BACKGROUND:Depression in both bipolar and major depressive disorder remains a major unmet need due to treatment resistance to the existing treatments. Emerging evidence implicates the renin-angiotensin system in regulating the cellular stress response relevant to depression, suggesting it as a novel therapeutic target for depression. Candesartan, a common hypertension medication, decreases neuroinflammation, oxidative and nitrosative pathway activation, and neurotrophic signalling of angiotensin II by predominantly blocking the angiotensin II type 1 receptors (AT1R). Given AT1R-induced activities are implicated in the pathophysiology of bipolar and major depressive disorder and with supportive pharmacoepidemiology data, candesartan may represent a novel antidepressant strategy. METHODS:The CADET Trials are 2 parallel 16-week double-blind randomized placebo-controlled trials of adjunctive candesartan (or placebo) for the treatment of bipolar depression (CADET-BD) and major depressive disorder (CADET-UD). Each trial aims to recruit 240 adult participants. The primary outcome is the between-group (ie, intervention vs. placebo) differential change from baseline to week 16 in depression symptoms as measured by the Montgomery Åsberg Depression Rating Scale. Secondary outcomes measure depression, mania, anxiety, quality of life, cost-effectiveness, functioning, substance use, cognition, and biological markers. FINDINGS:Findings are not yet available as the trial is ongoing. IMPLICATIONS:The CADET Trials examine the efficacy of candesartan in reducing depressive symptoms in both unipolar and bipolar depression, and whether its effects are mediated through the renin-angiotensin system. Candesartan is affordable, accessible, and well-tolerated. If effective, it could quickly be adopted into clinical practice as a new adjunctive medication for the treatment of these disorders.

Mood disorders involve complex neurobiological trajectories, making it difficult to identify predictors of their onset and progression. This prospective study disentangled markers of vulnerability from markers of illness recurrence by leveraging monozygotic twins discordant for mood disorders. We followed 136 monozygotic twins (66 affected [AT], 39 high-risk, and 31 low-risk unaffected twins [UT]; mean age 37.4 ± 9.1 years; 69.9% females) for 7.1 ± 0.8 years after baseline MRI. Cox regression examined associations between regional neuroanatomy (bilateral hippocampus, precuneus, anterior cingulate volumes; superior frontal gyrus [SFG] thickness) and: (1) time-to-first onset (UT) or (2) time-to-recurrence (AT), adjusting for age, sex, intracranial volume, and symptoms. In UT, thinner bilateral SFG and smaller left precuneus were associated with greater onset risk (HR = 1.1, p < 0.04). These regions showed an approximately linear relationship across structural quartiles, with progressively higher 7-year episode-free probability from Q1 (lowest measures) to Q4 (highest measures). In contrast, in AT, smaller precuneus and bilateral hippocampal volumes predicted higher recurrence risk (HR = 1.1, p < 0.037), following a threshold-like pattern, with markedly higher 7-year risk of a mood episode for individuals in Q1 (lowest volume) compared to the higher quartiles (Q2-Q4). Our findings indicate distinct neuroanatomical risk profiles: prefrontal thinning of SFG marks vulnerability to initial onset, potentially reflecting impaired cognitive control, while hippocampal atrophy predisposes to recurrence, possibly via stress-related neurotoxicity. These stage-specific biomarkers, identified under rigorous genetic control, highlight targeted prevention strategies: cognitive interventions preserving frontal integrity in high-risk populations, and hippocampal neuroprotection to sustain remission.

There is currently no known effective long-term treatment for cognitive impairments in bipolar disorder (BD) and understanding of the neurobiological mechanisms underlying cognitive impairments in BD is lacking. Identifying potential biomarkers for cognitive improvement is essential to aid targeted interventions. This study investigates the neural correlates of cognitive improvement versus lack of improvement over time in BD. Forty-six patients newly diagnosed with BD who recently began treatment in a specialized outpatient clinic and 38 healthy control individuals (HC) were assessed with a battery of neuropsychological tests and a verbal n-back working memory test during functional magnetic resonance imaging (fMRI) at baseline and follow-up (mean: 15 months). Patients were divided into two groups: those who improved cognitively over time, defined as global cognition change ≥ .2 SD, (BD+: n = 27) and those who showed a lack of normative improvement (BD-: n = 19). BD + showed hypoactivity in dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC) compared to HC, both at baseline and follow-up. Hypoactivity in these prefrontal regions correlated with poorer out-of-scanner working memory and executive function for BD- and HC, but not for the BD + group. While hypoactivity did not predict change in cognition for BD+, it did predict improvement in functioning for both patient subgroups. The findings from this exploratory study suggest that dlPFC hypoactivity may identify those who are likely to respond well to treatment and show an improvement in functioning over time.

