Systemic inflammation, oxidative damage and neurocognition predict telomere length in a transdiagnostic sample stratified by global DNA methylation levels.

Epigenetic mechanisms contribute to the maintenance of both type 2 diabetes mellitus (T2DM) and psychiatric disorders. Emerging evidence suggests that molecular pathways and neurocognitive performance regulate epigenetic dynamics in these disorders. The current combined and transdiagnostic study investigated whether inflammatory, oxidative stress, adhesion molecule, neurocognitive and functional performance are significant predictors of telomere dynamics in a sample stratified by global DNA methylation levels. Peripheral blood inflammation, oxidative stress and adhesion molecule biomarkers and neurocognitive function were assessed twice over a 1-year period in 80 individuals, including 16 with schizophrenia (SZ), 16 with bipolar disorder (BD), 16 with major depressive disorder (MDD), 15 with T2DM, and 17 healthy controls (HCs). Leukocyte telomere length (LTL) was measured by qRT-PCR using deoxyribonucleic acid (DNA) extracted from peripheral blood samples. A posteriori, individuals were classified based on their global methylation score (GMS) at baseline into two groups: the below-average methylation (BM) and above-average methylation (AM) groups. Hierarchical and k-means clustering methods, mixed one-way analysis of variance and linear regression analyses were performed. Overall, the BM group showed a significantly higher leukocyte telomere length (LTL) than the AM group at both time points (p = 0.02; η2p = 0.06). Moreover, the BM group had significantly lower levels of tumor necrosis factor alpha (TNF-α) (p = 0.03; η2p = 0.06) and C-reactive protein (CRP) (p = 0.03; η2p = 0.06) than the AM group at the 1-year follow-up. Across all participants, the regression models showed that oxidative stress (reactive oxygen species [ROS]) (p = 0.04) and global cognitive score [GCS] (p = 0.02) were significantly negatively associated with LTL, whereas inflammatory (TNF-α) (p = 0.04), adhesion molecule biomarkers (inter cellular adhesion molecule [ICAM]) (p = 0.009), and intelligence quotient [IQ] (p = 0.03) were significantly positively associated with LTL. Moreover, the model predictive power was increased when tested in both groups separately, explaining 15.8% and 28.1% of the LTL variance at the 1-year follow-up for the AM and BM groups, respectively. Heterogeneous DNA methylation in individuals with T2DM and severe mental disorders seems to support the hypothesis that epigenetic dysregulation occurs in a transdiagnostic manner. Our results may help to elucidate the interplay between epigenetics, molecular processes and neurocognitive function in these disorders. DNA methylation and LTL are potential therapeutic targets for transdiagnostic interventions to decrease the risk of comorbidities.

Inflammation and weight change related to neurocognitive and functional impairment in diabetes and psychiatric disorders.

INTRODUCTION: Obesity is a global pandemic associated with various cardio-metabolic and psychiatric disorders. Neurocognitive and functional deficits have been associated with several somatic and psychiatric disorders. Adiposity-related inflammation has recently emerged as a key risk factor for neurocognitive and functional impairments. This prospective transdiagnostic study aimed to investigate the role of adiposity-related inflammatory markers in neurocognitive and functional outcomes associated with weight changes. METHODS: Peripheral blood inflammatory and oxidative stress biomarkers and neurocognitive and functional performance were assessed twice over 1 year in 165 individuals, including 30 with schizophrenia, 42 with bipolar disorder, 35 with major depressive disorder, 30 with type 2 diabetes mellitus (T2DM), and 28 healthy controls. Participants were stratified by body mass index into categories of type 2 obesity (T2OB; n=30), type 1 obesity (T1OB; n=42), overweight (OW; n=53), and average weight (NW; n=40). Mixed one-way analysis of covariance and linear and binary logistic regression analyses were performed. RESULTS: Compared with NW, T2OB and T1OB were significantly associated with impaired neurocognitive and functional performance (p<0.01; η2p=0.06-0.12) and higher levels of C-reactive protein and platelets (PLT) (p<0.01; η2p=0.08-0.16), with small-to-moderate effect sizes. IL-6, IL-10, and PLT were key factors for detecting significant weight changes in T1OB and T2OB over time. Regression models revealed that inflammatory and oxidative stress biomarkers and cellular adhesion molecules were significantly associated with neurocognitive and functional performance (p<0.05). DISCUSSION: Obesity is characterized by neurocognitive and functional impairments alongside low-grade systemic inflammation. Adiposity-related inflammatory biomarkers may contribute to neurocognitive and functional decline in individuals with T2DM and psychiatric disorders. Our data suggest that these biomarkers facilitate the identification of specific subgroups of individuals at higher risk of developing obesity.

