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Objective: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available laboratory tests. We aimed to combine data from different molecular levels and tissues into a composite diagnostic and state biomarker., Methods: Expression levels of 19 candidate genes in peripheral blood, plasma levels of BDNF, NT-3, IL-6 and IL-18, leukocyte counts, and urinary markers of oxidative damage to DNA and RNA were measured in 37 adult rapid-cycling patients with BD in different affective states during a 6- to 12-month period and in 40 age- and gender-matched healthy individuals in a longitudinal, repeated measures design comprising a total of 211 samples. A composite biomarker was constructed using data-driven variable selection., Results: The composite biomarker discriminated between patients with BD and healthy control individuals with an area under the receiver operating characteristic curve (AUC) of 0.83 and a sensitivity of 73% and specificity of 71% corresponding with a moderately accurate test. Discrimination between manic and depressive states had a moderate accuracy, with an AUC of 0.82 and a sensitivity of 92% and a specificity of 40%., Conclusion: Combining individual biomarkers across tissues and molecular systems could be a promising avenue for research in biomarker models in BD., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Currently, the diagnosis in bipolar disorder relies on patient information and careful clinical evaluations and judgements with a lack of objective tests. Core clinical features of bipolar disorder include changes in behaviour. We aimed to investigate objective smartphone data reflecting behavioural activities to classify patients with bipolar disorder compared with healthy individuals., Methods: Objective smartphone data were automatically collected from 29 patients with bipolar disorder and 37 healthy individuals. Repeated measurements of objective smartphone data were performed during different affective states in patients with bipolar disorder over 12 weeks and compared with healthy individuals., Results: Overall, the sensitivity of objective smartphone data in patients with bipolar disorder versus healthy individuals was 0.92, specificity 0.39, positive predictive value 0.88 and negative predictive value 0.52. In euthymic patients versus healthy individuals, the sensitivity was 0.90, specificity 0.56, positive predictive value 0.85 and negative predictive value 0.67. In mixed models, automatically generated objective smartphone data (the number of text messages/day, the duration of phone calls/day) were increased in patients with bipolar disorder (during euthymia, depressive and manic or mixed states, and overall) compared with healthy individuals. The amount of time the smartphone screen was 'on' per day was decreased in patients with bipolar disorder (during euthymia, depressive state and overall) compared with healthy individuals., Conclusion: Objective smartphone data may represent a potential diagnostic behavioural marker in bipolar disorder and may be a candidate supplementary method to the diagnostic process in the future. Further studies including larger samples, first-degree relatives and patients with other psychiatric disorders are needed.

Background: Mood instability in bipolar disorder is associated with a risk of relapse. This study investigated differences in mood instability between patients with bipolar disorder type I and type II, which previously has been sparingly investigated., Methods: Patients with bipolar disorder type I (n = 53) and type II (n = 31) used a daily smartphone-based self-monitoring system for 9 months. Data in the present reflect 15.975 observations of daily collected smartphone-based data on patient-evaluated mood., Results: In models adjusted for age, gender, illness duration and psychopharmacological treatment, patients with bipolar disorder type II experienced more mood instability during depression compared with patients with bipolar disorder type I (B: 0.27, 95% CI 0.007; 0.53, p = 0.044), but lower intensity of manic symptoms. Patients with bipolar disorder type II did not experience lower mean mood or higher intensity of depressive symptoms compared with patients with bipolar disorder type I., Conclusions: Compared to bipolar disorder type I, patients with bipolar disorder type II had higher mood instability for depression. Clinically it is of importance to identify these inter-episodic symptoms. Future studies investigating the effect of treatment on mood instability measures are warranted. Trial registration NCT02221336.

Objective: Hair cortisol is a promising new biomarker of retrospective systemic cortisol concentration. In this study, we compared hair cortisol concentrations in patients with newly diagnosed bipolar disorder (BD), their unaffected first-degree relatives and healthy individuals and identified potential predictors of hair cortisol concentrations in patients with BD., Method: In a cross-sectional design, we compared hair cortisol concentrations in 181 patients with newly diagnosed/first episode BD, 42 of their unaffected first-degree relatives and 101 healthy age- and sex-matched individuals with no personal or first-degree family history of affective disorder. In patients with BD, we further investigated whether medication- and illness related variables, as well as measures of stressful life events in the preceding 12 months and childhood trauma, were associated with hair cortisol concentrations., Results: Hair cortisol concentrations were 35.1% (95%CI: 13.0-61.5) higher in patients with BD (P = 0.001) compared with healthy individuals in models adjusted for age and sex. Hair cortisol concentrations in unaffected first-degree relatives did not differ from healthy individuals (P = 0.8). In patients, neither medication, illness duration nor stress related variables were associated with hair cortisol concentrations., Conclusion: We found elevated hair cortisol concentrations in patients newly diagnosed with BD indicating the presence of physiological stress in early stages of BD., (Copyright © 2018 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.)

Background: Erythropoietin (EPO) has been suggested to improve metabolism and also cognition, but human studies are scarce. This randomised controlled trial aimed to investigate whether EPO treatment influences body composition and fat and glycated haemoglobin (HbA1c) and fasting glucose, and whether these changes would be associated with previous observed cognitive benefits of EPO., Method: In total, 84 non-obese patients with treatment-resistant unipolar depression or bipolar disorder in remission were randomised to 8 weekly EPO (40,000 IU) or saline (NaCl 0.9%) infusions in a double-blind, parallel-group design. Patients underwent dual X-ray absorptiometry scans at baseline and week 14 (6 weeks after treatment completion). Cognitive measures were assessed and fasting levels of cholesterol, lipoprotein fractions, triacylglycerides, glucose and HbA1c were obtained at baseline, week 9 and follow-up week 14., Results: In total, 79 patients had complete pre- and post-treatment data (EPO: N=40, saline: N=39). EPO had no cumulative effect on body composition and markers of fat metabolism. The EPO-treated group exhibited significantly lower HbA1c levels after 8 weeks treatment [F(1, 80)=8.51, p=0.005], however, 6 weeks after treatment termination a significantly higher fasting glucose levels [F(1, 79)=5.85, p=0.02] and HbA1c levels [F(1, 79)=5.85, p=0.02] were seen. The latter increase in HbA1c was further significantly correlated with a better cognitive outcome on verbal memory (r=0.25, p=0.03)., Conclusion: Repeated EPO infusions had no cumulative effect on body composition in this cohort of patients with affective disorders, however, EPO modulated HbA1c and fasting glucose and this was associated with patients' improvement of verbal memory.

