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Andrea Fagiolini,1 Ana González Pinto,2,3 Kamilla Woznica Miskowiak,4– 6 Pedro Morgado,7– 9 Allan H Young,10,11 Eduard Vieta12 1Department of Molecular and Developmental Medicine, Division of Psychiatry, University of Siena School of Medicine, Siena, 53100, Italy; 2Bioaraba Research Institute, Department of Psychiatry, Araba University Hospital, Vitoria, 01004, Spain; 3CIBERSAM, University of the Basque Country, Vitoria, Spain; 4Copenhagen Affective Disorder research Centre (CADIC), Psychiatric Centre, Copenhagen, Denmark; 5Copenhagen, Copenhagen University Hospital, Rigshospitalet, Denmark; 6Department of Psychology, University of Copenhagen, Copenhagen, Denmark; 7Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, 4710-057, Portugal; 8ICVS/3B’s, PT Government Associate Laboratory, Braga/Guimarães, 4710-057, Portugal; 9Clinical Academic Center-Braga (2CA), Braga, 4710-243, Portugal; 10Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK; 11South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Kent, UK; 12Bipolar and Depressive Disorders Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, SpainCorrespondence: Andrea Fagiolini, Department of Molecular and Developmental Medicine, Division of Psychiatry, University of Siena School of Medicine, Viale Bracci 12, Siena, 53100, Italy, Tel +39- 0577-586275, Email andreafagiolini@gmail.com; andrea.fagiolini@unisi.itObjective: Major depressive disorder (MDD) often co-occurs with dementia and other neurological disorders, and treatment with antidepressants can improve symptoms, quality of life, and survival in these patients. This narrative review provides an expert opinion about the role and effectiveness of trazodone in the treatment of older adults with MDD and cognitive impairment due to physical illnesses, such as dementia.Results: Because of its mechanism of action, trazodone can treat several depression symptoms often seen in people with dementia, including insomnia, agitation, anxiety, cognitive impairment, and irritability.Conclusion: Trazodone may be beneficial for patients with dementia or other neurological disorders comorbid with MDD, especially when the clinical picture of depression includes or is comorbid to symptoms of insomnia, irritability, inner tension, anxiety, or psychomotor agitation.Keywords: major depressive disorder, depression, dementia, cognitive impairment, trazodone

Beatrice Bortolato,1 Kamilla W Miskowiak,2 Cristiano A Köhler,3 Eduard Vieta,4 André F Carvalho3 1Department of Mental Health, ULSS 10 “Veneto Orientale”, Venice, Italy; 2Psychiatric Centre Copenhagen, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 3Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil; 4Bipolar Disorders Program, Institute of Neuroscience, Hospital Clínic Barcelona, IDIBAPS, CIBERSAM, University of Barcelona, Catalonia, Spain Abstract: Cognitive impairment is a core feature of schizophrenia (SZ) and bipolar disorder (BD). A neurocognitive profile characterized by widespread cognitive deficits across multiple domains in the context of substantial intellectual impairment, which appears to antedate illness onset, is a replicated finding in SZ. There is no specific neuropsychological signature that can facilitate the diagnostic differentiation of SZ and BD, notwithstanding, neuropsychological deficits appear more severe in SZ. The literature in this field has provided contradictory results due to methodological differences across studies. Meta-analytic techniques may offer an opportunity to synthesize findings and to control for potential sources of heterogeneity. Here, we performed a systematic review of meta-analyses of neuropsychological findings in SZ and BD. While there is no conclusive evidence for progressive cognitive deterioration in either SZ or BD, some findings point to more severe cognitive deficits in patients with early illness onset across both disorders. A compromised pattern of cognitive functioning in individuals at familiar and/or clinical risk to psychosis as well as in first-degree relatives of BD patients suggests that early neurodevelopmental factors may play a role in the emergence of cognitive deficits in both disorders. Premorbid intellectual impairment in SZ and at least in a subgroup of patients with BD may be related to a shared genetically determined influence on neurodevelopment. Keywords: schizophrenia, bipolar disorder, psychosis, neuropsychological tests, cognition, meta-analysis, psychiatry

Background: More ecologically valid tools are needed to better capture daily-life cognitive impairments in patients with mood or psychosis spectrum disorders in clinical settings and cognitive treatment trials. We developed the Cognition Assessment in Virtual Reality (CAVIR) test, which assesses daily-life cognitive skills in an immersive virtual reality kitchen scenario. This study investigated the validity and sensitivity of CAVIR, including its association with activities of daily living (ADL) ability., Methods: 70 symptomatically stable patients with mood or psychosis spectrum disorders and 70 healthy controls completed CAVIR and standard neuropsychological tests and were rated for clinical symptoms, functional capacity, and subjective cognition. In addition, patients' ADL ability was evaluated with the Assessment of Motor and Process Skills (AMPS)., Results: Higher global CAVIR performance correlated moderately with better global neuropsychological test scores (r s (138) = 0.60, p < 0.001) and showed a weak to moderate association with better ADL process ability in patients (r(45) = 0.40, p < 0.01), also after adjusting for sex and age (p s  ≤ 0.03). In comparison, neuropsychological performance, interviewer- and performance-based functional capacity, and subjective cognition were not significantly associated with ADL process ability (p s  ≥ 0.09). Further, CAVIR was sensitive to cognitive impairments in patients and was able to differentiate between patients with and without the ability to undertake regular employment., Limitations: The modest sample size and concomitant medication., Conclusion: Our results indicate that CAVIR is a sensitive measure of daily-life cognitive skills in patients with mood or psychosis spectrum disorders., Competing Interests: Declaration of competing interest Kamilla Miskowiak has received consultancy fees from Lundbeck, Angelini, Gedeon Richter, and Janssen-Cilag in the past four years, and Maj Vinberg has received consultancy fees from Lundbeck and Janssen-Cilag within the past three years. The remaining authors report no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Cognitive impairment is prevalent across neuropsychiatric disorders but there is a lack of treatment strategies with robust, enduring effects. Emerging evidence indicates that altitude-like hypoxia cognition training may induce long-lasting neuroplasticity and improve cognition. We will investigate whether repeated cognition training under normobaric hypoxia can improve cognitive functions in healthy individuals and patients with affective disorders and the neurobiological underpinnings of such effects., Methods: In sub-study 1, 120 healthy participants are randomized to one of four treatment arms in a double-blind manner, allowing for examination of separate and combined effects of three-week repeated moderate hypoxia and cognitive training, respectively. In sub-study 2, 60 remitted patients with major depressive disorder or bipolar disorder are randomized to hypoxia with cognition training or treatment as usual. Assessments of cognition, psychosocial functioning, and quality of life are performed at baseline, end-of-treatment, and at 1-month follow-up. Functional magnetic resonance imaging (fMRI) scans are conducted at baseline and 1-month follow-up, and [ 11 C]UCB-J positron emission tomography (PET) scans are performed at end-of-treatment to quantify the synaptic vesicle glycoprotein 2A (SV2A). The primary outcome is 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 with minimum n = 26 per treatment arm. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data is analyzed with the FMRIB Software Library, while PET data is quantified using the simplified reference tissue model (SRTM) with centrum semiovale as reference region., Discussion: The results will provide novel insights into whether repeated hypoxia cognition training increases cognition and brain plasticity, which can aid future treatment development strategies., Trial Registration: ClinicalTrials.gov, NCT06121206 . Registered on 31 October 2023., (© 2024. The Author(s).)

