Following the children of depressed parents from childhood to adult life: A focus on mood and anxiety disorders.

Background: Parental depression increases risk for anxiety and depression in offspring. The transition from adolescence to adulthood is a common risk period for onset of such disorders. However, relatively few studies have considered development of these disorders from childhood to adulthood including multiple assessments during this transition period. Method: Offspring of depressed parents aged 9-17 years at baseline were followed prospectively for 13 years (n = 337). Average length of follow-up was 16 months between the first and second waves, 13 months between the second and third, and 8 years between the third and fourth. Current (3-month) psychopathology was assessed at each wave using diagnostic interviews. We derived estimates of 3-month prevalence, age at first diagnosis, course and comorbidity of disorders. Social functioning in adult life was assessed at the final wave and we assessed how prior and current disorder impacted adult functioning. Results: A quarter of young people met criteria for a mood disorder and a third for anxiety disorder at least once. Mood and anxiety disorder prevalence increased from 4.5% and 15.8% respectively in childhood (9-11 years) to 22.3% and 20.9% respectively by age 23-28. Increased prevalence across the transition from adolescence to adulthood was particularly marked in males, while prevalence increased earlier in adolescence in females. Age at first diagnosis varied widely (mood disorder mean = 16.5 years (range 9-26); anxiety disorder mean = 14.5 years (range 9-28)). Over half (52%) reported functional impairment in early adulthood, 31% harmful alcohol use, and 10% self-harm or a suicide attempt. Both previous and current mood or anxiety disorder were associated with functional impairment in early adulthood. Conclusions: There is a prolonged risk period for mood and anxiety disorders in this group, with prevalence peaking in early adulthood. This highlights the need for prolonged vigilance and effective targeted interventions in the offspring of depressed parents.

Psychosis Recovery Orientation in Malawi by Improving Services and Engagement (PROMISE) protocol.

Malawi has a population of around 20 million people and is one of the world's most economically deprived nations. Severe mental illness (largely comprising psychoses and severe mood disorders) is managed by a very small number of staff in four tertiary facilities, aided by clinical officers and nurses in general hospitals and clinics. Given these constraints, psychosis is largely undetected and untreated, with a median duration of untreated psychosis (DUP) of around six years. Our aim is to work with people with lived experience (PWLE), caregivers, local communities and health leaders to develop acceptable and sustainable psychosis detection and management systems to increase psychosis awareness, reduce DUP, and to improve the health and lives of people with psychosis in Malawi. We will use the UK Medical Research Council guidance for developing and evaluating complex interventions, including qualitative work to explore diverse perspectives around psychosis detection, management, and outcomes, augmented by co-design with PWLE, and underpinned by a Theory of Change. Planned deliverables include a readily usable management blueprint encompassing education and community supports, with an integrated care pathway that includes Primary Health Centre clinics and District Mental Health Teams. PWLE and caregivers will be closely involved throughout to ensure that the interventions are shaped by the communities concerned. The effect of the interventions will be assessed with a quasi-experimental sequential implementation in three regions, in terms of DUP reduction, symptom remission, functional recovery and PWLE / caregiver impact, with quality of life as the primary outcome. As the study team is focused on long-term impact, we recognise the importance of having embedded, robust evaluation of the programme as a whole. We will therefore evaluate implementation processes and outcomes, and cost-effectiveness, to demonstrate the value of this approach to the Ministry of Health, and to encourage longer-term adoption across Malawi.

Specificity of polygenic signatures across symptom dimensions in bipolar disorder: an analysis of UK Bipolar Disorder Research Network data.

