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.

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.

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.

Affective cognition in response to infant stimuli in pregnant compared with non-pregnant women.

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.

Associations between aberrant working memory-related neural activity and cognitive impairments in somatically healthy, remitted patients with mood disorders.

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.

Emotional cognition subgroups in unaffected first-degree relatives of patients with mood disorders.

BACKGROUND: Patients with major depressive disorder (MDD) or bipolar disorder (BD) exhibit difficulties with emotional cognition even during remission. There is evidence for aberrant emotional cognition in unaffected relatives of patients with these mood disorders, but studies are conflicting. We aimed to investigate whether emotional cognition in unaffected first-degree relatives of patients with mood disorders is characterised by heterogeneity using a data-driven approach. METHODS: Data from 94 unaffected relatives (33 of MDD patients; 61 of BD patients) and 203 healthy controls were pooled from two cohort studies. Emotional cognition was assessed with the Social Scenarios Test, Facial Expression Recognition Test and Faces Dot-Probe Test. Hierarchical cluster analysis was conducted using emotional cognition data from the 94 unaffected relatives. The resulting emotional cognition clusters and controls were compared for emotional and non-emotional cognition, demographic characteristics and functioning. RESULTS: Two distinct clusters of unaffected relatives were identified: a relatively 'emotionally preserved' cluster (55%; 40% relatives of MDD probands) and an 'emotionally blunted' cluster (45%; 29% relatives of MDD probands). 'Emotionally blunted' relatives presented with poorer neurocognitive performance (global cognition p = 0.010), heightened subsyndromal mania symptoms (p = 0.004), lower years of education (p = 0.004) and difficulties with interpersonal functioning (p = 0.005) than controls, whereas 'emotionally preserved' relatives were comparable to controls on these measures. CONCLUSIONS: Our findings show discrete emotional cognition profiles that occur across healthy first-degree relatives of patients with MDD and BD. These emotional cognition clusters may provide insight into emotional cognitive markers of genetically distinct subgroups of individuals at familial risk of mood disorders.

Neural responses during down-regulation of negative emotion in patients with recently diagnosed bipolar disorder and their unaffected relatives.

BACKGROUND: Aberrant emotion regulation has been posited as a putative endophenotype of bipolar disorder (BD). We therefore aimed to compare the neural responses during voluntary down-regulation of negative emotions in a large functional magnetic resonance imaging study of BD, patients' unaffected first-degree relatives (URs), and healthy controls (HCs). METHODS: We compared neural activity and fronto-limbic functional connectivity during emotion regulation in response to aversive v. neutral pictures in patients recently diagnosed with BD (n = 78) in full/partial remission, their URs (n = 35), and HCs (n = 56). RESULTS: Patients showed hypo-activity in the left dorsomedial, dorsolateral, and ventrolateral prefrontal cortex (DMPFC and DLPFC) during emotion regulation while viewing aversive pictures compared to HCs, with URs displaying intermediate neural activity in these regions. There were no significant differences between patients with BD and HCs in functional connectivity from the amygdala during emotion regulation. However, exploratory analysis indicated that URs displayed more negative amygdala-DMPFC coupling compared with HCs and more negative amygdala-cingulate DLPFC coupling compared to patients with BD. At a behavioral level, patients and their URs were less able to dampen negative emotions in response aversive pictures. CONCLUSIONS: The findings point to deficient recruitment of prefrontal resources and more negative fronto-amygdala coupling as neural markers of impaired emotion regulation in recently diagnosed remitted patients with BD and their URs, respectively.

Do objective and subjective measures of cognitive impairment predict occupational status in patients with work-related stress? A clinical follow-up study.

