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Objectives: Cognitive impairment affects many patients with bipolar disorder (BD), and treatments with replicated pro-cognitive effects are lacking. This study aimed to assess the effect of Action-Based Cognitive Remediation (ABCR) vs control treatment on cognitive impairment in patients with BD., Methods: Patients with remitted BD with objective cognitive impairment were randomized to 10 weeks of ABCR vs control treatment, and assessed at baseline, after 2 weeks of treatment, at treatment completion and at 6 months follow-up. The primary outcome was a cognitive composite score. Secondary outcomes were executive function and observer-rated functional capacity. Tertiary measures included additional neuropsychological tests, performance-based functional capacity and quality of life. Data were analysed with linear mixed effects models., Results: In total, 64 participants were randomized; given three dropouts before the baseline assessments, data were analysed for 61 participants (ABCR: n = 32, control: n = 29). There was no effect on ABCR vs control on the primary cognitive composite score (P-values ≥.60). At treatment completion, there was a large effect of ABCR vs control on the secondary executive function measure (treatment effect= -0.16, 95% CI [-0.27, -0.05], P ≤ .01, d = 0.65), and on subjective cognitive functioning (treatment effect = -5.38, 95% CI [-8.13, -2.67], P ≤ .001, d = 0.80), which disappeared at follow-up. There was no treatment-effect on functioning, and no association between cognitive and functional change., Conclusions: There was no effect of ABCR on the cognitive composite score. However, there was an effect on executive function and subjective cognitive functioning suggesting that ABCR may be relevant for patients with executive dysfunction., Trial Registration: ClinicalTrials.gov identifier: NCT03295305., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We identified biologically relevant moderators of response to tumor necrosis factor (TNF)-α inhibitor, infliximab, among 60 individuals with bipolar depression. Data were derived from a 12-week, randomized, placebo-controlled clinical trial secondarily evaluating the efficacy of infliximab on a measure of anhedonia (i.e., Snaith-Hamilton Pleasure Scale). Three inflammatory biotypes were derived from peripheral cytokine measurements using an iterative, machine learning-based approach. Infliximab-randomized participants classified as biotype 3 exhibited lower baseline concentrations of pro- and anti-inflammatory cytokines and soluble TNF receptor-1 and reported greater pro-hedonic improvements, relative to those classified as biotype 1 or 2. Pretreatment biotypes also moderated changes in neuroinflammatory substrates relevant to infliximab's hypothesized mechanism of action. Neuronal origin-enriched extracellular vesicle (NEV) protein concentrations were reduced to two factors using principal axis factoring: phosphorylated nuclear factorκB (p-NFκB), Fas-associated death domain (p-FADD), and IκB kinase (p-IKKα/β) and TNF receptor-1 (TNFR1) comprised factor "NEV1," whereas phosphorylated insulin receptor substrate-1 (p-IRS1), p38 mitogen-activated protein kinase (p-p38), and c-Jun N-terminal kinase (p-JNK) constituted "NEV2". Among infliximab-randomized subjects classified as biotype 3, NEV1 scores were decreased at weeks 2 and 6 and increased at week 12, relative to baseline, and NEV2 scores increased over time. Decreases in NEV1 scores and increases in NEV2 scores were associated with greater reductions in anhedonic symptoms in our classification and regression tree model (r 2  = 0.22, RMSE = 0.08). Our findings provide preliminary evidence supporting the hypothesis that the pro-hedonic effects of infliximab require modulation of multiple TNF-α signaling pathways, including NF-κB, IRS1, and MAPK., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Background: Depressive episodes experienced in unipolar (UD) and bipolar (BD) disorders are characterized by anhedonia and have been associated with abnormalities in reward processes related to reward valuation and error prediction. It remains however unclear whether these deficits are associated with familial vulnerability to mood disorders., Methods: In a functional magnetic resonance imaging study, we evaluated differences in the expected value (EV) and reward prediction error (RPE) signals in ventral striatum (VS) and prefrontal cortex between three groups of monozygotic twins: affected twins in remission for either UD or BD (n = 53), their high-risk unaffected co-twins (n = 34), and low-risk twins with no family history of mood disorders (n = 25)., Results: Compared to low-risk twins, affected twins showed lower EV signal bilaterally in the frontal poles and lower RPE signal bilaterally in the VS, left frontal pole and superior frontal gyrus. The high-risk group did not show a significant change in the EV or RPE signals in frontostriatal regions, yet both reward signals were consistently lower compared with low-risk twins in all regions where the affected twins showed significant reductions., Conclusion: Our findings strengthen the notion that reduced valuation of expected rewards and reduced error-dependent reward learning may underpin core symptom of depression such as loss of interest in rewarding activities. The trend reduction in reward-related signals in unaffected co-twins warrants further investigation of this effect in larger samples and prospective follow-up to confirm possible association with increased familial vulnerability to mood disorders.

Post-partum psychosis (PPP) is a severe psychiatric emergency. The condition is rare and has generally not been an area of overwhelming research, and concordantly, early identification and treatment is a challenge. Research in the field suggests, that PPP often is a bipolar spectrum illness, and resent research has identified the most common symptoms. This review is an updated description of the phenotypical characteristics of the illness and treatment recommendations based on the newest research.

Introduction: Ketamine treatment is capable of significant and rapid symptom improvement in adults with treatment-resistant depression (TRD). A limitation of ketamine treatment in TRD is the relatively short duration of time to relapse (e.g., median 2-4 weeks). The objective of the systematic review herein is to identify strategies capable of prolonging the acute efficacy of ketamine in adults with TRD., Methods: PubMed/MEDLINE databases were searched from inception to December 2020 for clinical studies written in English using the following key terms: ketamine, prolong, and depression. A total of 454 articles were identified from the literature search which included all clinical studies regarding prolonging the antidepressant effects of ketamine. Twenty-two articles were included: ten randomized controlled trials (RCTs), eight prospective open-label trials, one retrospective chart review, and three case reports. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for data extraction. The primary outcome was prolonged effect, defined as statistically significant antidepressant effects following acute ketamine treatment., Results: A total of 454 articles were identified, and 22 articles were included. Different treatment modalites including pharmacological interventions, manualized-based psychotherapies, electroconvulsive therapy, transcranial magnetic stimulation, and intravenous monotherapy were examined to determine their impact on the prolongation of antidepressant effects following acute ketamine treatment. No treatment modality, other than repeat-dose IV ketamine, has demonstrated ability to significantly prolong the acute efficacy of IV ketamine in TRD., Conclusion: Hitherto, available open-label data and controlled trial data support repeat administration of IV ketamine as an effective strategy to prolong the efficacy of ketamine's antidepressant effects (although not the focus of the study herein, maintenance repeat-dose esketamine treatment is proven effective in esketamine responders). There is a need to identify multimodality strategies that are safe and capable of prolonging the efficacy of ketamine in adults with TRD.

Up to half of all patients with bipolar affective disorder (BP), develop a comorbid anxiety disorder during their lifetime. The consequences of comorbid anxiety in BP compared to BP without comorbid anxiety are serious, including more frequent and severe depressions and twice the risk of substance abuse and suicide attempts. In this review we argue, that due to the poorer prognosis of these conditions, it is important to diagnose comorbid anxiety when present, and to ensure proper treatment, which should be performed by a psychiatrist preferably specialised in affective disorders.