Inflammation and lipid metabolism as potential biomarkers of memory impairment across type 2 diabetes mellitus and severe mental disorders.

INTRODUCTION: Neurocognitive impairment is a transdiagnostic feature across several psychiatric and cardiometabolic conditions. The relationship between inflammatory and lipid metabolism biomarkers and memory performance is not fully understood. This study aimed to identify peripheral biomarkers suitable to signal memory decline from a transdiagnostic and longitudinal perspective. METHODS: Peripheral blood biomarkers of inflammation, oxidative stress and lipid metabolism were assessed twice over a 1-year period in 165 individuals, including 30 with schizophrenia (SZ), 42 with bipolar disorder (BD), 35 with major depressive disorder (MDD), 30 with type 2 diabetes mellitus (T2DM), and 28 healthy controls (HCs). Participants were stratified by memory performance quartiles, taking as a reference their global memory score (GMS) at baseline, into categories of high memory (H; n = 40), medium to high memory (MH; n = 43), medium to low memory (ML; n = 38) and low memory (L; n = 44). Exploratory and confirmatory factorial analysis, mixed one-way analysis of covariance and discriminatory analyses were performed. RESULTS: L group was significantly associated with higher levels of tumor necrosis factor-alpha (TNF-α) and lower levels of apolipoprotein A1 (Apo-A1) compared to those from the MH and H groups (p < 0.05; η2p = 0.06-0.09), with small to moderate effect sizes. Moreover, the combination of interleukin-6 (IL-6), TNF-α, c-reactive protein (CRP), Apo-A1 and Apo-B compounded the transdiagnostic model that best discriminated between groups with different degrees of memory impairment (χ2 = 11.9-49.3, p < 0.05-0.0001). CONCLUSIONS: Inflammation and lipid metabolism seem to be associated with memory across T2DM and severe mental illnesses (SMI). A panel of biomarkers may be a useful approach to identify individuals at greater risk of neurocognitive impairment. These findings may have a potential translational utility for early intervention and advance precision medicine in these disorders.

MICEmi: A method to identify cognitive endophenotypes of mental illnesses.

BACKGROUND: Characterizing neurocognitive endophenotypes of mental illnesses (MIs) could be useful for identifying at-risk individuals, increasing early diagnosis, improving disease subtyping, and proposing therapeutic strategies to reduce the negative effects of the symptoms, in addition to serving as a scientific basis to unravel the physiopathology of the disease. However, a standardized algorithm to determine cognitive endophenotypes has not yet been developed. The main objective of this study was to present a method for the identification of endophenotypes in MI research. METHODS: For this purpose, a 14-expert working group used a scoping review methodology and designed a method that includes a scoring template with five criteria and indicators, a strategy for their verification, and a decision tree. CONCLUSIONS: This work is ongoing since it is necessary to obtain external validation of the applicability of the method in future research.

Immune-Inflammatory Biomarkers Predict Cognition and Social Functioning in Patients With Type 2 Diabetes Mellitus, Major Depressive Disorder, Bipolar Disorder, and Schizophrenia: A 1-Year Follow-Up Study.