Hypoxia is more and more perceived as pivotal physiological driving force, allowing cells in the brain and elsewhere to acclimate to lowered oxygen (O 2 ), and abridged metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks, provoking a relative decrease in O 2 in relation to the acutely augmented requirement. We termed this fundamental, demand-dependent drop in O 2 availability "functional hypoxia." Major players in the hypoxia response are hypoxia-inducible factors (HIFs) and associated prolyl-hydroxylases. HIFs are transcription factors, stabilized by low O 2 accessibility, and control expression of a multitude of genes. Changes in oxygen, however, can also be sensed via other pathways, among them the thiol-oxidase (2-aminoethanethiol) dioxygenase. Considering the far-reaching biological response to hypoxia, hitherto mostly observed in rodents, we initiated a translational project, combining mild to moderate inspiratory with functional hypoxia. We had identified this combination earlier to benefit motor-cognitive attainment in mice. A total of 20 subjects were included: 13 healthy individuals and 7 patients with depression and/or autism spectrum disorder. Here, we show that motor-cognitive training under inspiratory hypoxia (12% O 2 ) for 3.5 h daily over 3 weeks is optimally tolerated. We present first signals of beneficial effects on general well-being, cognitive performance, physical fitness and psychopathology. Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia. To obtain reliable information regarding the "add-on" value of inspiratory on top of functional hypoxia, induced by motor-cognitive training, a single-blind study-with versus without inspiratory hypoxia-is essential and outlined here., Competing Interests: Conflict of Interest Statement The authors declare no conflict of interest.

Electroconvulsive therapy (ECT) demonstrates favorable outcomes in the management of severe depressive disorders. ECT has been consistently associated with volumetric increases in the amygdala and hippocampus. However, the underlying mechanisms of these structural changes and their association to clinical improvement remains unclear. In this cross-sectional structural MRI study, we assessed the difference in amygdala subnuclei and hippocampus subfields in n = 37 patients with either unipolar or bipolar disorder immediately after eighth ECT sessions compared to (n = 40) demographically matched patients in partial remission who did not receive ECT (NoECT group). Relative to NoECT, the ECT group showed significantly larger bilateral amygdala volumes post-treatment, with the effect originating from the lateral, basal, and paralaminar nuclei and the left corticoamydaloid transition area. No significant group differences were observed for the hippocampal or cortical volumes. ECT was associated with a significant decrease in depressive symptoms. However, there were no significant correlations between amygdala subnuclei volumes and symptom improvement. Our study corroborates previous reports on increased amygdalae volumes following ECT and further identifies the subnuclei driving this effect. However, the therapeutic effect of ECT does not seem to be directly related to structural changes in the amygdala., Competing Interests: Declaration of competing interest KWM has received consultancy fees from Lundbeck, Janssen, Angelini Pharma and Richter Gedeon in the past three years. JZP has within the last three years received honoraria from Lundbeck Pharma. LVK has within recent three years been a consultant for Lundbeck and Teva A/S. JM, SC, EBKS, ATYN, MBJ report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Postpartum depression (PPD) affects 30-50% of women with a history of previous depression or bipolar disorder and 8% of women with no history of depression. Negative cognitive biases in the perception of infant cues and difficulties with emotion regulation are replicated risk factors. Current interventions focus on detecting and treating rather than preventing PPD. The aim of this randomized controlled intervention trial is therefore to investigate the potential prophylactic effects of prenatal affective cognitive training for pregnant women at heightened risk of PPD., Methods: The study will enrol a total of 292 pregnant women: 146 at high risk and 146 at low risk of PPD. Participants undergo comprehensive assessments of affective cognitive processing, clinical depressive symptoms, and complete questionnaires at baseline. Based on the responses, pregnant women will be categorized as either at high or low risk of PPD. High-risk participants will be randomized to either prenatal affective cognitive training (PACT) or care as usual (CAU) immediately after the baseline testing. The PACT intervention is based on emerging evidence for efficacy of affective cognitive training approaches in depression, including cognitive bias modification, attention bias modification, mindfulness-inspired emotion regulation exercises, and working memory training. Participants randomised to PACT will complete five individual computerised and virtual reality-based training sessions over 5 weeks. The primary outcome is the difference between intervention arms in the incidence of PPD, assessed with an interview 6 months after birth. We will also assess the severity of depressive symptoms, rated weekly online during the first 6 weeks postpartum., Discussion: The results will have implications for future early prophylactic interventions for pregnant women at heightened risk of PPD. If the PACT intervention reduces the incidence of PPD, it can become a feasible, non-invasive prophylactic strategy during pregnancy, with positive mental health implications for these women and their children., Trial Registration: ClinicalTrials.gov NCT06046456 registered 21-09-2023, updated 08-07-2024., (© 2024. The Author(s).)