Background: Bipolar disorder (BD) and unipolar disorder (UD) are associated with cognitive deficits and abnormal neural activity in a "cognitive control network." There is an increased prevalence of cognitive dysfunction in psychiatric patients' first-degree relatives, which constitutes a risk factor for psychiatric illness onset. However, there is no treatment with enduring pro-cognitive efficacy. We found preliminary evidence for beneficial effects of eight weekly doses of recombinant human erythropoietin (EPO) on cognition in BD in a recent randomized controlled trial (RCT). The present RCT consists of two sub-studies that extend our previous work by investigating important novel aspects: (1) the effects of 12 weekly doses of EPO on cognition in first-degree relatives of patients with BD, UD, or schizophrenia; and (2) the effects of extending the treatment schedule from 8 to 12 weeks in remitted patients with BD or UD; and (3) assessment of early treatment-associated neural activity changes that may predict cognitive improvement., Methods: The trial comprises two parallel sub-studies with randomized, controlled, double-blinded, parallel group designs. First-degree relatives (sub-study 1; n = 52) and partially or fully remitted patients with BD or UD (sub-study 2; n = 52) with objectively verified cognitive dysfunction are randomized to receive weekly high-dose EPO (40,000 IU/mL) or placebo (saline) infusions for 12 weeks. Assessments of cognition and mood are conducted at baseline, after two weeks of treatment, after treatment completion, and at six-month follow-up. Functional magnetic resonance imaging (fMRI) is conducted at baseline and after two weeks of treatment. Psychosocial function is assessed at baseline, after treatment completion and six-month follow-up. The primary outcome is change in a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference by including 52 first-degree relatives and 52 patients with BD or UD, respectively. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data are analyzed with the FMRIB Software Library., Discussion: If this trial reveals pro-cognitive effects of EPO, this may influence future treatment of mood disorders and/or preventive strategies in at-risk populations. The fMRI analyses may unravel key neurobiological targets for pro-cognitive treatment., Trial Registration: ClinicalTrials.gov , NCT03315897. Registered on 20 October 2017.

There is an increased interest among patients with bipolar disorder for using medical cannabis. The aim of this review was to elucidate, whether medical cannabis has a potential role in the treatment of bipolar disorder. Only one study with two case reports has been conducted. The two manic patients showed no improvement during the treatment but tolerated cannabis, and no side effects were reported. Overall, there is a lack of evidence for the use of cannabis in bipolar disorder. Future randomised clinical trials are warranted.

Background: Cognitive deficits are prevalent in bipolar disorder during remission but effective cognition treatments are lacking due to insufficient insight into the neurobiological targets of cognitive improvement. Emerging data suggest that dorsal prefrontal cortex target engagement is a key neurocircuitry biomarker of pro-cognitive treatment effects., Aims: In this randomized controlled functional magnetic resonance imaging study, we test this hypothesis by investigating the effects of an ineffective cognitive remediation intervention on dorsal prefrontal response during strategic memory encoding and working memory engagement., Methods: Bipolar disorder patients in partial remission with subjective cognitive difficulties were randomized to receive 12-week group-based cognitive remediation ( n = 13) or to continue their standard treatment ( n = 14). The patients performed a strategic episodic picture encoding task and a spatial n-back working memory task under functional magnetic resonance imaging at baseline and following cognitive remediation or standard treatment., Results: The right dorsolateral prefrontal cortex was commonly activated by both strategic memory tasks across all patients. The task-related prefrontal engagement was not altered by cognitive remediation relative to standard treatment. The dorsolateral prefrontal cortex response was not significantly associated with recall accuracy or working memory performance., Conclusions: As hypothesized, no task-related change in prefrontal activity was observed in a negative cognitive remediation trial in remitted bipolar disorder patients. By complementing previous findings linking cognitive improvement with increased dorsolateral prefrontal cortex engagement, our negative findings provide additional validity evidence to the dorsal prefrontal target engagement biomarker model of cognitive improvement by strengthening the proposed causality between modulation of dorsolateral prefrontal cortex engagement and pro-cognitive effects.

Background: S100B is a calcium-binding protein located in glial cells; it is regarded as a potential biomarker in affective disorders., Aim: To review the literature investigating the role of S100B in patients with affective disorders., Method: A systematic review of original English language studies investigating S100B in serum, cerebrospinal fluid, plasma and lymphocytes, in patients with affective disorders, was conducted. The literature search was conducted within the PubMed database. Effect sizes were calculated to adjust for systematic measurement effects., Results: Twenty studies were included, with a total of 1292 participants. Of these, 398 patients had or have had depressive disorder, 301 patients had bipolar disorder and 593 were healthy controls. S100B levels in serum were consistently elevated in studies with statistically significant results which investigated acute affective episodes (comprising major depressive episode in major depressive disorder, and both manic and depressive episodes in patients with bipolar disorder), in comparison to healthy controls. There were few studies assessing S100B levels in cerebrospinal fluid, plasma or lymphocytes, and these had inconsistent results., Conclusion: The results indicated that elevated S100B levels might be associated with mood episodes in affective disorders. However, the role of S100B, and its possible impact in affective disorders, requires further investigation and at the present S100B does not have a role as clinically biomarker in affective disorder. Future longitudinal multicentre studies with larger transdiagnostic real life patient cohorts are warranted.