Background: Systemic, low-grade immune-inflammatory activity, together with social and neurocognitive performance deficits are a transdiagnostic trait of people suffering from type 2 diabetes mellitus (T2DM) and severe mental illnesses (SMIs), such as schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BD). We aimed to determine if immune-inflammatory mediators were significantly altered in people with SMIs or T2DM compared with healthy controls (HC) and whether these biomarkers could help predict their cognition and social functioning 1 year after assessment. Methods: We performed a prospective, 1-year follow-up cohort study with 165 participants at baseline (TB), including 30 with SZ, 42 with BD, 35 with MDD, 30 with T2DM, and 28 HC; and 125 at 1-year follow-up (TY), and determined executive domain (ED), global social functioning score (GSFS), and peripheral blood immune-inflammatory and oxidative stress biomarkers. Results: Participants with SMIs and T2DM showed increased peripheral levels of inflammatory markers, such as interleukin-10 (p < 0.01; η2 p = 0.07) and tumor necrosis factor-α (p < 0.05; η2 p = 0.08); and oxidative stress biomarkers, such as reactive oxygen species (ROS) (p < 0.05; η2 p = 0.07) and mitochondrial ROS (p < 0.01; η2 p = 0.08). The different combinations of the exposed biomarkers anticipated 46-57.3% of the total ED and 23.8-35.7% of GSFS for the participants with SMIs. Limitations: Participants' treatment, as usual, was continued without no specific interventions; thus, it was difficult to anticipate substantial changes related to the psychopharmacological pattern. Conclusion: People with SMIs show significantly increased levels of peripheral immune-inflammatory biomarkers, which may contribute to the neurocognitive and social deficits observed in SMIs, T2DM, and other diseases with systemic immune-inflammatory activation of chronic development. These parameters could help identify the subset of patients who could benefit from immune-inflammatory modulator strategies to ameliorate their functional outcomes.

Specific metabolic syndrome components predict cognition and social functioning in people with type 2 diabetes mellitus and severe mental disorders.

OBJECTIVE: Obesity and metabolic diseases such as metabolic syndrome (MetS) are more prevalent in people with type 2 diabetes mellitus (T2DM), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). MetS components might be associated with neurocognitive and functional impairments in these individuals. The predictive and discriminatory validity of MetS and its components regarding those outcomes were assessed from prospective and transdiagnostic perspectives. METHODS: Metabolic syndrome components and neurocognitive and social functioning were assessed in 165 subjects, including 30 with SZ, 42 with BD, 35 with MDD, 30 with T2DM, and 28 healthy controls (HCs). A posteriori, individuals were classified into two groups. The MetS group consisted of those who met at least three of the following criteria: abdominal obesity (AO), elevated triglycerides (TG), reduced high-density lipoprotein cholesterol (HDL), elevated blood pressure (BP), and elevated fasting glucose (FPG); the remaining participants comprised the No-MetS group. Mixed one-way analysis of covariance and linear and binary logistic regression analyses were performed. RESULTS: Cognitive impairment was significantly greater in the MetS group (n = 82) than in the No-MetS group (n = 83), with small effect sizes (p < 0.05; η²p = 0.02 - 0.03). In both groups, the most robust associations between MetS components and neurocognitive and social functioning were observed with TG and FPG (p < 0.05). There was also evidence for a significant relationship between cognition and BP in the MetS group (p < 0.05). The combination of TG, FPG, elevated systolic BP and HDL best classified individuals with greater cognitive impairment (p < 0.001), and TG was the most accurate (p < 0.0001). CONCLUSIONS: Specific MetS components are significantly associated with cognitive impairment across somatic and psychiatric disorders. Our findings provide further evidence on the summative effect of MetS components to predict cognition and social functioning and allow the identification of individuals with worse outcomes. Transdiagnostic, lifestyle-based therapeutic interventions targeted at that group hold the potential to improve health outcomes.

Transdiagnostic neurocognitive deficits in patients with type 2 diabetes mellitus, major depressive disorder, bipolar disorder, and schizophrenia: A 1-year follow-up study.

