Search

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: Neurocognitive impairments are associated with poor clinical and employment outcomes in individuals with affective disorders. However, little is known about their associations with long-term clinical outcomes such as psychiatric hospitalizations, and with socio-demographic indicators other than employment. In the largest longitudinal study of neurocognition in affective disorders to date, we investigate the role of neurocognitive impairments on psychiatric hospitalizations and socio-demographic conditions. Methods: The study included 518 individuals with bipolar or major depressive disorder. Neurocognitive assessments covered executive function and verbal memory domains. Longitudinal data on psychiatric hospitalization and socio-demographic conditions (employment, cohabitation, and marital status) for up to 11 years were obtained using National population-based registers. The primary and secondary outcomes were psychiatric hospitalizations (n = 398) and worsening of socio-demographic conditions (n = 518), in the follow-up period since study inclusion, respectively. Cox regression models were used to examine the association of neurocognition with future psychiatric hospitalizations and the worsening of socio-demographic conditions. Findings: Clinically significant impairment in verbal memory (z-score ≤ −1; defined by the ISBD Cognition Task Force), but not in executive function, was associated with a higher risk of future hospitalization, when adjusted for age, sex, hospitalization in the year preceding inclusion, depression severity, diagnosis, and type of clinical trial (HR = 1.84, 95% CI:1.05–3.25, p = 0.034; n = 398). The results remained significant even after accounting for illness duration. Neurocognitive impairments were not associated with the worsening of socio-demographic conditions (p ≥ 0.17; n = 518). Interpretation: Promoting neurocognitive function, especially verbal memory, may mitigate the risk of future psychiatric hospitalization in individuals with affective disorders. Funding: Lundbeckfonden (R279-2018-1145).

Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes. Persistent cognitive impairments occur in a large proportion of patients with bipolar disorder (BD) but their underlying pathological cellular processes are unclear. The aims of this longitudinal study of BD and healthy control (HC) participants were to investigate (i) the association of brain erythropoietin (EPO) and oxidative stress with cognitive functions and (ii) the changes in brain EPO during and after affective episodes. Participants underwent neurocognitive testing, lumbar punctures for cerebrospinal fluid (CSF) sampling and provided urine spot tests at baseline (all), after an affective episode (patients) and after one year (all). EPO was assayed in the CSF and oxidative stress metabolites related to RNA and DNA damage (8-dihydroguanosine [8-oxo-Guo], 8-hydroxy-2-deoxyguanosine [8-oxo-dG]) were assayed in the CSF and spot urine. Data was available for analyses for 60 BD and 37 HC participants. In unadjusted primary analyses, verbal memory decreased with increasing concentrations of CSF EPO and oxidative stress. In unadjusted explorative analyses, poorer verbal memory and psychomotor speed were associated with higher levels of oxidative stress. However, no associations between cognitive functions and CSF levels of EPO or oxidative stress were observed after adjustment for multiple testing. CSF EPO concentrations were unchanged during and after affective episodes. While CSF EPO correlated negatively with CSF DNA damage marker 8-oxo-dG, this association rendered non-significant after adjusting for multiple testing. In conclusion, EPO and oxidative stress do not seem to be robustly related to cognitive status in BD. Further insight into the cellular processes involved in cognitive impairments in BD is necessary to pave the way for novel therapeutic strategies to improve patients’ cognitive outcomes.

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.

Objective Many patients with work-related stress display cognitive impairment that may hamper recovery. We examined objective and subjective tools for screening of cognitive impairment in this patient group. Methods Patients were assessed with Danish versions of the objective Screen for Cognitive Impairment in Psychiatry (SCIP-D), standardized neuropsychological tests that tapped into the same cognitive domains, the self-assessed Cognitive Failure Questionnaire (CFQ), and several additional scales of symptom severity and psychosocial status. Concurrent validity of the SCIP-D and CFQ was assessed by calculation of Pearson’s correlation coefficients between the objective and subjective tools and the scores on more conventional standardized neuropsychological tests. Decision validity was assessed with logistic receiver-operating-characteristic analyses using a cut-score approach to the objective and the subjective test results to predict impairment detected by the standardized tests. Cognitive norms were established through the data of 79 healthy controls. SCIP-D scores were compared between patients and healthy controls with independent t-tests. Results We included 82 patients with work-related stress. The SCIP-D total scores were strongly associated with standardized neuropsychological tests (r=0.76, P

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.

