Neurocognitive subgroups among newly diagnosed patients with schizophrenia spectrum or bipolar disorders: A hierarchical cluster analysis.

Studies across schizophrenia (SZ) and bipolar disorder (BD) indicate common transdiagnostic neurocognitive subgroups. However, existing studies of patients with long-term illness precludes insight into whether impairments result from effects of chronic illness, medication or other factors. This study aimed to investigate whether neurocognitive subgroups across SZ and BD can be demonstrated during early illness stages. Data from overlapping neuropsychological tests were pooled from cohort studies of antipsychotic-naïve patients with first-episode SZ spectrum disorders (n = 150), recently diagnosed BD (n = 189) or healthy controls (HC) (n = 280). Hierarchical cluster analysis was conducted to examine if transdiagnostic subgroups could be identified based on the neurocognitive profile. Patterns of cognitive impairments and patient characteristics across subgroups were examined. Patients could be clustered into two, three and four subgroups, of which the three-cluster solution (with 83% accuracy) was selected for posthoc analyses. This solution revealed a subgroup covering 39% of patients (predominantly BD) who were cognitively relatively intact, a subgroup of 33% of patients (more equal distributions of SZ and BD) displaying selective deficits, particularly in working memory and processing speed, and a subgroup of 28% (mainly SZ) with global impairments. The globally impaired group exhibited lower estimated premorbid intelligence than the other subgroups. Globally impaired BD patients also showed more functional disability than cognitively relatively intact patients. No differences were observed across subgroups in symptoms or medications. Neurocognitive results can be understood by clustering analysis with similar clustering solutions occurring across diagnoses. The subgroups were not explained by clinical symptoms or medication, suggesting neurodevelopmental origins.

Cognitive impairments among patients in a long-COVID clinic: Prevalence, pattern and relation to illness severity, work function and quality of life.

BACKGROUND: A considerable proportion of people experience lingering symptoms after Coronavirus Disease 2019 (COVID-19). The aim of this study was to investigate the frequency, pattern and functional implications of cognitive impairments in patients at a long-COVID clinic who were referred after hospitalisation with COVID-19 or by their general practitioner. METHODS: Patients underwent cognitive screening and completed questionnaires regarding subjective cognition, work function and quality of life. Patients' cognitive performance was compared with that of 150 age-, sex-, and education-matched healthy controls (HC) and with their individually expected performance calculated based on their age, sex and education. RESULTS: In total, 194 patients were assessed, on average 7 months (standard deviation: 4) after acute COVID-19.44-53 % of the patients displayed clinically relevant cognitive impairments compared to HC and to their expected performance, respectively. Moderate to large impairments were seen in global cognition and in working memory and executive function, while mild to moderate impairments occurred in verbal fluency, verbal learning and memory. Hospitalised (n = 91) and non-hospitalised (n = 103) patients showed similar degree of cognitive impairments in analyses adjusted for age and time since illness. Patients in the cognitively impaired group were older, more often hospitalised, had a higher BMI and more frequent asthma, and were more often female. More objective cognitive impairment was associated with more subjective cognitive difficulties, poorer work function and lower quality of life. LIMITATIONS: The study was cross-sectional, which precludes causality inferences. CONCLUSIONS: These findings underscore the need to assess and treat cognitive impairments in patients at long-COVID clinics.

Trajectory of aberrant reward processing in patients with bipolar disorder - A longitudinal fMRI study.

