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.

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.

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.

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.

Neurocognitive heterogeneity in patients with bipolar disorder and their unaffected relatives: associations with emotional cognition.

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

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.

Mood, activity, and sleep measured via daily smartphone-based self-monitoring in young patients with newly diagnosed bipolar disorder, their unaffected relatives and healthy control individuals.

Diagnostic evaluations and early interventions of patients with bipolar disorder (BD) rely on clinical evaluations. Smartphones have been proposed to facilitate continuous and fine-grained self-monitoring of symptoms. The present study aimed to (1) validate daily smartphone-based self-monitored mood, activity, and sleep, against validated questionnaires and clinical ratings in young patients with newly diagnosed BD, unaffected relatives (UR), and healthy controls persons (HC); (2) investigate differences in daily smartphone-based self-monitored mood, activity, and sleep in young patients with newly diagnosed BD, UR, and HC; (3) investigate associations between self-monitored mood and self-monitored activity and sleep, respectively, in young patients with newly diagnosed BD. 105 young patients with newly diagnosed BD, 24 UR and 77 HC self-monitored 2 to 1077 days (median [IQR] = 65 [17.5-112.5]). There was a statistically significantly negative association between the mood item on Hamilton Depression Rating Scale (HAMD) and smartphone-based self-monitored mood (B = - 0.76, 95% CI - 0.91; - 0.63, p < 0.001) and between psychomotor item on HAMD and self-monitored activity (B = - 0.44, 95% CI - 0.63; - 0.25, p < 0.001). Smartphone-based self-monitored mood differed between young patients with newly diagnosed BD and HC (p < 0.001), and between UR and HC (p = 0.008) and was positively associated with smartphone-based self-reported activity (p < 0.001) and sleep duration (p < 0.001). The findings support the potential of smartphone-based self-monitoring of mood and activity as part of a biomarker for young patients with BD and UR. Smartphone-based self-monitored mood is better to discriminate between young patients with newly diagnosed BD and HC, and between UR and HC, compared with smartphone-based activity and sleep.Trial registration clinicaltrials.gov NCT0288826.

Aberrant cognition in newly diagnosed patients with bipolar disorder and their unaffected relatives.

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

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.

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.

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.

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.

The trajectory of emotional and non-emotional cognitive function in newly diagnosed patients with bipolar disorder and their unaffected relatives: A 16-month follow-up study.

Cognitive impairments are evident in remitted patients with bipolar disorder (BD) and their unaffected relatives (UR) compared to healthy controls (HC). However, the temporal course of cognition, and whether cognition is marked by neuroprogressive changes, remain unclear. In a large prospective study of newly diagnosed patients with BD, we assessed patients with BD (n = 266), UR (n = 105) and HC (n = 190) using an extensive cognitive battery of non-emotional and emotional cognition at baseline and 16-months follow-up. Cognitive change across groups was examined with linear mixed-model analyses. Results showed no evidence of trajectory differences between patients with BD, UR, and HC in neurocognition and emotional cognition (ps≥.10). Patients with BD showed stable impairments in global neurocognitive functioning over time, as well as within the domains of 'working memory and executive function' and 'attention and psychomotor speed', compared to HC. Patients who relapsed during the follow-up time were less successful at down-regulating emotions in positive social scenarios compared to HC. Unaffected relatives also displayed stable deficits in 'working memory and executive function' over time, with performance at intermediate levels between BD probands and HC. Finally, poorer neurocognition and positive emotion regulation were associated with more subsyndromal symptoms and functional impairments. In conclusion, we found no evidence of a neuroprogressive origin of cognitive impairments in the newly diagnosed BD or in their UR. Patients' and UR's impairments in working memory and executive function may reflect a stable cognitive trait-marker of familial risk. Difficulties with positive emotion regulation may be associated with illness progression in BD.

Associations between emotional and non-emotional cognition and subsequent mood episodes in recently diagnosed patients with bipolar disorder: A 16-month follow-up study.