BACKGROUND: Current definitions and clinical heterogeneity in bipolar disorder are major concerns as they obstruct aetiological research and impede drug development. Therefore, stratification of bipolar disorder is a high priority. To inform stratification, our analysis aimed to examine the patterns and relationships between polygenic liability for bipolar disorder, major depressive disorder (MDD), and schizophrenia with multidimensional symptom representations of bipolar disorder. METHODS: In this analysis, data from the UK Bipolar Disorder Research Network (BDRN) were assessed with the Operational Checklist for Psychotic Disorders. Individuals with bipolar disorder as defined in DSM-IV, of European ancestry (self-reported), aged 18 years or older at time of interview, living in the UK, and registered with the BDRN were eligible for inclusion. Psychopathological variables obtained via interview by trained research psychologists or psychiatrists and psychiatric case notes were used to identify statistically distinct symptom dimensions, calibrated with exploratory factor analysis and validated with confirmatory factor analysis (CFA). CFA was extended to include three polygenic risk scores (PRSs) indexing liability for bipolar disorder, MDD, and schizophrenia in a multiple indicator multiple cause (MIMIC) structural equation model to estimate PRS relationships with symptom dimensions. FINDINGS: Of 4198 individuals potentially eligible for inclusion, 4148 (2804 [67·6%] female individuals and 1344 [32·4%] male individuals) with a mean age at interview of 45 years (SD 12·03) were available for analysis. Three reliable dimensions (mania, depression, and psychosis) were identified. The MIMIC model fitted the data well (root mean square error of approximation 0·021, 90% CI 0·019-0·023; comparative fit index 0·99) and suggests statistically distinct symptom dimensions also have distinct polygenic profiles. The PRS for MDD was strongly associated with the depression dimension (standardised ß 0·125, 95% CI 0·080-0·171) and the PRS for schizophrenia was strongly associated with the psychosis dimension (0·108, 0·082-0·175). For the mania dimension, the PRS for bipolar disorder was weakly associated (0·050, 0·002-0·097). INTERPRETATION: Our findings support the hypothesis that genetic heterogeneity underpins clinical heterogeneity, suggesting that different symptom dimensions within bipolar disorder have partly distinct causes. Furthermore, our results suggest that a specific symptom dimension has a similar cause regardless of the primary psychiatric diagnosis, supporting the use of symptom dimensions in precision psychiatry. FUNDING: Wellcome Trust and UK Medical Research Council.

The role of brain structure in the association between pubertal timing and depression risk in an early adolescent sample (the ABCD Study®): A registered report.

BACKGROUND: Earlier pubertal timing is associated with higher rates of depressive disorders in adolescence. Neuroimaging studies report brain structural associations with both pubertal timing and depression. However, whether brain structure mediates the relationship between pubertal timing and depression remains unclear. METHODS: The current registered report examined associations between pubertal timing (indexed via perceived pubertal development), brain structure (cortical and subcortical metrics, and white matter microstructure) and depressive symptoms in a large sample (N = âˆ¼5000) of adolescents (aged 9-13 years) from the Adolescent Brain Cognitive Development (ABCD) Study. We used three waves of follow-up data when the youth were aged 10-11 years, 11-12 years, and 12-13 years, respectively. We used generalised linear-mixed models (H1) and structural equation modelling (H2 & H3) to test our hypotheses. HYPOTHESES: We hypothesised that earlier pubertal timing at Year 1 would be associated with increased depressive symptoms at Year 3 (H1), and that this relationship would be mediated by global (H2a-b) and regional (H3a-g) brain structural measures at Year 2. Global measures included reduced cortical volume, thickness, surface area and sulcal depth. Regional measures included reduced cortical thickness and volume in temporal and fronto-parietal areas, increased cortical volume in the ventral diencephalon, increased sulcal depth in the pars orbitalis, and reduced fractional anisotropy in the cortico-striatal tract and corpus callosum. These regions of interest were informed by our pilot analyses using baseline ABCD data when the youth were aged 9-10 years. RESULTS: Earlier pubertal timing was associated with increased depressive symptoms two years later. The magnitude of effect was stronger in female youth and the association remained significant when controlling for parental depression, family income, and BMI in females but not in male youth. Our hypothesised brain structural measures did not however mediate the association between earlier pubertal timing and later depressive symptoms. CONCLUSION: The present results demonstrate that youth, particularly females, who begin puberty ahead of their peers are at an increased risk for adolescent-onset depression. Future work should explore additional biological and socio-environmental factors that may affect this association so that we can identify targets for intervention to help these at-risk youth.

Association of trauma, post-traumatic stress disorder and non-affective psychosis across the life course: a nationwide prospective cohort study.

