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.

A systematic review of interventions in the early course of bipolar disorder I or II: a report of the International Society for Bipolar Disorders Taskforce on early intervention.

BACKGROUND: Given the likelihood of progressive illness in bipolar disorder (BD), it is important to understand the benefits and risks of interventions administered early in illness course. We conducted a systematic review of the effectiveness of interventions in the early course of BD I or II. METHODS: We completed a systematic search on MEDLINE, PsycINFO, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL and Google Scholar from 1/1/1979 till 14/9/2022. We included controlled trials examining intervention effects on symptomatic, course, functional and tolerability outcomes of patients in the 'early course' of BD I or II. We classified patients to be in early course if they (a) were seeking help for the first time for a manic episode, (b) had a lifetime history of up to 3 manic episodes, or (c) had up to 6 lifetime mood episodes. Evidence quality was assessed using the GRADE approach. RESULTS: From 4135 unique publications we included 25 reports representing 2212 participants in 16 randomized studies, and 17,714 participants from nine non-randomized studies. Available evidence suggested that in early illness course, lithium use was associated with lower recurrence risk compared with other mood stabilizers. Mood stabilizers were also associated with better global functioning, compared with the use of antipsychotics in the medium term. While summative findings regarding psychological therapies were limited by heterogeneity, family-focused and cognitive-behavioral interventions were associated with reduced recurrence risk or improved symptomatic outcomes. There was some evidence that the same pharmacological interventions were more efficacious in preventing recurrences when utilized in earlier rather than later illness course. CONCLUSIONS AND RECOMMENDATIONS: While there are promising initial findings, there is a need for more adequately powered trials to examine the efficacy and tolerability of interventions in youth and adults in early illness course. Specifically, there is a compelling need to compare the relative benefits of lithium with other pharmacological agents in preventing recurrences. In addition to symptomatic outcomes, there should be a greater focus on functional impact and tolerability. Effective pharmacological and psychological interventions should be offered to those in early course of BD, balancing potential risks using shared decision-making approaches.

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.

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 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.

The association between mixed symptoms, irritability and functioning measured using smartphones in bipolar disorder.

OBJECTIVE: To (i) validate patient-evaluated mixed symptoms and irritability measured using smartphones against clinical evaluations; (ii) investigate associations between mixed symptoms and irritability with stress, quality of life and functioning, respectively, in patients with bipolar disorder. METHODS: A total of 84 patients with bipolar disorder used a smartphone-based system for daily evaluation of mixed symptoms and irritability for nine months. Clinically evaluated symptoms, stress, quality of life and clinically rated functioning were collected multiple times during follow-up. RESULTS: Patients presented mild affective symptoms. Patient-reported mixed symptoms and irritability correlated with clinical evaluations. In analyses including confounding factors there was a statistically significant association between both mixed symptoms and irritability and stress (P < 0.0001) and between irritability and both quality of life and functioning (P < 0.0001) respectively. There was no association between mixed mood and both quality of life and functioning. CONCLUSION: Mixed symptoms and irritability can be validly self-reported using smartphones in patients with bipolar disorder. Mixed symptoms and irritability are associated with increased stress even during full or partial remission. Irritability is associated with decreased quality of life and functioning. The findings emphasize the clinical importance of identifying inter-episodic symptoms including irritability pointing towards smartphones as a valid tool.

New drug candidates for depression - a nationwide population-based study.

OBJECTIVE: To investigate whether continued use of non-aspirin NSAID, low-dose aspirin, high-dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population-based registers. METHODS: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in-patient or out-patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants. RESULTS: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low-dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident depression. CONCLUSION: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population-based registers to systematically identify drugs with repurposing potential.

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.

A multisystem composite biomarker as a preliminary diagnostic test in bipolar disorder.

OBJECTIVE: Diagnosis and management of bipolar disorder (BD) are limited by the absence of available laboratory tests. We aimed to combine data from different molecular levels and tissues into a composite diagnostic and state biomarker. METHODS: Expression levels of 19 candidate genes in peripheral blood, plasma levels of BDNF, NT-3, IL-6 and IL-18, leukocyte counts, and urinary markers of oxidative damage to DNA and RNA were measured in 37 adult rapid-cycling patients with BD in different affective states during a 6- to 12-month period and in 40 age- and gender-matched healthy individuals in a longitudinal, repeated measures design comprising a total of 211 samples. A composite biomarker was constructed using data-driven variable selection. RESULTS: The composite biomarker discriminated between patients with BD and healthy control individuals with an area under the receiver operating characteristic curve (AUC) of 0.83 and a sensitivity of 73% and specificity of 71% corresponding with a moderately accurate test. Discrimination between manic and depressive states had a moderate accuracy, with an AUC of 0.82 and a sensitivity of 92% and a specificity of 40%. CONCLUSION: Combining individual biomarkers across tissues and molecular systems could be a promising avenue for research in biomarker models in BD.