Background: Cognitive impairments are an emerging treatment target in mood disorders, but currently there are no evidence-based pro-cognitive treatments indicated for patients in remission. With this systematic review of randomised controlled trials (RCTs), the International Society for Bipolar Disorders (ISBD) Targeting Cognition Task force provides an update of the most promising treatments and methodological recommendations. Methods: The review included RCTs of candidate pro-cognitive interventions in fully or partially remitted patients with major depressive disorder or bipolar disorder. We followed the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE and Cochrane Library from January 2015, when two prior systematic reviews were conducted, until February 2021. Two independent authors reviewed the studies with the Revised Cochrane Collaboration's Risk of Bias tool for Randomised trials. Results: We identified 16 RCTs (N = 859) investigating cognitive remediation (CR; k = 6; N = 311), direct current or repetitive magnetic stimulation (k = 3; N = 127), or pharmacological interventions (k = 7; N = 421). CR showed most consistent cognitive benefits, with two trials showing improvements on primary outcomes. Neuromodulatory interventions revealed no clear efficacy. Among pharmacological interventions, modafinil and lurasidone showed early positive results. Sources of bias included small samples, lack of pre-screening for objective cognitive impairment, no primary outcome and no information on allocation sequence masking. Conclusions: Evidence for pro-cognitive treatments in mood disorders is emerging. Recommendations are to increase sample sizes, pre-screen for impairment in targeted domain(s), select one primary outcome, aid transfer to real-world functioning, investigate multimodal interventions and include neuroimaging.

Background Phenotypic heterogeneity is a major impediment to the elucidation of the neurobiology and genetics of bipolar disorder. Endophenotype could help in reducing heterogeneity by defining biological traits that are more direct expressions of gene effects. The aim of this review is to examine the recent literature on clinical, epidemiological, neurobiological, and genetic findings and to select and evaluate candidate endophenotypes for bipolar disorder. Evaluating putative endophenotype could be helpful in better understanding the neurobiology of bipolar disorder by improving the definition of bipolar-related phenotypes in genetic studies. In this manner, research on endophenotypes could be useful to improve psychopathological diagnostics in the long-run by dissecting psychiatric macro phenotypes into biologically valid components. Main body The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiarity, and clinical and biological plausibility. Numerous findings regarding brain function, brain structure, neuropsychology and altered neurochemical pathways in patients with bipolar disorder and their relatives deserve further investigation. Overall, major findings suggest a developmental origin of this disorder as all the candidate endophenotypes that we have been able to select are present both in the early stages of the disorder as well as in subjects at risk. Conclusions Among the stronger candidate endophenotypes, we suggest circadian rhythm instability, dysmodulation of emotion and reward, altered neuroimmune state, attention and executive dysfunctions, anterior cingulate cortex thickness and early white matter abnormalities. In particular, early white matter abnormalities could be the result of a vulnerable brain on which new stressors are added in young adulthood which favours the onset of the disorder. Possible pathways that lead to a vulnerable brain are discussed starting from the data about molecular and imaging endophenotypes of bipolar disorder.

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.

Emerging evidence indicates that mothers and non-mothers show different neurocognitive responses to infant stimuli. This study investigated mothers’ psychophysiological, cognitive and neuronal responses to emotional infant stimuli. A total of 35 mothers with 4-month-old infants and 18 control women without young children underwent computerized tests assessing neurocognitive processing of infant stimuli. Their eye gazes and eye fixations, galvanic skin responses (GSRs) and facial expressions towards infant emotional stimuli were recorded during the tasks. Participants underwent functional magnetic resonance imaging during which they viewed pictures of an unknown infant and, for mothers, their own infants. Mothers gazed more and had increased GSR towards infant stimuli and displayed more positive facial expressions to infant laughter, and self-reported more positive ratings of infant vocalizations than control women. At a neural level, mothers showed greater neural response in insula, dorsolateral prefrontal cortex and occipital brain regions within a predefined ‘maternal neural network’ while watching images of their own vs unknown infants. This specific neural response to own infants correlated with less negative ratings of own vs unknown infants’ signals of distress. Differences between mothers and control women without young children could be interpreted as neurocognitive adaptation to motherhood in the mothers.