BACKGROUND: We aimed to examine the temporal relationships between traumatic events (TE), post-traumatic stress disorder (PTSD) and non-affective psychotic disorders (NAPD). METHODS: A prospective cohort study of 1 965 214 individuals born in Sweden between 1971 and 1990 examining the independent effects of interpersonal and non-interpersonal TE on incidence of PTSD and NAPD using data from linked register data (Psychiatry-Sweden). Mediation analyses tested the hypothesis that PTSD lies on a causal pathway between interpersonal trauma and NAPD. RESULTS: Increasing doses of interpersonal and non-interpersonal TE were independently associated with increased risk of NAPD [linear-trend incidence rate ratios (IRR)adjusted = 2.17 [95% confidence interval (CI) 2.02-2.33] and IRRadjusted = 1.27 (95% CI 1.23-1.31), respectively]. These attenuated to a relatively small degree in 5-year time-lagged models. A similar pattern of results was observed for PTSD [linear-trend IRRadjusted = 3.43 (95% CI 3.21-3.66) and IRRadjusted = 1.45 (95% CI 1.39-1.50)]. PTSD was associated with increased risk of NAPD [IRRadjusted = 8.06 (95% CI 7.23-8.99)], which was substantially attenuated in 5-year time-lagged analyses [IRRadjusted = 4.62 (95% CI 3.65-5.87)]. There was little evidence that PTSD diagnosis mediated the relationship between interpersonal TE and NAPD [IRRadjusted = 0.92 (percentile CI 0.80-1.07)]. CONCLUSION: Despite the limitations to causal inference inherent in observational designs, the large effect-sizes observed between trauma, PTSD and NAPD in this study, consistent across sensitivity analyses, suggest that trauma may be a component cause of psychotic disorders. However, PTSD diagnosis might not be a good proxy for the likely complex psychological mechanisms mediating this association.

Developing and validating a prediction model of adolescent major depressive disorder in the offspring of depressed parents.

BACKGROUND: Parental depression is common and is a major risk factor for depression in adolescents. Early identification of adolescents at elevated risk of developing major depressive disorder (MDD) in this group could improve early access to preventive interventions. METHODS: Using longitudinal data from 337 adolescents at high familial risk of depression, we developed a risk prediction model for adolescent MDD. The model was externally validated in an independent cohort of 1,384 adolescents at high familial risk. We assessed predictors at baseline and MDD at follow-up (a median of 2-3 years later). We compared the risk prediction model to a simple comparison model based on screening for depressive symptoms. Decision curve analysis was used to identify which model-predicted risk score thresholds were associated with the greatest clinical benefit. RESULTS: The MDD risk prediction model discriminated between those adolescents who did and did not develop MDD in the development (C-statistic = .783, IQR (interquartile range) = .779, .778) and the validation samples (C-statistic = .722, IQR = -.694, .741). Calibration in the validation sample was good to excellent (calibration intercept = .011, C-slope = .851). The MDD risk prediction model was superior to the simple comparison model where discrimination was no better than chance (C-statistic = .544, IQR = .536, .572). Decision curve analysis found that the highest clinical utility was at the lowest risk score thresholds (0.01-0.05). CONCLUSIONS: The developed risk prediction model successfully discriminated adolescents who developed MDD from those who did not. In practice, this model could be further developed with user involvement into a tool to target individuals for low-intensity, selective preventive intervention.

Early-life inflammatory markers and subsequent psychotic and depressive episodes between 10 to 28 years of age.

Inflammation is implicated in depression and psychosis, including association of childhood inflammatory markers on the subsequent risk of developing symptoms. However, it is unknown whether early-life inflammatory markers are associated with the number of depressive and psychotic symptoms from childhood to adulthood. Using the prospective Avon Longitudinal Study of Children and Parents birth cohort (N = up-to 6401), we have examined longitudinal associations of early-life inflammation [exposures: interleukin-6 (IL-6), C-reactive protein (CRP) levels at age 9y; IL-6 and CRP DNA-methylation (DNAm) scores at birth and age 7y; and IL-6 and CRP polygenic risk scores (PRSs)] with the number of depressive episodes and psychotic experiences (PEs) between ages 10-28 years. Psychiatric outcomes were assessed using the Short Mood and Feelings Questionnaire and Psychotic Like Symptoms Questionnaires, respectively. Exposure-outcome associations were tested using negative binomial models, which were adjusted for metabolic and sociodemographic factors. Serum IL-6 levels at age 9y were associated with the total number of depressive episodes between 10 and 28y in the base model (n = 4835; ß = 0.066; 95%CI:0.020-0.113; pFDR = 0.041) which was weaker when adjusting for metabolic and sociodemographic factors. Weak associations were observed between inflammatory markers (serum IL-6 and CRP DNAm scores) and total number of PEs. Other inflammatory markers were not associated with depression or PEs. Early-life inflammatory markers are associated with the burden of depressive episodes and of PEs subsequently from childhood to adulthood. These findings support a potential role of early-life inflammation in the aetiology of depression and psychosis and highlight inflammation as a potential target for treatment and prevention.

