Search

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

Few studies have reported socio-economic status and functioning in patients newly diagnosed with bipolar disorder (BD) and their unaffected siblings (US).Socio-economic status and functioning were compared in a cross-sectional clinical study including 382 patients newly diagnosed with BD, 129 of their US, and 200 healthy control individuals (HC).Socio-economic status was lower in patients newly diagnosed with BD compared with HC within educational achievement, employment status, workability and relationship status (p 0.001, OR between 0.02 and 0.53). Regarding US and HC, US had lower educational achievement (p 0.001, OR = 0.27 [0.16; 0.46]), as the only affected socio-economic outcome. Functioning was substantially impaired according to the Functional Assessment Short Test (FAST) (p 0.001, Cohen's d = 2.12) and Work and Social Adjustment Scale (WSAS) (p 0.001, Cohen's d = 2.76) in patients newly diagnosed with BD compared with HC. US expressed the same pattern with impaired overall functioning. Within patients, the impaired functioning was associated with a longer illness duration.Patients had an illness duration of 10.5 [IQR: 6.1; 16.2] years, even though they were included shortly after a diagnosis of BD (0.3 [IQR: 0.1; 0.7] years), highlighting the obstacles of research in illness onset of BD.Patients newly diagnosed with BD, and to a lesser degree their US, exhibit lower socio-economic status and impaired overall functioning. These findings emphasise the importance of early diagnosis, treatment and focus on functional recovery and stress that intervention strategies and further research in high-risk individuals are needed.

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.

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.

Patients with mood disorders show heterogeneity in non-emotional cognition. However, it is unclear whether emotional cognition (EC) is characterised by similar heterogeneity. We aimed to investigate the heterogeneity in EC among remitted patients with mood disorders and explore its association with familial risk. Data from 269 partially or fully remitted patients with mood disorders, 87 of their unaffected relatives (UR) and 203 healthy controls (HC) were pooled from two cohort studies. Hierarchical cluster analysis was conducted using the EC data from patients. UR were categorised into groups consistent with their affected relatives’ cluster assignment. Clusters were compared to HC on EC, non-emotional cognition, clinical characteristics and functioning. We identified three clusters: an ‘emotionally preserved’ (57%), an ‘emotionally blunted’ (26%) and an ‘emotionally volatile’ cluster (17%). ‘Emotionally blunted’ and ‘emotionally volatile’ patients also presented more deficits in non-emotional cognition (global cognition read z=-0.3 and -0.5 respectively). Relatives of ‘emotionally preserved’ patients were more successful at dampening negative emotions (p=.01, d=0.39, 95% CI [-0.76,-0.09]), whereas UR of ‘emotionally impaired’ patients underperformed in verbal fluency (p=.03, d=0.46, 95% CI [.03, 0.68]) compared to HC. The existence of impaired EC groups in remitted mood disorder highlights a need to screen for and treat EC in mood disorders. Improved ability to dampen emotions in UR of ‘emotionally preserved’ patients may reflect a resilience marker while impaired verbal fluency in UR of ‘emotionally impaired’ patients may reflect distinct genetic risk profiles in these EC subgroups.

BackgroundAberrant 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).MethodsWe 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).ResultsPatients 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.ConclusionsThe 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.

BackgroundAround 40% of patients with bipolar disorder (BD) additionally have anxiety disorder. The prevalence of anxiety in patients with newly diagnosed BD and their first-degree relatives (UR) has not been investigated.ObjectiveTo investigate (1) the prevalence of a comorbid anxiety diagnosis in patients with newly diagnosed BD and their UR, (2) sociodemographic and clinical differences between patients with and without a comorbid anxiety diagnosis and (3) the association between smartphone-based patient-reported anxiety and observer-based ratings of anxiety and functioning, respectively.MethodsWe recruited 372 patients with BD and 116 of their UR. Daily smartphone-based data were provided from 125 patients. SCAN was used to assess comorbid anxiety diagnoses.FindingsIn patients with BD, the prevalence of a comorbid anxiety disorder was 11.3% (N=42) and 10.3% and 5.9% in partial and full remission, respectively. In UR, the prevalence was 6.9%. Patients with a comorbid anxiety disorder had longer illness duration (p=0.016) and higher number of affective episodes (p=0.011). Smartphone-based patient-reported anxiety symptoms were associated with ratings of anxiety and impaired functioning (pLimitationsThe SCAN interviews to diagnose comorbid anxiety disorder were carried out regardless of the participants’ mood state.Clinical implicationsThe lower prevalence of anxiety in newly diagnosed BD than in later stages of BD indicates that anxiety increases with progression of BD. Comorbid anxiety seems associated with poorer clinical outcomes and functioning and smartphones are clinically useful for monitoring anxiety symptoms.Trial registration numberClinicalTrials.gov Registry (NCT02888262).

