Longitudinal course of inflammatory-cognitive subgroups across first treatment severe mental illness and healthy controls.

BACKGROUND: While inflammation is associated with cognitive impairment in severe mental illnesses (SMI), there is substantial heterogeneity and evidence of transdiagnostic subgroups across schizophrenia (SZ) and bipolar (BD) spectrum disorders. There is however, limited knowledge about the longitudinal course of this relationship. METHODS: Systemic inflammation (C-Reactive Protein, CRP) and cognition (nine cognitive domains) was measured from baseline to 1 year follow-up in first treatment SZ and BD (n = 221), and healthy controls (HC, n = 220). Linear mixed models were used to evaluate longitudinal changes separately in CRP and cognitive domains specific to diagnostic status (SZ, BD, HC). Hierarchical clustering was applied on the entire sample to investigate the longitudinal course of transdiagnostic inflammatory-cognitive subgroups. RESULTS: There were no case-control differences or change in CRP from baseline to follow-up. We confirm previous observations of case-control differences in cognition at both time-points and domain specific stability/improvement over time regardless of diagnostic status. We identified transdiagnostic inflammatory-cognitive subgroups at baseline with differing demographics and clinical severity. Despite improvement in cognition, symptoms and functioning, the higher inflammation - lower cognition subgroup (75% SZ; 48% BD; 38% HC) had sustained inflammation and lower cognition, more symptoms, and lower functioning (SMI only) at follow-up. This was in comparison to a lower inflammation - higher cognition subgroup (25% SZ, 52% BD, 62% HC), where SMI participants showed cognitive functioning at HC level with a positive clinical course. CONCLUSIONS: Our findings support heterogenous and transdiagnostic inflammatory-cognitive subgroups that are stable over time, and may benefit from targeted interventions.

Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain.

Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n = 1235), we aimed to i) identify candidate peripheral markers (n = 25) associated with cognitive domains (n = 9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n = 10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n = 776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n = 474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high neuroinflammatory subgroup in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.

Genome-wide association study in 404,302 individuals identifies 7 significant loci for reaction time variability.

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome-wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a GWAS of RTV in participants of white British ancestry (n = 404,302) as well as a trans-ancestry GWAS meta-analysis (n = 44,873) to assess replication. We found 161 genome-wide significant single nucleotide polymorphisms (SNPs) distributed across 7 genomic loci in our discovery GWAS. Functional annotation of the variants implicated genes involved in synaptic function and neural development. The SNP-based heritability (h2SNP) estimate for RTV was 3%. We investigated genetic correlations between RTV and selected neuropsychological traits using linkage disequilibrium score regression, and found significant correlations with several traits, including a positive correlation with mean reaction time and schizophrenia. Despite the high genetic correlation between RTV and mean reaction time, we demonstrate distinctions in the genetic underpinnings of these traits. Lastly, we assessed the predictive ability of a polygenic score (PGS) for RTV, calculated using PRSice and PRS-CS, and found that the RTV-PGS significantly predicted RTV in independent cohorts, but that the generalisability to other ancestry groups was poor. These results identify genetic underpinnings of RTV, and support the use of RTV as an endophenotype for neurological and psychiatric disorders.

Inflammation and cognition in severe mental illness: patterns of covariation and subgroups.

