Clinical and personal predictors of functioning in affective disorders: Exploratory results from baseline and 6-month follow-up of a randomised controlled trial.

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.

Adults with both bipolar disorder and ADHD.

ADHD and bipolar disorder (BP) commonly coexist, and both share key symptoms, depending on affective state and emotional dysregulation. The overlap poses diagnostic challenges and may lead to underdiagnoses. Comorbid cases exhibit worsened symptom burden, increased psychiatric morbidity, admissions, and suicide attempts. Treating BP before ADHD is recommended. Stimulant use combined with mood stabilisers may be effective and relatively safe; however, this review finds that well-designed randomised controlled studies in the area is warranted.

Stable neural underpinnings of emotional cognition subgroups in patients newly diagnosed with bipolar disorder: A prospective fMRI study.

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.

Longitudinal changes in resting-state functional connectivity as markers of vulnerability or resilience in first-degree relatives of patients with bipolar disorder.

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.

APOE Genotype, ApoE Plasma Levels, Lipid Metabolism, and Cognition in Monozygotic Twins with, at Risk of, and without Affective Disorders.

Background: Lipids influence brain function and mental health. Understanding the role of apolipoproteins in affective disorders could provide valuable insights and potentially pave the way for novel therapeutic approaches. Methods: We examined the apolipoprotein E genotype and ApoE-levels, lipid profiles, and the correlation with cognition in 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected, AT), their unaffected co-twins (high-risk, HR), and twins with no personal or family history of affective disorder (low-risk, LR). Results: The APOE genotype was not associated with affective disorders. No significant group differences in ApoE levels were found between the three risk groups. Post hoc analysis group-wise comparisons showed higher ApoE levels in the AT than HR twins and in the concordant AT twin pairs relative to the discordant twin pairs. Within the discordant twin pairs, higher ApoE levels were observed in the affected twins (AT = 39.4 mg/L vs. HR = 36.8 mg/L, p = 0.037). Limitations: The present study could benefit from a larger sample size. We did not assess dietary habits. Conclusions: The results did not support our main hypothesis. However, exploratory post hoc analysis suggests a role for plasma ApoE and triglycerides in affective disorders. Future research is needed.

Struggling Can Also Show on the Inside: Current Knowledge of the Impact of Childhood Maltreatment on Biomarkers in Mood Disorders.

The link between childhood maltreatment and mood disorders is complex and involves multiple bio-psycho-social factors that affect multiple molecular pathways. The present narrative review aims to clarify the current understanding of the impact of childhood maltreatment on biomarkers in patients with mood disorders and their first-degree relatives. Neurotransmitters, such as serotonin, dopamine, norepinephrine, and hormones (eg the stress hormone cortisol), play a crucial role in regulating mood and emotion. Childhood maltreatment can alter and affect the levels and functioning of these neurotransmitters in the brain; further, childhood maltreatment can lead to structural and connectivity changes in the brain, hence contributing to the development of mood disorders and moderating illness presentation and modifying response to treatments. Childhood maltreatment information, therefore, appears mandatory in treatment planning and is a critical factor in therapeutic algorithms. Further research is needed to fully understand these pathways and develop new treatment modalities for individuals with mood disorders who have experienced childhood maltreatment and effective preventive interventions for individuals at risk of developing mood disorders.

A composite immune and vascular stress marker in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives.

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.

Effects of erythropoietin on cognitive impairment and prefrontal cortex activity across affective disorders: A randomized, double-blinded, placebo-controlled trial.

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.

Oxidation of DNA and RNA in young patients with newly diagnosed bipolar disorder and relatives.

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.

What methods are used in research of firsthand experiences with online self-harming and suicidal behavior? A scoping review.

BACKGROUND: Online self-harming and suicidal behavior is a novel and rapidly increasing phenomenon warranting comprehensive mapping of used research methods. AIM: To identify and map how knowledge on online self-harming and suicidal behavior is gathered, including how data are collected e.g. questionnaires and interviews. METHODS: The review follows the Joanna Briggs Institute Manual for Scoping Reviews in tandem with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. A keyword search of three electronic databases was conducted on two occasions, yielding 5422 records. Following duplicate removal, the records were screened based on the following inclusion criterions; (1) in English or Nordic language and published between 2011-2022, (2) presenting results for self-harming and/or suicidal behavior on social media and (3) using tools for either interview or questionnaire aiming at assessment of the experience of online self-harming and suicidal behavior from the perspective of the person who engages in the behavior. A total of 64 articles were included. RESULTS: 45 used questionnaires, 17 used interviews, and two studies mixed the two approaches. 17% of the studies had made some effort to ensure validity within the questionnaires and 15.8% gave full access to the interview guide. CONCLUSION: Research into online self-harming and suicidal behavior is characterized by a lack of validated measurements and methodological transparency. The results emphasize a need for further development, testing, and validation of questionnaires and greater openness and reflexivity in qualitative methodology to enable cross-study comparison and advance knowledge of this complex phenomenon.

Socio-economic status, functioning and cognition in young versus adult patients newly diagnosed with bipolar disorder and their unaffected relatives; results from a cross-sectional study.