Comprehensive knowledge of factors causing and sustaining functional impairment in patients with affective disorders is warranted. The aim is to investigate associations between clinical factors (such as affective symptoms) and personal factors (such as personality traits, coping strategies, and childhood trauma experiences) on functioning and improvement of functioning in patients with affective disorders. This exploratory study includes data from 103 patients with bipolar disorder and unipolar depressive disorder. Clinician-rated functioning was assessed at baseline using the Functioning Assessment Short Test (FAST), and performance-based functioning was assessed at baseline and 6-month follow-up using the Assessment of Motor and Process Skills (AMPS). Data on clinical and personal factors were collected at baseline. Personal factors were measured by the Eysenck Personality Inventory (EPQ), Coping Inventory for Stressful Situations (CISS) and Childhood Trauma Questionnaire (CTQ). Pearson correlations and multiple linear regression models were used to analyse the association of clinical and personal factors with baseline functioning (FAST) and to identify predictors of improvement in functioning (AMPS) from baseline to follow-up. At baseline, greater depressive symptom severity, the personality trait neuroticism, emotional coping, and childhood trauma all correlated with poorer functioning (higher FAST scores). In multiple linear regression models, depression severity, emotional coping and childhood trauma were significant predictors of poorer functioning. More childhood trauma was a predictor of less functional improvement measured by AMPS at 6-month follow-up. In conclusion, maladaptive coping styles and depressive symptoms contribute to functional impairment in patients with affective disorders, while childhood trauma has a negative impact on long-term functional outcomes., Competing Interests: Declaration of competing interest RS has within the last three years been a speaker/consultant for Lundbeck. KWM has received honoraria from Lundbeck, Janssen-Cilag, Gideon Richter and Angelini in the past three years. LVK has within the last three years been a consultant for Lundbeck and Teva. MV has within the last three years been a speaker/consultant for Lundbeck and JanssenCilag., (Copyright © 2024. Published by Elsevier Ltd.)

Bipolar disorder (BD) is often accompanied by persistent cognitive impairment. However, screening for cognitive impairment in the clinic is challenged by a lack of consensus on screening procedures. This study assesses cognitive impairment prevalence and screening feasibility in alignment with the International Society for Bipolar Disorder Targeting Cognition Task Force recommendations. Between January 2022 and May 2023, 136 newly diagnosed BD outpatients were assessed with the Screen for Cognitive Impairment in Psychiatry after 15-20 months of specialised care at the Copenhagen Affective Disorder Clinic. Cognitive impairment patterns and associations with cognitive complaints, perceived stress, and functioning were examined. Most screened patients (73 %) achieved full or partial remission, with 51 % being cognitively normal, 38 % showing global impairments, and 11 % displaying selective impairments. Among remitted patients, 56 % were cognitively normal, while 31 % and 13 % exhibited global or selective impairments, respectively. Both objectively impaired patient groups reported more subjective cognitive difficulties than those who were cognitively normal. The globally impaired group also demonstrated poorer functioning, more depressive symptoms and lower quality of life than cognitively normal patients. Across all patients, lower cognitive performance correlated with more cognitive complaints, lower functioning, lower quality of life, and more depressive symptoms. Cognitive screenings were relatively easily implementable, involving only a 1.5 h session including mood ratings, feedback and cognitive strategy discussion. The study highlights the clinical relevance and feasibility of cognitive screenings in BD patients, emphasizing the need for tailored interventions given frequent cognitive impairment in clinically stable individuals., Competing Interests: Declaration of competing interest KWM reports having received consultancy fees from Lundbeck, Angelini, Gideon Richter and Janssen-Cilag in the past three years. LVK reports having received consultancy fees from Lundbeck and Teva in the past three years. JM, TR, JLB, ZKO, LH and report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to investigate the neural underpinnings of emotional cognition subgroups in recently diagnosed patients with bipolar disorder (BD) and change over time over a 15-month follow-up period., Methods: Patients and healthy controls (HC) underwent emotional and nonemotional cognitive assessments and functional magnetic resonance imaging (fMRI) at the baseline (BD n = 87; HC n = 65) and at 15-month follow-up (BD n = 44; HC n = 38). Neural activity during emotion reactivity and regulation in response to aversive pictures was assessed during fMRI. Patients were clustered into subgroups based on their emotional cognition and, with HC, were compared longitudinally on cognition and neural activity during emotion reactivity and regulation., Results: Patients were optimally clustered into two subgroups: Subgroup 1 (n = 40, 46%) was characterized by heightened emotional reactivity in negative social scenarios, which persisted over time, but were otherwise cognitively intact. This subgroup exhibited stable left amygdala hyper-activity over time during emotion reactivity compared to subgroup 2. Subgroup 2 (n = 47, 54%) was characterized by global emotional cognitive impairments, including stable difficulties with emotion regulation over time. During emotion regulation across both time points, this group exhibited hypo-activity in the left dorsolateral prefrontal cortex. Additionally, patients in subgroup 2 had poorer nonemotional cognition, had more psychiatric hospital admissions and history of psychotic episodes than those in subgroup 1., Conclusions: Broad impairments in emotional cognition in approximately half of BD patients and associated nonemotional cognitive deficits may originate from insufficient recruitment of prefrontal resources, contributing to poorer clinical outcomes., (© 2024 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Physiological, neurocognitive, and psychological changes facilitates adaptation to motherhood. This cross-sectional study aimed to examine differences between pregnant and non-pregnant women in affective cognitive and psychophysiological responses to infant stimuli. We hypothesized that pregnant women would display (I) reduced negative emotional reactivity and perception of distressed infant stimuli, (II) increased attention toward infants compared to adults, and (III) greater psychophysiological response to infant distress. The sample comprised 22 pregnant women (22-38 weeks gestation) and 18 non-pregnant nulliparous women. Four computerized tasks were administered to measure affective cognitive processing of infant stimuli, while recording facial expressions, electrodermal activity, and eye gazes. Results indicated that pregnant women exhibited fewer negative facial expressions, reported less frustration when exposed to distressed infant cries, and showed greater attention to emotional infant faces compared to non-pregnant women, but the differences did not remain statistically significant after correction for multiple comparisons. No differences were observed in psychophysiological responses. The findings indicate a possible pregnancy-mediated effect regarding the cognitive processing of infant stimuli, potentially as preparation for motherhood. Future research with larger samples and longitudinal design is needed to understand the predictors, timing, and plasticity of cognitive changes during pregnancy.