BACKGROUND: Neurocognition impairments are critical factors in patients with major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), and also in those with somatic diseases such as type 2 diabetes mellitus (T2DM). Intriguingly, these severe mental illnesses are associated with an increased co-occurrence of diabetes (direct comorbidity). This study sought to investigate the neurocognition and social functioning across T2DM, MDD, BD, and SZ using a transdiagnostic and longitudinal approach. METHODS: A total of 165 participants, including 30 with SZ, 42 with BD, 35 with MDD, 30 with T2DM, and 28 healthy controls (HC), were assessed twice at a 1-year interval using a comprehensive, integrated test battery on neuropsychological and social functioning. RESULTS: Common neurocognitive impairments in somatic and psychiatric disorders were identified, including deficits in short-term memory and cognitive reserve (p < 0.01, η²p=0.08-0.31). Social functioning impairments were observed in almost all the disorders (p < 0.0001; η²p=0.29-0.49). Transdiagnostic deficits remained stable across the 1-year follow-up (p < 0.001; η²p=0.13-0.43) and could accurately differentiate individuals with somatic and psychiatric disorders (χ² = 48.0, p < 0.0001). LIMITATIONS: The initial sample size was small, and high experimental mortality was observed after follow-up for one year. CONCLUSIONS: This longitudinal study provides evidence of some possible overlap in neurocognition deficits across somatic and psychiatric diagnostic categories, such as T2DM, MDD, BD, and SZ, which have high comorbidity. This overlap may be a result of shared genetic and environmental etiological factors. The findings open promising avenues for research on transdiagnostic phenotypes of neurocognition in these disorders, in addition to their biological bases.

Is processing speed a valid neurocognitive endophenotype in bipolar disorder? Evidence from a longitudinal, family study.

BACKGROUND: Substantial evidence supports the existence of neurocognitive endophenotypes in bipolar disorder (BD), but very few longitudinal studies have included unaffected relatives. In a 5-year, follow-up, family study, we have recently suggested that deficits in manual motor speed and visual memory could be endophenotype candidates for BD. We aimed to explore whether this also applies to processing speed. METHODS: A sample of 348 individuals, including 163 BD patients, 65 unaffected first-degree relatives (BD-Rel) and 120 genetically unrelated healthy controls (HC), was assessed with the Digit Symbol Substitution Test (DSST) on two occasions over a 2-year period (T1, T2). DSST values were controlled for age, years of education, occupational status, and subsyndromic mood symptoms. Differences between groups were evaluated with ANCOVAs. RESULTS: At T1 BD performed significantly worse than HC (p < 0.001; Cohen's d = 1.38) and BD-Rel (p < 0.001; Cohen's d = 0.82). BD-Rel showed an intermediate performance with significant differences with HC (p < 0.01; Cohen's d = 0.50). Similarly, at T2 BD performed significantly worse than HC (p < 0.001; Cohen's d = 1.44) and BD-Rel (p < 0.01; Cohen's d = 0.51). BD-Rel performance was intermediate and significantly lower than that of HC (p < 0.01; Cohen's d = 0.97). A Repeated Measures ANOVA revealed no significant between-group differences in performance over time (p > 0.05). CONCLUSIONS: The results of this longitudinal, family study suggest that impaired processing speed may represent a suitable cognitive endophenotype for BD. Further research on the field is required to confirm these preliminary findings.

Grip Strength, Neurocognition, and Social Functioning in People WithType-2 Diabetes Mellitus, Major Depressive Disorder, Bipolar Disorder, and Schizophrenia.

BACKGROUND: Frailty is a common syndrome among older adults and patients with several comorbidities. Grip strength (GS) is a representative parameter of frailty because it is a valid indicator of current and long-term physical conditions in the general population and patients with severe mental illnesses (SMIs). Physical and cognitive capacities of people with SMIs are usually impaired; however, their relationship with frailty or social functioning have not been studied to date. The current study aimed to determine if GS is a valid predictor of changes in cognitive performance and social functioning in patients with type-2 diabetes mellitus and SMIs. METHODS: Assessments of social functioning, cognitive performance, and GS (measured with an electronic dynamometer) were conducted in 30 outpatients with type 2 diabetes mellitus, 35 with major depressive disorder, 42 with bipolar disorder, 30 with schizophrenia, and 28 healthy controls, twice during 1-year, follow-up period. Descriptive analyses were conducted using a one-way analysis of variance for continuous variables and the chi-squared test for categorical variables. Differences between groups for the motor, cognitive, and social variables at T1 and T2 were assessed using a one-way analysis of covariance, with sex and age as co-variates (p < 0.01). To test the predictive capacity of GS at baseline to explain the variance in cognitive performance and social functioning at T2, a linear regression analysis was performed (p < 0.05). RESULTS: Predictive relationships were found among GS when implicated with clinical, cognitive, and social variables. These relationships explained changes in cognitive performance after one year of follow-up; the variability percentage was 67.7%, in patients with type-2 diabetes mellitus and 89.1% in patients with schizophrenia. Baseline GS along with other variables, also predicted changes in social functioning in major depressive disorder, bipolar disorder, and schizophrenia, with variability percentages of 67.3, 36, and 59%, respectively. CONCLUSION: GS combined with other variables significantly predicted changes in cognitive performance and social functioning in people with SMIs or type-2 diabetes mellitus. Interventions aimed to improve the overall physical conditions of patients who have poor GS could be a therapeutic option that confers positive effects on cognitive performance and social functioning.

