures during functional magnetic resonance imaging and were instructed to down-regulate their emotional response through reappraisal or mental imagery, as well as to maintain the elicited emotion., Results: After adjusting for subsyndromal depressive symptoms, bilateral supplementary motor areas, posterior dorsal anterior cingulate cortices and the left frontal eye field showed less activity during reappraisal of unpleasant pictures in high-risk than low-risk participants. Notably, affected participants did not differ from high-risk or low-risk participants in neural response during reappraisal. There were no group differences in ventrolateral prefrontal cortex seed based functional connectivity during reappraisal or neural response during mental imagery or emotional reactivity., Conclusion: Lesser response in dorsal midline areas might reflect familial risk related abnormalities during down regulation of emotional reactivity through reappraisal., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive deficits are common in patients with bipolar disorder (BD) in remission and may be associated with glycogen synthase kinase-3 (GSK-3) activity, which is inhibited by lithium. GSK-3 may be a relevant treatment target for interventions tailored at cognitive disturbances in BD but the relation between GSK-3 activity, cognition and lithium treatment is unknown. We therefore investigated the possible association between GSK-3 activity and cognition and whether lithium treatment moderates this association in patients with BD. In a prospective 6-12 month follow-up study, GSK- 3β activity in peripheral blood mononuclear cells was measured concurrently with cognitive performance assessed using a comprehensive test battery in 27 patients with BD-I in early and late remission following a manic or mixed episode. The GSK-3β activity, measured as serine-9 phosphorylated GSK-3β (pGSK-3β) and the GSK-3β ratio (serine-9-pGSK-3β /total GSK-3β), was negatively associated with sustained attention (p = 0.009 and p = 0.042, respectively), but not with other cognitive domains or global cognition. A crossover interaction between lithium treatment and the GSK activity was observed, indicating that lower pGSK-3β levels (p = 0.015) and GSK ratio (p = 0.010) were associated with better global cognition in lithium users whereas the opposite association was observed in non-lithium treated patients. Findings were not statistically significant after Bonferroni correction. In conclusion, cognitive functioning may be associated with GSK-3 activity in patients with BD-I and lithium treatment may modulate this relationship. Future studies in larger sample sizes are warranted to confirm these associations., (Copyright © 2018 Elsevier B.V. and ECNP. All rights reserved.)

Background: Major depression and bipolar disorders aggregates in families and are linked with a wide range of neurobiological abnormalities including cortical gray matter (GM) alterations. Prospective studies of individuals at familial risk may expose the neural mechanisms underlying risk transmission., Methods: We used voxel based morphometry to investigate changes in regional GM brain volume, over a seven-year period, in 37 initially healthy individuals having a mono- or di-zygotic twin diagnosed with major depression or bipolar disorder (high-risk group; mean age 41.6 yrs.) as compared to 36 individuals with no history of affective disorders in the index twin and first-degree relatives (low-risk group; mean age 38.5 yrs.)., Results: Groups did not differ in regional GM volume changes over time. However, independent of time, high-risk twins had significantly greater GM volumes in bilateral dorsal anterior cingulate, inferior frontal gyrus and temporoparietal regions as compared to low-risk twins. Further, individuals who developed an affective disorder at follow-up (n = 12), had relatively the largest GM volumes, both at baseline and follow-up, in the right dorsal anterior cingulate cortex and right inferior frontal cortex compared to high- and low-risk twins who remained well at follow-up., Conclusion: This pattern of apparently stable grater regional GM volume may constitute a neural marker of an increased risk for developing an affective disorder in individuals at familial risk.