Objective There is an accumulation of stressful life events prior to the first mood episode, but the impact of previous severe life events on psychopathology in patients with bipolar disorder (BD) is not well studied. We aimed to examine the number of recent and lifetime life events in patients with newly diagnosed BD, their unaffected relatives (UR), and healthy controls (HC) as well as the impact of severe lifetime life events on the early course of BD. Methods We compared the number of recent and lifetime life events in 398 patients with newly diagnosed BD, 109 UR, and 214 HC. We subsequently dichotomized the patients with BD by >2 lifetime life events to investigate the associations of severe lifetime life events with clinical characteristics and affective symptoms. Results Patients with newly diagnosed BD reported significantly more life events in the last 12 months and lifetime before compared with UR and HC. Patients who reported >2 lifetime life events (n = 160) compared with patients with 0-2 life events (n = 238) had a significantly longer diagnostic delay (9.5 years ± 8.2 vs. 6.2 years ± 6.9), presented with more anxiety and depressive symptoms and had at least one previous suicide attempt (30.6% vs. 15.6%) and one previous admission (51.3% vs. 36.6%). Conclusion The experience of severe lifetime life events seems to impact the early course in BD in terms of longer diagnostic delay, more severe psychopathology including more admissions and a more than doubled risk for previous suicide attempts.

Background: Mood disorders are often associated with persistent cognitive impairments. However, pro-cognitive treatments are essentially lacking. This is partially because of poor insight into the neurocircuitry abnormalities underlying these deficits and their change with illness progression. Aims: This functional magnetic resonance imaging (fMRI) study investigates the neuronal underpinnings of cognitive impairments and neuronal change after mood episodes in remitted patients with bipolar disorder (BD) using a hippocampus-based picture encoding paradigm. Methods: Remitted patients with BD ( n=153) and healthy controls ( n=52) were assessed with neuropsychological tests and underwent fMRI while performing a strategic picture encoding task. A subgroup of patients ( n=43) were rescanned after 16 months. We conducted data-driven hierarchical cluster analysis of patients’ neuropsychological data and compared encoding-related neuronal activity between the resulting neurocognitive subgroups. For patients with follow-up data, effects of mood episodes were assessed by comparing encoding-related neuronal activity change in BD patients with and without episode(s). Results: Two neurocognitive subgroups were revealed: 91 patients displayed cognitive impairments while 62 patients were cognitively normal. No neuronal activity differences were observed between neurocognitive subgroups within the dorsal cognitive control network or hippocampus. However, exploratory whole-brain analysis revealed lower activity within a small region of middle temporal gyrus in impaired patients, which significantly correlated with poorer neuropsychological performance. No changes were observed in encoding-related neuronal activity or picture recall accuracy with the occurrence of mood episode(s) during the follow-up period. Conclusion: Memory encoding fMRI paradigms may not capture the neuronal underpinnings of cognitive impairment or effects of mood episodes.

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.

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 (β = −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.

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 B = − 0.44, 95% CI − 0.63; − 0.25, p p p = 0.008) and was positively associated with smartphone-based self-reported activity (p p Trial registration clinicaltrials.gov NCT0288826