Evidence suggests shared pathophysiologic mechanisms between severe mental illness (SMI) and cardiovascular disease (CVD). Drugs used for CVD, such as antithrombotic agents (ATAs), may therefore be repurposed for the treatment of SMI. We conducted the first systematic review and meta-analysis (PROSPERO registration CRD42024524420) of ATAs for SMI and reported results according to PRISMA guidelines. We searched MEDLINE, Embase, and PsycINFO (October 10, 2024) and performed random-effects meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and the certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. Primary outcomes were symptom severity, risk of recurrence, and tolerability. We included 12 randomized trials investigating aspirin, cilostazol, and dipyridamole in a total of 742 patients with schizophrenia, major depression, and bipolar disorder. Results showed that ATA treatment may reduce depressive symptoms in patients with SMI (SMD -0.62; 95 % CI -1.11 to -0.13; 8 studies; very low-certainty evidence). Based on studies with low risk of bias, ATA treatment may reduce PANSS total score compared with placebo (SMD -0.57; 95 % CI -0.86 to -0.28; 3 studies; very low-certainty evidence). Tolerability of ATAs may not differ from placebo (RR 0.89; 95 % CI 0.57-1.40; 9 studies; very low-certainty evidence). Given the low certainty of the evidence, effect estimates should be interpreted with caution. The therapeutic potential of ATAs in SMI remains uncertain. Well-powered RCTs investigating clinically relevant outcomes in clearly defined populations are needed.

INTRODUCTION:Cognitive impairment is a core feature of mood disorders that contributes to reduced functioning and poorer prognosis, thereby emerging as an important treatment target. Persistent trait-related impairments present within both affective and non-affective cognition. Nevertheless, the relationship between affective and non-affective cognitive domains remains unclear, including whether impairments in emotion regulation and facial expression recognition are secondary to deficits in non-affective cognition. Mapping out the hierarchical structure of affective and non-affective cognitive domains may elucidate core cognitive impairments that represent the most relevant treatment targets. METHODS:Network analysis was employed to explore the associations between affective and non-affective cognitive domains in individuals with mood disorders (N = 380) and healthy controls (HC; N = 225) pooled from two previous studies. Partial correlation networks were constructed separately for individuals with mood disorders and HC comprising measures of non-affective cognition (working memory and executive function, attention and processing speed, verbal learning, and verbal memory) and affective cognition (emotion regulation success, facial expression recognition speed and accuracy). RESULTS:For both mood disorders and HC, 'working memory and executive function' and 'attention and processing speed' emerged as central cognitive domains. Emotion regulation showed a significantly weaker association with 'working memory and executive function' in mood disorders relative to HC. Additionally, facial expression recognition speed was associated with 'attention and processing speed' across both groups. CONCLUSION:Our findings suggest that working memory, executive function, attention, and processing speed are core cognitive domains in mood disorders. Further, the weak association between executive function and emotion regulation in mood disorders may indicate a reduced reliance on cognitive control processes during emotion regulation. These findings underscore the importance of targeting both affective and non-affective cognition in pro-cognitive interventions to improve emotion regulation and potentially mitigate the risk of mood episodes.