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.

Is negative self-referent bias an endophenotype for depression? An fMRI study of emotional self-referent words in twins at high vs. low risk of depression.

BACKGROUND: Negative cognitive bias and aberrant neural processing of self-referent emotional words seem to be trait-marks of depression. However, it is unclear whether these neurocognitive changes are present in unaffected first-degree relatives and constitute an illness endophenotype. METHODS: Fifty-three healthy, never-depressed monozygotic or dizygotic twins with a co-twin history of depression (high-risk group: n = 26) or no first-degree family history of depression (low-risk group: n = 27) underwent neurocognitive testing and functional magnetic imaging (fMRI) as part of a follow-up cohort study. Participants performed a self-referent emotional word categorisation task and free word recall task followed by a recognition task during fMRI. Participants also completed questionnaires assessing mood, personality traits and coping strategies. RESULTS: High-risk and low-risk twins (age, mean ± SD: 40 ± 11) were well-balanced for demographic variables, mood, coping and neuroticism. High-risk twins showed lower accuracy during self-referent categorisation of emotional words independent of valence and more false recollections of negative words than low-risk twins during free recall. Functional MRI yielded no differences between high-risk and low-risk twins in retrieval-specific neural activity for positive or negative words or during the recognition of negative versus positive words within the hippocampus or prefrontal cortex. CONCLUSIONS: The subtle display of negative recall bias is consistent with the hypothesis that self-referent negative memory bias is an endophenotype for depression. High-risk twins' lower categorisation accuracy adds to the evidence for valence-independent cognitive deficits in individuals at familial risk for depression.

Continuation of lithium after a diagnosis of chronic kidney disease.

OBJECTIVE: To investigate whether continued lithium or anticonvulsant treatment after a first diagnosis of chronic kidney disease (CKD) was associated with progression to irreversible end-stage kidney disease. METHODS: Nationwide cohort study including all individuals in Denmark in a period from 1995 to 2012 with a diagnosis of CKD and (i) a history of lithium treatment (N = 754, among whom 238 patients had a diagnosis of bipolar disorder) or (ii) a history of anticonvulsant treatment (N = 5.004, among whom 199 patients had a diagnosis of bipolar disorder). End-stage CKD was defined as chronic dialysis or renal transplantation. RESULTS: Continuing lithium (HR = 0.58 (95% CI: 0.37-0.90) and continuing anticonvulsants (HR = 0.53 (95% CI: 0.44-0.64) were associated with decreased rates of end-stage CKD. In the subcohorts of patients with a diagnosis of bipolar disorder, continuing lithium was associated with decreased end-stage CKD (HR = 0.40 (95% CI: 0.17-0.98), whereas continuing anticonvulsants was not (HR = 0.70 (95% CI: 0.21-2.37). There were no interactions of continuing lithium and anticonvulsants. CONCLUSION: After an initial diagnosis of CKD, patients who are selected by their physicians to continue lithium treatment may not necessarily have an increased risk of developing end-stage CKD. Shifting to an anticonvulsant per se may not be associated with an advantage; however, this requires further investigation.

Methodological recommendations for cognition trials in bipolar disorder by the International Society for Bipolar Disorders Targeting Cognition Task Force.

OBJECTIVES: To aid the development of treatment for cognitive impairment in bipolar disorder, the International Society for Bipolar Disorders (ISBD) convened a task force to create a consensus-based guidance paper for the methodology and design of cognition trials in bipolar disorder. METHODS: The task force was launched in September 2016, consisting of 18 international experts from nine countries. A series of methodological issues were identified based on literature review and expert opinion. The issues were discussed and expanded upon in an initial face-to-face meeting, telephone conference call and email exchanges. Based upon these exchanges, recommendations were achieved. RESULTS: Key methodological challenges are: lack of consensus on how to screen for entry into cognitive treatment trials, define cognitive impairment, track efficacy, assess functional implications, and manage mood symptoms and concomitant medication. Task force recommendations are to: (i) enrich trials with objectively measured cognitively impaired patients; (ii) generally select a broad cognitive composite score as the primary outcome and a functional measure as a key secondary outcome; and (iii) include remitted or partly remitted patients. It is strongly encouraged that trials exclude patients with current substance or alcohol use disorders, neurological disease or unstable medical illness, and keep non-study medications stable. Additional methodological considerations include neuroimaging assessments, targeting of treatments to illness stage and using a multimodal approach. CONCLUSIONS: This ISBD task force guidance paper provides the first consensus-based recommendations for cognition trials in bipolar disorder. Adherence to these recommendations will likely improve the sensitivity in detecting treatment efficacy in future trials and increase comparability between studies.

The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder.

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