Background: Cognitive impairment is present in bipolar disorder (BD) during the acute and remitted phases and hampers functional recovery. However, there is currently no clinically available treatment with direct and lasting effects on cognitive impairment in BD. We will examine the effect of a novel form of cognitive remediation, action-based cognitive remediation (ABCR), on cognitive impairment in patients with BD, and explore the neural substrates of potential treatment efficacy on cognition., Methods/design: The trial has a randomized, controlled, parallel-group design. In total, 58 patients with BD in full or partial remission aged 18-55 years with objective cognitive impairment will be recruited. Participants are randomized to 10 weeks of ABCR or a control group. Assessments encompassing neuropsychological testing and mood ratings, and questionnaires on subjective cognitive complaints, psychosocial functioning, and quality of life are carried out at baseline, after 2 weeks of treatment, after the end of treatment, and at a six-month-follow-up after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and 2 weeks into treatment. The primary outcome is a cognitive composite score spanning verbal memory, attention, and executive function. Two complete data sets for 52 patients will provide a power of 80% to detect a clinically relevant between-group difference on the primary outcome. Behavioral data will be analyzed using mixed models in SPSS while MRI data will be analyzed with the FMRIB Expert Analysis Tool (FEAT). Early treatment-related changes in neural activity from baseline to week 2 will be investigated for the dorsal prefrontal cortex and hippocampus as the regions of interest and with an exploratory whole-brain analysis., Discussion: The results will provide insight into whether ABCR has beneficial effects on cognition and functioning in remitted patients with BD. The results will also provide insight into early changes in neural activity associated with improvement of cognition, which can aid future treatment development., Trial Registration: Clinicaltrials.gov , NCT03295305 . Registered on 26 September 2017.

Background: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking., Methods: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data., Results: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values., Conclusions: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

Background: Affective disorders have a long-term impact on psychiatric health and are caused by multiple interacting factors including familial risk, childhood adversity, life events and personality traits. Methods: In this study, monozygotic twins (MZ) at familial risk (indexed by affective disorder in their co-twin; high-risk group), affected MZ twins (indexed by a diagnosis with affective disorder) and MZ twins with no family history of affective disorder (low-risk group) were identified through cross-linking of nation-wide Danish registers. In total, 204 MZ twins were included and psychopathology, personality traits and life adversity were evaluated by semi-structured interviews and questionnaires. Results: Affected MZ twins presented with more subclinical affective symptoms and were functionally impaired as evidenced by higher unemployment rates and reduced functional status. The affected and the high-risk groups reported more childhood adversity and had experienced more stressful life events than the low-risk group. A direct comparison within the discordant twin pairs showed that the high-risk twins presented fewer affective symptoms, better functional status, more extraversion and lower neuroticism scores than their affected co-twins although they had equal levels of life adversity as their affected co-twins. Conclusion: These findings add to the evidence indicating that patients experience higher neuroticism, persistent subclinical symptoms and reduced socio-occupational function after affective episodes. Additionally, neuroticism and extraversion seem capable of moderating the sensitivity to exposure from the environment.

Background: Abnormalities in affective cognition are putative endophenotypes for bipolar and unipolar disorders but it is unclear whether some abnormalities are disorder-specific. We therefore investigated affective cognition in monozygotic twins at familial risk of bipolar disorder relative to those at risk of unipolar disorder and to low-risk twins., Methods: Seventy monozygotic twins with a co-twin history of bipolar disorder (n = 11), of unipolar disorder (n = 38) or without co-twin history of affective disorder (n = 21) were included. Variables of interest were recognition of and vigilance to emotional faces, emotional reactivity and -regulation in social scenarios and non-affective cognition., Results: Twins at familial risk of bipolar disorder showed increased recognition of low to moderate intensity of happy facial expressions relative to both unipolar disorder high-risk twins and low-risk twins. Bipolar disorder high-risk twins also displayed supraliminal attentional avoidance of happy faces compared with unipolar disorder high-risk twins and greater emotional reactivity in positive and neutral social scenarios and less reactivity in negative social scenarios than low-risk twins. In contrast with our hypothesis, there was no negative bias in unipolar disorder high-risk twins. There were no differences between the groups in demographic characteristics or non-affective cognition., Limitations: The modest sample size limited the statistical power of the study., Conclusions: Increased sensitivity and reactivity to positive social stimuli may be a neurocognitive endophenotype that is specific for bipolar disorder. If replicated in larger samples, this 'positive endophenotype' could potentially aid future diagnostic differentiation between unipolar and bipolar disorder., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, but its use is impeded by its cognitive side effects. Novel treatments that can counteract these side effects may therefore improve current treatment strategies for depression. The present randomized trial investigates (1) whether short-term add-on treatment with erythropoietin (EPO) can reduce the cognitive side -effects of ECT and (2) whether such effects are long-lasting. Further, structural and functional magnetic resonance imaging (MRI) will be used to explore the neural underpinnings of such beneficial effects of EPO. Finally, the trial examines whether potential protective effects of EPO on cognition are accompanied by changes in markers of oxidative stress, inflammation, and neuroplasticity., Methods/design: The trial has a double-blind, randomized, placebo-controlled, parallel group design. Patients with unipolar or bipolar disorder with current moderate to severe depression referred to ECT (N = 52) are randomized to receive four high-dose infusions of EPO (40,000 IU/ml) or placebo (saline). The first EPO/saline infusion is administered within 24 h before the first ECT. The following three infusions are administered at weekly intervals immediately after ECT sessions 1, 4, and 7. Cognition assessments are conducted at baseline, after the final EPO/saline infusion (3 days after eight ECT sessions), and at a 3 months follow-up after ECT treatment completion. The neuronal substrates for potential cognitive benefits of EPO are investigated with structural and functional MRI after the final EPO/saline infusion. The primary outcome is change from baseline to after EPO treatment (3 days after eight ECT sessions) in a cognitive composite score spanning attention, psychomotor speed, and executive functions. With a sample size of N = 52 (n = 26 per group), we have ≥ 80% power to detect a clinically relevant between-group difference in the primary outcome measure at an alpha level of 5% (two-sided test). Behavioral, mood, and blood-biomarker data will be analyzed using repeated measures analysis of covariance. Functional MRI data will be preprocessed and analyzed using the FMRIB Software Library., Discussion: If EPO is found to reduce the cognitive side effects of ECT, this could have important implications for future treatment strategies for depression and for the scientific understanding of the neurobiological etiology of cognitive dysfunction in patients treated with ECT., Trial Registration: ClinicalTrials.gov, NCT03339596 . Registered on 10 November 2017.