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

Background: Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD., Methods: We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials., Results: Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias., Conclusions: Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers., (© 2024 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Background: There is a significant contribution of genetic factors to the etiology of bipolar disorder (BD). Unaffected first-degree relatives of patients (UR) with BD are at increased risk of developing mental disorders and may manifest cognitive impairments and alterations in brain functional and connective dynamics, akin to their affected relatives., Methods: In this prospective longitudinal study, resting-state functional connectivity was used to explore stable and progressive markers of vulnerability i.e. abnormalities shared between UR and BD compared to healthy controls (HC) and resilience i.e. features unique to UR compared to HC and BD in full or partial remission (UR n = 72, mean age = 28.0 ± 7.2 years; HC n = 64, mean age = 30.0 ± 9.7 years; BD patients n = 91, mean age = 30.6 ± 7.7 years). Out of these, 34 UR, 48 BD, and 38 HC were investigated again following a mean time of 1.3 ± 0.4 years., Results: At baseline, the UR showed lower connectivity values within the default mode network (DMN), frontoparietal network, and the salience network (SN) compared to HC. This connectivity pattern in UR remained stable over the follow-up period and was not present in BD, suggesting a resilience trait. The UR further demonstrated less negative connectivity between the DMN and SN compared to HC, abnormality that remained stable over time and was also present in BD, suggesting a vulnerability marker., Conclusion: Our findings indicate the coexistence of both vulnerability-related abnormalities in resting-state connectivity, as well as adaptive changes possibly promoting resilience to psychopathology in individual at familial risk.

Aim: This naturalistic clinical study aims to investigate differences between newly diagnosed patients with bipolar type I (BDI) and bipolar type II (BDII) disorders in socio-demographic and clinical characteristics, affective symptoms, cognition, functioning and comorbidity with personality disorders., Methods: The BD diagnosis and type were confirmed using the Schedules for Clinical Assessment in Neuropsychiatry. Affective symptoms were assessed with the Young Mania Rating Scale, the Hamilton Depression Rating Scale, the Major Depressive Index, and the Altman Self-Rating Mania Scale. Functional impairment was assessed with the Functional Assessment Short Test. Cognitive impairment was evaluated by the Screen for Cognitive Impairment in Psychiatry and the Cognitive Complaints in Bipolar Disorder Rating Assessment. Finally, comorbid personality disorders were assessed with the Standardized Assessment of Personality-Abbreviated Scale and structured interview Structured Clinical Interview for DSM-disorders., Results: 383 newly diagnosed patients were included (BDI: n = 125; BDII: n = 258). Against expectations, we found no more depressive symptoms in BDII compared with BDI nor any differences in cognitive, childhood trauma or overall functional impairment. The only difference was lower occupational impairment in the BDII group., Limitations: The self-reported measures of cognitive difficulties and childhood trauma involved potential bias (recall or other). Despite BD being newly diagnosed a diagnostic delay was observed., Conclusion: Patients newly diagnosed with BDII and BDI had similar burdens of depressive symptoms and cognitive and overall functional impairment, however patients with BDI had lower occupational functioning. No statistically significant difference was found in prevalence of comorbid personality disorders between patients with BDI and BDII., Competing Interests: Declaration of competing interest KWM has received honoraria from Lundbeck, Allergan, Janssen and Angelini within the past three years. MV has received honoraria from Lundbeck and JanssenCilag within the last three years. LVK have been a consultant for Lundbeck and Teva within the past three years. KC, OVK, HLK and MFJ report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Bipolar disorders (BD) figures on top of the World Health Organization classification of disabling disorders. It is unclear if there are socioeconomic, functioning, and cognition differences in young patients newly diagnosed with BD and whether these are different for young and adult patients newly diagnosed with BD. Understanding these differences is important for tailored treatment and support., Methods: Participant groups included 401 patients newly diagnosed with BD, 145 of their unaffected first-degree relatives (UR) and 209 healthy control individuals (HC). First, we compared socio-economic status, functioning and cognition between young patients newly diagnosed with BD (150), UR (61) and HC (92) (15-25 years) and adult patients newly diagnosed with BD (251), UR (84) and HC (117) (>25 years), respectively. Second, within patients, we compared functioning and cognition between young and adult patients newly diagnosed with BD., Results: In both participant groups, patients newly diagnosed with BD, and to a lesser degree UR, had lower socio-economic status and impaired functioning and cognition compared with HC. Further, young patients newly diagnosed with BD were less functionally impaired, than adults newly diagnosed with BD, whereas cognition did not differ between groups., Limitations: Applied tools for assessments of functioning and cognition are not validated below age 18., Conclusions: Overall, lower socio-economic status and impaired functioning and cognition were found both in young and adult patients newly diagnosed with BD and their UR compared with young and adult HC, respectively. Young patients were less functionally impaired than adults, but cognition was similarly impaired., Competing Interests: Declaration of competing interest CS, SS, KC, HLK, MFJ, and KP have no competing interests. KS has given educational talks and received honoraria from Lundbeck within the past three years. KWM has received honoraria from Lundbeck, Allergan, Janssen and Angelini within the past three years. MV has received honoraria from Lundbeck and JanssenCilag within the last three years. LVK have been a consultant for Lundbeck and Teva within the past three years., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Competing Interests: Conflicts of interest KWM has received consultancy fees from Lundbeck, Gedeon Richter, Angelini and Janssen-Cilag in the past three years. HLK has received consultancy feed from Lundbeck in the past three years.

Objectives: Identification of comorbid attention-deficit/hyperactivity disorder (ADHD) in patients with bipolar disorder (BD) is complicated by overlapping cognitive symptoms and methodological challenges. This cross-sectional study investigated whether virtual reality (VR)-based cognitive assessment that mimics daily life cognitive challenges can aid in the detection of sustained attention impairment in BD individuals with comorbid ADHD (BD + ADHD)., Methods: Forty-nine fully or partially remitted outpatients with BD, of whom 14 (24%) had BD + ADHD, were assessed with the Cognition Assessment in Virtual Reality (CAVIR) test, including a sustained attention test that involves distractions, and the Screen for Cognitive Impairment in Psychiatry (SCIP). Patients were also rated for mood symptoms and functioning and completed questionnaires assessing subjective cognition and quality of life. Patients' cognitive impairment on the SCIP was estimated with reference to n  = 100 demographically comparable healthy control participants., Results: BD + ADHD participants exhibited more pronounced performance deficits on the CAVIR sustained attention test ( t (48) = 2.15, p = .037, d = .66). Notably, deficits on this test were proportional to self-reported daily life concentration difficulties in BD + ADHD individuals. Exploratory analyses revealed that BD + ADHD participants also displayed greater impairment on the SCIP working memory- and delayed verbal learning subtests and greater subjective cognitive complaints than BD patients without this comorbidity (p-levels < .001), but only the difference in subjective cognition survived correction for multiple comparisons ( F (1,47) = 14.13, p = .005, np2  = 0.24)., Conclusion: Screening for deficits in sustained attention with an ecologically valid VR test involving distracting stimuli may be useful for identifying BD + ADHD individuals.