Motor and Cognitive Performance in Patients with Liver Cirrhosis with Minimal Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) is associated with mild cognitive impairment and frailty. This study aims to identify cognitive and motor differences in cirrhotic patients with and without MHE, and the correlations between motor signs and cognitive performance. Gait, balance, hand strength and motor speed performance were evaluated in 66 cirrhotic patients (38 without and 28 with MHE, according to the Psychometric Hepatic Encephalopathy Score (PHES). Cognitive performance was measured with the Mini-Mental State Examination, Verbal Fluency Test, Aprendizaje Verbal España-Complutense Test (TAVEC), Wechsler Adult Intelligence Scale III, Hamilton Depression and Anxiety Rating Scale and Functioning Assessment Short Test (FAST). MHE patients performed worse than patients without MHE in cognitive and autonomous functioning, learning and long-term memory, and verbal fluency. The same pattern was found in gait, center of pressure movement, variability of hand strength performance and hand motor speed. In MHE patients, high correlations were found between balance and FAST test, gait velocity and verbal skills, hand strength variability and anxiety and depression, and motor speed and FAST and TAVEC. MHE patients showed worse motor and cognitive performance than patients without MHE. MHE patients could have impaired movement control expressed as bradykinesia, and this reduced motor performance could correlate with cognitive performance.

Visual memory dysfunction as a neurocognitive endophenotype in bipolar disorder patients and their unaffected relatives. Evidence from a 5-year follow-up Valencia study.

BACKGROUND: Scarce research has focused on Visual Memory (VM) deficits as a possible neurocognitive endophenotype of bipolar disorder (BD). The main aim of this longitudinal, family study with healthy controls was to explore whether VM dysfunction represents a neurocognitive endophenotype of BD. METHODS: Assessment of VM by Rey-Osterrieth Complex Figure Test (ROCF) was carried out on a sample of 317 subjects, including 140 patients with BD, 60 unaffected first-degree relatives (BD-Rel), and 117 genetically-unrelated healthy controls (HC), on three occasions over a 5-year period (T1, T2, and T3). BD-Rel group scores were analyzed only at T1 and T2. RESULTS: Performance of BD patients was significantly worse than the HC group (p < 0.01). Performance of BD-Rel was also significantly different from HC scores at T1 (p < 0.01) and T2 (p = 0.05), and showed an intermediate profile between the BD and HC groups. Only among BD patients, there were significant differences according to sex, with females performing worse than males (p = 0.03). Regarding other variables, education represented significant differences only in average scores of BD-Rel group (p = 0.01). LIMITATIONS: Important attrition in BD-Rel group over time was detected, which precluded analysis at T3. CONCLUSIONS: BD patients show significant deficits in VM that remain stable over time, even after controlling sociodemographic and clinical variables. Unaffected relatives also show stable deficits in VM. Accordingly, the deficit in VM could be considered a potential endophenotype of BD, which in turn may be useful as a predictor of the evolution of the disease. Further studies are needed to confirm these findings.

Efficacy of quetiapine XR vs. placebo as concomitant treatment to mood stabilizers in the control of subthreshold symptoms of bipolar disorder: Results from a pilot, randomized controlled trial.