Background: Prior studies in bipolar disorders (BD) have suggested that oxidative stress and cellular ageing play a key role in the pathophysiology of BD. Nevertheless, oxidative stress has not been investigated in patients with newly diagnosed BD and in their unaffected first-degree relatives (UR), compared with healthy control individuals (HC)., Methods: We investigated the level of systemic oxidative damage to DNA and RNA measured by urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels, respectively, in 360 patients with newly diagnosed BD, 92 of their UR and 197 HC., Results: Independent of lifestyle and demographic variables, levels of both 8-oxoGuo and 8-oxodG was 17.1% (B = 1.171, 95%CI = 1.125-1.219, p < 0.001) and 21.2% (B = 1.212, 95%CI = 1.145-1.283, p < 0.001) higher, respectively, in patients with BD compared with HC and 13.3% (B = 1.133, 95%CI = 1.069-1.200, p < 0.001) and 26.6% (B = 1.266, 95%CI = 1.167-1.374, p < 0.001) higher, respectively, in UR compared with HC. Neither 8-oxoGuo nor 8-oxodG levels differed between patients with BD and UR. These findings were replicated in patients in full or partial remission and were consistent both in BD type I and II., Conclusion: Overall, the findings of higher oxidative stress in patients with newly diagnosed BD and their UR suggest that systemic nucleoside damage by oxidative stress is present prior to onset and in the early stages of BD thereby potentially representing trait markers of BD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: DSM-IV states that criterion A for diagnosing hypomania/mania is mood change. The revised DSM-5 now states that increased energy or activity must be present alongside mood changes to diagnose hypomania/mania, thus raising energy/activity to criterion A. We set out to investigate how the change in criterion A affects the diagnosis of hypomanic/manic visits in patients with a newly diagnosed bipolar disorder., Results: In this prospective cohort study, 373 patients were included (median age = 32; IQR, 27-40). Women constituted 66% (n = 245) of the cohort and 68% of the cohort (n = 253) met criteria for bipolar type II, the remaining patients were diagnosed bipolar type I. Median number of contributed visits was 2 per subject (IQR, 1-3) and median follow-up time was 3 years (IQR, 2-4). During follow-up, 127 patients had at least one visit with fulfilled DSM-IV criterion A. Applying DSM-5 criterion A reduced the number of patients experiencing a hypomanic/manic visit by 62% at baseline and by 50% during longitudinal follow-up, compared with DSM-IV criterion A. Fulfilling DSM-5 criterion A during follow-up was associated with higher modified young mania rating scale score (OR = 1.51, CL [1.34, 1.71], p < 0.0001) and increased number of visits contributed (OR = 1.86, CL [1.52, 2.29], p < 0.0001)., Conclusion: Applying the stricter DSM-5 criterion A in a cohort of newly diagnosed bipolar patients reduced the number of patients experiencing a hypomanic/manic visit substantially, and was associated with higher overall young mania rating scale scores, compared with DSM-IV criterion A. Consequently, fewer hypomanic/manic visits may be detected in newly diagnosed bipolar patients with applied DSM-5 criterion A, and the upcoming ICD-11, which may possibly result in longer diagnostic delay of BD as compared with the DSM-IV.

Objective: The aim was to map rates and cumulative incidences of psychiatric disorders during lifetime for siblings to patients with a diagnosis of bipolar disorder compared with the general population., Methods: Danish nationwide population-based longitudinal register linkage study including 13,923 unaffected siblings to 19,955 patients with bipolar disorder and 278,460 unaffected control individuals from the general population matched according to year of birth and sex. Follow-up covered 22 years from 1995 to 2017., Results: Rates of 'any psychiatric disorder' among siblings compared with control individuals were constantly around twofold increased throughout lifespan whereas there was a bimodal age distribution of hazard ratios of bipolar disorder, unipolar disorder and use of alcohol or psychoactive drugs with the highest hazard ratios up to age 20 and above 60 years of age. Cumulative incidences from age 15 years of any psychiatric disorder were 44.2% at age 80 years for siblings versus 27.6% for control individuals and the corresponding numbers for bipolar disorder was 8.7% for siblings compared with 1.6% for control individuals., Conclusion: Strategies to prevent onset of psychiatric illness in individuals with a first-generation family history of bipolar disorder should not be limited to adolescence and early adulthood but should be lifetime, likely with differentiated age-specific strategies., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The upcoming conversion of the ICD-11 will subdivide patients with bipolar disorder (BD) into BD type I (BD-I) and BD type II (BD-II). This study aimed to investigate whether cognitive impairments could aid as objective cognitive biomarkers for recently diagnosed BD subtypes by comparing cognitive profiles between BD subtypes, their unaffected relatives (UR), and healthy controls (HC)., Methods: The sample included 76 patients with BD-I, 149 patients with BD-II, 28 UR of patients with BD-I (UR-I), 50 UR of patients with BD-II (UR-II) and 168 HC from the Bipolar Illness Onset study, who were assessed with an extensive non-affective and affective cognitive test battery., Results: The results showed no significant differences in affective or non-affective cognition between BD-I and BD-II. Compared to HC, patients with BD-I (but not BD-II) showed worse performance in verbal fluency (p = .01) and were slower at recognising fearful faces (p = .045), while patients with BD-II (but not BD-I) displayed generally poorer recognition of facial expressions (p = .02). Only UR-I showed lower performance on verbal fluency (p = .049) and aberrant affective cognition (ps≤.047) compared to HC., Limitations: The potential confounding effects of medication were not explored., Conclusions: The lack of significant differences in cognitive profiles between recently diagnosed BD-I and BD-II suggests that neither affective nor non-affective cognition are indicative of BD subtype., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Patients with bipolar disorder may have increased risk of physical diseases due to genetic and environmental factors, but no study has systematically mapped all physical comorbidities in such subjects. The aim was to map rates of all physical diseases among patients and siblings to patients with bipolar disorder., Methods: We used Danish nation-wide population-based longitudinal register linkage to identify 19.955 patients with bipolar disorder, their 13.923 siblings and 20 sex, age and calendar matched control individuals from the general population. Follow-up was from 1995 to 2017., Results: Bipolar disorder was associated with increased rates of all physical disease categories compared with rates for control individuals, except for cancer. Further, bipolar disorder was associated with increased rates of separate disorders including ischemic heart disease, diabetes, dementia, hypertension, hypercholesterolemia and hyperlipidemia, hypothyroidism and infections. In contrast, siblings to patients with bipolar disorder who were unaffected by bipolar disorder had increased rates of certain disorders, only, comprising infectious and parasitic diseases, and diseases of the nervous system, digestive system and genitourinary system., Limitations: Underdetection of physical disorders is likely because data are not available for persons who do not seek help for their disorders., Conclusions: Bipolar disorder was associated with increased rates of all physical diseases categories, except cancer, and with separate disorders, likely involving inflammatory components in the pathogenesis. In contrast, unaffected siblings to patients with bipolar disorder had increased rates of certain disorders, only., (Copyright © 2020. Published by Elsevier B.V.)

Background: Dissociation is a treatment-emergent adverse event commonly associated with IV ketamine, often measured using the 23-item Clinician-Administered Dissociative States Scale (CADSS). The objective of this study was to develop a short form version of the CADSS for easier clinical use., Methods: Retrospective data of 260 patients with treatment-resistant depression (TRD) receiving IV ketamine were randomly divided into two datasets. The first dataset (n = 130) was leveraged to develop a brief 6-item version of the CADSS (CADSS-6) based on items most sensitive to ketamine-induced dissociation. The CADSS-6 questions were then applied to the second dataset (n = 130) and the Spearman's correlation between the full-length CADSS and the CADSS-6 were assessed., Results: The CADSS-6 was developed from questions 1, 2, 6, 7, 15, and 22 from the full length CADSS. There was a strong significant correlation between the CADSS-6 total score and the CADSS total score at infusions 1 (rs(106) = 0.92, p < 0.001), 2 (rs(100) = 0.91, p < 0.001), 3(rs(99) = 0.95, p < 0.001) and 4 (rs(102) = 0.94, p < 0.001)., Limitations: The CADSS-6 was developed using a retrospective data; therefore, the scale remains unvalidated in this population., Conclusions: The CADSS-6 presented herein was sensitive to dissociation experienced by patients receiving IV ketamine. Overall, the CADSS-6 was strongly correlated at each infusion with the full-length CADSS. While future studies should look to validate the CADSS-6 in a TRD sample, this scale offers clinicians a brief assessment that can be used to characterize symptoms of dissociation., (Copyright © 2020. Published by Elsevier B.V.)

Background: Recent evidence suggests that neurocognitive impairments in remitted patients with bipolar disorder (BD) are heterogeneous. Our study aims to replicate recent findings of neurocognitive subgroups, and further explore whether these are related to impairments in affective cognition, in a large sample of remitted patients recently diagnosed with BD and their unaffected relatives compared to healthy controls (HCs)., Methods: Hierarchal cluster analysis was conducted using neurocognitive data from remitted patients with BD (n = 158). Relatives of patients with BD (n = 52) were categorised into groups consistent with their affected relative's cluster assignment. The neurocognitive clusters of patients with BD and relatives, respectively, were compared with HCs (n = 110) in neurocognition and affective cognition (i.e. emotion processing and regulation)., Results: Three discrete neurocognitive clusters were identified in patients with BD: a globally impaired (23.4%), a selectively impaired (31.0%) and a cognitively intact cluster (45.6%). The neurocognitive subgroups differed in affective cognition, with patients categorised as globally impaired exhibited most impairments in facial expression recognition and emotion regulation in social scenarios. First-degree relatives of cognitively impaired patients displayed impaired facial expression recognition but no impairments in non-emotional cognition., Conclusions: In a clinical sample of remitted patients recently diagnosed with BD 54.4% had either global or selective cognitive impairment, replicating results of previous studies in patients with longer illness duration. The results suggest that patterns of neurocognition are associated with differential impairments in affective cognition. Aberrant affective cognition in relatives of patients categorised as neurocognitively impaired indicates an inherited risk for BD.