ADHD in adults with recurrent depression.

BACKGROUND: Depression is highly heterogeneous in its clinical presentation. Those with attention deficit/hyperactivity disorder (ADHD) may be at risk of a more chronic and impairing depression compared to those with depression alone according to studies of young people. However, no studies to date have examined ADHD in recurrently depressed adults in mid-life. METHOD: In a sample of women in mid-life (n=148) taken from a UK based prospective cohort of adults with a history of recurrent depression, we investigated the prevalence of ADHD and the association of ADHD with clinical features of depression. RESULTS: 12.8% of the recurrently depressed women had elevated ADHD symptoms and 3.4% met DSM-5 diagnostic criteria for ADHD. None of the women reported having a diagnosis of ADHD from a medical professional. ADHD symptoms were associated with earlier age of depression onset, higher depression associated impairment, a greater recurrence of depressive episodes and increased persistence of subthreshold depression symptoms over the study period, higher levels of irritability and increased risk of self-harm or suicide attempt. ADHD symptoms were associated with increased risk of hospitalisation and receiving non-first-line antidepressant medication. LIMITATIONS: ADHD was measured using a questionnaire measure. We focussed on mothers in a longitudinal study of recurrent depression, so the findings may not apply to males or other groups. CONCLUSIONS: Higher ADHD symptoms appear to index a worse clinical presentation for depression. Clinical implications include that in women with early onset, impairing and recurrent depression, the possibility of underlying ADHD masked by depression needs to be considered.

Associations Between Schizophrenia Polygenic Liability, Symptom Dimensions, and Cognitive Ability in Schizophrenia.

Importance: Schizophrenia is a clinically heterogeneous disorder. It is currently unclear how variability in symptom dimensions and cognitive ability is associated with genetic liability for schizophrenia. Objective: To determine whether phenotypic dimensions within schizophrenia are associated with genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence. Design, Setting, and Participants: In a genetic association study, 3 cross-sectional samples of 1220 individuals with a diagnosis of schizophrenia were recruited from community, inpatient, and voluntary sector mental health services across the UK. Confirmatory factor analysis was used to create phenotypic dimensions from lifetime ratings of the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, and the MATRICS Consensus Cognitive Battery. Analyses of polygenic risk scores (PRSs) were used to assess whether genetic liability to schizophrenia, other neuropsychiatric disorders, and intelligence were associated with these phenotypic dimensions. Data collection for the cross-sectional studies occurred between 1993 and 2016. Data analysis for this study occurred between January 2019 and March 2021. Main Outcomes and Measures: Outcome measures included phenotypic dimensions defined from confirmatory factor analysis relating to positive symptoms, negative symptoms of diminished expressivity, negative symptoms of motivation and pleasure, disorganized symptoms, and current cognitive ability. Exposure measures included PRSs for schizophrenia, bipolar disorder, major depression, attention-deficit/hyperactivity disorder, autism spectrum disorder, and intelligence. Results: Of the 1220 study participants, 817 were men (67.0%). Participants' mean (SD) age at interview was 43.10 (12.74) years. Schizophrenia PRS was associated with increased disorganized symptom dimension scores in both a 5-factor model (ß = 0.14; 95% CI, 0.07-0.22; P = 2.80 × 10-4) and a 3-factor model across all samples (ß = 0.10; 95% CI, 0.05-0.15; P = 2.80 × 10-4). Current cognitive ability was associated with genetic liability to schizophrenia (ß = -0.11; 95% CI, -0.19 to -0.04; P = 1.63 × 10-3) and intelligence (ß = 0.23; 95% CI, 0.16-0.30; P = 1.52 × 10-10). After controlling for estimated premorbid IQ, current cognitive performance was associated with schizophrenia PRS (ß = -0.08; 95% CI, -0.14 to -0.02; P = 8.50 × 10-3) but not intelligence PRS. Conclusions and Relevance: The findings of this study suggest that genetic liability for schizophrenia is associated with higher disorganized dimension scores but not other symptom dimensions. Cognitive performance in schizophrenia appears to reflect distinct contributions from genetic liabilities to both intelligence and schizophrenia.