A potential relationship between dysregulation of immune/inflammatory pathways and cognitive impairment has been suggested in severe mental illnesses (SMI), such as schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, multivariate relationships between peripheral inflammatory/immune-related markers and cognitive domains are unclear, and many studies do not account for inter-individual variance in both cognitive functioning and inflammatory/immune status. This study aimed to investigate covariance patterns between inflammatory/immune-related markers and cognitive domains and further elucidate heterogeneity in a large SMI and healthy control (HC) cohort (SZ = 343, BD = 289, HC = 770). We applied canonical correlation analysis (CCA) to identify modes of maximum covariation between a comprehensive selection of cognitive domains and inflammatory/immune markers. We found that poor verbal learning and psychomotor processing speed was associated with higher levels of interleukin-18 system cytokines and beta defensin 2, reflecting enhanced activation of innate immunity, a pattern augmented in SMI compared to HC. Applying hierarchical clustering on covariance patterns identified by the CCA revealed a high cognition-low immune dysregulation subgroup with predominantly HC (24% SZ, 45% BD, 74% HC) and a low cognition-high immune dysregulation subgroup predominantly consisting of SMI patients (76% SZ, 55% BD, 26% HC). These subgroups differed in IQ, years of education, age, CRP, BMI (all groups), level of functioning, symptoms and defined daily dose (DDD) of antipsychotics (SMI cohort). Our findings suggest a link between cognitive impairment and innate immune dysregulation in a subset of individuals with severe mental illness.

Change in attitudes after a suicide prevention media campaign in the Mid-Norway region.

BACKGROUND: Suicide prevention media campaigns are one way of reaching people at increased suicide risk who would otherwise not seek help. This is the first study of a Norwegian campaign directed both at individuals at risk for suicide and at their social network. METHODS: We evaluated a media campaign consisting of outdoor posters, feature articles, film clips, and online banners in print, digital, and social media spread across the Mid-Norway region in late autumn 2022. This campaign material consisted of information about how to seek help for suicide thoughts and mental health problems and how to help a friend in similar situations. Before and after this campaign, 1149 adult individuals living in Mid-Norway participated in a survey on attitudes to suicide, mental ill health, and help-seeking. RESULTS: There were only marginal changes in attitudes and help-seeking literacy after the campaign. This result was sustained when controlling for age, sex, and campaign visibility. For males, there were a few changes in the negative direction, i.e. lack of willingness to seek help from family and friends, after the campaign. CONCLUSION: We conclude that the campaign did not seem to have the desired effect and suggest ways of improving future regional Norwegian media campaigns.

Anomalous self-experiences and neurocognitive functioning in adolescents at risk for psychosis: Still no significant associations found between these two vulnerability markers.

BACKGROUND: Anomalous self-experiences (ASEs) and neurocognitive impairments are considered essential domains of vulnerability for developing psychotic disorders. However, little research exists of possible associations between ASEs and neurocognitive functions in individuals at-risk for psychosis. The interconnections between ASEs and neurocognitive impairments should therefore be clarified as much as possible, especially in young individuals at risk. No previous studies have investigated these two fundamental domains in non-help-seeking adolescents at risk for developing psychosis. METHODS: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). Adolescents (N = 48, 94% females, mean age = 15.3) were invited to participate after completing a 14-year-old survey distributed by MoBA. At-risk adolescents were selected based on the 0.4% highest scores on 19 items assessing both psychotic-like experiences and ASEs. Five specifically selected and formulated items measuring ASEs were computed to an ASEs total score. Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery. RESULTS: Regression analyses revealed no significant relationships between ASEs and any neurocognitive domain. CONCLUSIONS: We did not find any significant associations between ASEs and neurocognitive functions in non-help-seeking adolescents at risk for psychotic disorders, which is in line with reports from other types of cohorts. Thus, ASEs and neurocognitive functions may be understood as two relatively separate domains that co-exist in at-risk states. These results underline the need for a wider scope when making predictions about future trajectories, e.g. the development of psychotic disorders. Including both ASEs and neurocognitive functioning in at-risk populations may increase the specificity of vulnerability criteria in this population and enhance our understanding of early psychosis psychopathology.

Marginal relationship between affective dispositions and neurocognitive function in patients with schizophrenia spectrum disorders.