OBJECTIVE: Cognitive impairment is a common complaint in prolonged work-related stress and may contribute to work disability. The objective was to evaluate the longitudinal impacts of objectively and subjectively measured cognitive impairment on occupational status and to evaluate the measurement's predictive properties regarding occupational prognosis in patients with work-related stress. METHODS: Patients with work-related stress (n = 82) were assessed with Danish versions of the Screen for Cognitive Impairment in Psychiatry (SCIP-D) and the Cognitive Failure Questionnaire (CFQ), as screeners of objective and subjective cognitive impairments, respectively. Patients were contacted via telephone at 6-month follow-up providing data on occupational status (employment vs. non-employment). Impacts of cognitive impairment on occupational status were evaluated using logistic regression analyses adjusting for other explanatory covariates (sociodemographic factors, comorbidities etc.). The predictive performance of SCIP-D and CFQ were evaluated using non-adjusted logistic regression analysis and receiver-operating-characteristics curves. RESULTS: There was a strong association between objective cognitive impairment measured with SCIP-D and non-employment when adjusting for other explanatory factors (OR adjusted 3.25, 95% CI 1.09-9.69). The association was attenuated but remained robust in the non-adjusted analysis (OR non-adjusted 1.74, 95% CI 1.08-2.81). Yet, a cut-score of SCIP-D performed inadequate as a sole predictor of occupational status. Subjective cognitive impairment was unrelated to subsequent occupational status. CONCLUSIONS: Objective-but not subjective-cognitive impairment was associated with subsequent non-employment. Our results suggest a predictive potential in objective measurements of cognitive impairment with significant implications for clinical assessment of patients with work-related stress.

Role of trazodone in treatment of major depressive disorder: an update.

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.

The longitudinal trajectory of emotion regulation and associated neural activity in patients with bipolar disorder: A prospective fMRI study.

OBJECTIVES: Impaired emotion regulation is a key feature of bipolar disorder (BD) that presents during acute mood episodes and in remission. The neural correlates of voluntary emotion regulation seem to involve deficient prefrontal top-down regulation already at BD illness onset. However, the trajectory of aberrant neuronal activity during emotion regulation in BD is unclear. METHODS: We investigated neural activity during emotion regulation in response to aversive pictures from the International Affective Picture System in patients with recently diagnosed BD (n = 43) in full or partial remission and in healthy controls (HC) (n = 38) longitudinally at baseline and 16 months later. RESULTS: Patients with BD exhibited stable hypo-activity in the left dorsomedial prefrontal cortex (DMPFC) and right dorsolateral prefrontal cortex (DLPFC) and impaired emotion regulation compared to HC over the 16 months follow-up time. More DLPFC hypo-activity during emotion regulation correlated with less successful down-regulation (r = 0.16, p = 0.045), more subsyndromal depression (r = -0.18, p = 0.02) and more functional impairment (r = -0.24, p = 0.002), while more DMPFC hypo-activity correlated with less efficient emotion regulation (r = 0.16, p = 0.048). Finally, more DMPFC hypo-activity during emotion regulation at baseline was associated with an increased likelihood of subsequent relapse during the 16 months follow-up time (ß = -2.26, 95% CI [0.01; 0.99], p = 0.048). CONCLUSION: The stable DLPFC and DMPFC hypo-activity during emotion regulation represents a neuronal trait-marker of persistent emotion regulation difficulties in BD. Hypo-activity in the DMPFC may contribute to greater risk of relapse.

Autism comorbidities show elevated female-to-male odds ratios and are associated with the age of first autism diagnosis.

OBJECTIVE: To investigate the association between the comorbidity rates in autism and sex, birth year and the age at which autism was first diagnosed and compare the relative impact of each. METHOD: Using the Danish National Patient Registry, cumulative incidences up to the age of 16 for 11 comorbid conditions (psychosis, affective disorders, anxiety disorders, conduct disorder, eating disorders, obsessive-compulsive disorder, attention-deficit hyperactivity disorder, epilepsy, tic disorders, sleep disorders or intellectual disability) were calculated for individuals with autism (N = 16,126) and non-autism individuals (N = 654,977). Individuals were further stratified based on the age at the first autism diagnoses and comorbid diagnoses up to the age of 16 were compared. RESULTS: Most comorbidities were significantly associated with birth year and sex. Female/male odds ratios for 8 of 11 comorbid conditions were up to 67% higher than the corresponding odds ratios in the non-autism population, including conditions that are generally more common in males than in females as well as conditions that are more common in females. All comorbidity rates were significantly associated with the age at the first autism diagnosis, which was a stronger predictor than sex and birth year for 8 conditions. CONCLUSIONS: Comorbidity rates for females exceed what would be expected based on the sex ratios among non-autistic individuals, indicating that the association between autism and comorbidity is stronger in females. Comorbidity rates are also highly dependent on the age at the first autism diagnosis, which may contribute to autism heterogeneity in research and clinical practice.