A data-driven investigation of relationships between bipolar psychotic symptoms and schizophrenia genome-wide significant genetic loci.

The etiologies of bipolar disorder (BD) and schizophrenia include a large number of common risk alleles, many of which are shared across the disorders. BD is clinically heterogeneous and it has been postulated that the pattern of symptoms is in part determined by the particular risk alleles carried, and in particular, that risk alleles also confer liability to schizophrenia influence psychotic symptoms in those with BD. To investigate links between psychotic symptoms in BD and schizophrenia risk alleles we employed a data-driven approach in a genotyped and deeply phenotyped sample of subjects with BD. We used sparse canonical correlation analysis (sCCA) (Witten, Tibshirani, & Hastie, ) to analyze 30 psychotic symptoms, assessed with the OPerational CRITeria checklist, and 82 independent genome-wide significant single nucleotide polymorphisms (SNPs) identified by the Schizophrenia Working group of the Psychiatric Genomics Consortium for which we had data in our BD sample (3,903 subjects). As a secondary analysis, we applied sCCA to larger groups of SNPs, and also to groups of symptoms defined according to a published factor analyses of schizophrenia. sCCA analysis based on individual psychotic symptoms revealed a significant association (p = .033), with the largest weights attributed to a variant on chromosome 3 (rs11411529), chr3:180594593, build 37) and delusions of influence, bizarre behavior and grandiose delusions. sCCA analysis using the same set of SNPs supported association with the same SNP and the group of symptoms defined "factor 3" (p = .012). A significant association was also observed to the "factor 3" phenotype group when we included a greater number of SNPs that were less stringently associated with schizophrenia; although other SNPs contributed to the significant multivariate association result, the greatest weight remained assigned to rs11411529. Our results suggest that the canonical correlation is a useful tool to explore phenotype-genotype relationships. To the best of our knowledge, this is the first study to apply this approach to complex, polygenic psychiatric traits. The sparse canonical correlation approach offers the potential to include a larger number of fine-grained systematic descriptors, and to include genetic markers associated with other disorders that are genetically correlated with BD.

Association Between Schizophrenia-Related Polygenic Liability and the Occurrence and Level of Mood-Incongruent Psychotic Symptoms in Bipolar Disorder.

Importance: Bipolar disorder (BD) overlaps schizophrenia in its clinical presentation and genetic liability. Alternative approaches to patient stratification beyond current diagnostic categories are needed to understand the underlying disease processes and mechanisms. Objective: To investigate the association between common-variant liability for schizophrenia, indexed by polygenic risk scores (PRSs), and psychotic presentations of BD. Design, Setting, and Participants: This case-control study in the United Kingdom used multinomial logistic regression to estimate differential PRS associations across categories of cases and controls. Participants included in the final analyses were 4436 cases of BD from the Bipolar Disorder Research Network. These cases were compared with the genotypic data for 4976 cases of schizophrenia and 9012 controls from the Type 1 Diabetes Genetics Consortium study and the Generation Scotland study. Data were collected between January 1, 2000, and December 31, 2013. Data analysis was conducted from March 1, 2016, to February 28, 2017. Exposures: Standardized PRSs, calculated using alleles with an association threshold of P < .05 in the second Psychiatric Genomics Consortium genome-wide association study of schizophrenia, were adjusted for the first 10 population principal components and genotyping platforms. Main Outcomes and Measures: Multinomial logit models estimated PRS associations with BD stratified by Research Diagnostic Criteria subtypes of BD, by lifetime occurrence of psychosis, and by lifetime mood-incongruent psychotic features. Ordinal logistic regression examined PRS associations across levels of mood incongruence. Ratings were derived from the Schedules for Clinical Assessment in Neuropsychiatry interview and the Bipolar Affective Disorder Dimension Scale. Results: Of the 4436 cases of BD, 2966 (67%) were female patients, and the mean (SD) age at interview was 46 [12] years. Across clinical phenotypes, there was an exposure-response gradient, with the strongest PRS association for schizophrenia (risk ratio [RR] = 1.94; 95% CI, 1.86-2.01), followed by schizoaffective BD (RR = 1.37; 95% CI, 1.22-1.54), bipolar I disorder subtype (RR = 1.30; 95% CI, 1.24-1.36), and bipolar II disorder subtype (RR = 1.04; 95% CI, 0.97-1.11). Within BD cases, there was an effect gradient, indexed by the nature of psychosis. Prominent mood-incongruent psychotic features had the strongest association (RR = 1.46; 95% CI, 1.36-1.57), followed by mood-congruent psychosis (RR = 1.24; 95% CI, 1.17-1.33) and BD with no history of psychosis (RR = 1.09; 95% CI, 1.04-1.15). Conclusions and Relevance: For the first time to date, a study shows a polygenic-risk gradient across schizophrenia and BD, indexed by the occurrence and level of mood-incongruent psychotic symptoms.