PURPOSE: Neurocognitive outcomes are frequently used as indicators of real-world functioning in schizophrenia spectrum disorders (SSD). These test results may be influenced by individual differences, such as affective dispositions. Here we investigate the relationship between positive and negative affect and neuropsychological test scores in a large, mixed-gender, population based group of participants without co-morbid substance abuse. MATERIALS AND METHODS: We assessed 129 male and female SSD patients with the Positive and Negative Affect Schedule (PANAS) and a comprehensive neuropsychological test battery. RESULTS AND CONCLUSIONS: The neuropsychological test scores were mainly predicted by age and gender, with small contributions from negative psychosis symptoms. There was a statistically significant relationship between Positive Affect and processing speed and between Negative Affect and verbal memory and executive function. However, the level of neurocognitive function variance explained by these affects was only 5%. Thus, the neurocognitive test results were not associated with trait affect in any clinically significant manner. This adds to previous findings of no relationship between affective dispositions and psychosis symptom variables in our participants. We suggest that affective traits constitute an independent dimension that may influence well-being, coping, and real-life outcome in SSD patients directly, and not through neurocognitive function.

Perinatal complications and executive dysfunction in early-onset schizophrenia.

BACKGROUND: The present study examined the association between perinatal obstetric complications and executive dysfunction in early-onset schizophrenia (EOS), compared to healthy controls. Higher incidences of obstetric complications and more severe executive dysfunctions characterize EOS. Research shows extensive brain maturation in newborns, suggesting them to be particularly vulnerable for perinatal insults. Executive function is mainly mediated by the prefrontal cortex, an area that matures last during pregnancy. Thus, exposure to perinatal complications may influence executive dysfunction in EOS. METHODS: The participants were 19 EOS patients and 54 healthy controls. Executive function was assessed with the D-KEFS Color Word Interference Test and the Wisconsin Card Sorting Test. Information on perinatal obstetric complications and Apgar 5-min scores were obtained from the Norwegian Medical Birth Registry. Associations between perinatal conditions and executive function were studied using stepwise regression analyses. RESULTS: Perinatal complications, and especially shorter gestational lengths, were significantly associated with significant executive dysfunctions in EOS. Perinatal complications did not affect executive function among healthy controls. A significant relationship between lower Apgar 5-min scores and executive dysfunction was found among both EOS patients and healthy controls. CONCLUSIONS: Exposure to perinatal complications, and particularly a shorter gestational length, was associated with increased executive dysfunction in EOS. Exposed healthy controls did not exhibit similar executive difficulties, suggesting that the EOS patients seemed especially vulnerable for executive deficits due to perinatal insults. The findings indicate that EOS youths learn more slowly and experience more difficulty with problem-solving, which carry important implications for clinical practice. Lower Apgar 5-min scores were associated with executive dysfunction in both groups. Low Apgar score at 5 min may therefore be an important early indicator of executive difficulties among adolescents, independent of diagnosis.

Do clinical characteristics predict the cognitive course in early-onset schizophrenia-spectrum disorders?

BACKGROUND: Being in a period with extensive brain maturation, adolescents with early-onset schizophrenia-spectrum disorders (EOS) provide unique neurodevelopmental data that may contribute to a better understanding of schizophrenia at all ages. Cognitive dysfunction is a central feature of schizophrenia and is more pronounced in EOS than in later onset illness. However, there is limited research on both the long-term course of global cognition in EOS, and how cognition over time is influenced by clinical characteristics during the early illness period. METHODS: Thirty-one EOS patients and 73 controls (age 12-18) were assessed on clinical variables at baseline (PANSS, duration of untreated psychosis [DUP], hospitalizations, suicide attempts, and remission). Neuropsychological assessments with the MATRICS Consensus Cognitive Battery (MCCB) were conducted at baseline and after both 1 and 2 years, and composite scores of total performances were calculated. The analyses were performed with a linear mixed model. RESULTS: The present study found that global cognition followed a stable course over the first years of the disease in EOS, though at a significantly lower level in EOS compared with the controls. We did not detect a relationship between DUP, remission, positive/negative symptoms, and hospitalizations on one hand, and long-term cognition on the other hand, but PANSS-general and suicide attempt history at baseline were identified as risk factors of longitudinal cognitive function. CONCLUSIONS: Though at different levels, the EOS group and the controls had a similar cognitive course over 2 years. Some baseline characteristics (psychotic symptoms, DUP, remission, and hospitalization) had no influence on cognition within the first 2 years of illness. In contrast, general symptoms and a history of suicide attempts at baseline were more potent risk factors of the cognitive course than the psychotic-specific symptoms, and should, therefore, be subject to specific attention in the evaluation and treatment of patients with early-onset psychosis.

