Sex effects on DNA methylation affect discovery in epigenome-wide association study of schizophrenia.

Sex differences in the epidemiology and clinical characteristics of schizophrenia are well-known; however, the molecular mechanisms underlying these differences remain unclear. Further, the potential advantages of sex-stratified meta-analyses of epigenome-wide association studies (EWAS) of schizophrenia have not been investigated. Here, we performed sex-stratified EWAS meta-analyses to investigate whether sex stratification improves discovery, and to identify differentially methylated regions (DMRs) in schizophrenia. Peripheral blood-derived DNA methylation data from 1519 cases of schizophrenia (male n = 989, female n = 530) and 1723 controls (male n = 997, female n = 726) from three publicly available datasets, and the TOP cohort were meta-analyzed to compare sex-specific, sex-stratified, and sex-adjusted EWAS. The predictive power of each model was assessed by polymethylation score (PMS). The number of schizophrenia-associated differentially methylated positions identified was higher for the sex-stratified model than for the sex-adjusted one. We identified 20 schizophrenia-associated DMRs in the sex-stratified analysis. PMS from sex-stratified analysis outperformed that from sex-adjusted analysis in predicting schizophrenia. Notably, PMSs from the sex-stratified and female-only analyses, but not those from sex-adjusted or the male-only analyses, significantly predicted schizophrenia in males. The findings suggest that sex-stratified EWAS meta-analyses improve the identification of schizophrenia-associated epigenetic changes and highlight an interaction between sex and schizophrenia status on DNA methylation. Sex-specific DNA methylation may have potential implications for precision psychiatry and the development of stratified treatments for schizophrenia.

A good life with psychosis: rate of positive outcomes in first-episode psychosis at 10-year follow-up.

BACKGROUND: More knowledge about positive outcomes for people with first-episode psychosis (FEP) is needed. An FEP 10-year follow-up study investigated the rate of personal recovery, emotional wellbeing, and clinical recovery in the total sample and between psychotic bipolar spectrum disorders (BD) and schizophrenia spectrum disorders (SZ); and how these positive outcomes overlap. METHODS: FEP participants (n = 128) were re-assessed with structured clinical interviews at 10-year follow-up. Personal recovery was self-rated with the Questionnaire about the Process of Recovery-15-item scale (total score ⩾45). Emotional wellbeing was self-rated with the Life Satisfaction Scale (score ⩾5) and the Temporal Experience of Pleasure Scale (total score ⩾72). Clinical recovery was clinician-rated symptom-remission and adequate functioning (duration minimum 1 year). RESULTS: In FEP, rates of personal recovery (50.8%), life satisfaction (60.9%), and pleasure (57.5%) were higher than clinical recovery (33.6%). Despite lower rates of clinical recovery in SZ compared to BD, they had equal rates of personal recovery and emotional wellbeing. Personal recovery overlapped more with emotional wellbeing than with clinical recovery (χ2). Each participant was assigned to one of eight possible outcome groups depending on the combination of positive outcomes fulfilled. The eight groups collapsed into three equal-sized main outcome groups: 33.6% clinical recovery with personal recovery and/or emotional wellbeing; 34.4% personal recovery and/or emotional wellbeing only; and 32.0% none. CONCLUSIONS: In FEP, 68% had minimum one positive outcome after 10 years, suggesting a good life with psychosis. This knowledge must be shared to instill hope and underlines that subjective and objective positive outcomes must be assessed and targeted in treatment.

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.

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.

Long-term course of cognitive functioning in bipolar disorder: A ten-year follow-up study.