BACKGROUND: Bipolar disorder (BD) is associated with impairments in both emotional and non-emotional cognition. Recently, cognitive impairments have attracted increasing research interest as markers of prognosis and possible treatment targets in patients with BD. However, there is a paucity of studies investigating cognitive predictors of prognosis in BD. METHODS: We assessed 148 recently diagnosed, symptomatically stable patients with BD with a battery of emotional and non-emotional cognitive tests and followed them up over 16 months as part of an ongoing cohort study. Multiple linear regression analyses were conducted to examine the associations between cognitive performance at baseline and the recurrence and duration of (hypo)manic and depressive episodes, respectively, with adjustment for age, sex, subsyndromal symptoms and time between assessments. RESULTS: Poorer recognition of negative facial expressions and more negative emotions in neutral daily life scenarios were associated with greater frequency (ps ≤ .04) and longer duration (ps ≤ .03) of subsequent (hypo)manic episodes over the 16-month follow-up period. In addition, poorer global cognition, attention and psychomotor speed, and verbal fluency were associated with more (hypo)manic episodes (ps ≤ .04). Finally, more difficulty down-regulating emotion in negative social scenarios was associated with depressive relapse (p = .007). It was a limitation that patients had a delayed diagnosis of seven years from their first mood episode despite being recently diagnosed. CONCLUSION: Trait-related cognitive impairments influence the early course in recently diagnosed patients with BD, particularly (hypo)manic relapse. Early prophylactic strategies targeting cognitive impairments may increase resilience and the course of illness in recently diagnosed patients with BD.

The longitudinal trajectory of emotional cognition in subgroups of recently diagnosed patients with bipolar disorder.

Although cross-sectional studies show heterogeneity in emotional cognition in bipolar disorder (BD), the temporal course within subgroups is unclear. In this prospective, longitudinal study we assessed the trajectories of emotional cognition subgroups within a 16-month follow-up period in recently diagnosed BD patients compared to healthy controls (HC). Recently diagnosed BD patients and HC underwent comprehensive emotional and non-emotional testing at baseline and again at follow-up. We employed hierarchical cluster analysis at baseline to identify homogenous emotional cognition subgroups of patients, and changes across the subgroups of BD and HC were assessed with linear mixed-model analyses. We found two emotional cognition subgroups: subgroup 1 (65%, n = 179), showing heightened negative emotional reactivity in neutral and negative social scenarios and faster recognition of emotional facial expressions than HC (ps<0.001, n = 190), and subgroup 2 (35%, n = 96) showing blunted reactivity in positive social scenarios, impaired emotion regulation, poorer recognition of positive and slower recognition of all facial expressions than HC (ps≤.03). Subgroup 1 exhibited normalization of the initial emotional cognition abnormalities in follow-up. In contrast, subgroup 2 showed a lack of improvement in reactivity positively-valenced emotional information. Patients in subgroup 2 presented more and longer mixed episodes during the follow-up time and were more often prescribed lithium. One third of patients display blunted emotional reactivity, impaired emotion regulation abilities and facial expression recognition difficulties also show persistent impairments and poorer course of illness. This subgroup may indicate a need for earlier and more targeted therapeutic interventions.

Personality disorders in patients with newly diagnosed bipolar disorder, their unaffected first-degree relatives and healthy control individuals.

OBJECTIVE: Bipolar disorder (BD) is often a progressive mood disorder with a high prevalence of comorbid personality disorder (PD) ranging from 25 to 73 %. Previous studies have included patients with various illness duration of BD. Longer illness duration may be associated with increased prevalence of comorbid PD. This study investigated the prevalence of comorbid personality disorders in patients with newly diagnosed BD and their unaffected first-degree relatives (UR) compared with healthy control individuals (HC). METHODS: We included 204 patients with newly diagnosed BD, 109 of their UR and 188 HC. To assess comorbid PD according to DSM-IV, the SCID-II-interview was performed in full or partial remission. Subthreshold PD was defined as scores above cut-off in the SCID-II self-report questionnaires. Functioning was assessed using the Functioning Assessment Short Test. RESULTS: In total 52 (25.5 %) of the patients with newly diagnosed BD fulfilled criteria for a comorbid PD. Regarding UR, 7 (6.4 %) fulfilled the criteria for a PD. Subthreshold PD were more prevalent in BD (82.8 %) and UR (53.0 %) than in HC (35.1 %), p-values < 0.003). Patients with comorbid PD presented with impaired functioning compared with patients without PD. LIMITATIONS: Clinical diagnostic distinction between PD and BD is challenged by overlapping symptoms. CONCLUSION: A quarter of patients with newly diagnosed BD fulfill criteria for a comorbid PD, already at the time of the diagnosis with BD. A comorbid PD is associated with larger functional impairments. This emphasizes the need for early assessment of comorbid PD at time of BD diagnosis.