Impaired neuropsychological profile in homicide offenders with schizophrenia.

BACKGROUND: Our ability to predict and prevent homicides committed by individuals with schizophrenia is limited. Cognitive impairments are associated with poorer functional outcome in schizophrenia, possibly also homicide. The aim of the current study was to investigate global and specific cognition among homicide offenders with schizophrenia (HOS). METHODS: Twenty-six HOS were compared to 28 individuals with schizophrenia and no history of violence (non-HOS), and a group of healthy controls (HC, n = 151). HOS and non-HOS participants were recruited from in- and outpatient units across Norway. An extensive neuropsychological test battery was administered. RESULTS: HOS participants performed significantly weaker than HC in all cognitive domains. Further, statistically significant differences between HOS and non-HOS participants were found for IQ (d = 0.52) and verbal learning (d = 0.82), with larger impairments in the HOS compared to the non-HOS group. CONCLUSIONS: Our results indicate that HOS participants show clinically significant impairments in global and specific cognition.

Factor analyzing the Norwegian MATRICS Consensus Cognitive Battery.

AIM: The MATRICS Consensus Cognitive Battery (MCCB) assesses seven cognitive domains with 10 subtests. This domain structure has not been demonstrated. Three factors have been produced in US samples. We examined the dimensional structure of the Norwegian MCCB. In addition, we studied the contribution of each subtest to the battery sum score. METHODS: The participants were 131 patients with schizophrenia spectrum disorders and 300 healthy controls. Their Norwegian MCCB test scores were subject to exploratory and confirmatory factor analysis and regression analysis. RESULTS: The theoretical MCCB factor structure was not shown. In the patient group, three-factor and two-factor models had acceptable fit. In both groups, the Symbol Coding, Spatial Span, Letter-Number Span, and Visual Learning subtests contributed most to the sum score. CONCLUSION: The theoretical domain structure of the MCCB could not be demonstrated in these Norwegian participants. Consonant with US studies, models with three and two factors had mediocre fit, and in the schizophrenia spectrum disorder group only. In both groups, the subtests Symbol Coding, Working Memory, and Learning were the most sensitive in tapping general neurocognitive performance, supporting US results. We conclude that in both Norway and the USA, the MCCB generates the same cognitive domains through factor analysis, but that these domains are not the ones suggested by the MATRICS project.

Neurocognitive profile in major depressive disorders: relationship to symptom level and subjective memory complaints.

BACKGROUND: The MATRICS Consensus Cognitive Battery (MCCB) was developed for schizophrenia patients, but is also being used to assess neurocognitive function in bipolar disorder. This study aims to describe neurocognitive differences in major depressive disorder patients and healthy controls with the MCCB, and to describe the relationship between depression symptom severity, subjective cognitive complaints, and objective cognitive test performance. METHODS: Thirty-three patients with major depressive disorder and 33 pairwise matched healthy controls were assessed with the MCCB. The patients were also assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Everyday Memory Questionnaire (EMQ). RESULTS: On all neurocognitive domains, the depression patients scored significantly lower than the controls. The level of impairment ranged from 21.0% (Working Memory) to 58.0% (Speed of Processing). There were significant associations between neurocognitive test performance and depression symptom severity, but not with subjective cognitive complaints. CONCLUSIONS: The MCCB was applicable in this study of major depressive disorder, and revealed significant neurocognitive dysfunction in this group. At least one fifth of the patients were impaired on all cognitive domains, with Speed of Processing and Reasoning/Problem Solving being most strongly affected. The objective test scores were significantly related to depression severity, but not to subjective cognitive complaints.