Objective: The Cortisol Awakening Response (CAR) measured as the transient increase in cortisol levels following morning awakening appears to be a distinct feature of the HPA axis. Patients with bipolar disorder (BD) experience daily stress, mood instability (MI) and studies have shown disrupted HPA-axis dynamics., Aims: to evaluate (1) patient-evaluated stress against the CAR, (2) associations between the CAR and mood symptoms, and (3) the effect of smartphone-based treatment on the CAR., Methods: Patients with BD (n = 67) were randomized to the use of daily smartphone-based monitoring (the intervention group) or to the control group for six months. Clinically rated symptoms according to the Hamilton Depression Rating Scale 17-items (HDRS), the Young Mania Rating Scale (YMRS), patient-evaluated perceived stress using Cohen's Perceived Stress Scale (PSS) and salivary awakening cortisol samples used for measuring the CAR were collected at baseline, after three and six months. In the intervention group, smartphone-based data on stress and MI were rated daily during the entire study period., Results: Smartphone-based patient-evaluated stress (B: 134.14, 95% CI: 1.35; 266.92, p = 0.048) and MI (B: 430.23, 95% CI: 52.41; 808.04, p = 0.026) mapped onto increased CAR. No statistically significant associations between the CAR and patient-evaluated PSS or the HDRS and the YMRS, respectively were found. There was no statistically significant effect of smartphone-based treatment on the CAR., Conclusion: Our data, of preliminary character, found smartphone-based patient-evaluations of stress and mood instability as read outs that reflect CAR dynamics. Smartphone-supported clinical care did not in itself appear to disturb CAR dynamics.

Background: Brain-derived neurotrophic factor (BDNF), which facilitates neuroplasticity and synaptogenesis, may be decreased in bipolar disorder, but has not been systematically investigated in people with newly diagnosed bipolar disorder and unaffected first-degree relatives., Aims: To compare BDNF levels in patients with newly diagnosed bipolar disorder, their unaffected first-degree relatives and healthy controls., Method: The study investigated plasma BDNF levels in patients (n = 371) with newly diagnosed bipolar disorder, their unaffected first-degree relatives (n = 98) and healthy controls (n = 200) using enzyme-linked immunosorbent assay. We further investigated associations between BDNF levels and illness-related variables and medication status., Results: BDNF levels were found to be 22.0% (95% CI 1.107-1.343) higher in patients with bipolar disorder compared with healthy controls (P < 0.001) and 15.6% higher in unaffected first-degree relatives compared with healthy controls (95% CI 1.007-1.327, P = 0.04), when adjusting for age and gender. Further, BDNF levels were positively associated with duration of illness at a trend level (P = 0.05), age (P = 0.001) and use of anti-epileptic medication (P = 0.05)., Conclusions: These findings suggest that BDNF levels are not decreased in the early stages of bipolar disorder and in unaffected first-degree relatives contrasting with prior findings during later stages of the illness.

Unipolar and bipolar disorders aggregate in families and have been associated with a reduced gray-matter volume in hippocampal and prefrontal cortex. Here we used structural MRI to clarify whether abnormalities in hippocampal subfield and prefrontal cortical morphology are associated with familial vulnerability (i.e., changes present both in patients and unaffected relatives compared to healthy individuals), resilience (i.e., changes differentiating unaffected relatives and patients), or sequalae of illness in a sample of monozygotic twins. We investigated regional differences in gray-matter volume extracted using FreeSurfer 6.0 between remitted affected twins (AT) with either unipolar or bipolar disorder (n = 67), unaffected discordant co-twins (UT, n = 39), and low-risk twins (LT, n = 31) with no personal or first-degree family history of affective disorders. The UT showed greater bilateral hippocampal volumes compared to AT. Between group differences in left hippocampal volume were driven by greater cornu ammonis 1-3 and 4, subiculum and subfield of dentate gyrus. For the right hippocampus, differences were driven by greater hippocampal tail and subiculum. There was a trend for UT having a larger left hippocampus than LT, but no significant differences in hippocampal volumes between AT and LT. Outside the hippocampus, AT showed a smaller volume of left dorsomedial prefrontal cortex compared to LT. Our results suggest that larger volume of specific hippocampal subfields may be associated with resilience in healthy relatives of patients with an affective illness. Moreover, a smaller volume of left dorsomedial prefrontal cortex may reflect a sequalae of illness.

Background: The relationship between cognitive function and relapse of affective episodes in bipolar disorder (BD) is rarely studied. The aim of this prospective, longitudinal, case-control study was to assess the trajectory of cognitive function and mood occilations within a one-year period in patients with BD relative to healthy control (HC) individuals., Methods: The sample included 86 outpatients with BD in euthymia, and 44 gender-and-age-matched HC. All participants were evaluated with clinical assessement and neuropsychological testing at baseline and during euthymia after a year. Further patients with BD were reevaluated if they developed a new affective episode during follow-up. The patients´ affective states were recorded on a weekly basis as asymptomatic, subthreshold level, major depression or (hypo)mania. Cognitive changes over time were measured for a global cognitive score and for the four cognitive domains: 'working memory and executive skills', 'psychomotor speed', 'sustained attention', and 'verbal learning and memory' in patients and HC., Results: The study showed that cognitive performance in patients with BD was unaltered compared to baseline when they stabilised in euthymia following an affective episode and, at the one-year follow-up. Cognitive performance showed practice effect, thus improved within a year across patients with BD and HC. Furthermore, cognitive functions were not related to clinical subtypes BDI/II, prior psychosis, the polarity of the relapse and week-to-week mood fluctuations during follow-up. Functioning correlated weakly to moderately with week-to-week mood fluctuations., Limitations: Modest sample size., Conclusion: A one-year trajectory of BD seems to have no direct negative impact on cognitive function., (Copyright © 2020. Published by Elsevier B.V.)

Background: Alterations in energy and activity in bipolar disorder (BD) differ between affective states and compared with healthy control individuals (HC). Measurements of activity could discriminate between BD and HC and in the monitoring of affective states within BD. The aims were to investigate differences in 1) passively collected smartphone-based location data (location data) between BD and HC, and 2) location data in BD between affective states., Methods: Daily, patients with BD and HC completed smartphone-based self-assessments of mood for up to nine months. Location data reflecting mobility patterns, routine and location entropy was collected daily. A total of 46 patients with BD and 31 HC providing daily data was included., Results: A total of 4,859 observations of smartphone-based self-assessments of mood and mobility patterns were available from patients with BD and 1,747 observations from HC. Patients with BD had lower location entropy compared with HC (B= -0.14, 95% CI= -0.24; -0.034, p=0.009). Patients with BD during a depressive state were less mobile compared with a euthymic state. Patients with BD during an affective state had lower location entropy compared with a euthymic state (p<0.0001). The AUC of combined location data was rather high in classifying patients with BD compared with HC (AUC: 0.83)., Limitations: Individuals willing to use smartphones for daily self-monitoring may represent a more motivated group., Conclusion: Alterations in location data reflecting mobility patterns may be a promising measure of illness and illness activity in patients with BD and may be used to monitor the effects of treatments., (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.)