INTRODUCTION: Cognitive impairments are common in bipolar disorder (BD), but the long-term course remains understudied. Longitudinal data on cognitive functioning from the start of the first treatment could help clarify pathophysiological processes that shape the illness outcome. We here aim to investigate the 10-year cognitive course in BD compared to healthy controls (HC) and the effects of clinical symptoms on cognitive trajectories. METHODS: Fifty-six BD participants recruited within their first year of treatment and 108 HC completed clinical and cognitive assessments at baseline and 10-year follow-up. We derived eight cognitive domain scores and a cognitive composite score, which were further investigated using linear mixed model analyses. Correlation analyses were used to assess associations between the composite score and depressive, manic and psychotic symptoms. RESULTS: BD participants performed poorer than HCs in all domains except mental speed and verbal fluency. Verbal learning and memory, verbal fluency and the composite score improved over time in both BD participants and HC, while short-term memory, mental speed, psychomotor speed and working memory were stable. We found no significant correlations between cognition and symptom level at either time point in BD participants. CONCLUSIONS: We found evidence of long-term cognitive stability or improvement in BD participants from first treatment to 10-year follow-up. Though the BD group was impaired in all domains except mental speed and verbal fluency, the change in cognitive functioning was parallel to that of HCs. These findings are not consistent with the notion of neuroprogression in BD.

Hypothalamic subunit volumes and relations to violence and psychopathy in male offenders with or without a psychotic disorder.

The hypothalamus is key to body homeostasis, including regulating cortisol, testosterone, vasopressin, and oxytocin hormones, modulating aggressive behavior. Animal studies have linked the morphology and function of the hypothalamus to aggression and affiliation, with a subregional pattern reflecting the functional division between the hypothalamic nuclei. We explored the relationship between hypothalamic subunit volumes in violent offenders with (PSY-V) and without (NPV) a psychotic disorder, and the association with psychopathy traits. 3T MRI scans (n = 628, all male 18-70 years) were obtained from PSY-V, n = 38, NPV, n = 20, non-violent psychosis patients (PSY-NV), n = 134, and healthy controls (HC), n = 436. The total hypothalamus volume and its eleven nuclei were delineated into five subunits using Freesurfer v7.3. Psychopathy traits were assessed with Psychopathy Checklist-revised (PCL-R). ANCOVAs and linear regressions were used to analyze associations with subunit volumes. Both groups with a history of violence exhibited smaller anterior-superior subunit volumes than HC (NPV Cohen's d = 0.56, p = 0.01 and PSY-V d = 0.38, p = 0.01). There were no significant differences between HC and PSY-NV. PCL-R scores were positively associated with the inferior tubular subunit on a trend level (uncorrected p = 0.045, Cohen's d = 0.04). We found distinct hypothalamic subunit volume reductions in persons with a history of violence independent of concomitant psychotic disorder but not in persons with psychosis alone. The results provide further information about the involvement of the hypothalamus in aggression, which ultimately may lead to the development of targeted treatment for the clinical and societal challenge of aggression and violent behavior.

Sex differences in social cognition among individuals with schizophrenia and in healthy control participants: a secondary analysis of published data.

PURPOSE: Sex differences are present among individuals experiencing schizophrenia. Whether these differences extend to social cognition is unclear. In this study, we investigated sex differences in emotion perception, social perception and theory of mind (ToM). METHODS: We examined sex differences between males and females with schizophrenia on five social cognitive tests. Healthy male and female control participants were included to examine if any sex difference was illness-specific. Emotion perception was measured with Pictures of Facial Affect (PFA) and Emotion in Biological Motion (EmoBio); social perception with the Relationships Across Domains Test (RAD); and ToM with the Movie for the Assessment of Social Cognition (MASC) and Hinting Task. RESULTS: Two-way analyses of variance revealed overall group differences for all tests, with healthy controls outperforming individuals with schizophrenia. Significant sex effects were present for PFA and Hinting Task. There were no significant interaction effects. Within-group independent samples t-tests yielded one significant sex difference, i.e., among healthy controls for PFA. CONCLUSIONS: Females had better facial emotion perception than males. This sex difference was statistically significant among healthy controls and medium-large among individuals experiencing schizophrenia. There were no significant sex differences for other social cognitive domains. The study did not find evidence for a general female advantage in social cognition.

Prescriptions of psychotropic and somatic medications among patients with severe mental disorders and healthy controls in a naturalistic study.