To investigate whether mood instability (MI) qualify as a trait marker for bipolar disorder (BD) we investigated: 1) differences in smartphone-based self-reported MI between three groups: patients with newly diagnosed BD, unaffected first-degree relatives (UR), and healthy control individuals (HC); 2) the correlation between MI and functioning, stress, and duration of illness, respectively; and 3) the validity of smartphone-based self-evaluated mood ratings as compared to observer-based ratings of depressed and manic mood.203 patients with newly diagnosed BD, 54 UR and 109 HC were included as part of the longitudinal Bipolar Illness Onset study. Participants completed daily smartphone-based mood ratings for a period of up to two years and were clinically assessed with ratings of depression, mania and functioning.Mood instability scores were statistically significantly higher in patients with BD compared with HC (mean=1.18, 95%CI: 1.12;1.24 vs 1.05, 95%CI: 0.98;1.13, p = 0.007) and did not differ between patients with BD and UR (mean=1.17, 95%CI: 1.07;1.28, p = 0.91). For patients, increased MI scores correlated positively with impaired functioning (p0.001), increased stress level (p0.001) and increasing number of prior mood episodes (p0.001). Smartphone-based mood ratings correlated with ratings of mood according to sub-item 1 on the Hamilton Depression Rating Scale 17-items and the Young Mania Rating Scale, respectively (p´s0.001).The study had a smaller number of UR than planned.Mood instability is increased in patients with newly diagnosed BD and unaffected relatives and associated with decreased functioning. The findings highlight MI as a potential trait marker for BD.

OBJECTIVE Bipolar disorder (BD) has been associated with abnormal reward functioning including pleasure-seeking and impulsivity. Here we sought to clarify whether these changes can be attributed to abnormalities in the neural processing of reward valuation or error prediction. Moreover, we tested whether abnormalities in these processes are associated with familial vulnerability to BD. METHODS We obtained functional magnetic resonance imaging data from patients with recently diagnosed BD (n = 85), their unaffected first-degree relatives (n = 44), and healthy control participants (n = 66) while they were performing a monetary card game. We used a region-of-interest approach to test for group differences in the activation of the midbrain, the ventral striatum, and the prefrontal cortex during reward valuation and error prediction. RESULTS Patients with BD showed decreased prediction error signal in ventrolateral prefrontal cortex and the unaffected relatives showed decreased prediction error signal in the supplementary motor area in comparison to healthy controls. There were no significant group differences in the activation of the ventral striatum during the task. In healthy controls, prediction error signal in dorsal anterior cingulate cortex correlated with an out-of-scanner measure of motor inhibition but this association was absent in patients and relatives. CONCLUSIONS The findings indicate that abnormal reward processing in BD is primarily related to deficits in the engagement of prefrontal regions involved in inhibitory control during error prediction. In contrast, deficient activation in supplementary motor cortex involved in planning of movement emerged as a familial vulnerability to BD.

Background: Emotion dysregulation has been suggested as an endophenotype of bipolar disorder (BD). Neuroimaging studies show aberrant neural activity during emotion regulation in remitted patients with BD and their unaffected first-degree relatives (UR) compared to healthy controls (HC). However, behavioural studies produce conflicting - generally negative findings - possibly due to limited sensitivity and ecological validity of current behavioural paradigms. Methods: This study aimed to explore emotion regulation in BD (n = 30) and UR (n = 26) relative to HC (n = 47) by using a novel emotion regulation task in virtual reality (VR). Participants were instructed to either react naturally to, or dampen, their emotional response to highly positive or highly negative scenarios presented in first-person 360-degree spherically camera-recorded VR environments. Participants also completed a more traditional computerised task of emotion regulation for comparison purposes. Results: Patients with BD exhibited difficulties with down-regulating their negative emotions in the VR paradigm compared to HC and UR (ps ≤ .04), whereas UR did not differ from HC (p = .97). There was no emotion regulation difference between groups in the more traditional computerised task (ps ≥ .40). Limitations: The small sample size limits generalisability. Conclusions: The results suggest trait-related reduced ability to down-regulate negative emotions in BD patients compared to HC in the VR paradigm, but not in the more traditional task of emotion regulation. This may indicate that VR provides a more sensitive measure relative to traditional paradigms. The findings provided no support for aberrant emotional regulation as an endophenotype of BD given the normal emotion regulation performance in UR.