Psychological and social difficulties in young non-help-seeking adolescents at risk for psychosis: insights from a large cohort study.

Background: This study used data from the Norwegian Mother, Father, and Child Cohort Study (MoBa), and explored the psychological and social challenges of 14-year-olds who report psychotic symptoms. Research on help-seeking youths indicates comorbid symptoms of depression, anxiety, and social deterioration, but less is known about non-help-seeking individuals who may not use healthcare services, possibly skewing comorbidity profiles. Also, findings suggest that adolescents manifesting psychotic symptoms refrain from pursuing help. This gap underscores the necessity of studying non-help-seeking adolescents to better understand their needs and the risks they face without intervention. Methods: We analyzed responses from adolescents who completed the 14-year questionnaire in MoBa (N = 127), identifying those as at risk by their high scores on psychosis-risk items, within the top 0.4% (N = 58). Comparative analyses were conducted against matched controls to assess differences in psychological and social functioning (N = 69). Results: Results indicated that the at-risk adolescents experience significantly more depression and anxiety and have lower self-esteem and poorer social functioning than controls. Social functioning parameters, including leisure activities, social competence, quality of parental relationship, and sense of school belonging, were significantly worse than those observed in controls. The results indicate a pronounced vulnerability among non-help-seeking adolescents at-risk, similar to issues seen in help-seeking youths. Conclusion: These findings highlight the importance of early identification and intervention strategies that reach beyond traditional clinical settings, suggesting the efficacy of population or community-based screenings to prevent long-term adverse outcomes. The study proposes a broader understanding of psychosis risk, stressing the importance of inclusive approaches to support at-risk adolescents effectively.

Neurocognitive function and delusion severity in schizophrenia spectrum disorders.

The role of basic neurocognitive function in delusions is unclear despite the association to difficulties in reasoning and decision-making. We investigated 812 individuals with schizophrenia spectrum disorders (SSD) using a broad neuropsychological test battery encompassing motor and mental processing speed, working memory, learning and memory, and executive function. Premorbid and current intellectual function was assessed with NART and WASI. Delusion level and other clinical symptoms were measured with the PANSS and GAF. Hierarchical and k-means cluster analysis using standardized scores showed the presence of two separate clusters where the group with the higher delusion level (n = 291) was characterized by more severe neurocognitive deficits (>1.5 standard deviations below the healthy control mean), higher PANSS scores, lower GAF scores, and lower intelligence levels compared to the cluster with mild impairments (n = 521). We conclude that a higher delusion level is related to neurocognitive deficits across domains. Further, the validity of the two separate clusters was indicated by significant differences in clinical symptoms, everyday function, and intellectual ability. Compared to those with mild delusion levels, SSD patients with higher delusion levels seem particularly disadvantaged, with co-occurring general symptoms and lower daily function, underscoring the need for clinical and psychosocial support programs. A limitation of this study is the cross sectional design. Longitudinal studies are needed to determine the causal relationship between delusions and neurocognitive function.