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.

Associations between cognition and subsequent mood episodes in patients with bipolar disorder and their unaffected relatives: A systematic review.

BACKGROUND: Bipolar disorder (BD) is highly recurrent and prevention of relapse and illness onset is an urgent treatment priority. This systematic review examined whether cognitive assessments can aid prediction of recurrence in patients with BD and/or illness onset in individuals at familial risk. METHODS: The review included longitudinal studies of patients with BD or individuals at familial risk of mood disorder that examined the association between cognitive functions and subsequent relapse or illness onset, respectively. We followed the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed/MEDLINE, EMBASE and PsychInfo databases from inception up until May 10th 2021. RESULTS: We identified 19 eligible studies; 12 studies investigated cognitive predictors of recurrence in BD (N = 36-76) and seven investigated cognitive predictors of illness onset in at-risk individuals (N = 84-234). In BD, general cognitive impairment, poorer verbal memory and executive function and positive bias were associated with subsequent (hypo)manic relapse -but with not depressive relapse or mood episodes in general. In first-degree relatives, impairments in attention, verbal memory and executive functions and positive bias were associated with subsequent illness onset. LIMITATIONS: The findings should be considered preliminary given the small-to-moderate sample sizes and scarcity of studies. CONCLUSIONS: Subject to replication, the associations between cognitive impairment and (hypo)mania relapse and illness onset may provide a platform for personalised treatment and prophylactic strategies.

Differential trajectory of cognitive functions in neurocognitive subgroups of newly diagnosed patients with bipolar disorder and their unaffected first-degree relatives - A longitudinal study.

BACKGROUND: Cognitive impairments exist in a large proportion of remitted patients with bipolar disorder (BD). However, no study has investigated the cognitive trajectories across neurocognitive subgroups of patients or their unaffected first-degree relatives (UR). METHODS: Newly diagnosed BD patients, UR and healthy controls (HC) underwent comprehensive cognitive testing at baseline and at 16-months follow-up. Hierarchical cluster analysis was conducted to identify homogeneous subgroups of patients based on their neurocognitive profile at baseline. Cognitive change across subgroups of patients and UR was assessed with linear mixed-model analyses. RESULTS: Data from baseline and follow-up were collected from 152 patients, 53 UR and 135 HC. Patients were clustered into three discrete neurocognitive subgroups: 'cognitively normal' (43%), 'mild-moderately impaired' (33%) and 'globally impaired' (24%). While 'mild-moderately impaired' patients and HC showed normative cognitive improvement over time in global cognition (p < .001), 'globally impaired' patients showed greater improvement than all groups (p < .001), whereas 'cognitively normal' patients showed a lack of normative improvement (p = .17). UR of impaired patients showed a lack of normative improvement in executive functions (p = .01). 'Globally impaired' patients also presented with stable impairments in facial expression recognition and emotion regulation. LIMITATIONS: Follow-up data was available for 62% of participants, possibly reflecting a selection bias. CONCLUSIONS: The greater cognitive improvement in 'globally impaired' patients partly speaks against neuroprogression. However, the lack of normative improvement in 'cognitively normal' patients could indicate negative effects of illness. Further follow-up assessments are warranted to clarify whether lack of normative improvement in executive function in UR represents an illness risk-marker.