BACKGROUND: Bipolar disorder (BD), and especially the mania phenotype, is characterized by heightened reward responsivity and aberrant reward processing. In this longitudinal fMRI study, we investigated neuronal response during reward anticipation as the computed expected value (EV) and outcome evaluation as reward prediction error (RPE) in recently diagnosed patients with BD. METHODS: Eighty remitted patients with BD and 60 healthy controls (HC) underwent fMRI during which they performed a card guessing task. Of these, 41 patients and 36 HC were re-scanned after 16 months. We compared reward-related neural activity between groups at baseline and longitudinally and assessed the impact of mood relapse. RESULTS: Patients showed lower RPE signal in areas of the ventrolateral prefrontal cortex (vlPFC) than HC. In these regions, the HC showed decrease in RPE signal over time, which was absent in patients. Patients further exhibited decreased EV signal in the occipital cortex across baseline and follow-up. Patients who remained in remission showed normalization of the EV signal at follow-up. Baseline activity in the identified regions was not associated with subsequent relapse. LIMITATIONS: Follow-up scans were only available in a relatively small sample. Medication status, follow-up time and BD illness duration prior to diagnosis varied. CONCLUSIONS: Lower RPE signal in the vlPFC in patients with BD at baseline and its lack of normative reduction over time may represent a trait marker of dysfunctional reward-based learning or habituation. The increase in EV signal in the occipital cortex over time in patients who remained in remission may indicate normalization of reward anticipation activity.

Trajectory of cognitive impairments over 1 year after COVID-19 hospitalisation: Pattern, severity, and functional implications.

The ongoing Coronavirus Disease (COVID-19) pandemic has so far affected more than 500 million people. Lingering fatigue and cognitive difficulties are key concerns because they impede productivity and quality of life. However, the prevalence and duration of neurocognitive sequelae and association with functional outcomes after COVID-19 are unclear. This longitudinal study explored the frequency, severity and pattern of cognitive impairment and functional implications 1 year after hospitalisation with COVID-19 and its trajectory from 3 months after hospitalisation. Patients who had been hospitalised with COVID-19 from our previously published 3-months study at the Copenhagen University Hospital were re-invited for a 1-year follow-up assessment of cognitive function, functioning and depression symptoms. Twenty-five of the 29 previously assessed patients (86%) were re-assessed after 1 year (11±2 months). Clinically significant cognitive impairments were identified in 48-56 % of patients depending on the cut-off, with verbal learning and executive function being most severely affected. This was comparable to the frequency of impairments observed after 3 months. Objectively measured cognitive impairments scaled with subjective cognitive difficulties, reduced work capacity and poorer quality of life. Further, cognitive impairments after 3 months were associated with the severity of subsequent depressive symptoms after 1 year. In conclusion, the stable cognitive impairments in approximately half of patients hospitalized with COVID-19 and negative implications for work functioning, quality of life and mood symptoms underline the importance of screening for and addressing cognitive sequelae after severe COVID-19.

Identifying social cognition subgroups in euthymic patients with bipolar disorder: a cluster analytical approach.

BACKGROUND: Bipolar disorder (BD) is associated with social cognition (SC) impairments even during remission periods although a large heterogeneity has been described. Our aim was to explore the existence of different profiles on SC in euthymic patients with BD, and further explore the potential impact of distinct variables on SC. METHODS: Hierarchical cluster analysis was conducted using three SC domains [Theory of Mind (ToM), Emotional Intelligence (EI) and Attributional Bias (AB)]. The sample comprised of 131 individuals, 71 patients with BD and 60 healthy control subjects who were compared in terms of SC performance, demographic, clinical, and neurocognitive variables. A logistic regression model was used to estimate the effect of SC-associated risk factors. RESULTS: A two-cluster solution was identified with an adjusted-performance group (N = 48, 67.6%) and a low-performance group (N = 23, 32.4%) with mild deficits in ToM and AB domains and with moderate difficulties in EI. Patients with low SC performance were mostly males, showed lower estimated IQ, higher subthreshold depressive symptoms, longer illness duration, and poorer visual memory and attention. Low estimated IQ (OR 0.920, 95% CI 0.863-0.981), male gender (OR 5.661, 95% CI 1.473-21.762), and longer illness duration (OR 1.085, 95% CI 1.006-1.171) contributed the most to the patients clustering. The model explained up to 35% of the variance in SC performance. CONCLUSIONS: Our results confirmed the existence of two discrete profiles of SC among BD. Nearly two-thirds of patients exhibited adjusted social cognitive abilities. Longer illness duration, male gender, and lower estimated IQ were associated with low SC performance.