Objective: To determine the effectiveness of intravenous (IV) ketamine on anxiety, irritability, agitation, and suicidality, in adults with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD)., Method: Adults (N = 201) with treatment-resistant MDD or BD received repeat-dose IV ketamine treatment at a community-based clinic. Mixed features were measured using symptoms of anxiety, irritability, and agitation (AIA), as measured by the Generalized Anxiety Disorder-7 (GAD-7) scale. The Quick Inventory for Depressive Symptomatology Self-Report-16 (QIDS-SR 16 ) was used to measure overall treatment response, and the QIDS-SR 16 suicidal ideation (SI) item was used to measure change in SI symptoms with ketamine treatment. The anxiety, irritability, and agitation items on the GAD-7 were used to assess effectiveness of IV ketamine in treating symptoms of mixed features., Results: In this retrospective analysis, 113 participants met AIA criteria. Participants with AIA experienced a significantly greater reduction in overall depressive symptoms (F(1, 558) = 9.49, P = .002), SI (F(1, 558) = 3.103, P = .079), anxiety (F(1, 198) = 5.52, P = .007), irritability (F(1, 198) = 28.35, P < .001), and agitation as measured by "trouble relaxing" (F(1, 198) = 6.70, P = .010) from baseline compared to the non-AIA group, regardless of number of treatments received., Conclusions: Our preliminary results suggest that IV ketamine is effective in rapidly treating AIA and SI in adults with treatment-resistant mood disorders. This observation suggests that IV ketamine could be considered a treatment alternative for adults with MDD or BD presenting with mixed features., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Bipolar disorder (BD) has been associated with abnormal reward functioning including pleasure-seeking and impulsivity. Here we sought to clarify whether these changes can be attributed to abnormalities in the neural processing of reward valuation or error prediction. Moreover, we tested whether abnormalities in these processes are associated with familial vulnerability to BD., Methods: We obtained functional magnetic resonance imaging data from patients with recently diagnosed BD (n = 85), their unaffected first-degree relatives (n = 44), and healthy control participants (n = 66) while they were performing a monetary card game. We used a region-of-interest approach to test for group differences in the activation of the midbrain, the ventral striatum, and the prefrontal cortex during reward valuation and error prediction., Results: Patients with BD showed decreased prediction error signal in ventrolateral prefrontal cortex and the unaffected relatives showed decreased prediction error signal in the supplementary motor area in comparison to healthy controls. There were no significant group differences in the activation of the ventral striatum during the task. In healthy controls, prediction error signal in dorsal anterior cingulate cortex correlated with an out-of-scanner measure of motor inhibition but this association was absent in patients and relatives., Conclusions: The findings indicate that abnormal reward processing in BD is primarily related to deficits in the engagement of prefrontal regions involved in inhibitory control during error prediction. In contrast, deficient activation in supplementary motor cortex involved in planning of movement emerged as a familial vulnerability to BD., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Changes in inflammatory and metabolic markers are implicated in the pathogenesis in both the development and progression of bipolar disorder (BD). Notwithstanding, these markers have not been investigated in newly diagnosed BD., Methods: We compared high-sensitive C-reactive protein (hs-CRP) and homocysteine (Hcy) levels in 372 patients with newly diagnosed BD, 106 unaffected first-degree relatives (URs), and 201 healthy control persons (HCs). Within the patient group, we also investigated possible associations between hs-CRP and Hcy, respectively, with illness-related characteristics and psychotropic medication., Results: No statistically significant differences in Hcy and hs-CRP levels were found when comparing BD and URs with HCs. Similarly, there were no differences when comparing only patients in remission or patients with affective symptoms, respectively, with HCs. Hcy levels were found to be 11.9% (95% CI: 1.030-1.219) higher in patients with BD when compared with their URs (p = 0.008), when adjusting for folate and cobalamin status, age, sex, and self-reported activity levels. Hcy levels were significantly associated with folate, cobalamin, gender, and age in all models (p < 0.05)., Conclusion: Our results do not support hs-CRP or Hcy as markers in newly diagnosed BD.

Background: In DSM-5 activity is a core criterion for diagnosing hypomania and mania. However, there are no guidelines for quantifying changes in activity. The objectives of the study were (1) to investigate daily smartphone-based self-reported and automatically-generated activity, respectively, against validated measurements of activity; (2) to validate daily smartphone-based self-reported activity and automatically-generated activity against each other; (3) to investigate differences in daily self-reported and automatically-generated smartphone-based activity between patients with bipolar disorder (BD), unaffected relatives (UR) and healthy control individuals (HC)., Methods: A total of 203 patients with BD, 54 UR, and 109 HC were included. On a smartphone-based app, the participants daily reported their activity level on a scale from -3 to + 3. Additionally, participants owning an android smartphone provided automatically-generated data, including step counts, screen on/off logs, and call- and text-logs. Smartphone-based activity was validated against an activity questionnaire the International Physical Activity Questionnaire (IPAQ) and activity items on observer-based rating scales of depression using the Hamilton Depression Rating scale (HAMD), mania using Young Mania Rating scale (YMRS) and functioning using the Functional Assessment Short Test (FAST). In these analyses, we calculated averages of smartphone-based activity measurements reported in the period corresponding to the days assessed by the questionnaires and rating scales., Results: (1) Smartphone-based self-reported activity was a valid measure according to scores on the IPAQ and activity items on the HAMD and YMRS, and was associated with FAST scores, whereas the majority of automatically-generated smartphone-based activity measurements were not. (2) Daily smartphone-based self-reported and automatically-generated activity correlated with each other with nearly all measurements. (3) Patients with BD had decreased daily self-reported activity compared with HC. Patients with BD had decreased physical (number of steps) and social activity (more missed calls) but a longer call duration compared with HC. UR also had decreased physical activity compared with HC but did not differ on daily self-reported activity or social activity., Conclusion: Daily self-reported activity measured via smartphone represents overall activity and correlates with measurements of automatically generated smartphone-based activity. Detecting activity levels using smartphones may be clinically helpful in diagnosis and illness monitoring in patients with bipolar disorder. Trial registration clinicaltrials.gov NCT02888262.

Objectives: (1) To investigate daily smartphone-based self-reported and automatically generated sleep measurements, respectively, against validated rating scales; (2) to investigate if daily smartphone-based self-reported sleep measurements reflected automatically generated sleep measurements and (3) to investigate the differences in smartphone-based sleep measurements between patients with bipolar disorder (BD), unaffected first-degree relatives (UR) and healthy control individuals (HC)., Methods: We included 203 patients with BD, 54 UR and 109 HC in this study. To investigate whether smartphone-based sleep calculated from self-reported bedtime, wake-up time and screen on/off time reflected validated rating scales, we used the Pittsburgh Sleep Quality Index (PSQI) and sleep items on the Hamilton Depression Rating Scale 17-item (HAMD-17) and the Young Mania Rating Scale (YMRS)., Findings: (1) Self-reported smartphone-based sleep was associated with the PSQI and sleep items of the HAMD and the YMRS. (2) Automatically generated smartphone-based sleep measurements were associated with daily self-reports of hours slept between 12:00 midnight and 06:00. (3) According to smartphone-based sleep, patients with BD slept less between 12:00 midnight and 06:00, with more interruption and daily variability compared with HC. However, differences in automatically generated smartphone-based sleep were not statistically significant., Conclusion: Smartphone-based data may represent measurements of sleep patterns that discriminate between patients with BD and HC and potentially between UR and HC., Clinical Implication: Detecting sleep disturbances and daily variability in sleep duration using smartphones may be helpful for both patients and clinicians for monitoring illness activity., Trial Registration Number: clinicaltrials.gov (NCT02888262)., Competing Interests: Competing interests: LVK and MV has been a consultant for Lundbeck within recent 3 years. JEB and MF are co-founders and shareholders of Monsenso ApS., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cognitive impairments in patients with bipolar disorder (BD) have been associated with reduced functioning., Aims: To investigate the association between (1) patient-evaluated cognitive function measured daily using smartphones and stress, quality of life and functioning, respectively, and (2) patient-evaluated cognitive function and objectively measured cognitive function with neuropsychological tests., Methods: Data from two randomized controlled trials were combined. Patients with BD (N = 117) and healthy controls (HC) (N = 40) evaluated their cognitive function daily for six to nine months using a smartphone. Patients completed the objective cognition screening tool, the Screen for Cognitive Impairment in Psychiatry and were rated with the Functional Assessment Short Test. Raters were blinded to smartphone data. Participants completed the Perceived Stress Scale and the WHO Quality of Life questionnaires. Data was collected at multiple time points per participant. p-values below 0.0023 were considered statistically significant., Results: Patient-evaluated cognitive function was statistically significant associated with perceived stress, quality of life and functioning, respectively (all p-values < 0.0001). There was no association between patient-evaluated cognitive function and objectively measured cognitive function (B:0.0009, 95% CI 0.0017; 0.016, p = 0.015). Patients exhibited cognitive impairments in subjectively evaluated cognitive function in comparison with HC despite being in full or partly remission (B: - 0.36, 95% CI - 0.039; - 0.032, p < 0.0001)., Conclusion: The present association between patient-evaluated cognitive function on smartphones and perceived stress, quality of life and functional capacity suggests that smartphones can provide a valid tool to assess disability in remitted BD. Smartphone-based ratings of cognition could not provide insights into objective cognitive function.

Objective: To evaluate the development and implementation of clinical practice guidelines for the management of depression globally., Methods: We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries., Findings: We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence., Conclusion: Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes., ((c) 2020 The authors; licensee World Health Organization.)