Objectives Cognitive impairment affects many patients with bipolar disorder (BD), and treatments with replicated pro-cognitive effects are lacking. This study aimed to assess the effect of Action-Based Cognitive Remediation (ABCR) vs control treatment on cognitive impairment in patients with BD. Methods Patients with remitted BD with objective cognitive impairment were randomized to 10 weeks of ABCR vs control treatment, and assessed at baseline, after 2 weeks of treatment, at treatment completion and at 6 months follow-up. The primary outcome was a cognitive composite score. Secondary outcomes were executive function and observer-rated functional capacity. Tertiary measures included additional neuropsychological tests, performance-based functional capacity and quality of life. Data were analysed with linear mixed effects models. Results In total, 64 participants were randomized; given three dropouts before the baseline assessments, data were analysed for 61 participants (ABCR: n = 32, control: n = 29). There was no effect on ABCR vs control on the primary cognitive composite score (P-values ≥.60). At treatment completion, there was a large effect of ABCR vs control on the secondary executive function measure (treatment effect= -0.16, 95% CI [-0.27, -0.05], P ≤ .01, d = 0.65), and on subjective cognitive functioning (treatment effect = -5.38, 95% CI [-8.13, -2.67], P ≤ .001, d = 0.80), which disappeared at follow-up. There was no treatment-effect on functioning, and no association between cognitive and functional change. Conclusions There was no effect of ABCR on the cognitive composite score. However, there was an effect on executive function and subjective cognitive functioning suggesting that ABCR may be relevant for patients with executive dysfunction. Trial registration ClinicalTrials.gov identifier: NCT03295305.

Individuals with borderline personality disorder (BPD) frequently display impairments in the identification of emotional facial expressions paralleled by a negativity bias. However, it remains unclear whether misperception of facial expressions is a key psychopathological marker of BPD. To address this question, the authors examined 43 women diagnosed with BPD and 56 healthy female controls using an emotion face identification task and a face dot-probe task together with measures on psychopathology. Compared to controls, women with BPD showed impaired identification of disgusted and angry faces concurrent with a bias to misclassify faces as angry, and a faster preconscious vigilance for fearful relative to happy facial expressions. Increased severity of borderline symptoms and global psychopathology in BPD patients were associated with reduced ability to identify angry facial expressions and a stronger negativity bias to anger. The findings indicate that BPD patients who misperceive face emotions have the greatest mental health issues.

Unipolar and bipolar disorders aggregate in families and have been associated with a reduced gray-matter volume in hippocampal and prefrontal cortex. Here we used structural MRI to clarify whether abnormalities in hippocampal subfield and prefrontal cortical morphology are associated with familial vulnerability (i.e., changes present both in patients and unaffected relatives compared to healthy individuals), resilience (i.e., changes differentiating unaffected relatives and patients), or sequalae of illness in a sample of monozygotic twins. We investigated regional differences in gray-matter volume extracted using FreeSurfer 6.0 between remitted affected twins (AT) with either unipolar or bipolar disorder (n = 67), unaffected discordant co-twins (UT, n = 39), and low-risk twins (LT, n = 31) with no personal or first-degree family history of affective disorders. The UT showed greater bilateral hippocampal volumes compared to AT. Between group differences in left hippocampal volume were driven by greater cornu ammonis 1-3 and 4, subiculum and subfield of dentate gyrus. For the right hippocampus, differences were driven by greater hippocampal tail and subiculum. There was a trend for UT having a larger left hippocampus than LT, but no significant differences in hippocampal volumes between AT and LT. Outside the hippocampus, AT showed a smaller volume of left dorsomedial prefrontal cortex compared to LT. Our results suggest that larger volume of specific hippocampal subfields may be associated with resilience in healthy relatives of patients with an affective illness. Moreover, a smaller volume of left dorsomedial prefrontal cortex may reflect a sequalae of illness.