Background: Persistent cognitive impairment is frequent across bipolar disorder (BD) and major depressive disorder (MDD), highlighting an urgent need for pro-cognitive treatments., Aim: This study investigated effects of erythropoietin (EPO) on cognitive impairment and dorsal prefrontal cortex (dPFC) activity in affective disorders., Methods: In this randomized, double-blinded, placebo-controlled trial, cognitively impaired patients with remitted BD or MDD received 1 weekly recombinant human EPO (40,000 IU/mL) or saline infusion for a 12-week period. Assessments were conducted at baseline, after 2 weeks of treatment (week 3), immediately after treatment (week 13) and at 6-months follow-up. Participants underwent functional MRI during performance on a n-back working memory (WM) task at baseline and week 3, and for a subgroup 6 weeks post-treatment (week 18). The primary outcome was a cognitive composite score at week 13, whereas secondary outcomes comprised sustained attention and functioning. WM-related dPFC activity was a tertiary outcome., Results: Data were analysed for 101 of the 103 included patients (EPO, n = 58; saline, n = 43). There were no effects of EPO over saline on any cognitive or functional outcomes or on WM-related dPFC activity., Conclusions: The absence of treatment-related changes in cognition and neural activity was unexpected and contrasts with multiple previous preclinical and clinical studies. It is possible that the lack of effects resulted from a recent change in the manufacturing process for EPO. Nevertheless, the findings support the validity of dPFC target engagement as a biomarker model for pro-cognitive effects, according to which treatments that do not improve cognition should not modulate dPFC activity., Trial Registrations: EudraCT no.: 2016-004023-24; ClinicalTrials.gov identifier: NCT03315897., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JMAC, JMAR, AEJ, KC, CFB, HM, HE, PMF, IH and MBJ report no conflicts of interest. JZP has within the last 3 years received honoraria from Lundbeck Pharma A/S. MV has within the last 3 years received consultancy fees from Janssen Cilag and Lundbeck. GMK has received honoraria as a speaker for Sage Biogen, Angelini and H Lundbeck and as a consultant for Sanos, Onsero, Pangea, Gilgamesh and Puretech Health. LVK has within recent 3 years been a consultant for Lundbeck and Teva. KWM has received consultancy fees from Lundbeck and Janssen in the past 3 years.

Excessive oxidative stress-generated nucleoside damage seems to play a key role in bipolar disorder (BD) and may present a trait phenomenon associated with familial risk and is one of the putative mechanisms explaining accelerated atherosclerosis and premature cardiovascular diseases (CVD) in younger patients with BD. However, oxidative stress-generated nucleoside damage has not been studied in young BD patients and their unaffected relatives (UR). Therefore, we compared oxidative stress-generated damage to DNA and RNA in young patients newly diagnosed with BD, UR, and healthy control individuals (HC). Systemic oxidative stress-generated DNA and RNA damage levels were compared by analyzing urinary levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine in participants aged 15-25 years, including 133 patients newly diagnosed with BD, 57 UR, and 83 HC. Compared with HC, damage to DNA was 21.8% higher in BD patients (B = 1.218, 95% CI = 1.111-1.335, p = <0.001) and 22.5% higher in UR (B = 1.225, 95% CI = 1.090-1.377, p = <0.002), while damage to RNA was 14.8% higher in BD patients (B = 1.148, 95% CI = 1.082-1.219, p = <0.001) and 14.0% higher in UR (B = 1.140, 95% CI = 1.055-1.230, p = < 0.001) in models adjusted for sex and age after correction for multiple comparison. Levels did not differ between patients with BD and UR. Our findings support higher oxidative stress-generated nucleoside damage being a trait phenomenon in BD associated with familial risk and highlight the importance of early diagnosis and treatment to prevent illness progression and development of premature CVD., (© 2024. The Author(s).)

Background: Electroconvulsive therapy (ECT) is an efficient and rapid-acting treatment indicated for severe depressive disorders. While ECT is commonly accompanied by transient memory decline, the brain mechanisms underlying these side effects remain unclear., Aims: In this exploratory functional magnetic resonance (fMRI) study, we aimed to compare effects of ECT versus pharmacological treatment on neural response during episodic memory encoding in patients with affective disorders., Methods: This study included 32 ECT-treated patients (major depressive disorder (MDD), n  = 23; bipolar depression, n  = 9) and 40 partially remitted patients in pharmacological treatment (MDD, n  = 24; bipolar disorder, n  = 16). Participants underwent neuropsychological assessment, a strategic picture encoding fMRI scan paradigm, and mood rating. The ECT group was assessed before ECT (pre-ECT) and 3 days after their eighth ECT session (post-ECT)., Results: Groups were comparable on age, gender, and educational years ( p s ⩾ 0.05). Within-group analyses revealed a selective reduction in verbal learning and episodic memory pre- to post-ECT ( p  = 0.012) but no decline in global cognitive performance ( p  = 0.3). Functional magnetic resonance imaging analyses adjusted for mood symptoms revealed greater activity in ECT-treated patients than pharmacologically treated No-ECT patients across left precentral gyrus (PCG), right dorsomedial prefrontal cortex (dmPFC), and left middle frontal gyrus (MFG). In ECT-treated patients, greater decline in verbal learning and memory performance from pre- to post-ECT correlated with higher PCG response ( r  = -0.46, p  = 0.008), but not with dmPFC or MFG activity ( p s ⩾ 0.1), post-ECT., Conclusions: Episodic memory decline was related to greater neural activity in the left PCG, but unrelated to increased dmPFC and MFG activity, immediately after ECT., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JZP has within the last 3 years received honoraria from Lundbeck Pharma A/S. LVK has within the last 3 years been a consultant for Lundbeck and Teva. KWM has received consultancy fees from Lundbeck, Janssen, Angelini Pharma and Richter Gedeon in the past 3 years. JMAC, ATYN, and MBJ report no conflicts of interest.