Influence of pre-treatment structural brain measures on effects of action-based cognitive remediation on executive function in partially or fully remitted patients with bipolar disorder.

Cognitive impairment is an emerging treatment target in patients with bipolar disorder (BD) but so far, no evidence-based treatment options are available. Recent studies indicate promising effects of Cognitive Remediation (CR) interventions, but it is unclear who responds most to these interventions. This report aimed to investigate whether pre-treatment dorsal prefrontal cortex (dPFC) thickness predicts improvement of executive function in response to Action-Based Cognitive Remediation (ABCR) in patients with BD. Complete baseline magnetic resonance imaging (MRI) data were available from 45 partially or fully remitted patients with BD from our randomized controlled ABCR trial (ABCR: n = 25, control group: n = 20). We performed cortical reconstruction and volumetric segmentation using FreeSurfer. Multiple linear regression analysis was conducted to assess the influence of dPFC thickness on ABCR-related executive function improvement, reflected by change in the One Touch Stocking of Cambridge performance from baseline to post-treatment. We also conducted whole brain vertex wise analysis for exploratory purposes. Groups were well-matched for demographic and clinical variables. Less pre-treatment dPFC thickness was associated with greater effect of ABCR on executive function (p = 0.02). Further, whole-brain vertex analysis revealed an association between smaller pre-treatment superior temporal gyrus volume and greater ABCR-related executive function improvement. The observed associations suggest that structural abnormalities in dPFC and superior temporal gyrus are key neurocircuitry treatment targets for CR interventions that target impaired executive function in BD.

Internet-based cognitive assessment tool: Sensitivity and validity of a new online cognition screening tool for patients with bipolar disorder.

BACKGROUND: The International Society for Bipolar Disorders Targeting Cognition Task Force recommends the Screen for Cognitive Impairment in Psychiatry (SCIP) to screen for cognitive impairment in bipolar disorder. However, SCIP must be administered by a healthcare professional, which is often impossible due to time and resource constraints. Web-based, self-administered cognition screening tools may enable assessment and monitoring of patients' cognition at a much larger scale to a reduced cost. For this purpose, we developed the Internet-Based Cognitive Assessment Tool (ICAT) as a modified web-based version of SCIP. This study aimed to investigate the sensitivity and validity of ICAT for cognition assessment in bipolar disorder. METHOD: Thirty-five patients with bipolar disorder in full or partial remission and 35 healthy controls completed ICAT on a computer, the standard paper-and-pencil SCIP and a subjective cognition questionnaire and were rated for mood symptoms and functioning at the Copenhagen Affective Disorders Research Centre. RESULTS: Patients displayed cognitive impairments compared to controls on the ICAT (t (61)=3.67, p<.001, d=0.93). There was a strong correlation between ICAT and SCIP Total Scores (r(61)=.72, p<.000) and moderate to strong correlations on subtest scores (r=.48-.63, ps<.001). Across all participants, lower ICAT scores correlated with more subjective cognitive complaints (r(59)=-.43, p<.001) and poorer psychosocial functioning (r(62)=-.47, p<.001). CONCLUSION: ICAT is a sensitive and valid web-based tool for cognition assessment in patients with bipolar disorder. This highlights ICAT as a novel web-based cognition screening tool that is feasible for largescale assessment and monitoring of cognition in the clinical management of bipolar disorder.

Assessment of the neuronal underpinnings of cognitive impairment in bipolar disorder with a picture encoding paradigm and methodological lessons learnt.

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 four months after COVID-19 hospital discharge: Pattern, severity and association with illness variables.