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.)

Low-grade inflammation has been found in patients with bipolar disorder (BD), but rarely assessed using leukocyte counts and findings are limited by lack of control for confounding factors. As a result, it is unclear whether BD per se is associated with peripheral inflammation. We pooled populations from two studies using similar longitudinal designs, including 300 blood samples from a total of 97 patients with BD and 133 blood samples from a total of 72 healthy control individuals (HC). Total leukocyte and neutrophil counts were measured together with interleukin (IL) - 6, IL-8, IL-18, tumor necrosis factor (TNF) - α and high sensitivity C-reactive protein (hsCRP). Adjusted for confounders, leukocyte counts were 23% higher and neutrophil counts were 30% higher in patients with BD compared with HC. There were no state-related differences in leukocyte or neutrophil counts. Lithium use, cigarette smoking as well as levels of IL-6, TNF-α and hsCRP were positively associated with leukocyte and neutrophil counts. Due to confounding issues it cannot be concluded that differences were related to bipolar disorder per se. Future studies are recommended to include leukocytes as markers of low-grade inflammation and to include relevant confounders in statistical analyses., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: For the first time to estimate the risk of recurrence among patients with a single manic/mixed episode by systematically reviewing prior studies on cohorts of adults, and cohorts of children and adolescents, respectively., Methods: A systematic literature search up to August 2017 was carried out including studies in which < 25% of the participants were estimated to have had a mood episode that required pharmacological treatment prior to the index manic or mixed episode at inclusion., Results: Three studies including a total of 293 adult patients with a single manic or mixed episode and three studies of children and adolescents including 126 patients were identified. In the adult studies, 31%, 40% and 42% experienced recurrence after recovery within 1 year, 59% after 2 years, and 58% after 4 years, respectively. In the studies on children and adolescents, 40% and 52% experienced recurrence after recovery within 1 year, 30% and 60% after 2 years and 64% and 67% after 4 to 5 years, respectively. Results from meta-analyses showed a 1-year rate of recurrence of 35% (95% confidence interval [CI]: 30-41%) in adults, and in adolescents/children, a 1-year rate of recurrence of 48% (95% CI: 38-58%), a 2-year rate of 46% (95% CI: 33-60%) and a 4-5-year rate of recurrence of 65% (95% CI: 52-77%; as data from different studies were included at 1, 2 and 5 years, rates of recurrence did not increase steadily with time)., Conclusions: The rate of recurrence is high among adults as well as children and adolescents. It is important that clinicians and patients as well as relatives are well informed about these high risks when deciding to start maintenance treatment or not following onset of a single manic or mixed episode., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with psychiatric disorders have a greater risk of mortality than the general population. Use or abuse of substances, including alcohol, play a crucial part in this context. Moreover, it is well known that drug use can worsen psychopathology and reduce treatment compliance. However, the magnitude of these problems among Danish psychiatric patients has not been studied previously., Aims: The aim of this study is to investigate substance use among psychiatric patients in the Capital Region of Denmark., Methods: Outpatients from five psychiatric units were asked to complete a questionnaire regarding their use of alcohol and other drugs of abuse. The questionnaire was based on the Alcohol Use Disorder Identification Test (AUDIT), supplemented by questions regarding use of tobacco and illicit drugs. The results were compared with those uses in the general population., Results: In total, 412 psychiatric patients participated in the study, and 33% had an AUDIT-score ≥8, indicating problematic alcohol use according to the AUDIT guidelines. The mean weekly alcohol intake was 9.7 ± 28.3 standard drinks, and 47% were current smokers with a mean daily use of 19.9 ± 13.8 cigarette equivalents. Compared to the general population, the psychiatric patients had higher odds of being current smokers and having used illicit drugs within the past month. Women with psychiatric disorders were twice as likely to binge drink on a monthly basis. No significant difference was found in the patients' AUDIT scores compared to the general population., Conclusions: Our findings demonstrate a substantial and problematic use of tobacco and illicit drugs among Danish psychiatric patients, greater than in the general population.

Background: Negative cognitive bias and aberrant neural processing of self-referent emotional words seem to be trait-marks of depression. However, it is unclear whether these neurocognitive changes are present in unaffected first-degree relatives and constitute an illness endophenotype., Methods: Fifty-three healthy, never-depressed monozygotic or dizygotic twins with a co-twin history of depression (high-risk group: n = 26) or no first-degree family history of depression (low-risk group: n = 27) underwent neurocognitive testing and functional magnetic imaging (fMRI) as part of a follow-up cohort study. Participants performed a self-referent emotional word categorisation task and free word recall task followed by a recognition task during fMRI. Participants also completed questionnaires assessing mood, personality traits and coping strategies., Results: High-risk and low-risk twins (age, mean ± SD: 40 ± 11) were well-balanced for demographic variables, mood, coping and neuroticism. High-risk twins showed lower accuracy during self-referent categorisation of emotional words independent of valence and more false recollections of negative words than low-risk twins during free recall. Functional MRI yielded no differences between high-risk and low-risk twins in retrieval-specific neural activity for positive or negative words or during the recognition of negative versus positive words within the hippocampus or prefrontal cortex., Conclusions: The subtle display of negative recall bias is consistent with the hypothesis that self-referent negative memory bias is an endophenotype for depression. High-risk twins' lower categorisation accuracy adds to the evidence for valence-independent cognitive deficits in individuals at familial risk for depression., (Copyright © 2017 Elsevier B.V. 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.