First-degree relatives of patients with bipolar disorder are at heightened risk of mood episodes, which may be attributed to the existence of endophenotypes i.e., heritable (neuro)biological changes present in patients and their unaffected relatives (UR). In this longitudinal MRI study, we aim to investigate the trajectories of aberrant reward-related functional changes identified in UR vs healthy controls (HC). Sixty-eight UR and 65 HC of similar age and gender distribution underwent MRI at baseline while performing a card guessing task. Of these, 29 UR and 36 HC were investigated with the same protocol following a 16-month period in average. We first identified brain regions showing group differences in the neural response to expected value (EV) and reward prediction error (PE) at baseline and analyzed how the reward-related response in these regions changed over time in UR vs HC. Relative to HC at baseline, UR showed lower EV signal in the right ventrolateral prefrontal cortex (vlPFC) and paracingulate gyrus and lower PE signal in the left vlPFC and dorsomedial PFC. The trajectories of these abnormalities in UR showed a normalization of the prefrontal EV signals, whereas the PE signals which correlated with depressive symptoms remained stable over time. While the UR showed both blunted EV and PE signals, none of these abnormalities increased over time, which is consistent with the observed stable mood symptoms., Competing Interests: Declaration of competing interest In the past three years KWM has received consultancy fees from Lundbeck and Janssen, LVK has been a consultant for Lundbeck and Teva, MV has been a consultant for Lundbeck and Janssen Cilag, GMK has received honoraria as speaker for Sage/Biogen and as a consultant for Sanos. The remining authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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

Background: Cognitive impairments are prevalent across mood disorders and psychosis spectrum disorders, but there is a lack of real-life-like cognitive training programmes. Fully immersive virtual reality has the potential to ensure motivating and engaging cognitive training directly relevant to patients' daily lives. We will examine the effect of a 4-week, intensive virtual reality-based cognitive remediation programme involving daily life challenges on cognition and daily life functioning in patients with mood disorders or psychosis spectrum disorders and explore the neuronal underpinnings of potential treatment efficacy., Methods: The trial has a randomized, controlled, double-blinded, parallel-group design. We will include 66 symptomatically stable outpatients with mood disorders or psychosis spectrum disorders aged 18-55 years with objective and subjective cognitive impairment. Assessments encompassing a virtual reality test of daily life cognitive skills, neuropsychological testing, measures of daily life functioning, symptom ratings, questionnaires on subjective cognitive complaints, and quality of life are carried out at baseline, after the end of 4 weeks of treatment and at a 3-month follow-up after treatment completion. Functional magnetic resonance imaging scans are performed at baseline and at the end of treatment. The primary outcome is a broad cognitive composite score comprising five subtasks on a novel ecologically valid virtual reality test of daily life cognitive functions. Two complete data sets for 54 patients will provide a power of 80% to detect a clinically relevant between-group difference in the primary outcome. Behavioural data will be analysed using linear mixed models in SPSS, while MRI data will be analysed with the FMRIB Expert Analysis Tool (FEAT). Treatment-related changes in neural activity from baseline to end of treatment will be investigated for the dorsal prefrontal cortex and hippocampus as the regions of interest., Discussion: The results will provide insight into whether virtual reality-based cognitive remediation has beneficial effects on cognition and functioning in symptomatically stable patients with mood disorders or psychosis spectrum disorders, which can aid future treatment development., Trial Registration: ClinicalTrials.gov NCT06038955. Registered on September 15, 2023., (© 2024. The Author(s).)

Background: Bipolar disorder (BD) is commonly associated with cognitive impairments, that directly contribute to patients' functional disability. However, there is no effective treatment targeting cognition in BD. A key reason for the lack of pro-cognitive interventions is the limited insight into the brain correlates of cognitive impairments in these patients. This is the first study investigating the resting-state neural underpinnings of cognitive impairments in different neurocognitive subgroups of patients with BD., Method: Patients with BD in full or partial remission and healthy controls (final sample of n = 144 and n = 50, respectively) underwent neuropsychological assessment and resting-state functional magnetic resonance imaging. We classified the patients into cognitively impaired (n = 83) and cognitively normal (n = 61) subgroups using hierarchical cluster analysis of the four cognitive domains. We used independent component analysis (ICA) to investigate the differences between the neurocognitive subgroups and healthy controls in resting-state functional connectivity (rsFC) in the default mode network (DMN), executive central network (ECN), and frontoparietal network (FPN)., Results: Cognitively impaired patients displayed greater positive rsFC within the DMN and less negative rsFC within the ECN than healthy controls. Across cognitively impaired patients, lower positive connectivity within DMN and lower negative rsFC within ECN correlated with worse global cognitive performance., Conclusion: Cognitive impairments in BD seem to be associated with a hyper-connectivity within the DMN, which may explain the failure to suppress task-irrelevant DMN activity during the cognitive performance, and blunted anticorrelation in the ECN. Thus, aberrant connectivity within the DMN and ECN may serve as brain targets for pro-cognitive interventions., (© 2023 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Emerging evidence highlights moderate hypoxia as a candidate treatment for brain disorders. This systematic review examines findings and the methodological quality of studies investigating hypoxia (10-16% O 2 ) for ≥14 days in humans, as well as the neurobiological mechanisms triggered by hypoxia in animals, and suggests optimal treatment protocols to guide future studies. We followed the preferred reporting items for systematic reviews and meta-analysis (PRISMA) 2020. Searches were performed on PubMed/MEDLINE, PsycInfo, EMBASE, and the Cochrane Library, in May-September 2023. Two authors independently reviewed the human studies with the following tools: (1) revised Cochrane collaboration's risk of bias for randomized trials 2.0; (2) the risk of bias in nonrandomized studies of interventions. We identified 58 eligible studies (k = 8 human studies with N = 274 individuals; k = 48 animal studies) reporting the effects of hypoxia on cognition, motor function, neuroimaging, neuronal/synaptic morphology, inflammation, oxidative stress, erythropoietin, neurotrophins, and Alzheimer's disease markers. A total of 75% of human studies indicated cognitive and/or neurological benefits, although all studies were evaluated ashigh risk of bias due to a lack of randomization and assessor blinding. Low-dose intermittent or continuous hypoxia repeated for 30-240 min sessions, preferably in combination with motor-cognitive training, produced beneficial effects, and high-dose hypoxia with longer (≥6 h) durations and chronic exposure produced more adverse effects. Larger and methodologically stronger translational studies are warranted.