Neuroimaging studies of bipolar disorder (BD) generally involve comparison with healthy controls (HC), which may mask neurobiological variability within the disorder. This study aims to assess the neural underpinnings of potential subgroups of BD patients based on functional activity in the emotion regulation network and its relation to illness characteristics and relapse risk. Eighty-seven remitted patients with recently diagnosed BD and 66 HC underwent functional magnetic resonance imaging (fMRI) while performing an emotion regulation task. Patients were re-assessed with clinical interviews after 16 (±5) months. Data-driven hierarchical cluster analysis was employed to investigate 'neuronal subgroups' of patients based on their neuronal activity in a pre-defined emotion regulation network. Relations between neuronal subgroups and illness characteristics and relapse rates were examined. Patients were allocated into two subgroups. Subgroup 1 (n=62, 75%) was characterized by exaggerated bilateral amygdala reactivity but normal prefrontal and temporo-parietal activation. Subgroup 2 (n= 22, 25%) showed widespread hypo-activity within all emotion regulation regions. Both subgroups were less successful at down-regulating their emotions than HC (F(2,146)=5.33, p=.006, ηp2=.07). Patients in subgroup 2 had a history of more and longer mixed episodes (ps≤.01). Importantly, heightened amygdala activity across all patients was associated with increased risk of relapse during a 16-month follow-up period (β=3.36, 95% CI [1.49;550.35], N=60, p=.03). The identified neuronal subgroups of patients with either amygdala hyper-activity or broad network hypo-activity during emotion regulation points to neurobiological heterogeneity among remitted patients with BD. Heightened amygdala reactivity may be a neuronal target for personalized treatments to prevent relapse.

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.

Objectives Cognitive impairment occurs in approximately 50% of remitted patients with bipolar disorder (BD). However, there exists no treatment with replicated and robust efficacy on cognition in BD. This is partially due to limited insight into the neuronal underpinnings of cognitive impairment in these patients. This is the first study to investigate neuronal underpinnings of cognitive impairment in a large functional magnetic resonance imaging (fMRI) dataset comparing neural activity patterns between distinct neurocognitive subgroups of partially or fully remitted patients with BD. Methods Patients (n = 153) and healthy controls (HC) (n = 52) underwent neuropsychological assessment and fMRI, during which they performed a verbal N-back working memory (WM) task. Based on hierarchical cluster analysis of neuropsychological test performance, patients were grouped into one of two neurocognitive subgroups (cognitively impaired, n = 91; cognitively normal compared to HC, n = 62) that were compared on WM-related neural activity. Results Cognitively impaired patients displayed WM-related hypo-activity in left dorsolateral prefrontal cortex and frontal and parietal regions within a cognitive control network (CCN) as well as hyper-activity in the default mode network (DMN) compared to cognitively normal patients. In contrast, cognitively normal patients only exhibited hypo-activity within a small cluster in the superior frontal gyrus relative to HC. Conclusions Cognitive impairment in BD seems to originate from a failure to recruit key regions in the CCN and to suppress task-irrelevant DMN activity during cognitive performance. These results highlight modulation of aberrant dorsal prefrontal and DMN activity as a putative target for pro-cognitive treatment in BD.

Prior studies in bipolar disorders (BD) have suggested that oxidative stress and cellular ageing play a key role in the pathophysiology of BD. Nevertheless, oxidative stress has not been investigated in patients with newly diagnosed BD and in their unaffected first-degree relatives (UR), compared with healthy control individuals (HC).We investigated the level of systemic oxidative damage to DNA and RNA measured by urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) levels, respectively, in 360 patients with newly diagnosed BD, 92 of their UR and 197 HC.Independent of lifestyle and demographic variables, levels of both 8-oxoGuo and 8-oxodG was 17.1% (B = 1.171, 95%CI = 1.125-1.219, p 0.001) and 21.2% (B = 1.212, 95%CI = 1.145-1.283, p 0.001) higher, respectively, in patients with BD compared with HC and 13.3% (B = 1.133, 95%CI = 1.069-1.200, p 0.001) and 26.6% (B = 1.266, 95%CI = 1.167-1.374, p 0.001) higher, respectively, in UR compared with HC. Neither 8-oxoGuo nor 8-oxodG levels differed between patients with BD and UR. These findings were replicated in patients in full or partial remission and were consistent both in BD type I and II.Overall, the findings of higher oxidative stress in patients with newly diagnosed BD and their UR suggest that systemic nucleoside damage by oxidative stress is present prior to onset and in the early stages of BD thereby potentially representing trait markers of BD.