Background:Depression in both bipolar and major depressive disorder remains a major unmet need due to treatment resistance to the existing treatments. Emerging evidence implicates the renin-angiotensin system in regulating the cellular stress response relevant to depression, suggesting it as a novel therapeutic target for depression. Candesartan, a common hypertension medication, decreases neuroinflammation, oxidative and nitrosative pathway activation, and neurotrophic signalling of angiotensin II by predominantly blocking the angiotensin II type 1 receptors (AT1R). Given AT1R-induced activities are implicated in the pathophysiology of bipolar and major depressive disorder and with supportive pharmacoepidemiology data, candesartan may represent a novel antidepressant strategy.MethodsThe CADET Trials are 2 parallel 16-week double-blind randomized placebo-controlled trials of adjunctive candesartan (or placebo) for the treatment of bipolar depression (CADET-BD) and major depressive disorder (CADET-UD). Each trial aims to recruit 240 adult participants. The primary outcome is the between-group (ie, intervention vs. placebo) differential change from baseline to week 16 in depression symptoms as measured by the Montgomery & Aring;sberg Depression Rating Scale. Secondary outcomes measure depression, mania, anxiety, quality of life, cost-effectiveness, functioning, substance use, cognition, and biological markers.Findings:Findings are not yet available as the trial is ongoing.Implications:The CADET Trials examine the efficacy of candesartan in reducing depressive symptoms in both unipolar and bipolar depression, and whether its effects are mediated through the renin-angiotensin system. Candesartan is affordable, accessible, and well-tolerated. If effective, it could quickly be adopted into clinical practice as a new adjunctive medication for the treatment of these disorders.

Introduction Bipolar II disorder (BDII) accounts for the majority of patients with bipolar disorder (BD), yet evidence supporting first-line mood stabilising treatment with lithium and lamotrigine is scarce, and the certainty of the evidence is very low. This highlights a critical evidence gap within psychiatric care. The lithium versus lamotrigine-bipolar randomised controlled trial (RCT) aims to compare lithium and lamotrigine on self-rated day-to-day mood instability (MI) and other patient-centred outcomes in BDII, hypothesising the superiority of lithium.Methods and analysis A two-arm, single-blind, parallel-group, superiority RCT with a target sample size of 200 patients (accounting for attrition), recruiting patients with newly diagnosed BDII from specialised outpatient mood disorder clinics in the capital region of Copenhagen, Denmark. Participants are randomised in a 1:1 ratio to receive either lithium or lamotrigine for 6 months. The primary outcome is MI, assessed via daily smartphone-based mood ratings. MI is chosen as the primary outcome measure due to its internal validity as a real-life measure for patients and external validity as it reflects both illness severity and functional impairment. Secondary outcomes include the proportion of participants showing a non-response to treatment and observer-rated changes in depressive symptoms over 6 months, measured using the six-item version of the Hamilton Depression Rating Scale. Primary analyses will follow the intention-to-treat principle using linear mixed models. The trial is monitored by the good clinical practice.Recruitment commenced on 8 May 2024, and the final participant follow-up (last patient last visit) is expected on 1 December 2027.Ethics and dissemination The trial has received approvals from the Danish Research Ethics Committee, the Danish Medicines Agency (EU CT No. 2023–5 09 607-32-00) and the Capital Region Data Agency (P-2023-307). Results will be published in peer-reviewed journals.Trial registration number Clinicaltrials.gov/NCT06184581.

Background: Cancer and mental disorders may influence one another, yet research on the risk of developing a new-onset mental disorder following cancer, other than depression, remains limited. Methods:: In a nationwide register-based study, patients were followed from incident cancer diagnosis between 1995 and 2015 until end of follow-up 2023, excluding those with preexisting mental disorders. Patients were matched with cancer-free individuals on age, sex, socioeconomic position and comorbidities. We estimated incidence rates (IR) of mental disorders through psychiatric diagnoses and psychotropic medication prescriptions, as well as hazard ratios (HR) in comparison to cancer-free individuals. Results: We included 289,391 cancer patients and 1,031,057 population-matched cancer-free comparisons. Across the cancer cohort, 116,118 developed any incident mental disorder, with a HR of 2.3 [95%-CI: 2.3-2.3] and varying rates across tumor types. IR and HR were highest in the first year after cancer diagnosis and decreased rapidly thereafter, yet the HR remained elevated exceeding ten years. Highest IRs and HRs were observed for anxiety, depression and substance use disorders. Our results were confirmed by several sensitivity analyses. Conclusion: The incidence and risk elevation of incident mental disorders in cancer patients vary based on sex, cancer type, time since diagnosis and type of mental disorder.