Background: Persistent cognitive deficits are prevalent in patients with bipolar disorder (BD) and unipolar disorder (UD), but treatments effectively targeting cognition in these mood disorders are lacking. This is partly due to poor insight into the neuronal underpinnings of cognitive deficits., Methods: The aim of this functional magnetic resonance imaging (fMRI) study was to investigate the neuronal underpinnings of working memory (WM)-related deficits in somatically healthy, remitted patients with BD or UD ( n = 66) with cognitive and functional impairments compared to 38 healthy controls (HC). The participants underwent neuropsychological testing and fMRI, while performing a visuospatial and a verbal N -back WM paradigm., Results: Relative to HC, patients exhibited hypo -activity across dorsolateral prefrontal cortex as well as frontal and parietal nodes of the cognitive control network (CCN) and hyper -activity in left orbitofrontal cortex within the default mode network (DMN) during both visuospatial and verbal WM performance. Verbal WM-related response in the left posterior superior frontal gyrus (SFG) within CCN was lower in patients and correlated positively with out-of-scanner executive function performance across all participants., Conclusions: Our findings suggest that cognitive impairments across BD and UD are associated with insufficient recruitment of task-relevant regions in the CCN and down-regulation of task-irrelevant orbitofrontal activity within the DMN during task performance. Specifically, a lower recruitment of the left posterior SFG within CCN during verbal WM was associated with lower cognitive performance.