The ongoing Coronavirus Disease 2019 (COVID-19) pandemic has affected more than 100 million people and clinics are being established for diagnosing and treating lingering symptoms, so called long-COVID. A key concern are neurological and long-term cognitive complications. At the same time, the prevalence and nature of the cognitive sequalae of COVID-19 are unclear. The present study aimed to investigate the frequency, pattern and severity of cognitive impairments 3-4 months after COVID-19 hospital discharge, their relation to subjective cognitive complaints, quality of life and illness variables. We recruited patients at their follow-up visit at the respiratory outpatient clinic, Copenhagen University Hospital, Bispebjerg, approximately four months after hospitalisation with COVID-19. Patients underwent pulmonary, functional and cognitive assessments. Twenty-nine patients were included. The percentage of patients with clinically significant cognitive impairment ranged from 59% to 65% depending on the applied cut-off for clinical relevance of cognitive impairment, with verbal learning and executive functions being most affected. Objective cognitive impairment scaled with subjective cognitive complaints, lower work function and poorer quality of life. Cognitive impairments were associated with d-dimer levels during acute illness and residual pulmonary dysfunction. In conclusion, these findings provide new evidence for frequent cognitive sequelae of COVID-19 and indicate an association with the severity of the lung affection and potentially restricted cerebral oxygen delivery. Further, the associations with quality of life and functioning call for systematic cognitive screening of patients after recovery from severe COVID-19 illness and implementation of targeted treatments for patients with persistent cognitive impairments.

Effects of psychological and pharmacological interventions on anxiety symptoms in patients with bipolar disorder in full or partial remission: A systematic review.

BACKGROUND: Anxiety symptoms are prevalent in bipolar disorder (BD) even during periods of remission and impede treatment efficacy, prognosis and functional capacity. This highlights a pressing clinical need to identify novel effective anxiety treatments. This systematic review aimed to evaluate the evidence within the field. METHODS: Following PRISMA guidelines, we conducted a systematic search on PubMed, PsycInfo, EMBASE and Cochrane Library for randomised controlled trials (RCTs) targeting anxiety in remitted BD patients. RESULTS: We identified 10 RCTs investigating the effects of psychological or pharmacological treatments on anxiety in remitted BD patients. Two studies of transdiagnostic personalised cognitive behavioural therapy (CBT) found a treatment-related reduction in anxiety. This evidence was preliminary given small sample size and use of self-report measures in a single-blind trial design, respectively. The remaining six psychological intervention trials provided more preliminary evidence due to several methodological challenges. The two pharmacological studies found anxiolytic effects of add-on olanzapine or methylene blue to lithium treatment, respectively. Nevertheless, this evidence should be interpreted with caution given high drop-out rates and substantial side-effects that may have impeded blinding. LIMITATIONS: We did not conduct a quantitative meta-analysis. CONCLUSIONS: There is preliminary evidence for beneficial effects of modified CBT and add-on pharmacotherapy on residual anxiety in BD. Future trials should pre-screen participants for anxiety, define one clinician-rated anxiety measurement as a primary outcome, and employ intention-to-treat analysis to assess treatment effect. This will advance treatment development and enable personalised approaches to address residual anxiety in BD, which has great clinical relevance.

Cognitive processing of infant stimuli in pregnant women with and without affective disorders and the association to postpartum depression.

Pregnancy and childbirth are among the strongest risk factors for depression but the neurocognitive mechanisms underlying this enhanced risk are unknown. This study investigated emotional and non-emotional cognition in 57 pregnant women with or without an affective disorder during their third trimester, and the association between cognitive biases and subsequent postpartum depression (PPD). Of the pregnant women, 22 had a diagnosis of unipolar disorder (UD) and seven of bipolar disorder (BD) in full or partial remission, while 28 had no history of affective disorder. We included a control group of 29 healthy non-pregnant women. First, participants were interviewed, completed non-emotional and emotional cognitive tests and lastly filled out questionnaires. The participants were assessed two times after birth: at a home visit shortly after birth, and with a telephone interview to assess PPD in the first six months after birth. Healthy pregnant women rated infant cries less negatively than non-pregnant women, possibly reflecting preparation for motherhood. Pregnant women with UD exhibited a negative bias in ratings of infant cries, whereas pregnant women with BD showed a positive bias in ratings of infant happy faces and recognition of adult facial expressions. Across all pregnant women, more negative ratings of infant cries were associated with enhanced risk of PPD. Negatively biased perception of infant cries during pregnancy may thus signal vulnerability toward PPD.