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.

Effect of immersive virtual reality-based cognitive remediation in patients with mood or psychosis spectrum disorders: study protocol for a randomized, controlled, double-blinded trial.

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.

Differences in clinical presentation between newly diagnosed bipolar I and II disorders: A naturalistic study.

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.

Effect of erythropoietin on cognitive side-effects of electroconvulsive therapy in depression: A randomized, double-blind, placebo-controlled trial.

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.

Trajectory of reward-related abnormalities in unaffected relatives of patients with bipolar disorder - A longitudinal fMRI study.

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.

Associations between short-chain fatty acid levels and mood disorder symptoms: a systematic review.

Background: Available evidence points to a possible role of Short Chain Fatty Acids (SCFAs) in mood disorders. This is the first systematic review to map the associations between SCFA levels and mood disorder symptoms.Methods: Following the PRISMA guidelines, the databases PubMed, Embase, and PsycINFO were searched for studies that assessed SCFA levels in human populations with mood disorder symptoms, or animal models of mood disorder. Risk of bias was assessed by the Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) checklist.Results: 19 studies were included and could be divided into animal (n=8) and human studies (n=11), with the animal studies including 166 animals and 100 controls, and the human studies including 662 participants and 330 controls. The studies were characterized by heterogeneity and methodological challenges on multiple parameters, limiting the validity and transferability of findings. Notably, only two of the clinical studies assessed the presence of mood disorder with diagnostic criteria, and no studies of mania or bipolar disorder met the inclusion criteria.Discussion: Despite significant methodological limitations, associations between SCFA levels and depressive symptoms were reported in most of the studies. However, the direction of these associations and the specific SCFAs identified varied. The quantification of SCFA levels in mood disorders is an emerging yet sparsely studied research field. Although there is some evidence suggesting a link between SCFAs and depressive symptoms, the directionality of effects and mechanisms are unclear and the relation to manic symptoms is uninvestigated.

Assessment of functional ability in affective disorders.

This review investigates that up to 50% of patients with affective disorders present with impaired overall functioning, also in remitted phases. Nevertheless, functioning is often overlooked in clinical settings and not incorporated as an essential outcome in research. It is recommended clinically and in research to use the International Classification of Functioning (ICF), e.g. the semi-structured interview Functioning Assessment Short Test (FAST) to ensure a common language and coordination cross-sectionally, interdisciplinarily and across mental and physical diseases.

Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

The effect of smartphone-based monitoring and treatment including clinical feedback versus smartphone-based monitoring without clinical feedback in bipolar disorder: the SmartBipolar trial-a study protocol for a randomized controlled parallel-group trial.

INTRODUCTION: A substantial proportion of patients with bipolar disorder experience daily subsyndromal mood swings, and the term "mood instability" reflecting the variability in mood seems associated with poor prognostic factors, including impaired functioning, and increased risk of hospitalization and relapse. During the last decade, we have developed and tested a smartphone-based system for monitoring bipolar disorder. The present SmartBipolar randomized controlled trial (RCT) aims to investigate whether (1) daily smartphone-based outpatient monitoring and treatment including clinical feedback versus (2) daily smartphone-based monitoring without clinical feedback or (3) daily smartphone-based mood monitoring only improves mood instability and other clinically relevant patient-related outcomes in patients with bipolar disorder. METHODS AND ANALYSIS: The SmartBipolar trial is a pragmatic randomized controlled parallel-group trial. Patients with bipolar disorder are invited to participate as part of their specialized outpatient treatment for patients with bipolar disorder in Mental Health Services in the Capital Region of Denmark. The included patients will be randomized to (1) daily smartphone-based monitoring and treatment including a clinical feedback loop (intervention group) or (2) daily smartphone-based monitoring without a clinical feedback loop (control group) or (3) daily smartphone-based mood monitoring only (control group). All patients receive specialized outpatient treatment for bipolar disorder in the Mental Health Services in the Capital Region of Denmark. The trial started in March 2021 and has currently included 150 patients. The outcomes are (1) mood instability (primary), (2) quality of life, self-rated depressive symptoms, self-rated manic symptoms, perceived stress, satisfaction with care, cumulated number and duration of psychiatric hospitalizations, and medication (secondary), and (3) smartphone-based measures per month of stress, anxiety, irritability, activity, and sleep as well as the percentage of days with presence of mixed mood, days with adherence to medication and adherence to smartphone-based self-monitoring. A total of 201 patients with bipolar disorder will be included in the SmartBipolar trial. ETHICS AND DISSEMINATION: The SmartBipolar trial is funded by the Capital Region of Denmark and the Independent Research Fund Denmark. Ethical approval has been obtained from the Regional Ethical Committee in The Capital Region of Denmark (H-19067248) as well as data permission (journal number: P-2019-809). The results will be published in peer-reviewed academic journals, presented at scientific meetings, and disseminated to patients' organizations and media outlets. TRIAL REGISTRATION: Trial registration number: NCT04230421. Date March 1, 2021. Version 1.

Early longitudinal changes in brain structure and cognitive functioning in remitted patients with recently diagnosed bipolar disorder.

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.