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.

Cognitive impairment has emerged as a key treatment priority in neuropsychiatric disorders. However, there is a lack of treatments with solid and lasting efficacy on cognition. A neurocircuitry-based biomarker model of pro-cognitive effects is critically needed to select among new candidate treatments. In a recent review of functional magnetic resonance imaging (fMRI) studies in mood disorders, we found that cognitive impairments are consistently accompanied by aberrant (hypo- and hyper-) activity in the dorsal prefrontal cortex (PFC) and the default mode network (DMN), and that activity change in these regions commonly occurs with cognitive improvements. Here, we (i) review the putative model from our recent review article, which explains the discrepant findings regarding the direction of aberrant dorsal PFC activity and treatment-related activity change in mood disorders. Inspired by the Research Domain Criteria project, we do this in order to (ii) examine whether a similar pattern of activity change occurs across distinct neuropsychiatric disorders and thereby provides a common biomarker for pro-cognitive effects. Lastly, we (iii) discuss whether dorsal PFC and DMN target engagement is a putative transdiagnostic neurocircuitry-based biomarker model for pro-cognitive effects, and (iv) outline the necessary next steps to address this question.

BackgroundDepressive episodes experienced in unipolar (UD) and bipolar (BD) disorders are characterized by anhedonia and have been associated with abnormalities in reward processes related to reward valuation and error prediction. It remains however unclear whether these deficits are associated with familial vulnerability to mood disorders.MethodsIn a functional magnetic resonance imaging study, we evaluated differences in the expected value (EV) and reward prediction error (RPE) signals in ventral striatum (VS) and prefrontal cortex between three groups of monozygotic twins: affected twins in remission for either UD or BD (n = 53), their high-risk unaffected co-twins (n = 34), and low-risk twins with no family history of mood disorders (n = 25).ResultsCompared to low-risk twins, affected twins showed lower EV signal bilaterally in the frontal poles and lower RPE signal bilaterally in the VS, left frontal pole and superior frontal gyrus. The high-risk group did not show a significant change in the EV or RPE signals in frontostriatal regions, yet both reward signals were consistently lower compared with low-risk twins in all regions where the affected twins showed significant reductions.ConclusionOur findings strengthen the notion that reduced valuation of expected rewards and reduced error-dependent reward learning may underpin core symptom of depression such as loss of interest in rewarding activities. The trend reduction in reward-related signals in unaffected co-twins warrants further investigation of this effect in larger samples and prospective follow-up to confirm possible association with increased familial vulnerability to mood disorders.

Motherhood involves functional brain adaptations within a broad neural network purported to underlie sensitive caregiving behavior. Bipolar disorder (BD) is associated with aberrant brain response to emotional faces within a similar network, which may influence BD mothers’ sensitivity to infant faces. This functional magnetic resonance imaging (fMRI) study aimed to investigate whether mothers with BD display aberrant neural responses to own infant faces compared to healthy mothers. Twenty-six mothers with BD in remission and 35 healthy mothers underwent fMRI during which they viewed happy and distressed still facial photographs of their own and of unknown infants. After the scan, mothers viewed the pictures again on a computer screen and rated the intensity of infants’ facial emotions and their own emotional response to infant face images. Mothers with BD displayed lower left dorsolateral prefrontal cortex (dlPFC) response compared to healthy mothers to own vs. unknown infant faces specifically and abnormal positive functional connectivity between the left and right amygdala and prefrontal regions. BD mothers further displayed stronger deactivation of precuneus and occipital regions to all happy vs. distressed infant faces. After the scan, they rated their infants’ distress and own response to their infants’ distressed faces less negatively than healthy mothers. Blunted dlPFC response and aberrant fronto-limbic connectivity while viewing own infant faces and less negative ratings of own infants’ distress in BD mothers may affect their responses to their own infants in real-life mother-infant interactions.