Characteristics influencing expected cognitive performance during hypoglycaemia in type 2 diabetes.

BACKGROUND: Acute hypoglycaemia is associated with cognitive impairment in patients with type 2 diabetes. However, there is limited understanding of the relationship between patients' expected cognitive difficulties and their objectively-measured deficits during non-severe hypoglycaemia. OBJECTIVE: This report investigates demographic and clinical factors associated with the discrepancy between expected (i.e., self-evaluated) and measurable (i.e., neuropsychological) cognitive functions in patients with type 2 diabetes during acute non-severe hypoglycaemia. METHODS: We performed an analysis of factors associated with the relationship between expected and measurable cognitive performance for data collected from a cohort of patients with type 2 diabetes (N = 25). Patients attended two experimental visits during which we performed hyper-insulinaemic glucose clamping; (i) non-severe hypoglycaemic clamp (plasma glucose (PG): 3.1 ±â€¯0.3 mmol/L) and (ii) normoglycaemic clamp (PG: 5.8 ±â€¯0.3 mmol/L), as part of a double-blinded cross-over study. During hypoglycaemia, patients' expected cognitive performance was assessed with a visual analogue scale after which objective cognitive functions were assessed with a neuropsychological test battery. We computed a global 'cognitive discrepancy' composite variable with score values on a scale between -10 and +10 using a novel statistical formula that creates a discrepancy score between subjective and objective cognition. Positive values reflect more expected than objectively-measured difficulties, while negative values reflect disproportionately more objectively-measured than expected cognitive difficulties. We used paired samples t-tests to compare degree of cognitive discrepancy between conditions of hypo- and normoglycaemia, while multiple regression analysis was performed to identify factors associated with the degree and direction of the cognitive discrepancy. The significance level for the analyses was p ≤ 0.05 (two-tailed). RESULTS: Patients generally underestimated their cognitive abilities (M = 1.6, SD = 3.3) during hypoglycaemia compared to normoglycaemia (M = -1.0, SD = 3.5) (p = 0.2), t(23) = 2.9, p < 0.01. Underestimation of cognitive capacity during hypoglycaemia was more pronounced for patients with younger age (ß = 0.5, p = 0.02), higher verbal IQ (ß = 0.5, p = 0.03), and more hypoglycaemia-related shakiness (ß = 0.4, p = 0.03). LIMITATIONS: The modest sample size limits the generalizability of the findings. CONCLUSIONS: Patients with type 2 diabetes underestimated their cognitive abilities during non-severe hypoglycaemic states, especially those with younger age, higher IQ, and more hypoglycaemia-related shakiness. These patients may thus have excessive preoccupations with their cognitive difficulties in relation to cognitively challenging daily life situations.

Clinical characteristics associated with the discrepancy between subjective and objective cognitive impairment in depression.