Patients with bipolar disorder (BD) do not always achieve full remission between episodes. Subthreshold symptoms (depressive, manic or mixed) represent a major cause of relapse and disability in these patients. Immediate release (IR) and extended release (XR) formulations of quetiapine are both indicated for short and long-term treatment of BD. The aim of this study was to evaluate the efficacy of quetiapine XR vs placebo in subthreshold symptomatology when added to previous mood stabilizer treatment. A pilot phase IIIB, multicentre, prospective, placebo controlled, randomized, double blinded study of 12 weeks follow-up was performed (NCT01197846). Patients were randomized to quetiapine XR 300mg or placebo once daily. The primary outcome was the mean change between quetiapine XR and placebo from baseline to study endpoint (week 6) in the Montgomery-Åsberg Depression Rating Scale (MADRS). Quetiapine XR 300mg (n=16) significantly improved depressive subthreshold symptoms compared with placebo (n=16) after 6 weeks (P=0.021). Early response (reduction of at least the 20% of the MADRS total score) and remission rate (reduction in MADRS total score <8 and YMRS<8) did not show differences between groups. Quetiapine XR did not show superiority vs placebo when evaluating subthreshold manic symptoms, instead it was superior when evaluating functioning (GAF score) in BD type I patients (P=0.005). The most common adverse events were somnolence (9.1%), increased appetite, dry mouth and dizziness (6.8%). Quetiapine XR 300mg once daily was significantly more effective than placebo in depressive subthreshold symptoms. Adverse events were consistent with the known side effects of quetiapine.

Mild cognitive decline. A position statement of the Cognitive Decline Group of the European Innovation Partnership for Active and Healthy Ageing (EIPAHA).

INTRODUCTION: Mild cognitive impairment (MCI) is a term used to describe a level of decline in cognition which is seen as an intermediate stage between normal ageing and dementia, and which many consider to be a prodromal stage of neurodegeneration that may become dementia. That is, it is perceived as a high risk level of cognitive change. The increasing burden of dementia in our society, but also our increasing understanding of its risk factors and potential interventions, require diligent management of MCI in order to find strategies that produce effective prevention of dementia. AIM: To update knowledge regarding mild cognitive impairment, and to bring together and appraise evidence about the main features of clinical interest: definitions, prevalence and stability, risk factors, screening, and management and intervention. METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSION: MCI describes a level of impairment in which deteriorating cognitive functions still allow for reasonable independent living, including some compensatory strategies. While there is evidence for some early risk factors, there is still a need to more precisely delineate and distinguish early manifestations of frank dementia from cognitive impairment that is less likely to progress to dementia, and furthermore to develop improved prospective evidence for positive response to intervention. An important limitation derives from the scarcity of studies that take MCI as an endpoint. Strategies for effective management suffer from the same limitation, since most studies have focused on dementia. Behavioural changes may represent the most cost-effective approach.

The switch from conventional to atypical antipsychotic treatment should not be based exclusively on the presence of cognitive deficits. A pilot study in individuals with schizophrenia.

BACKGROUND: Atypical antipsychotics provide better control of the negative and affective symptoms of schizophrenia when compared with conventional neuroleptics; nevertheless, their heightened ability to improve cognitive dysfunction remains a matter of debate. This study aimed to examine the changes in cognition associated with long-term antipsychotic treatment and to evaluate the effect of the type of antipsychotic (conventional versus novel antipsychotic drugs) on cognitive performance over time. METHODS: In this naturalistic study, we used a comprehensive neuropsychological battery of tests to assess a sample of schizophrenia patients taking either conventional (n = 13) or novel antipsychotics (n = 26) at baseline and at two years after. RESULTS: Continuous antipsychotic treatment regardless of class was associated with improvement on verbal fluency, executive functions, and visual and verbal memory. Patients taking atypical antipsychotics did not show greater cognitive enhancement over two years than patients taking conventional antipsychotics. CONCLUSIONS: Although long-term antipsychotic treatment slightly improved cognitive function, the switch from conventional to atypical antipsychotic treatment should not be based exclusively on the presence of these cognitive deficits.

Neurocognitive endophenotypes (endophenocognitypes) from studies of relatives of bipolar disorder subjects: a systematic review.