BackgroundDeveloping treatments for cognitive impairment is key to improving the functioning of people with mood disorders. Neuroimaging may assist in identifying brain-based efficacy markers. This systematic review and position paper by the International Society for Bipolar Disorders Targeting Cognition Task Force examines the evidence from neuroimaging studies of pro-cognitive interventions.MethodsWe included magnetic resonance imaging (MRI) studies of candidate interventions in people with mood disorders or healthy individuals, following the procedures of the Preferred Reporting Items for Systematic reviews and Meta-Analysis 2020 statement. Searches were conducted on PubMed/MEDLINE, PsycInfo, EMBASE, Cochrane Library, and Clinicaltrials.gov from inception to 30th April 2021. Two independent authors reviewed the studies using the National Heart, Lung, Blood Institutes of Health Quality Assessment Tool for Controlled Intervention Studies and the quality of neuroimaging methodology assessment checklist.ResultsWe identified 26 studies (N = 702). Six investigated cognitive remediation or pharmacological treatments in mood disorders (N = 190). In healthy individuals, 14 studies investigated pharmacological interventions (N = 319), 2 cognitive training (N = 73) and 4 neuromodulatory treatments (N = 120). Methodologies were mostly rated as ‘fair’. 77% of studies investigated effects with task-based fMRI. Findings varied but most consistently involved treatment-associated cognitive control network (CCN) activity increases with cognitive improvements, or CCN activity decreases with no cognitive change, and increased functional connectivity. In mood disorders, treatment-related default mode network suppression occurred.ConclusionsModulation of CCN and DMN activity is a putative efficacy biomarker. Methodological recommendations are to pre-declare intended analyses and use task-based fMRI, paradigms probing the CCN, longitudinal assessments, mock scanning, and out-of-scanner tests.

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.

BackgroundThe association between impaired social cognition and bipolar disorder (BD) is well established. However, to our knowledge, there has not been a recent systematic review that characterizes disparate dimensions of social cognition in BD. Herein, this systematic review and meta-analysis aimed to synthesize the literature on core aspects of social cognition (i.e., Theory of Mind, emotion recognition, and social judgment) to identify potential areas of impairment.MethodsOnline databases (i.e., PubMed, Cochrane Libraries, PsycINFO) and Google Scholar were searched from inception to May 2021. Studies with populations ages ≥16 with DSM-IV or DSM-5 defined BD (I or II) either in a euthymic or symptomatic state were included. The risk of bias was measured using the ROBINS-1 tool, and the quality of the sources was evaluated using GRADE criteria. The results of the studies were quantitatively measured by synthesizing Hedge's g effect sizes through a random effects meta-analytic approach.ResultsA total of 29 studies were included in the final review (i.e., 12 studies on the Theory of Mind, 11 on emotion recognition, and 6 on social judgment). Overall, results demonstrated social cognition to be moderately impaired in individuals with BD (d = 0.59). The individual domains ranged in effect size (0.38 < d < 0.70), providing evidence for variation in impairment within social cognition.DiscussionIndividuals with BD exhibit clinically significant deficits in social cognition during euthymic and symptomatic states. Social cognition impairments in individuals with BD are an important therapeutic target for treatment discovery and development.

Importance COVID-19 is associated with clinically significant symptoms despite resolution of the acute infection (i.e., post-COVID-19 syndrome). Fatigue and cognitive impairment are amongst the most common and debilitating symptoms of post-COVID-19 syndrome. Objective To quantify the proportion of individuals experiencing fatigue and cognitive impairment 12 or more weeks following COVID-19 diagnosis, and to characterize the inflammatory correlates and functional consequences of post-COVID-19 syndrome. Data sources Systematic searches were conducted without language restrictions from database inception to June 8, 2021 on PubMed/MEDLINE, The Cochrane Library, PsycInfo, Embase, Web of Science, Google/Google Scholar, and select reference lists. Study selection Primary research articles which evaluated individuals at least 12 weeks after confirmed COVID-19 diagnosis and specifically reported on fatigue, cognitive impairment, inflammatory parameters, and/or functional outcomes were selected. Data extraction & synthesis Two reviewers independently extracted published summary data and assessed methodological quality and risk of bias. A meta-analysis of proportions was conducted to pool Freeman-Tukey double arcsine transformed proportions using the random-effects restricted maximum-likelihood model. Main outcomes & measures The co-primary outcomes were the proportions of individuals reporting fatigue and cognitive impairment, respectively, 12 or more weeks following COVID-19 infection. The secondary outcomes were inflammatory correlates and functional consequences associated with post-COVID-19 syndrome. Results The literature search yielded 10,979 studies, and 81 studies were selected for inclusion. The fatigue meta-analysis comprised 68 studies, the cognitive impairment meta-analysis comprised 43 studies, and 48 studies were included in the narrative synthesis. Meta-analysis revealed that the proportion of individuals experiencing fatigue 12 or more weeks following COVID-19 diagnosis was 0.32 (95% CI, 0.27, 0.37; p