Background: Information on the association between bipolar disorder (BD), sexual satisfaction, sexual function, sexual distress and quality of life (QoL) is sparse. This study aims, in women with BD, to (i) investigate sexual dysfunction, sexual distress, general sexual satisfaction and QoL; (ii) explore whether sexual distress was related to affective symptoms and (iii) investigate whether QoL was associated with sexual distress. The study is a questionnaire survey in an outpatient cohort of women with BD using: Changes in Sexual Functioning Questionnaire, Female Sexual Distress Scale, Altman Self-Rating Mania Scale (ASRM), Major Depression Inventory (MDI) and The World Health Organisation Quality of Life-Brief., Results: In total, 61 women (age range 19-63, mean 33.7 years) were recruited. Overall, 54% reported sexual distress (n = 33) and 39% were not satisfied with their sexual life (n = 24). Women with BD were significantly more sexually distressed in comparison with Danish women from the background population but they did not have a higher prevalence of impaired sexual function. Better sexual function was positively associated with ASRM scores while MDI scores were associated with more distress. Finally, the group of non-sexually distressed women with BD reported higher QoL scores compared with the sexually distressed group., Conclusions: Women with BD exhibited a high prevalence of sexual distress and their sexual function seemed associated with their actual mood symptoms and perception of QoL.

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.)

The brain-derive neurotrophic factor (BDNF) may play an important role in the course of depression. We aimed to study the associations between peripheral whole blood BDNF levels in healthy individuals with and without a family history of depression. BDNF levels were significantly increased in healthy individuals with (n = 76), compared with healthy individuals without (n = 39) a family history of depression and persisted after adjustment for age and gender differences. Higher BDNF levels were associated with increasing age and seasonality. A family history of depression may contribute to an elevation of peripheral BDNF levels in healthy individuals., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Negative bias and aberrant neural processing of emotional faces are trait-marks of depression but findings in healthy high-risk groups are conflicting., Methods: Healthy middle-aged dizygotic twins (N = 42) underwent functional magnetic resonance imaging (fMRI): 22 twins had a co-twin history of depression (high-risk) and 20 were without co-twin history of depression (low-risk). During fMRI, participants viewed fearful and happy faces while performing a gender discrimination task. After the scan, they were given a faces dot-probe task, a facial expression recognition task and questionnaires assessing mood, personality traits and coping., Results: Unexpectedly, high-risk twins showed reduced fear vigilance and lower recognition of fear and happiness relative to low-risk twins. During face processing in the scanner, high-risk twins displayed distinct negative functional coupling between the amygdala and ventral prefrontal cortex and pregenual anterior cingulate. This was accompanied by greater fear-specific fronto-temporal response and reduced fronto-occipital response to all emotional faces relative to baseline. The risk groups showed no differences in mood, subjective state or coping., Conclusions: Less susceptibility to fearful faces and negative cortico-limbic coupling during emotional face processing may reflect neurocognitive compensatory mechanisms in middle-aged dizygotic twins who remain healthy despite their familial risk of depression.

Background: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups., Aims: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking., Methods: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data., Results and Conclusions: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Introduction: Bipolar disorder is an often disabling mental illness with a lifetime prevalence of 1%-2%, a high risk of recurrence of manic and depressive episodes, a lifelong elevated risk of suicide and a substantial heritability. The course of illness is frequently characterised by progressive shortening of interepisode intervals with each recurrence and increasing cognitive dysfunction in a subset of individuals with this condition. Clinically, diagnostic boundaries between bipolar disorder and other psychiatric disorders such as unipolar depression are unclear although pharmacological and psychological treatment strategies differ substantially. Patients with bipolar disorder are often misdiagnosed and the mean delay between onset and diagnosis is 5-10 years. Although the risk of relapse of depression and mania is high it is for most patients impossible to predict and consequently prevent upcoming episodes in an individual tailored way. The identification of objective biomarkers can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Accurate diagnosis of bipolar disorder in its early stages could help prevent the long-term detrimental effects of the illness.The present Bipolar Illness Onset study aims to identify (1) a composite blood-based biomarker, (2) a composite electronic smartphone-based biomarker and (3) a neurocognitive and neuroimaging-based signature for bipolar disorder., Methods and Analysis: The study will include 300 patients with newly diagnosed/first-episode bipolar disorder, 200 of their healthy siblings or offspring and 100 healthy individuals without a family history of affective disorder. All participants will be followed longitudinally with repeated blood samples and other biological tissues, self-monitored and automatically generated smartphone data, neuropsychological tests and a subset of the cohort with neuroimaging during a 5 to 10-year study period., Ethics and Dissemination: The study has been approved by the Local Ethical Committee (H-7-2014-007) and the data agency, Capital Region of Copenhagen (RHP-2015-023), and the findings will be widely disseminated at international conferences and meetings including conferences for the International Society for Bipolar Disorders and the World Federation of Societies for Biological Psychiatry and in scientific peer-reviewed papers., Trial Registration Number: NCT02888262., Competing Interests: Competing interests: LVK has within the preceding three years been a consultant for Lundbeck, AstraZeneca and Sunovion. KWM has received consultancy fees in the past three years from Lundbeck and Allergan. MFJ has been a consultant for Eli-Lilly and Lundbeck. MV has within the preceding three years been a consultant for AstraZeneca and Servier. FK has been a speaker for Ache, Daiichi Sankyoand Janssen. MP is a consultant for Roche Pharmaceuticals. RSM: Advisory boards: Lundbeck, Pfizer, AstraZeneca, Eli-Lilly, Janssen, Ortho Purdue, Johnson & Johnson, Moksha8, Sunovion, Mitsubishi, Takeda, Forest, Otsuka, Bristol-Myers Squibb, Shire. Speaker fees: Lundbeck, Pfizer, AstraZeneca, Eli-Lilly, Janssen Ortho, Purdue, Johnson & Johnson, Moksha8, Sunovion, Mitsubishi, Takeda, Forest, Otsuka, Bristol-Myers Squibb, Shire. Research grants: Lundbeck, Janssen Ortho, Shire, Purdue, AstraZeneca, Pfizer, Otsuka, Allergan. HEP has received a research grant from Boehringer Ingelheim. GMK has received honoraria as Field Editor of the International Journal of Neuropsychopharmacology and as scientific advisor for H Lundbeck A/S. JB and MF are co-founders and shareholders in Monsenso. LBN, RFS and WFG declare no competing interests. The validity of the research cannot be influenced by any of these potential secondary interests (such as financial gain or personal relationship)., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder (BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain. The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD., Methods: Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory test outside the scanner., Results: During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dlPFC) (P=.016). Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dlPFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI. Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes (P≤.006), with deficits being most pronounced in Val homozygotes., Conclusions: The association between Val allelic load, dlPFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Many patients with bipolar disorder (BD) experience debilitating cognitive deficits, with risk of impaired occupational and psychosocial functioning. However, knowledge of how these deficits impact the patients' ability to perform Activities of Daily Living (ADL), tasks related to self-care and domestic life is limited. We explored the relation between impaired cognitive function and the ability to perform ADL in patients with BD. A total of 42 outpatients (mean age 36 years (range 19.0-58.0 years), 69% women) with BD in remission and with subjective cognitive complaints (≥ 13 on the Cognitive Complaints in Bipolar Disorder Rating Assessment questionnaire (COBRA)) were included. Objective neurocognitive function was evaluated with a short comprehensive cognitive test battery and ADL ability was evaluated with the performance-based Assessment of Motor and Process Skills (AMPS) in the homes of the patients. Our findings indicate that low processing speed correlated with decreased ADL ability, and processing speed as measured by the cognitive test battery thus seems to be significantly related to patients' ability to live independently in the community. Overall, adding a performance based test to assess ADL ability in patients with BD home-surroundings seems to provide new insights regarding the effect of cognitive impairment in patients with BD., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