BACKGROUND: There is growing interest to research neurocognition as a putative endophenotype for subjects with bipolar disorders (BD). The authors sought to review the available literature focused on relatives of subjects with bipolar disorder (BD-Rels) and identify suitable cognitive candidates to endophenotypes or endophenocognitypes. METHOD: A systematic review was conducted in Medline, EMBASE and PsycINFO databases (1980-July 2007), supplemented with a manual search of reference lists. RESULTS: Twenty-three cross-sectional papers of discordant twins (4 studies), genetic high-risk subjects (7), and different BD-Rel groups (12) met the inclusion criteria and evaluated 532 BD-Rels. Impairments on the broad domain of verbal learning/memory were found in 6 out of 11 studies (54%), as well as in 3 of 9 reports (33%) of working memory. Moreover, BD-Rels showed deficits in visual-spatial learning and memory (1/6 reports; 17%), alternating attention (1/8; 12.5%), psychomotor speed (2/10; 20%), and abstraction/cognitive flexibility, sustained attention and selective attention (2/8 each; 25%). Scores of general intelligence were lower than those of controls in 2/16 (12.5%) reports, but fell well within the average range in all studies. No study that assessed immediate memory or verbal fluency (6 each) reported impairments in BD-Rels. Finally, language, social cognition, and motor and planning skills are neglected areas of research. CONCLUSIONS: Overall, the neurocognitive profile in BD-Rels is still unclear, and the evidence in support of the presence of cognitive deficits seems quite sparse. Verbal learning/memory and verbal working memory seem to be the most suitable endophenocognitypes for BD. Conversely, healthy family members would have an intact performance on immediate memory, verbal fluency, and probably on general intelligence. The possibility that BD-Rels show less cognitive efficiency compared to healthy controls also on other functions must be addressed by future studies with larger samples, comprehensive neuropsychological assessments, and, ideally, longitudinal designs.

Neurocognitive and clinical predictors of functional outcome in patients with schizophrenia and bipolar I disorder at one-year follow-up.

OBJECTIVE: Many studies have reported that cognitive ability may be predictive of the functional outcome for patients with schizophrenia. However, no study has prospectively examined these aspects in schizophrenia and bipolar disorders simultaneously. The present study attempted to analyze if neurocognition and clinical status predicts the real-life functioning for patients with schizophrenia or bipolar I disorder, using a longitudinal design. METHOD: Forty-seven schizophrenic and 43 bipolar I outpatients were assessed twice with a neurocognitive battery (Executive Functions, Working Memory, Verbal Memory, Visual Memory, Visual-Motor Processing, Vigilance, Vocabulary and Motor Speed tasks), clinical scales (the Positive and Negative Symptom Scale, the Hamilton Rating Scale for Depression and the Clinician Administered Rating Scale for Mania) and functional outcome measures (the Global Assessment of Functioning Scale, the WHO's Disability Assessment Scale and occupational adaptation level) over a one-year follow-up period. The cognitive performance of the patients was compared, at baseline and one year later, with that of 25 healthy subjects. RESULTS: In schizophrenia patients, global functioning one year later was predicted by a composite neurocognitive score and three specific domain (verbal memory, motor speed, vocabulary). Symptoms appeared to explain less of the variance in functioning. In bipolar I patients, changes in the composite neurocognitive score over one year, deficits in the visual/motor processing domain, severity of symptoms (psychotic, excitatory and affective symptoms) and premorbid adjustment at the first assessment were the variables that better predicted functioning or disability changes over follow-up period. CONCLUSIONS: Although the relationships between cognition, symptoms and functional capacity differ for schizophrenia or bipolar I patients, neuropsychological performance seems to be a principal longitudinal predictor of functioning in both disorders. Baseline neurocognition and cognitive changes over 12 months predicted changes in functioning over the same period, but only in bipolar I patients. These cognitive domains could be potential neurocognitive endophenotypes (endophenocognitypes) with regard to bipolar I disorder.

Specificity of cognitive deficits in bipolar disorder versus schizophrenia. A systematic review.

BACKGROUND: More and more epidemiological, genetic and neuroimaging studies show similarities between bipolar disorder (BD) and schizophrenia (SZ). Cognitive functions are known to be highly impaired in SZ and are increasingly studied in BD. When both populations are compared, the conclusions appear to be contradictory. The purpose of this review is to help define the profile of cognitive deficits in BD and in SZ. METHODS: A systematic review of the literature of neuropsychological studies comparing BD and SZ was made, beginning in January 1990 and ending in January 2005. Thirty-eight studies met the required quality criteria and were included in this review. RESULTS: Bipolar patients exhibit extensive cognitive abnormalities with a pattern of deficits that is not unique to this disease. However, when compared to schizophrenic patients, bipolar patients demonstrate a lesser degree of deficits, particularly concerning premorbid and current intelligence quotient and perhaps attention, verbal memory and executive functions. When looking into effect sizes, there seem to be different profiles even in studies finding no significant differences. CONCLUSIONS: The neuropsychological differences reported between both groups could be due to the presence of psychotic features, to environmental factors (stressful events, duration of the disease and number of hospitalisations) and could also be related to differences during the neurodevelopmental phase. Further studies should confirm whether these results are truly related to different neurobiological backgrounds.