Background: The calcium binding protein S100B and brain derived neurotrophic factor (BDNF) are both biomarkers implicated in neuronal processes in the central nervous system and seem to be associated with affective disorders. Here we investigated both markers in a sample of monozygotic (MZ) twins with, at risk of and without affective disorders, aiming to evaluate whether these markers have a role as causal factors- or trait markers for affective disorders., Method: We measured serum S100B and plasma BDNF levels in 204 monozygotic twins (MZ) with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk)., Results: No significant group differences in S100B and BDNF levels were found between the three groups. Exploratory analysis revealed that higher S100B levels were correlated with lower cognitive performance., Limitations: The cross-sectional design cannot elucidate the two neuronal biomarkers role as causal factors. We would have preferred a higher sample size in the high- and low-risk groups., Conclusion: The present result did not support a role for S100B and BDNF as neither causal factors nor trait markers for affective disorders. Elevated S100B levels may associate with impaired cognition, but further studies are warranted., Competing Interests: Declaration of Competing interest MV has received consultancy fees from Lundbeck, Sunovion and Janssen in the past three years. LVK has within the preceding three years been a consultant for Sunovion and Lundbeck. KWM has received consultancy fees from Lundbeck, Allergan and Janssen in the past three years. The remaining authors declare no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Background: Patients with bipolar disorder (BD) experience persistent impairments in both affective and non-affective cognitive function, which is associated with a worse course of illness and poor functional outcomes. Nevertheless, the temporal progression of cognitive dysfunction in BD remains unclear and the identification of objective endophenotypes can inform the aetiology of BD., Methods: The present study is a cross-sectional investigation of cognitive baseline data from the longitudinal Bipolar Illness Onset-study. One hundred seventy-two remitted patients newly diagnosed with BD, 52 of their unaffected relatives (UR), and 110 healthy controls (HC) were compared on a large battery of behavioural cognitive tasks tapping into non-affective (i.e. neurocognitive) and affective (i.e. emotion processing and regulation) cognition., Results: Relative to HCs, patients with BD exhibited global neurocognitive deficits (ps < 0.001), as well as aberrant emotion processing and regulation (ps ⩽ 0.011); including decreased emotional reactivity to positive social scenarios, impaired ability to down-regulate positive emotion, as well as a specific deficit in the ability to recognise surprised facial expressions. Their URs also showed a trend towards difficulties identifying surprised faces (p = 0.075). No other differences in cognitive function were found for URs compared to HCs., Conclusions: Neurocognitive deficits and impairments within emotion processing and regulation may be illness-related deficits of BD that present after illness-onset, whereas processing of emotional faces may represent an early risk marker of BD. However, longitudinal studies are needed to examine the association between cognitive impairments and illness progression in BD.

Background: Metabolic syndrome (MetS) is associated with reduced life expectancy in patients with affective disorders, however, whether MetS also plays a role before the onset of affective disorder is unknown. We aimed to investigate whether MetS, inflammatory markers or oxidative stress act as risk factors for affective disorders, and whether MetS is associated with increased inflammation and oxidative stress., Methods: We conducted a high-risk study including 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk). Metabolic Syndrome was ascertained according to the International Diabetes Federation (IDF) criteria. Inflammatory markers and markers of oxidative stress were analyzed from fasting blood and urine samples, respectively., Results: The affected and the high-risk group had a significantly higher prevalence of MetS compared to the low-risk group (20% v. 15% v. 2.5%, p = 0.0006), even after adjusting for sex, age, smoking and alcohol consumption. No differences in inflammatory and oxidative markers were seen between the three groups. Further, MetS was associated with alterations in inflammatory markers, and oxidative stress was modestly correlated with inflammation., Conclusion: Metabolic syndrome is associated with low-grade inflammation and may act as a risk factor and a trait marker for affective disorders. If confirmed in longitudinal studies, this suggests the importance of early intervention and preventive approaches targeted towards unhealthy lifestyle factors that may contribute to later psychopathology.

Objectives: To investigate whether mood instability (MI) qualify as a trait marker for bipolar disorder (BD) we investigated: 1) differences in smartphone-based self-reported MI between three groups: patients with newly diagnosed BD, unaffected first-degree relatives (UR), and healthy control individuals (HC); 2) the correlation between MI and functioning, stress, and duration of illness, respectively; and 3) the validity of smartphone-based self-evaluated mood ratings as compared to observer-based ratings of depressed and manic mood., Methods: 203 patients with newly diagnosed BD, 54 UR and 109 HC were included as part of the longitudinal Bipolar Illness Onset study. Participants completed daily smartphone-based mood ratings for a period of up to two years and were clinically assessed with ratings of depression, mania and functioning., Results: Mood instability scores were statistically significantly higher in patients with BD compared with HC (mean=1.18, 95%CI: 1.12;1.24 vs 1.05, 95%CI: 0.98;1.13, p = 0.007) and did not differ between patients with BD and UR (mean=1.17, 95%CI: 1.07;1.28, p = 0.91). For patients, increased MI scores correlated positively with impaired functioning (p<0.001), increased stress level (p<0.001) and increasing number of prior mood episodes (p<0.001). Smartphone-based mood ratings correlated with ratings of mood according to sub-item 1 on the Hamilton Depression Rating Scale 17-items and the Young Mania Rating Scale, respectively (p´s<0.001)., Limitation: The study had a smaller number of UR than planned., Conclusion: Mood instability is increased in patients with newly diagnosed BD and unaffected relatives and associated with decreased functioning. The findings highlight MI as a potential trait marker for BD., Competing Interests: Declaration of Competing Interest SS, KC, HLK, SM and KS declare no competing interests. MFJ, LVK, MV has within recent three years been a consultant for Lundbeck. JEB, MF are co-founders and shareholders of Monsenso ApS., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Sleep disturbances are a central feature in bipolar disorder (BD) that often persist in remission and seem to be present also in unaffected first-degree relatives (UR) of patients with BD, presenting a possible risk factor for later onset of BD. However, it is unknown if these disturbances are associated with unhealthy life-style as reflected in low levels of physical activity. We investigated sleep disturbances and physical activity levels in patients with newly diagnosed BD in full or partial remission, their UR and healthy controls (HC)., Methods: Sleep patterns and physical activity were compared in 227 patients with newly diagnosed BD, 76 UR and 148 HC. The Pittsburgh Sleep Quality Index (PSQI) and the International Physical Activity Questionnaire (IPAQ) were used to assess sleep disturbances and physical activity, respectively., Results: In sex- and age-adjusted analyses, patients with BD exhibited more sleep disturbances and lower physical activity compared with UR and HC, respectively. Unaffected relatives reported significantly longer sleep latency and a non-significant trend towards more overall sleep disturbances compared with HC., Conclusions: Sleep disturbances and less physical activity are present in patients with newly diagnosed BD in partial or full remission. Individuals at familiar risk of BD reported longer sleep latency and similar physical activity compared with HC. Further prospective studies are needed to clarify whether these discrete sleep disturbances act as risk factor for later onset of BD and whether increased physical activity in high-risk individuals may act as a protective factor against development of psychiatric illness.

Background: Treatment development that targets cognitive impairment is hampered by a lack of biomarkers that can predict treatment efficacy. Erythropoietin (EPO) improves verbal learning and memory in mood disorders, and this scales with an increase in left hippocampal volume. This study investigated whether pretreatment left hippocampal volume, interhemisphere hippocampal asymmetry or both influenced EPO treatment response with respect to verbal learning., Methods: Data were available for 76 of 83 patients with mood disorders from our previous EPO trials (EPO = 37 patients; placebo = 39 patients). We performed cortical reconstruction and volumetric segmentation using FreeSurfer. We conducted multiple linear regression and logistic regression to assess the influence of left hippocampal volume and hippocampal asymmetry on EPO-related memory improvement, as reflected by change in Rey Auditory Verbal Learning Test total recall from baseline to post-treatment. We set up a corresponding exploratory general linear model in FreeSurfer to assess the influence of prefrontal cortex volume on verbal learning improvement, controlling for age, sex and total intracranial volume., Results: At baseline, more rightward (left < right) hippocampal asymmetry — but not left hippocampal volume per se — was associated with greater effects of EPO versus placebo on verbal learning (p ≤ 0.05). Exploratory analysis indicated that a larger left precentral gyrus surface area was also associated with improvement of verbal learning in the EPO group compared to the placebo group (p = 0.002)., Limitations: This was a secondary analysis of our original EPO trials., Conclusion: Rightward hippocampal asymmetry may convey a positive effect of EPO treatment efficacy on verbal learning., Clinical Trial Registration: Clinicaltrials.gov NCT00916552, Competing Interests: K. Miskowiak reports consultancy fees from Lundbeck, Allergan and Janssen within the past 3 years. M. Vinberg reports consultancy fees from Lundbeck within the last 3 years. H. Siebner has received honoraria as a speaker from Sanofi Genzyme and Novartis, as a consultant from Sanofi Genzyme and as senior editor of NeuroImage from Elsevier. He has received royalties as a book editor from Springer Publishers. He also holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen, that is sponsored by the Lundbeck Foundation (grant R186-2015-2138). L. Kessing reports having been a consultant for Lundbeck, AstraZeneca and Sunovion within the last 3 years. No other authors report competing interests., (© 2020 Joule Inc. or its licensors)