PURPOSE: Psychotropic and somatic medications are both used in treating severe mental disorders (SMDs). Realistic estimates of the prevalence of use across medication categories are needed. We obtained this in a clinical cohort of patients with SMD and healthy controls (HCs). MATERIALS AND METHODS: Prescriptions filled at Norwegian pharmacies the year before and after admittance to the Thematically Organized Psychosis (TOP) study were examined in 1406 patients with SMD (mean age 32.5 years, 48.2% women) and 920 HC (34.1 years, 46.2% women). Using data from the Norwegian Prescription Database (NorPD), the number of users in different anatomical therapeutic chemical (ATC) categories was compared using logistic regression. Population estimates were used as reference data. RESULTS: Use of antipsychotics (N05A), antiepileptics (N03A), antidepressants (N06A), anxiolytics (N05B), hypnotics and sedatives (N05C), anticholinergics (N04A), psychostimulants, attention deficit hyperactivity disorder and nootropic agents (N06B) and drugs for addiction disorders (N07B) was significantly more prevalent in patients with SMD than HC. Use of diabetes treatment (A10), antithrombotic drugs (B01), beta blockers (C07), lipid modifiers (C10), and thyroid and endocrine therapeutics (H03) was also more prevalent in patients with SMD, but with two exceptions somatic medication use was comparable to the general population. Among HC, there was low prevalence of use for most medication categories. CONCLUSION: Patients were using psychiatric medications, but also several types of somatic medications, more often than HC. Still, somatic medication use was mostly not higher than in the general population. The results indicate that HC had low use of most medication types.

Course of intellectual functioning in schizophrenia and bipolar disorder: a 10-year follow-up study.

BACKGROUND: Intellectual functioning (IQ) is lower in schizophrenia patients compared to healthy controls, with bipolar patients intermediate between the two. Declines in IQ mark the onset of schizophrenia, while stability is generally found post-onset. There are to date few studies on long-term IQ development in bipolar disorder. This study presents 10-year follow-up data on IQ, including premorbid IQ estimates, to track the developmental course from pre-onset levels to long-term outcomes in both patient groups compared to healthy controls. METHODS: We included 139 participants with schizophrenia, 76 with bipolar disorder and 125 healthy controls. Mixed model analyses were used to estimate developmental slopes for IQ scores from estimated premorbid level (NART IQ) through baseline (WASI IQ) measured within 12 months post-onset, to 10-year follow-up (WASI IQ), with pairwise group comparisons. The best fit was found using a model with a breakpoint at baseline assessment. RESULTS: Only the schizophrenia group had significant declines from estimated premorbid to baseline IQ levels compared to controls. When comparing patient groups, schizophrenia patients had steeper declines than the bipolar group. Increases in IQ were found in all groups over the follow-up period. CONCLUSIONS: Trajectories of IQ from premorbid level to 10-year follow-up indicated declines from estimated premorbid level to illness onset in both patient groups, followed by increases during the follow-up period. Schizophrenia patients had a steeper decline than bipolar patients. During follow-up, increases indicate developmental improvement for both patient groups, but with a maintained lag compared to healthy controls due to lower premorbid levels.

Childhood trauma, antipsychotic medication, and symptom remission in first-episode psychosis.

BACKGROUND: To what extent psychotic symptoms in first-episode psychosis (FEP) with a history of childhood interpersonal trauma (CIT) are less responsive to antipsychotic medication is not known. In this longitudinal study, we compare symptom trajectories and remission over the first 2 years of treatment in FEP with and without CIT and examine if differences are linked to the use of antipsychotics. METHODS: FEP (N = 191) were recruited from in- and outpatient services 1997-2000, and assessed at baseline, 3 months, 1 and 2 years. Inclusion criteria were 15-65 years, actively psychotic with a DSM-IV diagnosis of psychotic disorder and no previous adequate treatment for psychosis. Antipsychotic medication is reported as defined daily dosage (DDD). CIT (<18) was assessed with the Brief Betrayal Trauma Survey, and symptomatic remission based on scores from the Positive and Negative Syndrome Scale. RESULTS: CIT (n = 63, 33%) was not associated with symptomatic remission at 2 years follow-up (71% in remission, 14% in relapse), or time to first remission (CIT 12/ no-CIT 9 weeks, p = 0.51). Those with CIT had significantly more severe positive, depressive, and excited symptoms. FEP with physical (N = 39, 20%) or emotional abuse (N = 22, 14, 7%) had higher DDD at 1 year (p < 0.05). Mean DDD did not excerpt a significant between-group effect on symptom trajectories of positive symptoms. CONCLUSION: Results indicate that antipsychotic medication is equally beneficial in the achievement of symptomatic remission in FEP after 2 years independent of CIT. Still, FEP patients with CIT had more severe positive, depressive, and excited symptoms throughout.