Unmasking patient diversity: Exploring cognitive and antidepressive effects of electroconvulsive therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is an established treatment for depression, but more data on effectiveness and safety in clinical practice is needed. The aim of this register-based study was to investigate short-term effectiveness and cognitive safety after ECT, evaluated by clinicians and patients. Secondary, we investigated predictors for remission and cognitive decline. METHODS: The study included 392 patients from the Regional Register for Neurostimulation Treatment in Western Norway. Depressive symptoms and cognitive function were assessed with Montgomery-Åsberg Depression Rating Scale and Mini-Mental State Examination (clinician-rated) and Beck Depression Inventory and Everyday Memory Questionnaire (patient-rated). Assessments were done prior to ECT-series and a mean of 1.7 days after (range 6 days before and 12 days after) end of ECT-series. Paired samples t-tests were extended by detailed, clinically relevant subgroups. Predictors were examined using logistic regression. RESULTS: Clinician- and patient-rated remission rates were 49.5 and 41.0%, respectively. There was a large reduction in depressive symptoms and a small improvement in cognition after ECT, but we also identified subgroups with non-response of ECT in combination with cognitive decline (4.6% clinician-rated, 15.7% patient-rated). Positive predictors for patient- and clinician-rated remission were increasing age, shorter duration of depressive episode, and psychotic features. Antipsychotic medication at the commencement of treatment and previous ECT-treatment gave higher odds of clinician-rated remission, whereas higher pretreatment subjective depression level was associated with lower odds for patient-rated remission. Clinician-rated cognitive decline was predicted by higher pretreatment MMSE scores, whereas psychotic features, increasing age, and greater pretreatment subjective memory concerns were associated with lower odds for patient-rated cognitive decline. CONCLUSIONS: Our study supports ECT as an effective and safe treatment, although subgroups have a less favorable outcome. ECT should be considered at an early stage for older patients suffering from depression with psychotic features. Providing comprehensive and balanced information from clinicians and patients perspectives on effects and side effects, may assist in a joint consent process.

Neurocognitive function and mortality in patients with schizophrenia spectrum disorders.

Individuals with schizophrenia spectrum disorders (SSD) have significantly lower life-expectancy than healthy people. Previously, we have identified baseline neurocognitive function in general and verbal memory and executive function in particular as related to mortality nearly two decades later. In this study, we aim to replicate these findings with a larger and age-matched sample. The patient group consisted of 252 individuals, 44 of whom were deceased and 206 alive. Neurocognition was assessed with a comprehensive battery. Results showed that the deceased group, compared to the living group, had significantly more severe neurocognitive deficits across nearly all domains. There were no differences in sex, remission status, psychosis symptoms, or function level between the groups. Immediate verbal memory and executive function were the strongest predictors of survival status. These results were nearly identical to our previous studies, and we conclude that baseline neurocognitive function is an important predictor for mortality in SSD. Clinicians should be mindful of this relationship in patients with significant cognitive deficits.

A ten-year longitudinal repeated assessment study of cognitive improvement in patients with first-episode schizophrenia and healthy controls: The Oslo Schizophrenia Recovery (OSR) study.

The mapping of cognitive trajectories after a first episode of schizophrenia has been the aim in several studies, but the longitudinal course of cognitive impairments remains an important question. Due to methodological limitations, it has been challenging to pinpoint specific periods of improvement or stability in cognitive functioning over time. The objective of this study is to further clarify the longitudinal course of cognitive change after a first episode of schizophrenia through frequent repeated measurement. A total of 56 persons participated in the study (28 first episode patients and 28 healthy pairwise matched controls) with 79 % of patients retained at the 10-year follow-up. The Oslo Schizophrenia Recovery study has a repeated measurement design and includes data from nine cognitive assessments over 10 years. Cognition was assessed with the MATRICS Consensus Cognitive Battery, which is well suited for repeated measurements. Data were analyzed with linear multilevel models. The results challenge some of the views about the course of cognitive impairment in first-episode schizophrenia patients. Using quadratic time effects in our analyses and balancing the patient group with regards to the most relevant confounding demographic variables such as age, gender, and education, we showed that cognitive deficits change and improve more than in healthy individuals until year 6, when both groups stabilize. The patient group improved on some of the most important cognitive domains associated with functional outcome with 63.5 % full recovery at 10-year follow-up.

Genome-wide association study in 404,302 individuals identifies 7 significant loci for reaction time variability.