BackgroundCognitive impairment experienced by people with bipolar disorders (BD) or major depressive disorder (MDD) is associated with impaired psychosocial function and poorer quality of life. Sleep disturbance is another core symptom of mood disorders which may be associated with, and perhaps worsen, cognitive impairments. The aim of this systematic review was to critically assess the relationship between sleep disturbance and cognitive impairment in mood disorders.MethodsIn this systematic review, relevant studies were identified using electronic database searches of PsychINFO, MEDLINE, Embase and Web of Science.FindingsFourteen studies were included; eight investigated people with BD, five investigated people with MDD, and one included both people with MDD and people with BD. One study was an intervention for sleep disturbance and the remaining thirteen studies used either a longitudinal or cross-sectional observational design. Ten studies reported a significant association between subjectively measured sleep disturbance and cognitive impairment in people with MDD or BD after adjusting for demographic and clinical covariates, whereas no such association was found in healthy participants. Two studies reported a significant association between objectively measured sleep abnormalities and cognitive impairment in mood disorders. One study of cognitive behavioural therapy for insomnia modified for BD (CBTI-BD) found an association between improvements in sleep and cognitive performance in BD.InterpretationThere is preliminary evidence to suggest a significant association between sleep disturbance and cognitive impairment in mood disorders. These findings suggest that identifying and treating sleep disturbance may be important when addressing cognitive impairment in mood disorders.

Autism is a developmental condition, where symptoms are expected to occur in childhood, but a significant number of individuals are diagnosed with autism for the first time in adulthood. Here we use the National Danish Patient Registry to investigate diagnoses given in childhood among those that are diagnosed with autism in adulthood (N = 2199). We found that most childhood diagnoses were given after the age of 12, and attention-deficit hyperactivity disorder, affective disorders, anxiety, and stress disorders were the most prevalent childhood diagnoses. However, 69% of males and 61% of females with adult autism diagnoses had not received any of the included diagnoses before the age of 18. In most cases, the late autism diagnosis is therefore unlikely to be explained by either misdiagnosis or diagnostic overshadowing. This result is at odds with the prevailing notion that autistic symptoms tend to diminish with age. Therefore, further research is warranted to examine how early signs of autism may have manifested among these individuals, and how similar they are to autistic people diagnosed earlier in their development. Milder to moderate cases of psychiatric conditions that have been solely treated by family physician or school psychologists may not be fully included in our dataset.

There is a pressing need for measures of real-life cognitive functioning in patients with mood or psychotic disorders in clinical settings and treatment trials targeting cognition. We developed the first immersive virtual reality cognition assessment tool, the Cognition Assessment in Virtual Reality (CAVIR), which assesses verbal memory, processing speed, attention, working memory and planning skills in an interactive virtual reality kitchen scenario. This study investigates the sensitivity and validity of the CAVIR for cognitive impairments in mood and psychotic disorders and its association with functioning and neuropsychological performance. Symptomatically stable patients with mood disorders (MD; n = 40) or psychosis spectrum disorders (PSD; n = 41) and healthy control participants (HC; n = 40) completed the CAVIR and standard neuropsychological tests and were rated for clinical symptoms and daily functioning. We found that the CAVIR was sensitive to cognitive impairments across MD and PSD with large effect sizes (MD: F(73) = 11.61, p < .01, ηp2 = 0.14; PSD: F(72) = 18.24, p < .001, ηp2 = 0.19). There was a moderate to strong positive correlation between performance on the CAVIR and on neuropsychological tests (r(121) = 0.58, p < .001), which prevailed after adjustment for age, years of education and verbal IQ (B = 0.67, p < .001). Lower CAVIR scores correlated moderately with more observer-rated and performance-based functional disability (r(121) = -0.30, p < .01 and r(68) = 0.44, p < .001, respectively), also after adjustment for age, years of education and verbal IQ (B = 0.03, p < .001). In conclusion, the CAVIR is a sensitive and valid instrument for measuring real-life cognitive impairments in mood and psychotic disorders. After further psychometric assessments, the CAVIR can be implemented in clinical settings and trials targeting cognition.