Persistent cognitive dysfunctions in bipolar I disorder and schizophrenic patients: a 3-year follow-up study.

BACKGROUND: Neurocognitive impairment has consistently been considered a central and stable feature in schizophrenia. As this possibility has been far less studied in bipolar disorder, we aimed to prospectively investigate the stability and specificity of cognitive performance in bipolar disorder compared to schizophrenia. METHODS: Fifteen DSM-IV bipolar type I patients and 15 schizophrenic patients were assessed twice with a comprehensive neuropsychological battery and the Positive and Negative Syndrome Scale over a 3-year follow-up. The cognitive performance of the groups was compared at baseline and 3 years later as a mean with that of 26 healthy volunteers. Endpoint and baseline assessments were also compared for each patient group in order to evaluate the stability of cognitive impairment. RESULTS: At both time points, bipolar and schizophrenic patients showed significant deficits on most of the cognitive tasks compared to healthy subjects. Overall, the cross-sectional cognitive profile was similar for both patient groups. Moreover, after controlling for age and length of illness, the two groups' cognitive function did not differ over time in any test. With the exception of the Stroop color-word interference task, performance at baseline for each test but neither length of illness nor diagnostic category predicted the endpoint performance. CONCLUSION: This preliminary study suggests that cognitive impairment is also mainly stable over time in bipolar I disorder and thus not specific to schizophrenia.

Specific executive/attentional deficits in patients with schizophrenia or bipolar disorder who have a positive family history of psychosis.

Neurocognitive impairments are well documented in patients with schizophrenia and their healthy first-degree biological relatives. Less is known about neuropsychological performance in bipolar disorders, but some studies indicate that, compared to schizophrenia, bipolar disorder displays a similar profile pattern with less severe deficits. The genetic and environmental contributions to the development of neurocognitive deficits are also unclear. This study explored the effect of a family history (FH) of psychotic disorders in first-degree relatives on a variety of cognitive domains (abstraction and flexibility, verbal fluency, verbal memory, motor activity and visual-motor processing/attention) in 30 patients with schizophrenia, and 24 type I bipolar patients. After adjusting the results for age, gender, education level and pre-morbid intelligence, patients with schizophrenia or bipolar disorder with positive FH (n=18) performed significantly worse than patients with negative FH (n=36) on the visual-motor processing/attention domain. These findings were independent of the specific diagnosis. Moreover, when logistic regression analysis was performed, poor Digit Symbol performance was the only predictor of belonging to the positive FH group. Our results are compatible with the existence of some common genetic factors between the illnesses, as well as the involvement of identical, or at least similar, disordered brain systems in both disorders. These findings are discussed within the context of the continuum model of psychosis.

Abnormal motor asymmetry only during bimanual movement in schizophrenic patients compared with healthy subjects.

In schizophrenia, research on motor asymmetry has focused on the direction and the degree of handedness using unimanual motor tests and tasks. However, typically both hands collaborate in the production of most manual movements. This study explored motor asymmetry exhibited during unimanual and bimanual tasks in schizophrenic and healthy subjects using a new experimental motor battery. Specifically, the authors investigated the motor indices of laterality during finger-tapping and hand-turning tasks in four unimanual and four bimanual conditions in 84 schizophrenic and 31 healthy subjects, all right-handed. The schizophrenic patients showed reduced motor asymmetries only during bimanual tapping compared with healthy subjects due to reduction in right-hand performance. These results stress the importance of considering bimanual conditions in the assessment of motor asymmetries, and suggest that it is necessary to use bimanual tasks to test hypotheses about abnormal motor lateralization in schizophrenia.