Introduction: Bipolar disorder (BD) is often accompanied by trait-related cognitive impairments, but it is unclear which neurocircuitry abnormalities give rise to these impairments and whether neurocircuitry differences are exacerbated with illness progression. This longitudinal fMRI study of recently diagnosed BD patients investigates whether aberrant working memory (WM) related activity in the cognitive control network is accentuated by new affective episodes. Methods: Forty-seven recently diagnosed BD patients in full or partial remission and 38 healthy controls were assessed with neurocognitive tests and fMRI during the performance of a verbal n-back WM task at baseline and follow-up (15.4 months in average). Results: Patients showed WM-related hypo-activity in dorsal prefrontal cortex (dPFC) and impaired cognitive function within attention and psychomotor speed, WM and executive function, and verbal learning and memory compared to controls at baseline. During the follow-up period, 26 patients experienced at least one affective episode (BD+), while 21 remained in remission (BD-). There was no deterioration in cognitive performance in BD+ compared to BD- patients. Nevertheless, BD+ displayed increased WM-related dPFC activity at follow-up compared with BD- patients. This change in dPFC response was independent of mood symptoms and medication. Limitations: The study did not account for type or frequency of affective episodes. Conclusion: The study identifies cognitive impairment and WM-related hypo-activity in dPFC early during the course of BD. Increased high-load WM related dPFC activity over the follow-up period in BD+ versus BD- patients in the absence of changes in cognitive performance may reflect an episode-related reduction in PFC efficiency.

Background: DSM-IV states that criterion A for diagnosing hypomania/mania is mood change. The revised DSM-5 now states that increased energy or activity must be present alongside mood changes to diagnose hypomania/mania, thus raising energy/activity to criterion A. We set out to investigate how the change in criterion A affects the diagnosis of hypomanic/manic visits in patients with a newly diagnosed / first episode bipolar disorder. Results: In this prospective cohort study, 373 patients were included (median age=32; IQR, 27-40). Women constituted 66% (n=245) of the cohort and 68% of the cohort (n=253) met criteria for bipolar type II, the remaining patients were diagnosed bipolar type I. Median number of contributed visits was 2 per subject (IQR, 1-3) and median follow-up time was 3 years (IQR, 2-4). During follow-up, 127 patients had at least one visit with fulfilled DSM-IV criterion A. Applying DSM-5 criterion A reduced the number of patients experiencing a hypomanic/manic visit by 62% at baseline and by 50% during longitudinal follow-up, compared with DSM-IV criterion A. Fulfilling DSM-5 criterion A during follow-up was associated with higher modified young mania rating scale score (OR=1.51, CL [1.34, 1.71], p Conclusion: Applying the stricter DSM-5 criterion A in a cohort of newly diagnosed bipolar patients reduced the number of patients experiencing hypomanic/manic visit substantially, and was associated with higher overall young mania rating scale scores, compared with DSM-IV criterion A. Overall, fewer hypomanic/manic visits may be detected in newly diagnosed /first episode bipolar patients with applied DSM-5 criterion A. Consequently, with the DSM-5 criteria applied less severe bipolar disorders may be overlooked, especially early during the course of illness, and result in a diagnostic delay. Further studies are warranted on this issue.

Background The upcoming conversion of the ICD-11 will subdivide patients with bipolar disorder (BD) into BD type I (BD-I) and BD type II (BD-II). This study aimed to investigate whether cognitive impairments could aid as objective cognitive biomarkers for recently diagnosed BD subtypes by comparing cognitive profiles between BD subtypes, their unaffected relatives (UR), and healthy controls (HC). Methods The sample included 76 patients with BD-I, 149 patients with BD-II, 28 UR of patients with BD-I (UR-I), 50 UR of patients with BD-II (UR-II) and 168 HC from the Bipolar Illness Onset study, who were assessed with an extensive non-affective and affective cognitive test battery. Results The results showed no significant differences in affective or non-affective cognition between BD-I and BD-II. Compared to HC, patients with BD-I (but not BD-II) showed worse performance in verbal fluency (p = .01) and were slower at recognising fearful faces (p = .045), while patients with BD-II (but not BD-I) displayed generally poorer recognition of facial expressions (p = .02). Only UR-I showed lower performance on verbal fluency (p = .049) and aberrant affective cognition (ps≤.047) compared to HC. Limitations The potential confounding effects of medication were not explored. Conclusions The lack of significant differences in cognitive profiles between recently diagnosed BD-I and BD-II suggests that neither affective nor non-affective cognition are indicative of BD subtype.