Impulsivity across severe mental disorders: a cross-sectional study of immune markers and psychopharmacotherapy.

BACKGROUND: Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. METHODS: Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. RESULTS: Impulsivity  was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. CONCLUSIONS: We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.

Theory of mind in schizophrenia: a comparison of subgroups with low and high IQ.

BACKGROUND: Social cognitive impairment is common in schizophrenia, but it is unclear if it is present in individuals with high IQ. This study compared theory of mind (ToM) in schizophrenia participants with low or high IQ to healthy controls. METHODS: One hundred and nineteen participants (71 healthy controls, 17 high IQ (IQ ≥115), and 31 low IQ (IQ ≤95) schizophrenia participants) were assessed with the Movie for the Assessment of Social Cognition, providing scores for total, cognitive, and affective ToM, along with overmentalizing, undermentalizing, and no-mentalizing errors. IQ was measured with Wechsler Abbreviated Scale of Intelligence; clinical symptoms with the Positive and Negative Syndrome Scale. RESULTS: Healthy controls performed better than the low IQ schizophrenia group for all ToM scores, and better than the high IQ schizophrenia group for the total score and under- and no-mentalizing errors. The high IQ group made fewer overmentalizing errors and had better total and cognitive ToM than the low IQ group. Their number of overmentalizing errors was indistinguishable from healthy controls. CONCLUSION: Global ToM impairment was present in the low IQ schizophrenia group. Overmentalizing was not present in the high IQ group and appears related to lower IQ. Intact higher-level reasoning may prevent the high IQ group from making overmentalizing errors, through self-monitoring or inhibition. We propose that high IQ patients are chiefly impaired in lower-level ToM, whereas low IQ patients also have impaired higher-level ToM. Conceivably, this specific impairment could help explain the lower functioning reported in persons with intact IQ.

Psychopathy subdomains in violent offenders with and without a psychotic disorder.

BACKGROUND: Violence in psychosis has been linked to antisocial behavior and psychopathy traits. Psychopathy comprises aspects of interpersonal, affective, lifestyle, and antisocial traits which may be differently involved in violent offending by persons with psychotic disorders. We explored psychopathy subdomains among violent offenders with and without a psychotic disorder. METHODS: 46 males, with a history of severe violence, with (n = 26; age 35.85 ± 10.34 years) or without (n = 20; age 39.10 ± 11.63 years) a diagnosis of a psychotic disorder, were assessed with the Psychopathy Checklist-Revised (PCL-R). PCL-R was split into subdomains following the four-facet model. Group differences in total and subdomain scores were analyzed with a general linear model with covariates. RESULTS: Total PCL-R scores did not differ between the groups (p = 0.61, Cohen's d = 0.17). The violent offenders without psychotic disorders had higher facet 2 scores than the patient group with psychotic disorders (p = 0.029, Cohen's d = 0.77). Facet 1, 3, or 4 scores did not differ between the groups. Controlling for age did not alter the results. CONCLUSION: Patients with a psychotic disorder and a history of severe violence have lower affective psychopathy scores than violent offenders without psychotic disorders. This observation may point toward distinct underlying mechanisms for violence and may provide a target for focused treatment and prevention.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. METHODS: We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. RESULTS: We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. CONCLUSIONS: Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.

Clinical determinants of hospital treated deliberate self-harm repetition: A time to recurrent event analysis.