The phenomenology and underlying pathophysiology of bipolar disorder (BD) are heterogeneous. The identification of putative endophenotypes for BD can aid in the investigation of unique patho-etiological pathways, which may lead to the development of personalised preventative and therapeutic approaches for this multi-faceted disorder. We included original studies involving unaffected first-degree relatives of BD patients (URs) and a healthy control (HC) comparison group with no first-degree family history of mental disorders, investigating: 'cold' and 'hot' cognition and functional and structural neuroimaging. Seventy-seven cross-sectional studies met the inclusion criteria. The present review revealed that URs in comparison with HCs showed: (i) widespread deficits in verbal memory, sustained attention, and executive function; (ii) abnormalities in the reactivity to and regulation of emotional information along with aberrant reward processing, and heightened attentional interference by emotional stimuli; and (iii) less consistency in the findings regarding structural and resting state neuroimaging, and electrophysiological measures., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aim: In a naturalistic clinical study of patients in the early stages of bipolar disorders the aim was to assess differences between patients with bipolar I (BD I) and bipolar II (BD II) disorders on clinical characteristics including affective symptoms, subjective cognitive complaints, functional level, the presence of comorbid personality disorders and coping strategies., Methods: Diagnoses were confirmed using the Structured Clinical Interview for DSM-IV Disorders. Clinical symptoms were rated with the Young Mania Rating Scale and the Hamilton Depression Rating Scale, and functional status using the Functional Assessment Short Test. Cognitive complaints were assessed using the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, the presence of comorbid personality disorders using the Standardized Assessment of Personality - Abbreviated Scale and coping style using the Coping Inventory for Stressful Situations., Results: In total, 344 patients were included (BD I (n=163) and BD II (n=181). Patients with BD II presented with significantly more depressive symptoms, more cognitive complaints, lower overall functioning, and a higher prevalence of comorbid personality disorders. Finally, they exhibited a trend towards using less adaptive coping styles., Limitation: It cannot be omitted that some patients may have progressed from BD II to BD I. Most measures were based on patient self report., Conclusions: Overall, BD II was associated with a higher disease burden. Clinically, it is important to differentiate BD II from BD I and research wise, there is a need for tailoring and testing specific interventions towards BD II., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder., Methods: In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy., Results: Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohen's d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohen's d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality., Limitations: Small sample size, open-label design, lack of a placebo group., Conclusions: Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Personalized medicine is a model in which a patient's unique clinical, genetic, and environmental characteristics are the basis for treatment and prevention. Aim, method, and results: This review aims to describe the current tools, phenomenological features, clinical risk factors, and biomarkers used to provide personalized medicine. Furthermore, this study describes the target areas in which they can be applied including diagnostics, treatment selection and response, assessment of risk of side-effects, and prevention., Discussion and Conclusion: Personalized medicine in psychiatry is challenged by the current taxonomy, where the diagnostic categories are broad and great biological heterogeneity exists within each category. There is, thus, a gap between the current advanced research prospects and clinical practice, and the current taxonomy is, thus, a poor basis for biological research. The discussion proposes possible solutions to narrow this gap and to move psychiatric research forward towards personalized medicine.