Objective To perform a systematic review and meta-analysis of studies investigating neurocognition in euthymic youths with bipolar disorder (BD) compared to healthy controls (HCs). Method A systematic literature search was conducted in the PubMed/MEDLINE, PsycINFO, and EMBASE databases from inception up until March 23, 2016, for original peer-reviewed articles that investigated neurocognition in euthymic youths with BD compared to HCs. Effect sizes (ES) for individual tests were extracted. In addition, results were grouped according to cognitive domain. This review complied with the PRISMA statement guidelines. Results A total of 24 studies met inclusion criteria (N = 1,146; 510 with BD). Overall, euthymic youths with BD were significantly impaired in verbal learning, verbal memory, working memory, visual learning, and visual memory, with moderate to large ESs (Hedge's g 0.76−0.99); significant impairments were not observed for attention/vigilance, reasoning and problem solving, and/or processing speed. Heterogeneity was moderate to large (I2 ≥ 50%) for most ES estimates. Differences in the definition of euthymia across studies explained the heterogeneity in the ES estimate for verbal learning and memory. We also found evidence for other potential sources of heterogeneity in several ES estimates including co-occurring attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders, and the use of medications. In addition, the use of different neuropsychological tests appeared to contribute to heterogeneity of some estimates (e.g., attention/vigilance domain). Conclusion Euthymic youths with BD exhibit significant cognitive dysfunction encompassing verbal learning and memory, working memory, and/or visual learning and memory domains. These data indicate that for a subset of individuals with BD, neurodevelopmental factors may contribute to cognitive dysfunction.

BackgroundRecent 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).MethodsHierarchal 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).ResultsThree 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.ConclusionsIn 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.

Background: Impairments in affective cognition are part of the neurocognitive profile and possible treatment targets in bipolar disorder (BD), but the findings are heterogeneous. The International Society of Bipolar Disorder (ISBD) Targeting Cognition Task Force conducted a systematic review to (i) identify the most consistent findings in affective cognition in BD, and (ii) provide suggestions for affective cognitive domains for future study and meta‐analyses.Methods: The review included original studies reporting behavioral measures of affective cognition in BD patients vs controls following the procedures of the Preferred Reporting Items for Systematic reviews and Meta‐Analysis (PRISMA) statement. Searches were conducted on PubMed/MEDLINE, EMBASE, and PsychInfo from inception until November 2018.Results: A total of 106 articles were included (of which nine included data for several affective domains); 41 studies assessed emotional face processing; 23 studies investigated reactivity to emotional words and images; 3 investigated explicit emotion regulation; 17 assessed implicit emotion regulation; 31 assessed reward processing and affective decision making. In general, findings were inconsistent. The most consistent findings were trait‐related difficulties in facial emotion recognition and implicit emotion regulation, and impairments in reward processing and affective decision making during mood episodes. Studies using eye‐tracking and facial emotion analysis revealed subtle trait‐related abnormalities in emotional reactivity.Conclusion: The ISBD Task Force recommends facial expression recognition, implicit emotion regulation, and reward processing as domains for future research and meta‐analyses. An important step to aid comparability between studies in the field would be to reach consensus on an affective cognition test battery for BD.

The phenomenology and underlying pathophysiology of bipolar disorder (BD) are heterogeneous. The identification of putative endophenotypes for BD can aid in the investigation of unique patho-etiological pathways, which may lead to the development of personalised preventative and therapeutic approaches for this multi-faceted disorder. We included original studies involving unaffected first-degree relatives of BD patients (URs) and a healthy control (HC) comparison group with no first-degree family history of mental disorders, investigating: ‘cold’ and ‘hot’ cognition and functional and structural neuroimaging. Seventy-seven cross-sectional studies met the inclusion criteria. The present review revealed that URs in comparison with HCs showed: (i) widespread deficits in verbal memory, sustained attention, and executive function; (ii) abnormalities in the reactivity to and regulation of emotional information along with aberrant reward processing, and heightened attentional interference by emotional stimuli; and (iii) less consistency in the findings regarding structural and resting state neuroimaging, and electrophysiological measures.

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.