INTRODUCTION: Psychiatric disorders are strongly associated with hospital treated deliberate self-harm (DSH). However, the effect of specific disorders on risk for DSH repetition in sex-age-subgroups is understudied. The present study aims to assess the influence of various specific psychiatric disorders on risk for subsequent DSH repetition by way of time to recurrent event analysis on a national cohort of DSH patients. MATERIAL AND METHODS: Individuals aged 18 and older presenting to somatic hospital for DSH during the period 2008-2018 was identified through national registers. A parametric shared frailty survival analysis was used to investigate the impact of various psychiatric disorders on risk of DSH repetition. RESULTS: The cohort consisted of 39,508 individuals of which 8634 (21.8%) presented with 24,028 repeated episodes of hospital treated DSH. Borderline personality disorder increased the risk of DSH repetition in females (adjusted HR 1.49, CI 1.41-1.57), while alcohol use disorder (HR 1.12, CI 1.04-1.19) and substance use disorders (adjusted HR 1.22, CI 1.14-1.32) increased the risk of repetition in males. The strongest impact of psychiatric disorder on risk of repetition was found among the elderly. Previous history of DSH was associated with the highest increased risk of repetition. CONCLUSION: Prior history of DSH was strongly associated with DSH repetition, but the influence of psychiatric disorder varied significantly by specific diagnoses and by sex and age of the patients. Efforts to prevent DSH repetition should be age and gender specific and designed to meet the needs of people with different specific psychiatric disorders.

Basic self-disturbance trajectories in clinical high risk for psychosis: a one-year follow-up study.

Basic self-disturbance (BSD) has been proposed as a driver of symptom development in schizophrenia spectrum disorders (SSDs). In a one-year follow-up of 32 patients (15-30 years) at putative risk for psychosis, we investigated trajectories of BSD levels from baseline to follow-up, and associations between clinical characteristics at baseline and follow-up, including follow-up levels of BSD (assessed with the EASE). Clinical high risk (CHR) for psychosis status and symptom severity were assessed with the SIPS/SOPS scales and also according to the cognitive basic symptoms high-risk criteria (COGDIS). DSM-IV diagnoses, functioning and other clinical characteristics were assessed with standard clinical instruments. Higher severity of negative symptoms and meeting COGDIS criteria at baseline were associated with higher BSD levels at follow-up. All measured at follow-up, higher BSD levels correlated with higher severity of positive, negative, disorganization and general symptoms, and with a lower level of global functioning. We found higher BSD levels at follow-up in subjects with schizotypal personality disorder (SPD) at baseline (n = 5) and in SSDs at follow-up (n = 12, including nine with SPD). Mean BSD levels decreased significantly from baseline to follow-up, but individual trajectories varied considerably. Increased BSD levels were associated with higher baseline BSD levels, non-remission of positive symptoms and functional decline. Overall, the current study indicates that subgroups in the CHR population with a higher risk of non-remission or deterioration may be identified by supplementing CHR criteria with assessment of BSD and negative symptoms.

Affective lability and social functioning in severe mental disorders.

Social functioning is impaired in severe mental disorders despite clinical remission, illustrating the need to identify other mechanisms that hinder psychosocial recovery. Affective lability is elevated and associated with an increased clinical burden in psychosis spectrum disorders. We aimed to investigate putative associations between affective lability and social functioning in 293 participants with severe mental disorders (schizophrenia- and bipolar spectrum), and if such an association was independent of well-established predictors of social impairments. The Affective Lability Scale (ALS-SF) was used to measure affective lability covering the dimensions of anxiety-depression, depression-elation and anger. The interpersonal domain of the Social Functioning Scale (SFS) was used to measure social functioning. Correlation analyses were conducted to investigate associations between affective lability and social functioning, followed by a hierarchical multiple regression and follow-up analyses in diagnostic subgroups. Features related to premorbid and clinical characteristics were entered as independent variables together with the ALS-SF scores. We found that higher scores on all ALS-SF subdimensions were significantly associated with lower social functioning (p < 0.005) in the total sample. For the anxiety-depression dimension of the ALS-SF, this association persisted after controlling for potential confounders such as premorbid social functioning, duration of untreated illness and current symptoms (p = 0.019). Our results indicate that elevated affective lability may have a negative impact on social functioning in severe mental disorders, which warrants further investigation. Clinically, it might be fruitful to target affective lability in severe mental disorders to improve psychosocial outcomes.