Objective: There is no established efficacious treatment for cognitive dysfunction in unipolar and bipolar disorder. This may be partially due to lack of consensus regarding the need to screen for cognitive impairment in cognition trials or which screening criteria to use. We have demonstrated in 2 randomized placebo-controlled trials that 8 weeks of erythropoietin (EPO) treatment has beneficial effects on verbal memory across unipolar and bipolar disorder, with 58% of EPO-treated patients displaying a clinically relevant memory improvement as compared to 15% of those treated with placebo., Methods: We reassessed the data from our 2 EPO trials conducted between September 2009 and October 2012 to determine whether objective performance-based memory impairment or subjective self-rated cognitive impairment at baseline was related to the effect of EPO on cognitive function as assessed by Rey Auditory Verbal Learning Test (RAVLT) total recall with multiple logistic regression adjusted for diagnosis, age, gender, symptom severity, and education levels., Results: We included 79 patients with an ICD-10 diagnosis of unipolar or bipolar disorder, of whom 39 received EPO and 40 received placebo (saline). For EPO-treated patients with objective memory dysfunction at baseline (n = 16) (defined as RAVLT total recall ≤ 43), the odds of a clinically relevant memory improvement were increased by a factor of 290.6 (95% CI, 2.7-31,316.4; P = .02) compared to patients with no baseline impairment (n = 23). Subjective cognitive complaints (measured with the Cognitive and Physical Functioning Questionnaire) and longer illness duration were associated with small increases in patients' chances of treatment efficacy on memory (53% and 16% increase, respectively; P ≤ .04). Diagnosis, gender, age, baseline depression severity, and number of mood episodes did not significantly change the chances of EPO treatment success (P ≥ .06). In the placebo-treated group, the odds of memory improvement were not significantly different for patients with or without objectively defined memory dysfunction (P ≥ .59) or subjective complaints at baseline (P ≥ .06)., Conclusions: Baseline objectively assessed memory impairments and-to a lesser degree-subjective cognitive complaints increased the chances of treatment efficacy on cognition in unipolar and bipolar disorder., Trial Registration: ClinicalTrials.gov identifier: NCT00916552., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Smartphones are useful in symptom-monitoring in bipolar disorder (BD). Objective smartphone data reflecting illness activity could facilitate early treatment and act as outcome in efficacy trials. A total of 29 patients with BD presenting with moderate to severe levels of depressive and manic symptoms used a smartphone-based self-monitoring system during 12 weeks. Objective smartphone data on behavioral activities were collected. Symptoms were clinically assessed every second week using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. Objective smartphone data correlated with symptom severity. The more severe the depressive symptoms (1) the longer the smartphone's screen was "on"/day, (2) more received incoming calls/day, (3) fewer outgoing calls/day were made, (4) less answered incoming calls/day, (5) the patients moved less between cell towers IDs/day. Conversely, the more severe the manic symptoms (1) more outgoing text messages/day sent, (2) the phone calls/day were longer, (3) the fewer number of characters in incoming text messages/day, (4) the lower duration of outgoing calls/day, (5) the patients moved more between cell towers IDs/day. Further, objective smartphone data were able to discriminate between affective states. Objective smartphone data reflect illness severity, discriminates between affective states in BD and may facilitate the cooperation between patient and clinician. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information., Methods: A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data., Results: 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor., Conclusion: Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Background: Neurocognitive impairment in remitted patients with bipolar disorder contributes to functional disabilities. However, the pattern and impact of these deficits are unclear., Methods: We pooled data from 193 fully or partially remitted patients with bipolar disorder and 110 healthy controls. Hierarchical cluster analysis was conducted to determine whether there are discrete neurocognitive subgroups in bipolar disorder. The pattern of the cognitive deficits and the characteristics of patients in these neurocognitive subgroups were examined with analyses of covariance and least significance difference pairwise comparison., Results: Three discrete neurocognitive subgroups were detected: one that was cognitively intact (46.1%), one that was selectively impaired with deficits in processing speed (32.6%), and one that was globally impaired across verbal learning, working memory, and executive skills (21.2%). The globally and selectively impaired subgroups were characterized by greater perceived stress and subjective cognitive complaints, poorer work and social adjustment, and reduced quality of life compared to patients who were cognitively intact., Limitations: The study design was cross-sectional which limits inferences regarding the causality of the findings., Conclusion: Globally and selectively impaired bipolar disorder patients displayed more functional disabilities than those who were cognitively intact. The present findings highlight a clinical need to systematically screen for cognitive dysfunction in remitted bipolar disorder and to target residual cognitive dysfunction in future treatment strategies., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: The neurobiological mechanisms mediating an increased risk to develop affective disorders remain poorly understood. In a group of individuals with a family history of major depressive (MDD) or bipolar disorder (BD), we investigated the microstructural properties of white matter fiber tracts, that is, cingulum bundle, uncinate fasciculus, anterior limb of the internal capsule, and corpus callosum, that facilitate the communication between brain regions implicated in affective disorders., Method: Eighty-nine healthy mono- or dizygotic twins with a co-twin diagnosed with MDD or BD (high-risk) and 57 healthy twins with a co-twin with no familial history of affective disorders (low-risk) were included in a diffusion tensor imaging study., Result: The high-risk group showed decreased fractional anisotropy (FA), a measure of water diffusion directionality, and increased radial diffusivity in the anterior region of corpus callosum compared to the low-risk group. This abnormality was not associated with zygosity or type of depressive disorder of co-twin., Conclusion: The observed decreased anterior callosal fiber FA in the high-risk group may be indicative of a compromised interhemispheric communication between left and right frontal regions critically involved in mood regulation. Reduced anterior callosal FA may act as a vulnerability marker for affective disorders in individuals at familial risk., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study investigated a high-risk sample in order to elucidate risk factors for affective disorder. Healthy monozygotic (MZ) and dizygotic (DZ) twins with and without a co-twin with a history of affective disorder were identified through nationwide registers. Two risk groups were identified: the high-risk group comprised twins at risk of developing affective disorder (DZ or MZ twin; index co-twin affected); the low risk group (control group) comprised twins at low risk of developing affective disorder (DZ or MZ twin; index co-twin not affected). At baseline 234 participants were divided into groups according to their risk for affective disorder; they were followed up at 6-month intervals with posted questionnaires assessing depression. After a mean follow-up period of 7 years, the participants were invited to participate in an individual interview. A total of 36 participants (31 high-risk twins and 5 low-risk twins) developed a psychiatric disorder during the 7-year follow-up period: 24 developed mood disorder (67%), 7 anxiety disorder (19%) and 5 (14%) substance abuse, schizophrenia or personality disorder.   The results showed that familial risk, impaired stress tolerance and discrete cognitive dysfunction seem to be core predictors of affective illness. It is possible to identify a cluster of prodromal symptoms encompassing subclinical anxiety and depressive symptoms, higher neuroticism and cognitive problems. The cognitive problems may further be related to the cross-sectional finding that high-risk twins had lower hippocampal volumes. Further, 2 genetic polymorphisms: the 5-HTTLPR and the brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms were not directly associated with familial risk for affective disorder and did not predict illness onset. Similarly, salivary cortisol levels and whole-blood BDNF levels did not predict subsequent illness. The more complex 2-way interactions between 5-HTTLPR and life events suggested that high-risk individuals and individuals carrying the short s allele are exposed to more stressors and that this seems to contribute to an overall enhanced risk and thus accelerate the onset of illness. Low-risk individuals seem to experience fewer life events and may exhibit resilience to their adverse psychological effects. Overall, having a 1st-degree relative with affective disorder matters. This thesis demonstrates that high-risk studies are informative, allowing observation and investigation of the pathological processes that occur prior to the onset of illness. There is a lack of prospective intervention studies assessing psychopathology in well-defined, high-risk samples and it is obvious that future research must transcend diagnostic boundaries in order to have an impact on prevention. Furthermore, there is a need to move beyond the notion of ''magic bullets'', instead developing an integrated paradigm encompassing clusters of biomarkers related to behavioural measures of developmental psychopathology. Finally, as most psychiatric treatment developed to date target end-state disorders, the identification of high-risk individuals and mapping of individual risk profiles should be a priority in order to facilitate early treatment and prevention.