The relationship between depression symptoms and sleep in major depressive episodes (MDE) is complex. In this trial, 103 patients with a MDE entered morning and evening depression scores (0-10; 10 = no depression) and sleep parameters in an electronic system for 28 days after discharge from inpatient wards. Mean diurnal variation (difference between evening and morning depression scores) was 0.33 (SE = 0.10; p = 0.0009) with very large day-to-day variations. Morning depression symptoms were associated with length of sleep period in a non-linear association, with least depression symptoms at 8 h of sleep increasing for longer and shorter sleep time (p = 0.04). Morning depression symptoms were also found to increase with a later sleep midpoint (p < 0.001), a delay in sleep onset (p = 0.0001) and wakeups (p < 0.0001). In conclusion, a long and short sleep duration, late sleep-timing, sleep onset delays and wakeups, were associated with more morning depression symptoms. These explorative results should be investigated in Randomized Clinical Trials (RCTs), to test the casual relation and if confirmed, be used clinically in depression treatment to qualify the use of methods working on sleep timing and sleep maintenance like Cognitive Behavioural Therapy for insomnia (CBT-I). Trial Registration ClinicalTrials.gov NCT02679768; https://clinicaltrials.gov/study/NCT02679768 .

INTRODUCTION:Depression and sub-diagnostic depressive syndromes are prevalent and associated with suffering and reduced life expectancy. Access to care is limited even in countries with developed healthcare systems. In this context, it is important to strengthen the self-management expertise of people suffering from depressive symptoms. Smartphones offer the possibilities for improved self-management based on long-term monitoring of symptoms.The present multicentre randomised controlled trial (the Protecting mental health in times of change (MENTINA) trial) aims to evaluate whether (1) daily smartphone-based monitoring and automatic rule-based feedback+smartphone-based outcome evaluations versus (2) smartphone-based outcome evaluations alone will improve depressive symptoms and other clinically relevant outcomes in participants with current depressive symptoms and/or one or more prior depressive episodes during a 12-month trial period. METHODS AND ANALYSIS:The MENTINA trial is a multicentre randomised controlled parallel-group trial conducted in Denmark, Germany and Spain. Participants with current depressive symptoms and/or one or more previous depressive episodes are invited to participate. The included participants will be randomised to (1) daily smartphone-based monitoring and automatic rule-based feedback+outcome evaluations via smartphone (intervention group) or (2) outcome evaluations via smartphone alone (control group). All participants can continue with ongoing treatment in case they receive it. The trial started in May 2025 and has currently included 115 participants. The outcomes are differences between the intervention group and the control group in (1) Patient Health Questionnaire 9-items (PHQ-9) measured every 14th day during the 12-month trial period (primary), (2) WHO Quality of Life-BREF, Generalised Anxiety Disorder-7, monthly change in PHQ-9, proportion of participants with ≥50% reduction in PHQ-9, remission rate defined as PHQ-9≤9 and ≥5-point improvement, PHQ-9 scores after 6 months, area under the curve for PHQ-9 over the 12 months trial period, subgroup analyses in PHQ-9 in participants with or without lifetime depression, Perceived Stress Scale, user-reported healthcare contacts, usability of the app and negative effects, number of depressive episodes+duration and depressive-free days based on PHQ-9. A total of 660 participants will be included in the MENTINA trial. ETHICS AND DISSEMINATION:The MENTINA trial is funded by the European Union under Grant Agreement No. 101 080 651. Ethical approval and approval from Medical Agencies have been obtained from Denmark (CIV-25-02-051094), Germany (CIV-25-02-05109) and Spain (CIV-25-02-051094). The results will be published in peer-reviewed academic journals, presented at scientific meetings and disseminated to patients' organisations and media outlets. TRIAL REGISTRATION NUMBER:NCT06919133. PROTOCOL VERSION:Version 6, January 2026.

OBJECTIVES:Persons with bipolar disorder (BD) often present with cognitive complaints even in the absence of objective cognitive impairment as measured with neuropsychological tests. It remains unclear whether cognitive complaints reflect negative bias or illness-related decline from premorbid functioning, affecting functioning and quality of life (QoL). METHODS:Data from n = 498 persons with BD and n = 320 healthy controls (HC) were included from a database based on seven studies. We calculated IQ-objective cognition discrepancy scores (-10 to +10; negative scores = lower cognitive performance than premorbid IQ, i.e., estimated 'loss of function') and subjective-objective cognitive discrepancy scores (-10 to +10; negative scores = less subjective than objective difficulties; positive scores = more subjective than objective impairments). We investigated associations between these variables and subjective cognitive complaints, functioning, and QoL with multiple regression models. RESULTS:Subjective cognitive complaints were associated with poorer global cognitive performance relative to premorbid IQ (i.e., estimated 'loss of function'). More subjective than objective cognitive difficulties was associated with diminished functioning and QoL. A similar association was seen for objective cognitive performance. CONCLUSIONS:Subjective complaints may indicate a decline from premorbid cognitive function, even if objective cognitive performance is within the normal range after illness onset. More subjective than objective impairment correlates with poorer functioning and QoL. Hence, cognitive management initiatives should be centered around patients with cognitive complaints independent of objective cognitive status.