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.

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

Objective: We aimed to evaluate the effect of weight loss induced by a carbohydrate-reduced high-protein (CRHP) diet on physical and mental health and cognition. Methods: In this randomized parallel trial, 72 adults with type 2 diabetes and overweight or obesity (mean±SD, HbA1c: 7.4±0.7% and BMI: 33±5 kg/m2) were randomly assigned to CRHP diet (C30E%/P30E%/F40E%) or control diet (CD: C50E%/P17E%/F33E%) for 6 weeks. The two diets were intended to induce similar weight losses (~6%). Physical and mental component summary (PCS and MCS) scores were assessed from the short-form 36 questionnaire (SF-36), and global cognition, verbal memory, psychomotor speed and executive function from a neuropsychological test battery. Results: Both groups achieved a 5.8 kg (~6%) weight loss and improved PCS (median (IQR), CD: 2.7 (1.1;4.2)% and CRHP: 2.1 (0.7;3.7)%; both p Conclusion: Weight loss improves physical health independently of diet composition, and carbohydrate restriction may further benefit mental health, without adversely affecting overall cognition. Disclosure N. J. Jensen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp & Dohme; Novo Nordisk; Sanofi, Research Support; Self; Novo Nordisk, Boehringer Ingelheim, Speaker’s Bureau; Self; AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. F. Magkos: None. K. Miskowiak: Consultant; Self; Lundbeck. J. Rungby: None. S. B. Haugaard: None. T. Krarup: None. M. N. Thomsen: None. H. Z. Wodschow: None. M. J. Skytte: None. A. Samkani: None. A. Astrup: Consultant; Self; Groupe Ethique et Sante, France, Employee; Self; Novo Nordisk Foundation, Other Relationship; Self; Flaxslim ApS, Denmark, Gelesis, Personalized Weight Management Research Consortium ApS (Gluco-Diet. dk). J. Frystyk: n/a. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. M. Larsen: None. Funding Arla Foods; Danish Dairy Research Foundation

Trials targeting cognition in bipolar disorder (BD) are advised to include a measure of functional capacity as key secondary or co-primary outcome to assess whether treatment efficacy on cognition translates into enhanced functional capacity. However, it is unclear which measure of functional capacity shows the strongest association with objectively-measured cognition and may thus be best suited for inclusion in cognition trials.Participants (N = 58) with BD in partial or full remission with objective cognitive impairment and healthy controls (N = 37) were assessed with mood ratings and were given a comprehensive battery of neuropsychological tests and a questionnaire assessing subjective cognitive function, respectively. They were also assessed with performance-based, interview-based and self-reported measures of functional capacity. Associations between objective and subjective cognition and measures of functional capacity were assessed with correlation analyses. For significant correlations, multiple regression analyses were conducted to assess if the associations remained significant after adjustment for clinical and demographic variables.Objectively-measured cognition was directly associated with performance-based functional capacity (β = 0.37, p 0.01) also after adjustment for clinical and demographic variables, but not with self-reported or interview-based functional capacity (ps ≥0 .20). In contrast, subjective cognitive complaints were associated with self-reported (β = 0.59, p 0.01) and interview-based functional capacity (β = 0.47, p 0.01), but not performance-based functional capacity (ps ≥ 0.28).The cross-sectional design and modest sample size.A performance-based measure of functional capacity seems most feasible for inclusion as a secondary outcome in cognition trials to capture improved functional capacity following treatment-related improvements in cognition.