Background: Patients with bipolar disorder (BD) who are presenting with cognitive impairment and associated structural brain abnormalities have generally a poorer clinical outcome. This study aims to map the early longitudinal trajectories in brain structure and cognition in patients with recently diagnosed BD., Methods: Fully or partially remitted patients with a recent diagnosis of BD and matched healthy controls (HC) underwent structural MRI and neuropsychological testing at baseline (BD n = 97; HC n = 66) and again following an average of 16 (range 6-27) months (BD n = 50; HC n = 38). We investigated the differential trajectories in BD vs. HC in cortical gray matter volume and thickness, total cerebral white matter, hippocampal and amygdala volumes, estimated brain age, and cognitive functioning using linear mixed models. Within patients, we further investigated whether brain structural abnormalities detected at baseline were associated with subsequent mood episodes., Results: Compared to HC, patients showed a decline in total white matter volume over time and they had a larger amygdala volume, both at baseline and at follow-up time. Patients further showed lower cognitive performance at both times of investigation with no significant change over time. There were no differences between patients and HC in cortical gray matter volume or thickness, hippocampal volume, or brain-aging patterns., Conclusions: Cognitive impairment and amygdala enlargement may represent stable markers of BD early in the course of illness, whereas subtle white matter decline may result from illness progression., Competing Interests: Declaration of competing interest In the past three years, KWM has received consultancy fees from Lundbeck and Janssen, LVK has within recent three years been a consultant for Lundbeck and Teva, GMK has received honoraria as a speaker for Sage Biogen and as a consultant for Sanos, MV has received consultancy fee from Lundbeck and Janssen-Cilag, and LNY has been on speaker/advisory boards for, or has received research grants from Abbvie, Alkermes, Allergan, Canadian Network for Mood and Anxiety Treatments (CANMAT), Canadian Institutes of Health Research (CIHR), DSP, Gideon Richter, Intracellular Therapies, Merck, Sanofi and Sunovion. The rest of the authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Childhood trauma (CT) are frequently reported by patients with bipolar disorder (BD), but it is unclear whether and how CT contribute to patients' cognitive and psychosocial impairments. We aimed to examine the impact of CT on cognition and psychosocial functioning in a large sample of 345 patients with BD and 183 healthy control participants (HC) using the Childhood Trauma Questionnaire, neurocognitive tests and ratings of mood symptoms and functioning., Results: Patients showed broad cognitive impairments across memory, attention and executive function and functional disability despite being in partial or full remission and had higher levels of CT than HC. Higher levels of CT correlated with impairments across almost all cognitive domains and lower psychosocial functioning across BD patients and HC. Of these, the associations between CT and poorer working memory and lower psychosocial functioning, respectively, prevailed after adjusting for clinical and demographical variables. Diagnosis of BD and estimated verbal intelligence did not moderate these associations. Analysis of CT sub-categories showed that working memory impairments were related particularly to childhood physical and emotional abuse, while psychosocial difficulties were related to physical and emotional neglect., Conclusions: CT may have negative implications for working memory and psychosocial functioning across both BD and healthy populations. If the findings are replicated, this would suggest that early interventions that reduce the frequency of CT in vulnerable families may aid children's cognitive and psychosocial development., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Cognitive impairment affects many patients with bipolar disorder (BD). No pro-cognitive treatment with robust efficacy exists partly due to limited insight into underlying neurobiological abnormalities., Methods: This magnetic resonance imaging (MRI) study investigates structural neuronal correlates of cognitive impairment in BD by comparing brain measures in a large sample of cognitively impaired versus cognitively intact patients with BD or cognitively impaired patients with major depressive disorder (MDD) and healthy controls (HC). Participants underwent neuropsychological assessments and MRI scans. The cognitively impaired and - intact BD and MDD patient groups were compared with each other and HC regarding prefrontal cortex measures, hippocampus shape/volume, and total cerebral white (WM) and grey matter (GM)., Results: Cognitively impaired BD patients showed lower total cerebral WM volume than HC, which scaled with poorer global cognitive performance and more childhood trauma. Cognitively impaired BD patients also showed lower adjusted GM volume and thickness in the frontopolar cortex than HC but greater adjusted GM volume in the temporal cortex than cognitively normal BD patients. Cognitively impaired BD patients showed decreased cingulate volume than cognitively impaired MDD patients. Hippocampal measures were similar across all groups., Limitations: The cross-sectional study design prevented insights into causal relationships., Conclusions: Lower total cerebral WM and regional frontopolar and temporal GM abnormalities may constitute structural neuronal correlates of cognitive impairment in BD, of which the WM deficits scale with the degree of childhood trauma. The results deepen the understanding of cognitive impairment in BD and provide a neuronal target for pro-cognitive treatment development., Competing Interests: Declaration of competing interest KWM reports having received consultancy fees from Lundbeck and Janssen-Cilag in the past three years. LVK reports having received consultancy fees from H. Lundbeck and Teva in the past three years. GMK has received honoraria as a speaker for Sage Biogen and as an advisor for Sanos. JLJ, JM, JZP, MBJ reports no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is the most common mood disorder and a leading cause of disability worldwide. Trazodone, a triazolopyridine serotonin receptor antagonist and reuptake inhibitor (SARI) antidepressant approved for major depressive disorder (MDD) in adults, has established efficacy that is comparable to other available antidepressants, and is effective for a range of depression symptoms, including insomnia, which is one of the most common and bothersome symptoms of depression. Also, trazodone's pharmacodynamic properties allow it to avoid the side effects of insomnia, anxiety and sexual dysfunction often associated with selective serotonin reuptake inhibitor antidepressants. In this narrative review, we have summarized recent clinical trials and real-world data on trazodone, including the recently introduced once-daily formulation, which has single dose pharmacokinetic properties that maintain effective blood trazodone levels for 24 h, while avoiding concentration peaks associated with side effects. This, combined with a low incidence of weight gain, and sexual dysfunction, may improve adherence to treatment. The most common adverse effects of trazodone are somnolence, headache, dizziness and xerostomia. It has minimal anticholinergic activity but may be associated infrequently with orthostatic hypotension (especially in patients with cardiovascular disease or older adults), QT interval prolongation, cardiac arrhythmias, and rare episodes of priapism. The low liability for activating side effects, the efficacy on symptoms such as insomnia and psychomotor agitation and the rapid onset of action make it useful for many depressed patients, both in monotherapy at nominal dosages of 150-300 mg/day, and in combination with other antidepressants at lower dosages., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Postpartum depression (PPD) is a severe mental illness affecting 10-15% of mothers. Emerging evidence indicates that negative neurocognitive bias in response to infant distress during pregnancy marks an increased risk of PPD. This proof-of-concept study aimed to investigate the association between negatively biased neurocognitive processing of infant distress during pregnancy and subsequent PPD and to explore the feasibility of an online risk screening tool. In the second or third trimester of pregnancy, 87 participants underwent two online tests of reactivity to and evaluation of infant distress and completed questionnaires regarding psychosocial risk factors. After birth, participants rated their depressive symptoms online and underwent a diagnostic telephone interview concerning PPD. Irrespective of depressive symptoms during pregnancy, negative reactivity to and evaluation of infant distress predicted PPD (reactivity: Exp(B)=1.33, p = 0.04) and depressive symptoms after birth (reactivity: B = 0.04, p = 0.048; evaluation: B = 0.10, p = 0.04). The negative reactivity toward infant distress showed high sensitivity and moderate specificity (89% and 77%, respectively), while the evaluation of infant distressed cries showed lower sensitivity and specificity (67% and 66%, respectively). The relatively small sample size prevented the inclusion of additional risk variables in the regression models. The replication of an association between negative neurocognitive bias during pregnancy with PPD risk is noteworthy and has clinical implications in terms of early prevention. However, the low response rate indicates that this tool is not feasible in its current form. Future larger-scale studies are needed to further investigate candidate risk factors in a brief online screening tool., Competing Interests: Conflict of Interest KWM has received honoraria from Lundbeck, Janssen and Angelini Pharma in the past three years. AJB and MSV have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Bipolar disorder (BD) and major depressive disorder (MDD) are associated with cognitive and functional impairment. Cognitive impairment is often associated with dorsal prefrontal cortex (dPFC) hypo-activity, but the neuronal correlates of functional disability is largely unknown. In this study, 91 patients with affective disorders in full or partial remission (BD, n = 67; MDD, n = 24) with objectively verified cognitive impairment and substantial functional disability underwent neuropsychological assessment and functional magnetic resonance imaging (fMRI) scan during which they completed a strategic picture-encoding task. For comparison, 36 matched healthy controls underwent an identical test protocol. Patients showed encoding-related hypo-activity in the dPFC compared to controls. In patients, lower right dlPFC activity was associated with poorer overall functioning and more antipsychotic drug use. In conclusion, memory impairments were underpinned by failure to recruit the dPFC during task performance which was associated with impaired functioning in fully or partially remitted patients with affective disorders. This aberrant neurocircuitry activity has implications for the design of future pro-cognitive interventions that aim to improve not only cognition but also real-world functioning., Competing Interests: Declaration of Competing Interest JMac, JMar, JZP, PMF, and MBJ report no conflicts of interest. MV has within the last three years received consultancy fees from Janssen Cilag and Lundbeck. GMK has received honoraria as a speaker for Sage Biogen and as a consultant for Sanos. LVK has within recent three years been a consultant for Lundbeck and Teva. KWM has received consultancy fees from Lundbeck and Janssen in the past three years., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Studies across schizophrenia (SZ) and bipolar disorder (BD) indicate common transdiagnostic neurocognitive subgroups. However, existing studies of patients with long-term illness precludes insight into whether impairments result from effects of chronic illness, medication or other factors. This study aimed to investigate whether neurocognitive subgroups across SZ and BD can be demonstrated during early illness stages. Data from overlapping neuropsychological tests were pooled from cohort studies of antipsychotic-naïve patients with first-episode SZ spectrum disorders (n = 150), recently diagnosed BD (n = 189) or healthy controls (HC) (n = 280). Hierarchical cluster analysis was conducted to examine if transdiagnostic subgroups could be identified based on the neurocognitive profile. Patterns of cognitive impairments and patient characteristics across subgroups were examined. Patients could be clustered into two, three and four subgroups, of which the three-cluster solution (with 83% accuracy) was selected for posthoc analyses. This solution revealed a subgroup covering 39% of patients (predominantly BD) who were cognitively relatively intact, a subgroup of 33% of patients (more equal distributions of SZ and BD) displaying selective deficits, particularly in working memory and processing speed, and a subgroup of 28% (mainly SZ) with global impairments. The globally impaired group exhibited lower estimated premorbid intelligence than the other subgroups. Globally impaired BD patients also showed more functional disability than cognitively relatively intact patients. No differences were observed across subgroups in symptoms or medications. Neurocognitive results can be understood by clustering analysis with similar clustering solutions occurring across diagnoses. The subgroups were not explained by clinical symptoms or medication, suggesting neurodevelopmental origins., Competing Interests: Declaration of competing interest KWM has received consultancy fees from Lundbeck, Allergan and Janssen in the past three years. LVK has received consultancy fees from Lundbeck and Teva in the past three years. BHE has received lecture fees and/or is part of Advisory Boards of Bristol-Myers Squibb, Eli Lilly and Company, Janssen-Cilag, Otsuka Pharma Scandinavia AB, Takeda Pharmaceutical Company and Lundbeck Pharma A/S. Dr. Glenthøj has been the leader of a Lundbeck Foundation Center of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (CINS) (January 2009–December 2021), which was partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. All grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. She has no other conflicts to disclose. CKL, KSA, BF, HLK report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients' cognitive outcomes., Competing Interests: Declaration of competing interest Authors KWM reports having received honoraria from Janssen, Allergan and Lundbeck in the past three years. LVK reports having been a consultant for Lundbeck within the preceding three years. UBK, AHS, SGH, MM, MW and JF report no potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)