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a GWAS of RTV in participants of white British ancestry (n = 404,302) as well as a trans-ancestry GWAS meta-analysis (n = 44,873) to assess replication. We found 161 genome-wide significant single nucleotide polymorphisms (SNPs) distributed across 7 genomic loci in our discovery GWAS. Functional annotation of the variants implicated genes involved in synaptic function and neural development. The SNP-based heritability (h2SNP) estimate for RTV was 3%. We investigated genetic correlations between RTV and selected neuropsychological traits using linkage disequilibrium score regression, and found significant correlations with several traits, including a positive correlation with schizophrenia. We assessed the predictive ability of a polygenic score (PGS) for RTV, calculated using PRSice and PRS-CS, and found that the RTV-PGS significantly predicted RTV in independent cohorts, but that the generalizability to other ancestry groups was poor. These results identify genetic underpinnings of RTV, and support the use of RTV as an endophenotype for neurological and psychiatric disorders.

Intra- and inter-individual cognitive variability in schizophrenia and bipolar spectrum disorder: an investigation across multiple cognitive domains.

There is substantial cognitive heterogeneity among patients with schizophrenia (SZ) and bipolar disorders (BD). More knowledge about the magnitude and clinical correlates of performance variability could improve our understanding of cognitive impairments. Using double generalized linear models (DGLMs) we investigated cognitive mean and variability differences between patients with SZ (n = 905) and BD spectrum disorders (n = 522), and healthy controls (HC, n = 1170) on twenty-two variables. The analysis revealed significant case-control differences on 90% of the variables. Compared to HC, patients showed larger intra-individual (within subject) variability across tests and larger inter-individual (between subject) variability in measures of fine-motor speed, mental processing speed, and inhibitory control (SZ and BD), and in verbal learning and memory and intellectual functioning (SZ). In SZ, we found that lager intra -and inter (on inhibitory control and speed functions) individual variability, was associated with lower functioning and more negative symptoms. Inter-individual variability on single measures of memory and intellectual function was additionally associated with disorganized and positive symptoms, and use of antidepressants. In BD, there were no within-subject associations with symptom severity. However, greater inter-individual variability (primarily on inhibitory control and speeded functions) was associated with lower functioning, more negative -and disorganized symptoms, earlier age at onset, longer duration of illness, and increased medication use. These results highlight larger individual differences in patients compared to controls on various cognitive domains. Further investigations of the causes and correlates of individual differences in cognitive function are warranted.

A systematic review of premorbid cognitive functioning and its timing of onset in schizophrenia spectrum disorders.

Cognitive impairments are core features of established schizophrenia spectrum disorders (SSD). However, it remains unclear whether specific cognitive functions are differentially impaired pre-onset and at what age these impairments can be detected. The purpose of this review was to elucidate these issues through a systematic summary of results from longitudinal studies investigating impairment in specific cognitive domains as antecedents of SSD. Relevant studies were identified by electronic and manual literature searches and included any original study of cognitive domains any time pre-onset of SSDs that included a control group. Effect sizes were calculated by domain for studies comparing high-risk participants who developed SSD with those who did not. The strongest evidence for impairment pre-onset was for mental processing speed, verbal learning and memory, executive function, and social cognition. Some verbal impairments, like language abilities at age 3 and verbal learning and memory at age 7, may develop as static deficits. Conversely, some non-verbal impairments, like mental processing speed, visuospatial abilities, and visual working memory manifest as developmental lag and become significant later in life. Most effect sizes were small to moderate, except for verbal fluency (d' = 0,85), implying this impairment as central in high-risk participants who develop SSD. The present review documents extensive cognitive impairments pre-onset of SSD, and that these impairments start early in life, in line with the neurodevelopmental hypothesis of schizophrenia. Increased knowledge about cognitive impairments preonset can provide a better basis for understanding the complex pathogenesis of SSD as well as informing cognitive remediation programs.