Background: Most people will also experience symptoms of stress at some point. Smartphone use has increased during the last decade and may be a new way of monitoring stress. Thus, it is of interest to investigate whether automatically generated smartphone data reflecting smartphone use is associated with subjective stress in healthy individuals. Aims: to investigate whether automatically generated smartphone data (e.g. the number of outgoing sms/day) was associated with (1) smartphone-based subjectively reported perceived stress, (2) perceived stress (Cohen's Perceived Stress Scale (PSS)) (3) functioning (Functioning Assessment Short Test (FAST)) and (4) non-clinical depressive symptoms (Hamilton Depression Rating Scale 17-items (HDRS)). Methods: A cohort of 40 healthy blood donors used an app for daily self-assessment of stress for 16 weeks. At baseline participants filled out the PSS and were clinically evaluated using the FAST and the HDRS. The PSS assessment was repeated at the end of the study. Associations were estimated with linear mixed effect regression and linear regression models. Results: There were no statistically significant associations between automatically generated smartphone data and perceived stress, functioning or severity of depressive symptoms, respectively (e.g. the number of outgoing text messages/day and self-assessed stress ( B =  0.30, 95% CI : -0.40; 0.99, p =  .40). Conclusions: Participants presented with low levels of stress during the study. Automatically generated smartphone data was not able to catch potential subjective stress among healthy individuals in the present study. Due to the small sample and low levels of stress the results should be interpreted with caution.

Background: Recently, the MONARCA I randomized controlled trial (RCT) was the first to investigate the effect of smartphone-based monitoring in bipolar disorder (BD). Findings suggested that smartphone-based monitoring sustained depressive but reduced manic symptoms. The present RCT investigated the effect of a new smartphone-based system on the severity of depressive and manic symptoms in BD., Methods: Randomized controlled single-blind parallel-group trial. Patients with BD, previously treated at The Copenhagen Clinic for Affective Disorder, Denmark and currently treated at community psychiatric centres, private psychiatrists or GPs were randomized to the use of a smartphone-based system or to standard treatment for 9 months. Primary outcomes: differences in depressive and manic symptoms between the groups., Results: A total of 129 patients with BD (ICD-10) were included. Intention-to-treat analyses showed no statistically significant effect of smartphone-based monitoring on depressive (B = 0.61, 95% CI -0.77 to 2.00, p = 0.38) and manic (B = -0.25, 95% CI -1.1 to 0.59, p = 0.56) symptoms. The intervention group reported higher quality of life and lower perceived stress compared with the control group. In sub-analyses, the intervention group had higher risk of depressive episodes, but lower risk of manic episodes compared with the control group., Conclusions: There was no effect of smartphone-based monitoring. In patient-reported outcomes, patients in the intervention group reported improved quality of life and reduced perceived stress. Patients in the intervention group had higher risk of depressive episodes and reduced risk of manic episodes. Despite the widespread use and excitement of electronic monitoring, few studies have investigated possible effects. Further studies are needed.

Introduction: The DSM-5 has introduced elevated/irritable mood and increased activity/ energy as equal and necessary criterion A symptoms for a diagnosis of (hypo)mania. The impact of these changes is poorly elucidated. The aim of the study was to investigate differences in the prevalence of elevated/irritable mood with and without co-occurring increased activity, and the associations between these, in patients with an ICD-10 and DSM-IV diagnosis of BD, using real life daily smartphone-based patient-reported measures of mood, irritability and activity., Methods: Data from two RCTs investigating the effect of smartphone-based treatment in patients with BD were combined. Patients with BD (N = 117) evaluated mood, irritability and activity level daily for six to nine months via a smartphone-based system. Analyses in this study are exploratory post hoc analyses based on previously published data., Results: During the follow-up period, patients reported elevated mood 8.0% of the time, irritability 28.4% of the time and increased activity 20.6% of the time. Co-occurring elevated/irritable mood and activity were prevalent 0.12% of the time for four consecutive days (duration criteria for a hypomanic episode) compared to 24% of the time with elevated/irritable mood without co-occurring increased activity. In linear mixed effect models accommodating for inter-individual and intra-individual variation, there was a statistically significant positive association between mood and activity (B: 0.14, 95% CI: 0.046; 0.24, p = 0.004). There was no association between irritability and activity (p = 0.23)., Conclusion: Based on real life daily assessments, the prevalence of (hypo)manic episodes is substantial reduced as a result of the introduction of DSM-5 and with potentially clinical consequences., Competing Interests: Declaration of Competing Interest MFJ has no conflicts of interest. MF and JEB are co-founders and shareholders in Monsenso ApS. EMC has been a consultant for Eli Lilly, Astra Zeneca, Servier, Bristol-Myers Squibb, Lundbeck, and Medilink within the last three years. MV has a been consultant for Lundbeck, Janssen and Sunovion and LVK have been consultants for Lundbeck within the last three years., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The efficacy of antidepressant treatment is fair, but the efficacy is considerably lower in patients failing two or more trials underscoring the need for new treatment options. Our study evaluated the augmenting antidepressant effect of 8-weeks transcranial pulsed electromagnetic field (T-PEMF) therapy in patients with treatment-resistant depression., Methods: A multicenter 8-week single-arm cohort study conducted by the Danish University Antidepressant Group., Results: In total, 58 participants (20 men and 38 women) with a moderate to severe depression as part of a depressive disorder according to ICD-10 who fulfilled criteria for treatment resistance were included, with 19 participants being nonresponders to electroconvulsive therapy during the current depressive episode. Fifty-two participants completed the study period. Scores on the Hamilton Depression Scale 17-items version (HAM-D17) decreased significantly from baseline (mean = 20.6, SD 4.0) to endpoint (mean = 12.6, SD 7.1; N = 58). At endpoint, utilizing a Last Observation Carried Forward analysis, 49 and 28% of those participants with, respectively, a nonchronic current episode (≤2 years; N = 33) and a chronic current episode (>2 years; N = 25) were responders, that is, achieved a reduction of 50% or more on the HAM-D17 scale. At endpoint, respectively, 30 and 16% obtained remission, defined as HAM-D17 ≤ 7. On the Hamilton Scale 6-item version (HAM-D6), respectively, 51 and 16% obtained remission, defined as HAM-D6 ≤ 4., Conclusions: The findings indicate a potential beneficial role of T-PEMF therapy as an augmentation treatment to ongoing pharmacotherapy in treatment-resistant depression.

Background: Non-adherence to medication is associated with increased risk of relapse in patients with bipolar disorder (BD)., Objectives: To (1) validate patient-evaluated adherence to medication measured via smartphones against validated adherence questionnaire; and (2) investigate characteristics for adherence to medication measured via smartphones., Methods: Patients with BD (n=117) evaluated adherence to medication daily for 6-9 months via smartphones. The Medication Adherence Rating Scale (MARS) and the Rogers' Empowerment questionnaires were filled out. The 17-item Hamilton Depression Rating Scale, the Young Mania Rating Scale and the Functional Assessment Short Test were clinically rated. Data were collected multiple times per patient. The present study represents exploratory pooled reanalyses of data collected as part of two randomised controlled trials., Findings: During the study 90.50% of the days were evaluated as 'medication taken', 6.91% as 'medication taken with changes' and 2.59% as 'medication not taken'. Adherence to medication measured via smartphones was valid compared with the MARS (B: -0.049, 95% CI -0.095 to -0.003, p=0.033). Younger age and longer illness duration were significant predictors for non-adherence to medication (model concerning age: B: 0.0039, 95% CI 0.00019 to 0.0076, p=0.040). Decreased affective symptoms measured with smartphone-based patient-reported mood and clinical ratings as well as decreased empowerment were associated with non-adherence., Conclusions: Smartphone-based monitoring of adherence to medication was valid compared with validated adherence questionnaire. Younger age and longer illness duration were predictors for non-adherence. Increased empowerment was associated with adherence., Clinical Implications: Using smartphones for empowerment of adherence using patient-reported measures may be helpful in everyday clinical settings., Trial Registration Number: NCT01446406 and NCT02221336., Competing Interests: Competing interests: MFJ has no conflicts of interest. MF and JEB are co-founders and shareholders in Monsenso ApS. EMC has been a consultant for Eli Lilly, AstraZeneca, Servier, Bristol-Myers Squibb, Lundbeck and Medilink. MV has been a consultant for Lundbeck within the last 3 years. LVK has been a consultant for Lundbeck during the recent 3 years., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cognitive impairments in bipolar disorder (BD) such as memory deficits are associated with poor functional outcomes and it has been suggested that the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism contributes to individual variability in memory function in BD. The current study investigated the relationship between the BDNF Val66Met polymorphism, neural activity during a picture-encoding task, and subsequent memory recall. Methods: A total of 70 patients with BD grouped according to genotype [ValVal or Met carriers (MetVal/MetMet)] underwent fMRI while performing a picture-encoding task. Memory for the encoded pictures was tested with a subsequent free recall memory task. Results: There was no difference between the ValVal homozygotes and Met carriers in the involvement of hypothesized memory encoding regions i.e. hippocampus and dorsal prefrontal cortex (dPFC). However, an exploratory whole-brain analysis showed greater encoding-related lateral occipital cortex activity in Met carriers. Behaviorally, Met carriers also showed better free recall of the encoded pictures. Conclusions: We found no effect of the BDNF genotype on encoding-related hippocampal and dPFC activity in BD, although Met carriers showed superior memory performance after the scan, which could be related to more efficient perceptual processing during encoding., (Copyright © 2019 Hørlyck, Macoveanu, Vinberg, Kessing, Siebner and Miskowiak.)