BACKGROUND: Patients with unipolar disorder (UD) commonly experience cognitive dysfunction during symptomatic and remitted phases. However, it is not necessarily the patients with the greatest subjective complaints, who display the largest objectively-measured deficits on neuropsychological tests. OBJECTIVE: This report investigated the demographic and clinical factors associated with the discrepancy between subjective and objective measures of cognition in two separate depressed patient populations in Denmark and New Zealand, respectively, using a new methodology. METHODS: Data from 137 depressed patients and 103 healthy controls including neuropsychological test scores, self-reported cognitive difficulties, and ratings of mood were pooled from two studies conducted in Copenhagen, Denmark, and Christchurch, New Zealand, respectively. Cognitive discrepancy scores were calculated using a novel methodology, with positive values indicating disproportionately more subjective than objective difficulties (i.e., "sensitivity") and negative values indicating more objective than subjective impairments (i.e., "stoicism"). RESULTS: In the Danish partially remitted patient sample, greater 'sensitivity' was associated with more subsyndromal depression severity (standardized Beta (std. ß )= 0.4, p < 0.01)), illness duration (std. ß = 0.4, p < 0.01), and younger age (std. ß = 0.6, p < 0.001). This association was replicated in the New Zealand sample of more symptomatic patients (p-values ≤ 0.05). LIMITATIONS: The cross-sectional design hampered causal inferences. We had obtained different measures of objective and subjective cognition from the two studies. CONCLUSIONS: Patients with more depressive symptoms and younger age overreported cognitive impairments across all illness states. The use of an objective cognition screener thus seems particularly relevant for these patients to assess whether subjective complaints are accompanied by measurable cognitive deficits.

Is aberrant affective cognition an endophenotype for affective disorders? - A monozygotic twin study.

BACKGROUND: Identification of endophenotypes can improve prevention, detection and development of new treatments. We therefore investigated whether aberrant affective cognition constitutes an endophenotype for affective disorders by being present in monozygotic (MZ) twins with unipolar or bipolar disorder in partial remission (i.e. affected) and their unaffected co-twins (i.e. high-risk) relative to twins with no family history of affective disorder (i.e. low-risk). METHODS: We conducted an assessor blind cross-sectional study from 2014 to 2017 of MZ twins using Danish population-based registers in recruitment. Twins attended one test session involving neurocognitive testing, clinical ratings and questionnaires. Main outcomes were attention to and recognition of emotional facial expressions, the memory of emotional self-referential words, emotion regulation and coping strategies. RESULTS: Participants were 103 affected, 44 high-risk and 36 low-risk MZ twins. Groups were demographically well-balanced and showed comparable non-affective cognitive performance. We observed no aberrant affective cognition in affected and high-risk relative to low-risk twins. However, high-risk twins displayed attentional avoidance of emotional faces (ps ⩽ 0.009) and more use of task-oriented coping strategies (p = 0.01) compared with affected twins. In contrast did affected twins show more emotion-oriented coping than high- and low-risk twins (ps ⩽ 0.004). CONCLUSIONS: Our findings provide no support of aberrant affective cognition as an endophenotype for affective disorders. High-risk twins' attentional avoidance of emotional faces and greater use of task-oriented coping strategies may reflect compensatory mechanisms.

Remitted affective disorders and high familial risk of affective disorders associate with aberrant intestinal microbiota.

OBJECTIVE: Affective disorders seem associated with aberrant intestinal microbiota but whether this pattern also occurs in individuals at increased heritable risk is unknown. We investigated associations between gut microbiota profiles and affective disorders by comparing monozygotic (MZ) twins concordant (affected twins with unipolar or bipolar disorder in remission) and discordant to affective disorders (high-risk) with MZ twins without affective disorders (low-risk). METHODS: Stool samples were collected from 128 MZ twins and the microbiome was profiled using 16S rDNA sequencing of the V3-V4 region. RESULTS: Affected twins had a lower diversity and an absence of a specific operational taxonomical unit (OTU) in comparison with low-risk twins. The high-risk twins exhibited the same pattern although the lower diversity was only at a trend level. The OTU belonged to the family Christensenellaceae. The findings were not explained by lifestyle factors (smoking, alcohol consumption, body mass index, or psychotropic medication). CONCLUSION: Affected twins in remission and high-risk twins presented aberrant gut microbiota with depletion of a specific OTU. If replicated, this reduced relative sequence absence may together with the globally altered microbiota composition act as a vulnerability marker by accentuating the effect of gene-environment interactions in individuals genetically disposed for an affective disorder.