Cognitive deficits are a core feature across psychiatric disorders. Emerging evidence indicates that metabolic pathways are highly relevant for the substrates and phenomenology of the cognitive domain. Herein, we aimed to determine the effects of liraglutide, a GLP-1R agonist, on brain structural/volumetric parameters in adults with a mood disorder. This is the secondary analysis of a 4-week, pilot, proof-of-concept, open-label study. Participants (N=19) exhibiting impairments in executive function with either major depressive disorder (MDD) or bipolar disorder (BD) were recruited. Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy. Structural magnetic resonance imaging (MRI) scanning was obtained at baseline and endpoint. Results showed that at endpoint there was significant weight loss (mean: 3.15%; p<0.001). Changes in frontal and striatal volumes were significantly correlated with changes in body mass index (BMI), indicating the weight loss was associated with volume increase in most regions (e.g. r=-0.561, p=0.042 in the left superior frontal area). After adjusting for intracranial volume, age, gender, and BMI, we observed significant changes from baseline to endpoint in multiple regions (e.g. RR: 1.011, p=0.049 in the left rostral middle frontal area). Changes in regional volumes were associated with improvement in executive function (e.g. r=0.698, p=0.003 for the right superior frontal area). Adjunctive liraglutide results in clinically significant weight loss, with corresponding improvement in cognitive function; changes in cognitive function were partially moderated by changes in brain morphometry, underscoring the interrelationship between weight and brain structure/function., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Aim: This study investigated the effect of repeated infusions of recombinant human erythropoietin (EPO) on markers of inflammation in patients with affective disorders and whether any changes in inflammatory markers were associated with improvements on verbal memory., Methods: In total, 83 patients were recruited: 40 currently depressed patients with treatment-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (sub-study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS)⩽14) (sub-study 2). In both sub-studies, patients were randomised in a double-blind, parallel-group design to receive eight weekly intravenous infusions of EPO (Eprex; 40,000IU/ml) or saline (0.9% NaCl). Plasma concentrations of interleukin 6 (IL-6), interleukin 18 (IL-18) and high sensitive c-reactive protein (hsCRP) were measured at week 1 (baseline) and weeks 5, 9 and 14. HDRS-17 and neuropsychological function was assessed at weeks 1, 9 and 14 using a test battery including the RAVLT Auditory Verbal Learning Test (primary depression and primary cognition outcomes in the original trial)., Results: EPO had no cumulative effect on plasma levels of IL-6 or IL-18 but increased hsCRP levels in patients with TRD (mean±SD change in ng/L: EPO: 0.43±1.64; Saline: -0.90±2.43; F(1,39)=4.78, p=0.04). EPO had no effects on inflammatory markers in BD. There was no correlation between change in inflammatory markers and change in verbal memory., Conclusions: Repeated EPO infusions had no effect on IL-6 and IL-18 levels but produced a modest increase in hsCRP levels in patients with TRD. Changes over time in inflammatory markers were not correlated with changes in cognition suggesting that modulation of the inflammatory pathway is not a putative mechanism of the EPO-associated improvement of cognition in affective disorders., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This is a secondary data analysis from our erythropoietin (EPO) trials. We examine (I) whether EPO improves speed of complex cognitive processing across bipolar and unipolar disorder, (II) if objective and subjective baseline cognitive impairment increases patients׳ chances of treatment-efficacy and (III) if cognitive improvement correlates with better subjective cognitive function, quality of life and socio-occupational capacity. Patients with unipolar or bipolar disorder were randomized to eight weekly EPO (N=40) or saline (N=39) infusions. Cognition, mood, quality of life and socio-occupational capacity were assessed at baseline (week 1), after treatment completion (week 9) and at follow-up (week 14). We used repeated measures analysis of covariance to investigate the effect of EPO on speed of complex cognitive processing. With logistic regression, we examined whether baseline cognitive impairment predicted treatment-efficacy. Pearson correlations were used to assess associations between objective and subjective cognition, quality of life and socio-occupational capacity. EPO improved speed of complex cognitive processing across affective disorders at weeks 9 and 14 (p≤0.05). In EPO-treated patients, baseline cognitive impairment increased the odds of treatment-efficacy on cognition at weeks 9 and 14 by a factor 9.7 (95% CI:1.2-81.1) and 9.9 (95% CI:1.1-88.4), respectively (p≤0.04). Subjective cognitive complaints did not affect chances of treatment-efficacy (p≥0.45). EPO-associated cognitive improvement correlated with reduced cognitive complaints but not with quality of life or socio-occupational function. As the analyses were performed post-hoc, findings are only hypothesis-generating. In conclusion, pro-cognitive effects of EPO occurred across affective disorders. Neuropsychological screening for cognitive dysfunction may be warranted in future cognition trials., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Background: Persistent cognitive dysfunction in depression and bipolar disorder (BD) impedes patients' functional recovery. Erythropoietin (EPO) increases neuroplasticity and reduces cognitive difficulties in treatment-resistant depression (TRD) and remitted BD. This magnetic resonance imaging study assessed the neuroanatomical basis for these effects., Methods: Patients with TRD who were moderately depressed or BD in partial remission were randomized to 8 weekly EPO (40,000 IU) or saline infusions in a double-blind, parallel-group design. Patients underwent magnetic resonance imaging, memory assessment with the Rey Auditory Verbal Learning Test, and mood ratings with the Beck Depression Inventory, Hamilton Depression Rating Scale, and Young Mania Rating Scale at baseline and week 14. Hippocampus segmentation and analysis of hippocampal volume, shape, and gray matter density were conducted with FMRIB Software Library tools. Memory change was analyzed with repeated-measures analysis of covariance adjusted for depression symptoms, diagnosis, age, and gender., Results: Eighty-four patients were randomized; 1 patient withdrew and data collection was incomplete for 14 patients; data were thus analyzed for 69 patients (EPO: n = 35, saline: n = 34). Compared with saline, EPO was associated with mood-independent memory improvement and reversal of brain matter loss in the left hippocampal cornu ammonis 1 to cornu ammonis 3 and subiculum. Using the entire sample, memory improvement was associated with subfield hippocampal volume increase independent of mood change., Conclusions: EPO-associated memory improvement in TRD and BD may be mediated by reversal of brain matter loss in a subfield of the left hippocampus. EPO may provide a therapeutic option for patients with mood disorders who have impaired neuroplasticity and cognition., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Inflammatory system dysregulation may be involved in the pathophysiology of bipolar disorder with peripheral cytokine levels varying between affective states; however, the evidence is based primarily on case-control studies and limited by methodological issues. The objectives of the present study were to assess alterations of peripheral cytokine levels between affective states in rapid cycling bipolar disorder patients and to compare these with levels in healthy control subjects. In a longitudinal design, repeated measurements of plasma levels of IL-6, IL-10, IL-18, IL-1β and TNF-α were obtained in affective states of varying polarity during 6-12 months in 37 rapid cycling bipolar disorder patients and compared with repeated measurements in 40 age- and gender matched healthy control subjects, using rigorous laboratory-, clinical- and statistical methodology. Adjusting for demographical, clinical- and lifestyle factors, levels of IL-6 (p<0.05) and IL-18 (p<0.005) were significantly elevated in rapid cycling bipolar disorder patients in a manic/hypomanic state, compared with a depressed and a euthymic state. Compared with healthy control subjects, unadjusted levels of IL-6 (p<0.05) and IL-18 (p<0.05) were elevated in manic/hypomanic bipolar disorder patients. Levels of IL-10 and IL-1β were undetectable in the majority of samples; high TNF-α assay variability was found. The results support a role for altered peripheral immune response signaling in rapid cycling bipolar disorder and suggest that IL-6 and IL-18 could be markers of manic episodes., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Genetic polymorphisms seem to influence the response on antidepressant treatment and moderate the impact of stress on depression. The present study aimed to assess, whether allelic variants and stressful life events interact on the clinical outcome of depression. In a sample of 290 systematically recruited patients diagnosed with a single depressive episode according to ICD-10, we assessed the outcome of antidepressant treatment and the presence of stressful life events in a 6-month period preceding onset of depression by means of structured interviews. Further, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophan hydroxylase, and the serotonin receptors 1A, 2A, and 2C. We found no evidence that the effects of the genetic polymorphisms on treatment outcome were dependent on stressful life events experienced by the individual prior to onset of depression., (2009 Elsevier B.V. and ECNP. All rights reserved.)