Bipolar disorder (BD) is a mental disorder characterized by recurrent relapses of affective episodes, cognitive impairment, illness progression, and reduced life expectancy. Increased systemic oxidatively generated nucleoside damage have been found in some neurodegenerative disorders and in BD. As the first, this naturalistic prospective, longitudinal follow-up case-control study investigated cerebrospinal fluid (CSF) oxidative stress markers 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) that relate to RNA and DNA damage, respectively. Patients with BD (n = 86, 51% female) and gender-and-age-matched healthy control individuals (HC; n = 44, 44% female) were evaluated at baseline (T0), during (T1) and after a new affective episode (T2), if it occurred, and after a year (T3). Cerebrospinal and urine oxidative stress markers were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. CSF-8-oxoGuo was statistically significantly higher by 18% (p = 0.003) in BD versus HC at T0, and by 22% (p = 0) at T3. CSF-8-oxoGuo had increased by 15% (p = 0.042) from T0 to T3, and by 14% (p = 0.021) from T2 to T3 in patients, who experienced an episode during follow-up. CSF-8-oxodG had increased by 26% (p = 0.054) from T0 to T2 and decreased by 19% (p = 0.041) from T2 to T3 in patients, who experienced an episode during follow-up. CSF-8-oxoGuo did not show a statistically significant change in HC during the one-year follow-up. CSF and urine-8-oxoGuo levels correlated moderately. In conclusion, CSF oxidative stress marker of RNA damage 8-oxoGuo showed both state and trait dependence in BD and stability in HC. Central RNA damage may be a potential biomarker for BD.

A core symptom of mood disorders is cognitive impairment in attention, memory and executive functions. Erythropoietin (EPO) is a candidate treatment for cognitive impairment in unipolar and bipolar disorders (UD and BD) and modulates cognition-related neural activity across a fronto-temporo-parietal network. This report investigates predicting the pharmacological treatment from functional magnetic resonance imaging (fMRI) data using a supervised machine learning approach. A total of 84 patients with UD or BD were included in a randomized double-blind parallel-group study in which they received eight weekly infusions of either EPO (40 000 IU) or saline. Task fMRI data were collected before EPO/saline infusions started (baseline) and 6 weeks after last infusion (follow-up). During the scanning sessions, participants were given an n-back working memory and a picture encoding task. Linear classification models with different regularization techniques were used to predict treatment status from both cross-sectional data (at follow-up) and longitudinal data (difference between baseline and follow-up). For the n-back and picture encoding tasks, data were available and analyzed for 52 (EPO; n = 28, Saline; n = 24) and 59 patients (EPO; n = 31, Saline; n = 28), respectively. We found limited evidence that the classifiers used could predict treatment status at a reliable level of performance (≤60% accuracy) when tested using repeated cross-validation. There was no difference in using cross-sectional versus longitudinal data. Whole-brain multivariate decoding applied to pharmaco-fMRI in small to moderate samples seems to be suboptimal for exploring data driven neuronal treatment mechanisms., (Copyright © 2019 Nielsen, Madsen, Vinberg, Kessing, Siebner and Miskowiak.)

Background: Mental imagery abnormalities feature across affective disorders including bipolar disorder (BD) and unipolar depression (UD). Maladaptive emotional imagery has been proposed as a maintenance factor for affective symptomatology and a target for mechanism-driven psychological treatment developments. Where imagery abnormalities feature beyond acute affective episodes, further opportunities for innovation arise beyond treatments, such as for tertiary/relapse prevention (e.g., in remitted individuals) or primary prevention (e.g., in non-affected but at-risk individuals). The aim of our study was to investigate for the first time the presence of possible mental imagery abnormalities in affected individuals in remission and at-risk individuals for affective disorders using a familial risk design. Methods: A population-based cohort of monozygotic twins was recruited through linkage between the Danish national registries ( N =204). Participants were grouped as: affected (remitted BD/UD; n = 115); high-risk (co-twin with history of BD/UD; n = 49), or low-risk (no co-twin history of BD/UD; n = 40). Twins completed mental imagery measures spanning key subjective domains (spontaneous imagery use and emotional imagery) and cognitive domains (imagery inspection and imagery manipulation). Results: Affected twins in remission reported enhanced emotional mental imagery compared to both low- and high-risk twins. This was characterized by greater impact of i) intrusive prospective imagery (Impact of Future Events Scale) and ii) deliberately-generated prospective imagery of negative scenarios (Prospective Imagery Task). There were no significant differences in these key measures between affected BD and UD twins in remission. Additionally, low- and high-risk twins did not significantly differ on these emotional imagery measures. There were also no significant differences between the three groups on non-emotional measures including spontaneous imagery use and cognitive stages of imagery. Conclusions: Abnormalities in emotional prospective imagery are present in monozygotic twins with affective disorders in remission-despite preserved cognitive stages of imagery-but absent in unaffected high-risk twins, and thus do not appear to index familial risk (i.e., unlikely to qualify as "endophenotypes"). Elevated emotional prospective imagery represents a promising treatment/prevention target in affective disorders., (Copyright © 2019 Di Simplicio, Lau-Zhu, Meluken, Taylor, Kessing, Vinberg, Holmes and Miskowiak.)

Objective: Mood instability in patients with bipolar disorder has been associated with impaired functioning and risk of relapse. The present study aimed to investigate whether increased mood instability is associated with increased perceived stress and impaired quality of life and functioning in patients with bipolar disorder., Methods: A total of 84 patients with bipolar disorder used a smartphone-based self-monitoring system on a daily basis for 9 months. Data on perceived stress, quality of life, and clinically rated functioning were collected at five fixed time points for each patient during follow-up. A group of 37 healthy individuals served as a control comparison of perceived stress, quality of life, and psychosocial functioning., Results: The majority of patients presented in full or partial remission. As hypothesized, mood instability was significantly associated with increased perceived stress (B: 10.52, 95% CI: 5.25; 15.77, P < 0.0001) and decreased quality of life (B: -12.17, 95% CI. -19.54; -4.79, P < 0.0001) and functioning (B: -12.04, 95% CI: -19.08; -4.99, P < 0.0001) in patients with bipolar disorder. There were no differences in mood instability according to prescribed psychopharmacological treatment. Compared with healthy individuals, patients reported substantially increased perceived stress and experienced decreased quality of life and decreased functioning based on researcher-blinded evaluation., Conclusion: Mood instability in bipolar disorder is associated with increased perceived stress and decreased quality of life and functioning even during full or partial remission. There is a need to monitor and identify subsyndromal inter-episodic symptoms. Future studies investigating the effect of treatment on mood instability are highly warranted., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: More than half of patients with bipolar disorder (BD) experience anxiety, which is associated with impaired functioning. In patients with BD, the present study aimed (1) to validate daily patient-reported symptoms of anxiety measured using smartphones against clinically rated symptoms of anxiety, (2) to estimate the prevalence of anxiety symptoms, and (3) to investigate the associations between patient-reported anxiety symptoms and stress, quality of life and functioning., Methods: A total of 84 patients with BD evaluated their anxiety symptoms daily for nine months using a smartphone-based system. Data on clinically evaluated symptoms of anxiety and functioning and patient-reported stress and quality of life were collected from each patient at five fixed time points during follow-up., Results: The patients presented mild affective symptoms only. The reporting of anxiety symptoms was evaluated for validity according to clinically evaluated anxiety scores based on the two anxiety sub-items of the Hamilton Depression Rating Scale. The patients experienced symptoms of anxiety 19.3% of the time. There were statistically significant associations between anxiety and stress, quality of life and functioning (all p-values < 0.0001)., Conclusion: In patients with BD in full or partial remission, the self-reporting of anxiety symptoms using smartphones was validated. Anxiety is associated with increased stress, decreased quality of life and functioning even during full or partial remission. Identifying anxiety symptoms thus has clinical impact, which suggests that smartphones may serve as a valid tool., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Lithium is recommended as a first line treatment for bipolar disorders. However, only 30% of patients show an optimal outcome and variability in lithium response and tolerability is poorly understood. It remains difficult for clinicians to reliably predict which patients will benefit without recourse to a lengthy treatment trial. Greater precision in the early identification of individuals who are likely to respond to lithium is a significant unmet clinical need., Structure: The H2020-funded Response to Lithium Network (R-LiNK; http://www.r-link.eu.com/ ) will undertake a prospective cohort study of over 300 individuals with bipolar-I-disorder who have agreed to commence a trial of lithium treatment following a recommendation by their treating clinician. The study aims to examine the early prediction of lithium response, non-response and tolerability by combining systematic clinical syndrome subtyping with examination of multi-modal biomarkers (or biosignatures), including omics, neuroimaging, and actigraphy, etc. Individuals will be followed up for 24 months and an independent panel will assess and classify each participants' response to lithium according to predefined criteria that consider evidence of relapse, recurrence, remission, changes in illness activity or treatment failure (e.g. stopping lithium; new prescriptions of other mood stabilizers) and exposure to lithium. Novel elements of this study include the recruitment of a large, multinational, clinically representative sample specifically for the purpose of studying candidate biomarkers and biosignatures; the application of lithium-7 magnetic resonance imaging to explore the distribution of lithium in the brain; development of a digital phenotype (using actigraphy and ecological momentary assessment) to monitor daily variability in symptoms; and economic modelling of the cost-effectiveness of introducing biomarker tests for the customisation of lithium treatment into clinical practice. Also, study participants with sub-optimal medication adherence will be offered brief interventions (which can be delivered via a clinician or smartphone app) to enhance treatment engagement and to minimize confounding of lithium non-response with non-adherence., Conclusions: The paper outlines the rationale, design and methodology of the first study being undertaken by the newly established R-LiNK collaboration and describes how the project may help to refine the clinical response phenotype and could translate into the personalization of lithium treatment.