Effect of electroconvulsive therapy on neural response to affective pictures: A randomized, sham-controlled fMRI study.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression but its neurocognitive mechanisms are unclear. This randomized, sham-controlled functional magnetic resonance imaging (fMRI) study explored the effects of a single ECT on neural response to affective pictures. Twenty-seven patients with major depressive disorder were randomized to a single active ECT (N = 15) or sham (N = 12) session in a double-blind, parallel-group design. On the following day, patients underwent fMRI during which they viewed pleasant, unpleasant and neutral pictures and performed a free recall test after the scan. Mood symptoms were assessed before ECT/sham and at the time of fMRI. Subsequently, all patients continued active ECT as usual. Mood symptoms were reassessed after six active ECT sessions. A single ECT vs. sham session reduced neural response to unpleasant vs. pleasant pictures in the medial prefrontal cortex, a region showing greater response in the more depressed patients. This effect occurred in the absence of between-group differences in picture recall, mood symptoms or concomitant medication. In conclusion, modulation of medial prefrontal hyper-activity during encoding of negative affective information may be a common mechanism of distinct biological depression treatments.

Neural correlates of improved recognition of happy faces after erythropoietin treatment in bipolar disorder.

OBJECTIVE: Bipolar disorder is associated with impairments in social cognition including the recognition of happy faces. This is accompanied by imbalanced cortico-limbic response to emotional faces. We found that EPO improved the recognition of happy faces in patients with bipolar disorder. This randomized, controlled, longitudinal fMRI study explores the neuronal underpinnings of this effect. METHOD: Forty-four patients with bipolar disorder in full or partial remission were randomized to eight weekly erythropoietin (EPO; 40 000 IU) or saline (NaCl 0.9%) infusions in a double-blind, parallel-group design. Participants underwent whole-brain fMRI at 3T, mood ratings and blood tests at baseline and week 14. During fMRI, participants viewed happy and fearful faces and performed a gender discrimination task. RESULTS: Thirty-four patients had complete pre- and post-treatment fMRI data (EPO: N = 18, saline: N = 16). Erythropoietin vs. saline increased right superior frontal response to happy vs. fearful faces. This correlated with improved happiness recognition in the EPO group. Erythropoietin also enhanced gender discrimination accuracy for happy faces. These effects were not influenced by medication, mood, red blood cells or blood pressure. CONCLUSIONS: Together with previous findings, the present observation suggests that increased dorsal prefrontal attention control is a common mechanism of EPO-associated improvements across several cognitive domains.

Increased sensitivity to positive social stimuli in monozygotic twins at risk of bipolar vs. unipolar disorder.

BACKGROUND: Abnormalities in affective cognition are putative endophenotypes for bipolar and unipolar disorders but it is unclear whether some abnormalities are disorder-specific. We therefore investigated affective cognition in monozygotic twins at familial risk of bipolar disorder relative to those at risk of unipolar disorder and to low-risk twins. METHODS: Seventy monozygotic twins with a co-twin history of bipolar disorder (n = 11), of unipolar disorder (n = 38) or without co-twin history of affective disorder (n = 21) were included. Variables of interest were recognition of and vigilance to emotional faces, emotional reactivity and -regulation in social scenarios and non-affective cognition. RESULTS: Twins at familial risk of bipolar disorder showed increased recognition of low to moderate intensity of happy facial expressions relative to both unipolar disorder high-risk twins and low-risk twins. Bipolar disorder high-risk twins also displayed supraliminal attentional avoidance of happy faces compared with unipolar disorder high-risk twins and greater emotional reactivity in positive and neutral social scenarios and less reactivity in negative social scenarios than low-risk twins. In contrast with our hypothesis, there was no negative bias in unipolar disorder high-risk twins. There were no differences between the groups in demographic characteristics or non-affective cognition. LIMITATIONS: The modest sample size limited the statistical power of the study. CONCLUSIONS: Increased sensitivity and reactivity to positive social stimuli may be a neurocognitive endophenotype that is specific for bipolar disorder. If replicated in larger samples, this 'positive endophenotype' could potentially aid future diagnostic differentiation between unipolar and bipolar disorder.

Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.