Structural brain abnormalities associated with cognitive impairments in bipolar disorder.

OBJECTIVE: Cognitive impairment has been highlighted as a core feature of bipolar disorder (BD) that often persists during remission. The specific brain correlates of cognitive impairment in BD remain unclear which impedes efficient therapeutic approaches. In a large sample of remitted BD patients, we investigated whether morphological brain abnormalities within dorsal prefrontal cortex (PFC) and hippocampus were related to cognitive deficits. METHODS: Remitted BD patients (n = 153) and healthy controls (n = 52) underwent neuropsychological assessment and structural MRI. Based on hierarchical cluster analysis of neuropsychological test performance, patients were classified as either cognitively impaired (n = 91) or cognitively normal (n = 62). The neurocognitive subgroups were compared amongst each other and with healthy controls in terms of dorsal PFC cortical thickness and volume, hippocampus shape and volume, and total cerebral grey and white matter volumes. RESULTS: Cognitively impaired patients displayed greater left dorsomedial prefrontal thickness compared to cognitively normal patients and healthy controls. Hippocampal grey matter volume and shape were similar across patient subgroups and healthy controls. At a whole-brain level, cognitively impaired patients had lower cerebral white matter volume compared to the other groups. Across all participants, lower white matter volume correlated with more impaired neuropsychological test performance. CONCLUSIONS: Our findings associate cognitive impairment in bipolar disorder with cerebral white matter deficits, factors which may relate to the observed morphological changes in dorsomedial PFC possibly due to increased neurocognitive effort to maintain symptom stability in these remitted patients.

Thirty-year cardiovascular risk score in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives.

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

Glycogen Synthase Kinase-3ß: Variation over Time and the Possible Association with Mood and Cognition in Healthy Individuals.

Evidence indicates a role for glycogen synthase kinase-3ß (GSK-3ß) in the pathophysiology of mood disorders and in cognitive disturbances; however, the natural variation in GSK-3ß activity over time is unknown. We aimed to investigate GSK-3ß activity over time and its possible correlation with emotional lability, subjective mood fluctuations and cognitive function in healthy individuals. Thirty-seven healthy subjects were evaluated with neuropsychological tests and blood samples at baseline and 12-week follow-up. Total GSK-3ß and serine-9-phosphorylated GSK-3ß in peripheral blood mononuclear cells were quantitated using enzyme immunometric assays. The activity of GSK-3ß (serine-9-phosphorylated GSK-3ß/total GSK-3ß) was lower at baseline compared with follow-up. No significant mean change over time was observed in levels of total GSK-3ß and serine-9-phosphorylated GSK-3ß. Exploratory analysis revealed lower activity of GSK-3ß in spring and summer compared with the fall season. No correlation was observed between GSK-3ß activity and emotional lability, subjective mood fluctuations or cognitive function. The results suggest that intra- and interindividual variation in GSK-3ß activity over time could contribute to the heterogeneity of findings in clinical studies. The stability of GSK-3ß activity and the role of potential moderators of GSK-3ß activity warrant further investigation. Clinical studies of GSK-3ß should consider including repeated measures of both cases and healthy individuals.

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.

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.

Implementing cognitive screenings for outpatients with bipolar disorder following optimised treatment in a specialised mood disorder clinic.

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.

Neural correlates of episodic memory decline following electroconvulsive therapy: An exploratory functional magnetic resonance imaging study.

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 (ps ⩾ 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 (ps ⩾ 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.

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.

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.