Abnormal processing of emotional information and regulation are core trait-related features of bipolar disorder (BD) but evidence from behavioural studies is conflicting. This study aimed to investigate trait-related abnormalities in emotional reactivity and regulation in BD using novel sensitive behavioural measures including facial expressions and eye movements. Fifteen patients with BD in full or partial remission and 16 healthy controls (HCs) were given a computerised task in which they were instructed to 'react to' unpleasant and neutral pictures or 'dampen' their emotional response to aversive pictures. Participants rated their emotional response after each picture block, and eye-movements and facial expressions were recorded. Patients generally gazed less at unpleasant and neutral pictures during emotion processing and regulation. During emotional reactivity, patients exhibited stronger facial expressions to neutral pictures, a lack of facial expressions to unpleasant pictures, and more surprised facial expressions to both neutral and unpleasant pictures compared to HCs. The results point to subtle abnormalities in visual gaze patterns and facial displays of emotion between patients with BD during emotion processing and regulation. Aberrant eye-movements and facial displays could provide a more sensitive measure of emotional reactivity in BD than traditional behavioural measures, which could aid future diagnostic accuracy.

Objectives Cognitive dysfunction affects a substantial proportion of patients with bipolar disorder (BD), and genetic-imaging paradigms may aid in the elucidation of mechanisms implicated in this symptomatic domain. The Val allele of the functional Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is associated with reduced prefrontal cortex dopamine and exaggerated working memory-related prefrontal activity. This functional magnetic resonance imaging (fMRI) study investigated for the first time whether the COMT Val158Met genotype modulates prefrontal activity during spatial working memory in BD. Methods Sixty-four outpatients with BD in full or partial remission were stratified according to COMT Val158Met genotype (ValVal [n=13], ValMet [n=34], and MetMet [n=17]). The patients completed a spatial n-back working memory task during fMRI and the Cambridge Neuropsychological Test Automated Battery (CANTAB) Spatial Working Memory test outside the scanner. Results During high working memory load (2-back vs 1-back), Val homozygotes displayed decreased activity relative to ValMet individuals, with Met homozygotes displaying intermediate levels of activity in the right dorsolateral prefrontal cortex (dlPFC) (P=.016). Exploratory whole-brain analysis revealed a bilateral decrease in working memory-related dlPFC activity in the ValVal group vs the ValMet group which was not associated with differences in working memory performance during fMRI. Outside the MRI scanner, Val carriers performed worse in the CANTAB Spatial Working Memory task than Met homozygotes (P≤.006), with deficits being most pronounced in Val homozygotes. Conclusions The association between Val allelic load, dlPFC activity and WM impairment points to a putative role of aberrant PFC dopamine tonus in the cognitive impairments in BD.

Spontaneous trait inferences (STIs) are ubiquitous and occur when perceivers spontaneously infer actor traits from actor behaviors. Previous research has elucidated the processes underlying STIs, but little work has focused on the functions of STIs. This article proposes that these unintentional early inferences serve a general approach or avoidance function. Two studies are reported in which external approach and avoidance motivations elicited via flexion–extension (Study 1) or physical warmth (Study 2) affect the encoding of trait-implying behavioral statements in a valence-matching manner. The results suggest that somatic states can act as cues that affect unintentional social information processing independently of the actual experience of the psychological states associated with those somatic states. Implications for a functional perspective on STIs are discussed.

Emotion dysregulation is a core feature of bipolar disorder (BD) that persists into periods of remission. Neuroimaging studies show aberrant neural responses during emotion regulation (ER) in patients with BD relative to healthy controls, but behavioural evidence for ER deficits is sparse and conflicting. This study aimed to explore ER in BD using a novel, personally relevant experimental paradigm. Twenty patients with BD and 20 patients with unipolar disorder (UD), in full or partial remission, and 20 healthy controls were given a novel computerised test. Participants were instructed to react naturally or dampen their emotional response to positive and negative social scenarios and associated self-beliefs. They were also given an established experimental task for comparison, involving reappraisal of negative affective picture stimuli, as well as a questionnaire of habitual ER strategies. BD patients showed reduced ability to down-regulate emotional responses in negative, but not positive, social scenarios relative to healthy controls and UD patients. In contrast, there were no between-group differences in the established ER task or in self-reported habitual reappraisal strategies. Findings highlight the novel social scenario paradigm as a sensitive test for detection of ER difficulties in BD.