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.)

Background: Cognitive dysfunction is common in major depressive disorder (MDD) and a critical determinant of health outcome. Anhedonia is a criterion item toward the diagnosis of a major depressive episode (MDE) and a well-characterized domain in MDD. We sought to determine the extent to which variability in self-reported cognitive function correlates with anhedonia., Method: A post hoc analysis was conducted using data from (N=369) participants with a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR)-defined diagnosis of MDD who were enrolled in the International Mood Disorders Collaborative Project (IMDCP) between January 2008 and July 2013. The IMDCP is a collaborative research platform at the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Canada, and the Cleveland Clinic, Cleveland, Ohio. Measures of cognitive function, anhedonia, and depression severity were analyzed using linear regression equations., Results: A total of 369 adults with DSM-IV-TR-defined MDD were included in this analysis. Self-rated cognitive impairment [ie, as measured by the Adult ADHD Self-Report Scale (ASRS)] was significantly correlated with a proxy measure of anhedonia (r=0.131, p=0.012). Moreover, total depression symptom severity, as measured by the total Montgomery-Åsberg Depression Rating Scale (MADRS) score, was also significantly correlated with self-rated measures of cognitive dysfunction (r=0.147, p=0.005). The association between anhedonia and self-rated cognitive dysfunction remained significant after adjusting for illness severity (r=0.162, p=0.007)., Conclusions: These preliminary results provide empirical data for the testable hypothesis that anhedonia and self-reported cognitive function in MDD are correlated yet dissociable domains. The foregoing observation supports the hypothesis of overlapping yet discrete neurobiological substrates for these domains.

Objective: Erythropoietin (EPO) improves verbal memory and reverses subfield hippocampal volume loss across depression and bipolar disorder (BD). This study aimed to investigate with functional magnetic resonance imaging (fMRI) whether these effects were accompanied by functional changes in memory-relevant neuro-circuits in this cohort., Method: Eighty-four patients with treatment-resistant unipolar depression who were moderately depressed or BD in remission were randomized to eight weekly EPO (40 000 IU) or saline infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings, and blood tests at baseline and week 14. During fMRI, participants performed a picture encoding task followed by postscan recall., Results: Sixty-two patients had complete data (EPO: N = 32, saline: N = 30). EPO improved picture recall and increased encoding-related activity in dorsolateral prefrontal cortex (dlPFC) and temporo-parietal regions, but not in hippocampus. Recall correlated with activity in the identified dlPFC and temporo-parietal regions at baseline, and change in recall correlated with activity change in these regions from baseline to follow-up across the entire cohort. The effects of EPO were not correlated with change in mood, red blood cells, blood pressure, or medication., Conclusion: The findings highlight enhanced encoding-related dlPFC and temporo-parietal activity as key neuronal underpinnings of EPO-associated memory improvement., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The mechanisms underlying bipolar disorder (BD) and the associated medical burden are unclear. Damage generated by oxidation of nucleosides may be implicated in BD pathophysiology; however, evidence from in vivo studies is limited and the extent of state-related alterations is unclear. This prospective study investigated for we believe the first time the damage generated by oxidation of DNA and RNA strictly in patients with type I BD in a manic or mixed state and subsequent episodes and remission compared with healthy control subjects. Urinary excretion of 8-oxo-deoxyguanosine (8-oxodG) and 8-oxo-guanosine (8-oxoGuo), valid markers of whole-body DNA and RNA damage by oxidation, respectively, was measured in 54 patients with BD I and in 35 healthy control subjects using a modified ultraperformance liquid chromatography and mass spectrometry assay. Repeated measurements were evaluated in various affective phases during a 6- to 12-month period and compared with repeated measurements in healthy control subjects. Independent of lifestyle and demographic variables, a 34% (P<0.0001) increase in RNA damage by oxidation across all affective states, including euthymia, was found in patients with BD I compared with healthy control subjects. Increases in DNA and RNA oxidation of 18% (P<0.0001) and 8% (P=0.02), respectively, were found in manic/hypomanic states compared with euthymia, and levels of 8-oxodG decreased 15% (P<0.0001) from a manic or mixed episode to remission. The results indicate a role for DNA and RNA damage by oxidation in BD pathophysiology and a potential for urinary 8-oxodG and 8-oxoGuo to function as biological markers of diagnosis, state and treatment response in BD., Competing Interests: LVK has within the preceding 3 years been a consultant for Lundbeck and AstraZeneca. MV has within the preceding 3 years been a consultant for Servier, AstraZeneca and Lundbeck. The remaining authors declare no conflict of interest.

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.)