This expert opinion paper addresses the critical balance between lithium’s therapeutic efficacy in recurrent mood disorders and its potential renal side effects. The objective is to provide evidence-based guidelines to enhance clinical decision-making, prevent emergence of, and mitigate risks associated with lithium-induced renal impairment. An extensive review of epidemiological, observational, and experimental studies on lithium-induced renal impairment, focusing on its pathophysiology, clinical manifestations, and risk factors was conducted. Expert consensus and recent data were integrated to develop a management algorithm for renal monitoring and intervention. Lithium remains the gold standard for mood stabilization in bipolar disorders, with robust evidence supporting its role in recurrence prevention and suicide risk reduction. While mild to moderate renal impairment is recognized as a risk factor, newer studies show a lower incidence of severe outcomes, such as end-stage kidney disease, necessitating dialysis treatment and renal transplantation, especially with appropriate monitoring, as compared to older studies. This paper addresses pathophysiological mechanisms, including arginine vasopressin resistance and chronic interstitial nephritis, alongside risk factors like rapid initial decline in glomerular filtration rate, early age at treatment initiation, cumulative dosage, mean serum levels of lithium and episodes of lithium intoxication. Effective management strategies, including judicious dosing, routine monitoring, and early nephrology referral, can significantly improve outcomes. Lithium remains an invaluable treatment for recurrent mood disorders, and its benefits often outweigh the risks when managed appropriately. This paper provides a practical framework for clinicians to address renal concerns, emphasizing the importance of systematic monitoring and individualized care. The paper underscores the need for continued research and education of clinicians and patients to optimize lithium use while safeguarding patient health.

AIMS:Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are highly heritable and linked to fronto-limbic circuit dysfunction. This longitudinal fMRI study examined whether baseline responses of the amygdala, anterior cingulate cortex (ACC), and ventrolateral prefrontal cortex (vlPFC) evoked by facial emotional expressions predicted first-onset or recurrence of mood episodes over 7 years in monozygotic twins. METHODS:The sample comprised 68 unaffected twins (UT) without a history of mood disorders but varying familial risk, and 62 affected twins (AT) in remission from MDD or BD. At baseline, participants underwent functional Magnetic Resonance Imaging (fMRI) of fearful and happy face processing and completed behavioral measures of emotional processing, which were repeated at follow-up. RESULTS:Lower baseline activation of the bilateral amygdala (left hazard ratio, HR = 1.69, 95% CI 1.15-2.45; right HR = 1.80, 95% CI 1.23-2.25), dorsal ACC (HR = 1.27, 95% CI 1.02-1.57), and right anterior vlPFC (HR = 2.28, 95% CI 1.56-3.26) by fearful (vs. happy) faces was associated with higher risk of first-onset mood episodes in the UT group. In the AT group, baseline fronto-limbic emotional activations were not associated with recurrence risk. Behaviorally, the UT group that later developed a mood episode showed slower recognition of happy faces and greater avoidance of subliminal fearful faces compared with the UT group that remained well. CONCLUSION:Dysfunctional fronto-limbic processing of facial emotions indicates increased propensity to develop a mood disorder, but is not associated with increased risk for recurrence of mood episodes. This dissociation suggests that distinct neural mechanisms underlie the first-onset versus the recurrence of mood disorders.