Objective: This study reanalyzed data from a randomized placebo-controlled trial that failed to find an effect of the selective serotonin reuptake inhibitor escitalopram on neuroticism and state anxiety in a nonclinical sample. The purpose was to test for unique effects on two neuroticism factors, trait anxiety and mood instability, and to explore whether neuroticism moderated the effect of escitalopram on state anxiety., Methods: The sample included 80 adults who had a first-degree relative with major depression but without any psychiatric disorders themselves. Participants were randomized to escitalopram 10 mg/day or placebo for 4 weeks. Neuroticism was assessed with the Eysenck Personality Questionnaire (EPQ) and state anxiety with the Hamilton Anxiety Rating Scale (HAM-A)., Results: The main effects on the neuroticism factors were not statistically significant, although there was a significant interaction such that the effect of escitalopram compared with placebo on HAM-A scores was statistically significant in participants with higher levels of EPQ trait anxiety, even after controlling for baseline HAM-A scores. A similar interaction with EPQ mood instability was nonsignificant., Conclusion: A potential beneficial effect of escitalopram on neuroticism may be driven by reductions in anxiety., (© 2019 John Wiley & Sons, Ltd.)

Objectives: Bipolar disorder is associated with a decreased life expectancy of 8-12 years. Cardiovascular disease is the leading cause of excess mortality. For the first time, we investigated the Framingham 30-year risk score of cardiovascular disease in patients with newly diagnosed/first-episode bipolar disorder, their unaffected first-degree relatives and healthy individuals., Methods: In a cross-sectional study, we compared the Framingham 30-year risk score of cardiovascular disease in 221 patients with newly diagnosed/first-episode bipolar disorder, 50 of their unaffected first-degree relatives and 119 healthy age- and sex-matched individuals with no personal or first-degree family history of affective disorder. Among patients with bipolar disorder, we further investigated medication- and illness-related variables associated with cardiovascular risk., Results: The 30-year risk of cardiovascular disease was 98.5% higher in patients with bipolar disorder ( p  = 0.017) and 85.4% higher in unaffected first-degree relatives ( p  = 0.042) compared with healthy individuals in models adjusted for age and sex. When categorizing participants in low cardiovascular risk without considering age and sex distribution among participants, 81% of patients were at low risk, versus 92% of unaffected relatives and 89% of healthy individuals. Of the patients 209 (94.6%) were diagnosed within the preceding 2 years. Smoking was more prevalent among patients with bipolar disorder (45.2%) and their unaffected first-degree relatives (20.4%) compared with healthy individuals (12.8%). Similarly, dyslipidemia was more common among patients with bipolar disorder compared with healthy individuals. Treatment with psychotropic medication with metabolic adverse effects was associated with higher 30-year cardiovascular disease risk score, whereas we did not find illness-related variables associated with cardiovascular risk among patients with bipolar disorder., Conclusion: We found an enhanced cardiovascular disease risk score in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives, which points to a need for specific primary preventive interventions against smoking and dyslipidemia in these populations.

Background: Aberrant neural and cognitive response to emotional faces has been observed in people at familial risk of an affective disorder. In this functional MRI study of monozygotic twins, we explored neural correlates of the attentional avoidance of emotional faces that we had previously observed in high-risk versus affected twins, and whether an abnormal neural response to emotional faces represents a risk endophenotype., Methods: We recruited unaffected monozygotic twins with a co-twin history of mood episodes (high-risk), monozygotic twins with previous mood episodes (affected) and monozygotic twins with no personal or first-degree history of mood episodes (low-risk) between December 2014 and January 2017 based on a nationwide register linkage. Participants viewed fearful and happy faces while performing a gender discrimination task during functional MRI (fMRI) and performed emotional faces dot-probe and facial expression recognition tasks outside the scanner., Results: A total of 129 monozygotic twins underwent whole-brain fMRI. Highrisk twins (n = 38) displayed greater medial and superior prefrontal response to emotional faces than affected twins (n = 62). This greater activity correlated with stronger attentional avoidance of emotional faces in high-risk twins. In contrast, high-risk and affected twins showed no aberrant neural activity to emotional faces compared with low-risk twins (n = 29)., Limitations: A limitation of this study was its cross-sectional design., Conclusion: Greater recruitment of the medial and superior prefrontal cortex during implicit emotion processing in high-risk versus affected twins may represent a compensatory or resilience mechanism. In contrast, aberrant neural response to emotional faces does not seem to be a risk endophenotype for affective disorders., Competing Interests: C. Harmer has received consultancy fees from P1vital Ltd, Lundbeck, Servier and Eli-Lilly, and is a company director of Oxford Psychologists Ltd. She has also received grant income from GSK, UCB, Janssen Inc, Lundbeck, Servier and AstraZeneca. H. Siebner discloses honoraria as journal editor from Elsevier Publishers and book editor from Springer Publishing, as well as honoraria as speaker from Genzyme and MerckSerono, and grant support from Biogen-idec within the last 3 years. M. Vinberg discloses consultancy fees from Lundbeck within the last 3 years. L. Kessing has been a consultant for Sunovion within the last 3 years. K. Miskowiak reports having received consultancy fees from Lundbeck and Allergan in the past 3 years. No other competing interests declared., (© 2019 Joule Inc. or its licensors)

Objective: To (i) validate patient-evaluated mixed symptoms and irritability measured using smartphones against clinical evaluations; (ii) investigate associations between mixed symptoms and irritability with stress, quality of life and functioning, respectively, in patients with bipolar disorder., Methods: A total of 84 patients with bipolar disorder used a smartphone-based system for daily evaluation of mixed symptoms and irritability for nine months. Clinically evaluated symptoms, stress, quality of life and clinically rated functioning were collected multiple times during follow-up., Results: Patients presented mild affective symptoms. Patient-reported mixed symptoms and irritability correlated with clinical evaluations. In analyses including confounding factors there was a statistically significant association between both mixed symptoms and irritability and stress (P < 0.0001) and between irritability and both quality of life and functioning (P < 0.0001) respectively. There was no association between mixed mood and both quality of life and functioning., Conclusion: Mixed symptoms and irritability can be validly self-reported using smartphones in patients with bipolar disorder. Mixed symptoms and irritability are associated with increased stress even during full or partial remission. Irritability is associated with decreased quality of life and functioning. The findings emphasize the clinical importance of identifying inter-episodic symptoms including irritability pointing towards smartphones as a valid tool., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)