Premorbid characteristics of patients with DSM-IV psychotic disorders.

INTRODUCTION: Psychotic disorder not otherwise specified (PNOS) is considered part of the psychosis spectrum, together with schizophrenia spectrum disorders (SSD) and psychotic bipolar spectrum disorders (PBD). The atypical clinical presentations of PNOS conditions may lead to uncertainty regarding treatment choices and expected outcomes. PNOS is understudied, and little is known about patients' premorbid characteristics including premorbid adjustment, prevalence of early cannabis use and childhood trauma. Knowledge about early illness phases can increase our understanding of this diagnostic group. METHODS: We included 1099 participants from the Norwegian TOP-study; 688 with narrow SSD diagnoses (schizophrenia, schizoaffective disorder, schizophreniform disorder), 274 with PBD (psychotic bipolar 1 and bipolar NOS) and 137 with PNOS diagnosed with the SCID-I for DSM-IV. Participants were assessed with the Premorbid Adjustment Scale (PAS) divided into the areas of premorbid academic and social functioning. We obtained information on age at first exposure to cannabis and use of cannabis before the age of 16. The participants also provided information regarding early traumatic experiences using the Childhood Trauma Questionnaire (CTQ). RESULTS: Participants with PNOS and SSD had poorer premorbid academic functioning than those with PBD (F2, 1029 = 7.81, p < 0.001, pη2 = 0.015). Premorbid social adjustment was significantly worse in the SSD group compared to the PBD group (F2, 1024 = 3.10, p = 0.045, pη2 = 0.006), with PNOS in the middle position. Significantly more of the participants with PNOS (17.5%) and SSD (11.5%) used cannabis before the age of 16 compared with PBD (5.3%, Wald χ2 = 6.86, p = 0.03). There were no significant differences between the three groups regarding mean CTQ scores or in the proportion of participants who had experienced at least one type of childhood adversity. CONCLUSIONS: Participants with PNOS appear as more similar to participants with SSD than to those with PBD regarding early premorbid adjustment and early cannabis use. The results indicate that many conditions classified as PNOS have functional impairments and problematic substance use from an early age. The prevalence of childhood adversities are high in all three groups.

COVID-19 lockdown - who cares? The first lockdown from the perspective of relatives of people with severe mental illness.

BACKGROUND: Informal care is vital to many people with severe mental illness under normal circumstances. Little is known about how extraordinary circumstances affect relatives with a family member with mental illness. This study investigated the consequences of the first COVID-19 lockdown in Norway from the perspective of relatives of persons with psychotic- and/or bipolar disorders: What were the challenges and for whom? METHOD: Relatives were invited to complete an online survey shortly after the first lockdown was initiated. Both quantitative and qualitative data were collected concerning experiences of relatives' own and their affected family members' health and situation. Two hundred and seventy-nine relatives completed the survey, mostly mothers and partners. RESULTS: One-third of the relatives reported considerable deterioration in their family members' mental health, and a substantial minority worried about severe self-harm or suicide. Main themes in the qualitative analyses were "Isolation and its effects on mental health", "Worrying about the pandemic and its consequences", "Increased symptomatology" and "Suicide". Being a relative during the lockdown put heavy strain on the relatives' own health, in particular disturbance of sleep, concentration, and the ability to take care of others in the family. Relatives of family members with psychotic bipolar disorder, not currently in treatment, or living with their family experienced the situation especially challenging. CONCLUSIONS: Many relatives found the first lockdown hard for their family. Efforts to integrate relatives' perspectives in health care and contingency plans under normal circumstances could potentially alleviate some of the extra burden experienced by families during extraordinary circumstances.