Abstract Moderate hypoxia is increasingly recognized as a physiological driver of neuroprotection and neuroregeneration. In this first randomised, double-blind, controlled, four-arm trial, we demonstrate the cognitive and neuroplastic effects of cognitive training under moderate inspiratory hypoxia in humans. Healthy volunteers underwent three weeks of either cognitive or sham training under normobaric hypoxia (12% O 2 ) or normoxia (20% O 2 ) for 3.5 hours daily, six days per week. Participants were assessed at baseline, treatment completion, and one-month follow-up. The primary outcome was change in a broad cognitive composite score. Additional cognitive, blood-based, and neuroimaging outcomes were assessed, including measurement of the presynaptic protein SV2A with [ 11 C]UCB-J positron emission tomography (PET) and neural activity through functional magnetic resonance imaging (fMRI). In total, 126 participants were randomised to hypoxia-cognitive training (H-CT: n =36), hypoxia-sham training (H-ST: n =30), normoxia- cognitive training (N-CT: n =30), or normoxia-sham training (N-ST: n =30). Intention-to-treat analyses showed no effect of H-CT relative to N-ST in the primary outcome at treatment completion (primary endpoint; treatment effect=0.11, 95% CI=[-0.06;0.28], p =0.19), but improvements emerged at follow-up (treatment effect=0.17, 95% CI=[0.01;0.34], p =0.04). N-CT induced transient improvement in the primary outcome at treatment completion (treatment effect=0.20, 95% CI=[0.02;0.38], p =0.03), which rendered non-significant at follow-up. Finally, H-ST showed no significant cognitive change relative to N-ST. Moderate hypoxia was safe and well-tolerated. Cognitive benefits were accompanied by decreased hippocampal presynaptic density measured with [ 11 C]UCB-J PET. In conclusion, three weeks of H-CT can enhance cognition with associated effects on neuroplasticity, although with a delayed onset of effects on cognition.

BACKGROUND:Dysregulation in circadian rhythms, including sleep abnormalities, is a central feature in bipolar disorder during all illness phases. This exploratory post hoc study investigated the association between variation in sleep and instability in mood based on day-to-day patient-reported smartphone-based data in patients with bipolar disorder. METHODS:Data from patients with bipolar disorder from two prior studies (A-Bipolar and SMART-Bipolar) were included for exploratory analyses. Patients provided daily smartphone-based evaluations of sleep and mood. A total of 370 patients with bipolar disorder each providing data for six months were included in the analyses. We analysed how various summaries of sleep variation were associated with mood instability, using linear mixed effect regression models. RESULTS:There was a positive association between variation in sleep for both the prior three days (1.22, 95%CI: (1.19; 1.24), p < 0.0001) as well as the prior week (1.40,95% CI: (1.36, 1.44), p < 0.0001)) and mood instability. Interestingly, increasing sleep up to a certain point around eight hours was associated with decreased mood instability. Increasing sleep after this point was associated with increased mood instability. The estimated inflection point for this choice of knots was 8.05 h (95% CI: 7.20,8.90) for the A-bipolar study and 8.24 h (95% CI: 6.24,10.24) for SMART-Bipolar study. LIMITATIONS:Analyses were exploratory and post hoc. Sleep and mood were patient-reported. Findings should be interpreted with caution. Temporal ordering of the associations cannot be concluded. CONCLUSION:In this exploratory study of patients with bipolar disorder, short-term fluctuations in sleep were significantly associated with increased mood instability, highlighting the dynamic interplay between circadian regulation and affective variability.

Mood disorders are characterized by considerable cognitive heterogeneity. However, little is known about high cognitive performance and its associations with relevant clinical outcomes. High cognitive performance in persons with mood disorders and high-risk unaffected relatives (UR) may be an expression of resilience to illness-related neuropathology. Cross-sectional data from persons with mood disorders (n = 212), unaffected relatives (UR) (n = 96), and healthy controls (HC) (n = 152) were pooled from two cohort studies, during which participants completed neuropsychological test batteries comprising both non-emotional and emotional cognition. Participants were grouped into ‘high’ or ‘normal cognitive performance’ subgroups based on their global cognitive performance. Groups were compared to investigate high-performing persons with mood disorders and relatives, respectively, in demographic and clinical variables and emotional cognition. Resulting subgroups were persons with mood disorders with high (P-HP = 67) and normal cognitive performance (P-NP = 135), UR with high (UR-HP = 41) and normal cognitive performance (UR-NP = 52) and HC with high (HC-HP = 86) and normal cognitive performance (HC-NP = 66). P-HP were characterized by fewer experiences of physical abuse, fewer mood episodes and improved functioning compared to P-NP. Both P-HP and UR-HP experienced more overall childhood trauma, compared to HC-HP. All cognitively high-performing subgroups exhibited faster recognition of emotional faces compared to their corresponding normally performing group. High cognitive performance was associated with favorable clinical outcomes and improved functioning in persons with mood disorders and high-risk UR. Given this association, above-average enhancement of cognition beyond normalization may aid functional recovery.