BackgroundMetabolic syndrome (MetS) is associated with reduced life expectancy in patients with affective disorders, however, whether MetS also plays a role before the onset of affective disorder is unknown. We aimed to investigate whether MetS, inflammatory markers or oxidative stress act as risk factors for affective disorders, and whether MetS is associated with increased inflammation and oxidative stress.MethodsWe conducted a high-risk study including 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk). Metabolic Syndrome was ascertained according to the International Diabetes Federation (IDF) criteria. Inflammatory markers and markers of oxidative stress were analyzed from fasting blood and urine samples, respectively.ResultsThe affected and the high-risk group had a significantly higher prevalence of MetS compared to the low-risk group (20%v.15%v.2.5%,p= 0.0006), even after adjusting for sex, age, smoking and alcohol consumption. No differences in inflammatory and oxidative markers were seen between the three groups. Further, MetS was associated with alterations in inflammatory markers, and oxidative stress was modestly correlated with inflammation.ConclusionMetabolic syndrome is associated with low-grade inflammation and may act as a risk factor and a trait marker for affective disorders. If confirmed in longitudinal studies, this suggests the importance of early intervention and preventive approaches targeted towards unhealthy lifestyle factors that may contribute to later psychopathology.

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.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.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").In the Danish partially remitted patient sample, greater 'sensitivity' was associated with more subsyndromal depression severity (standardized Beta (std. β )= 0.4, p 0.01)), illness duration (std. β = 0.4, p 0.01), and younger age (std. β = 0.6, p 0.001). This association was replicated in the New Zealand sample of more symptomatic patients (p-values ≤ 0.05).The cross-sectional design hampered causal inferences. We had obtained different measures of objective and subjective cognition from the two studies.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.

During the past two decades, it has been amply documented that neuropsychiatric disorders (NPDs) disproportionately account for burden of illness attributable to chronic non-communicable medical disorders globally. It is also likely that human capital costs attributable to NPDs will disproportionately increase as a consequence of population aging and beneficial risk factor modification of other common and chronic medical disorders (e.g., cardiovascular disease). Notwithstanding the availability of multiple modalities of antidepressant treatment, relatively few studies in psychiatry have primarily sought to determine whether improving cognitive function in MDD improves patient reported outcomes (PROs) and/or is cost effective. The mediational relevance of cognition in MDD potentially extrapolates to all NPDs, indicating that screening for, measuring, preventing, and treating cognitive deficits in psychiatry is not only a primary therapeutic target, but also should be conceptualized as a transdiagnostic domain to be considered regardless of patient age and/or differential diagnosis.

BackgroundAtypical neurocognitive responses to emotional stimuli are core features of unipolar depression (UD) and bipolar disorder (BD). For mothers with these mood disorders, this may influence interactions with their infants and consequently infant development. The study aimed to investigate psychophysiological and cognitive responses to infant emotional stimuli, and their relation to mother–infant interaction and infant development, in mothers with BD or UD in full or partial remission.MethodsFour months after birth, mothers' cognitive responses to emotional infant stimuli were assessed with computerized tasks, while their facial expressions, galvanic skin responses (GSR), gazes, and fixations were recorded. Infant development and mother–infant interactions were also assessed.ResultsWe included 76 mothers: 27 with BD, 13 with UD, and 36 without known psychiatric disorders, and their infants. Mothers with BD and UD were in full or partial remission and showed blunted GSR and spent less time looking at infant stimuli (unadjusted p values < 0.03). Mothers with BD showed subtle positive neurocognitive biases (unadjusted p valuesp values < 0.02). Across all mothers, some measures of atypical infant emotion processing correlated with some measures of delays in infant development and suboptimal mother–infant interaction (unadjusted p valuesConclusionsMothers with mood disorders in full or partial remission showed atypical cognitive and psychophysiological response to emotional infant stimuli, which could be associated with mother–infant interactions and infant development. The study is explorative, hypothesis generating, and should be replicated in a larger sample. Investigation of the long-term implications of reduced maternal sensitivity is warranted.