This in memoriam honours Professor Jules Angst, MD, and reflects on his major contributions to mood disorder research, psychiatric classification, longitudinal clinical studies, and lithium prophylaxis. It also commemorates his enduring influence on IGSLi, clinical psychiatry, and generations of researchers and clinicians.

BACKGROUND:Numerous studies have explored the possibility of developing automatic detection pipelines that can seamlessly diagnose patients with bipolar disorder (BD) and other mental illnesses. Such novel diagnostic tools increasingly rely on data sources, such as facial movements, whose relationships to BD have yet to be fully elucidated. As such, these detection pipelines offer limited clinical value, despite promising performance estimates. A vital next step toward achieving clinically reliable models is to conduct granular interpretability analyses to determine which subsets of facial movements are responsible for determining patient or control class membership. MATERIALS AND METHODS:In this work, we rely on facial movements encoded as Action Units (AUs) of 32 participants recorded while watching emotional film clips. Our objective is to delineate the specific facial micro-movements responsible for the differences between patients with BD and controls by applying the interpretable Fisher's Linear Discriminant Analysis (LDA) in a binary, supervised classification design. RESULTS:We report how the movement of brow lowering (AU4) differentiates patients from controls with AUROC scores up to 69%. CONCLUSIONS:Our exploratory study argues for the necessity of devising inherently interpretable machine learning models for the clinical domain. Furthermore, we critically discuss the implications of identifying AU4 as a key discriminative feature and assess the clinical value of specific facial movements for the diagnostic process.

BACKGROUND:In this study, a classifier (hyperplane) is determined to distinguish the neural responses during emotion regulation versus viewing images in healthy adults and then applied to determine (i) the effectiveness of the emotion regulation response (defined as emotion regulation distance from the hyperplane [DFHER]) in independent samples of healthy adults, patients with BD, and the patients' unaffected relatives (URs) and (ii) the association of DFHER with the duration of future (hypo)manic and depressive episodes for patients with BD over a 16-month follow-up period. METHODS:Study participants (N = 226) included 65 healthy adults (35 used for support vector machine [SVM] learning [HCTrain] and 30 kept as an independent test sample [HCTest]), 87 patients with newly diagnosed BD (67% BD type 2) and 74 URs. BOLD response data came from an emotion regulation task. Clinical symptoms were assessed at baseline fMRI and after 16 months of specialized treatment. RESULTS:The SVM ML analysis identified a hyperplane with 75.7% accuracy. Patients with BD showed reduced DFHER relative to the HCTest and UR groups. Reduced DFHER was associated with reduced improvement in psychosocial functioning during the 16-month follow-up time (B = -1.663, p = 0.02). CONCLUSIONS:The neural response during emotion regulation can be relatively well distinguished in healthy adults via ML. Patients with newly diagnosed BD show significant disruption in the recruitment of this emotion regulation response. Disrupted may indicate a reduced capacity for functional improvement during specialized treatment in a mood disorder clinic.

INTRODUCTION:This study investigated whether having a familial risk of affective disorders, subclinical psychopathology, functioning, personality traits, stressful life events, and childhood trauma predict the onset or recurrence of affective episodes. METHOD:The present study is a 7-year follow-up study of a baseline sample of 204 monozygotic twins (MZ) with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk), and healthy twins with no personal or familial history of affective disorder (low-risk). RESULTS:During the 7.0-year median follow-up time, 59.3 % of the affected twins had a recurrence of an affective episode, 33.3 % of high-risk twins, and 7.5 % of low-risk twins had an onset. Familial risk and being affected were predictors for onset and recurrence. Including the whole sample, subclinical symptoms, functioning, stressful life events, and the personality trait neuroticism were statistically significant predictors of onset and recurrence. Regarding the individual risk groups, increasing age was a significant predictor of increased hazard in the affected risk group and lower hazard in the low-risk group. CONCLUSION:This follow-up study revealed that the most potent predictors for onset or recurrence were familial risk and having an affective disorder at baseline. Subclinical depressive symptoms, personality traits, stressful life events, and impaired functioning were significant contributors to onset risk and recurrence. These findings highlight the need to integrate relevant risk factors into daily clinical settings and integrate the most well-established factors as potential targets for primary care interventions.