Cognitive decline and dementia risk in older adults with psychotic symptoms: a prospective cohort study.

OBJECTIVES: To study the temporal association between psychotic symptoms with cognitive decline and incident dementia. DESIGN: Population-based prospective cohort study. SETTING: General population in England and Wales. PARTICIPANTS: A subsample of 2,025 participants of the Medical Research Council Cognitive Function and Ageing Study, representing a study sample of 11,916 nondemented adults age 65 years or older. MEASUREMENTS: Baseline presence of psychotic symptoms was assessed with the Geriatric Mental State. Cognitive decline (Cambridge Cognitive Examination) and incident dementia (Automated Geriatric Examination for Computer Assisted Taxonomy diagnosis) were evaluated at 2, 6, and 10 years from baseline. RESULTS: A total of 330 participants reported baseline symptoms of paranoid delusions, misidentification, or hallucinations, estimated to represent 13.4% of the older general population without dementia. Psychotic symptoms were cross-sectionally associated with worse cognitive functioning, and individuals with psychotic symptoms displayed more rapid cognitive decline from baseline to a 6-year follow-up, especially in nonmemory functions, than people without such symptoms. They further carried an increased overall risk of later dementia (odds ratio = 2.76, 95% confidence interval = 1.75-4.36). The risk increment was observed independently of baseline cognition, depression, anxiety, and vascular risk factors, increased with increasing numbers of psychotic symptoms, and was highest in people age 65-74 years. CONCLUSIONS: Older adults with psychotic symptoms are vulnerable to develop dementia and might be a promising target for indicated prevention strategies. Their neuropsychological functioning should be evaluated on a regular basis.

Kraepelin was right: a latent class analysis of symptom dimensions in patients and controls.

Phenotypic heterogeneity within patients and controls may explain why the genetic variants contributing to schizophrenia risk explain only a fraction of the heritability. The aim of this study is to investigate quantitative and qualitative differences in psychosis symptoms in a sample including psychosis patients, their relatives, and community controls. We combined factor analysis and latent class analysis to analyze variation in Comprehensive Assessment of Symptoms and History lifetime-rated symptoms in 4286 subjects. The Wechsler Adult Intelligence Scale-Intelligence Quotient (N = 2663) and the Camberwell Assessment of Need rating scale (N = 625) were assessed in a subsample. Variation in 5 continuous dimensions (disorganization, positive, negative, mania, and depression) was accounted for by the presence of 7 homogeneous classes (Kraepelinian schizophrenia, affective psychosis, manic-depression, deficit nonpsychosis, depression, healthy, and no symptoms). Eighty-five percent of the schizophrenia patients was assigned to the Kraepelinian schizophrenia class (characterized by high scores on the 5 dimensions, low IQ, and poor outcome) while 15% was assigned to the affective psychosis class (relatively low disorganization and negative scores, normal IQ, and good outcome). In bipolar patients (91% bipolar I), 41% was assigned to the Kraepelinian schizophrenia class, 44% to the affective psychosis class, and 10% to the manic-depression class. Latent class membership was associated with intelligence in psychosis patients and in their relatives but not in community controls. In conclusion, symptom heterogeneity is more pronounced in bipolar disorder compared with schizophrenia. Reducing phenotypic heterogeneity within psychosis patients and controls may facilitate etiological research.

Prior psychiatric hospitalization is associated with excess mortality in patients hospitalized with non-cardiac chest pain: a data linkage study based on the full Scottish population (1991-2006).

AIMS: Non-cardiac chest pain (NCCP) is considered a benign condition. We investigate case-fatality following an incident hospitalization for NCCP and determine whether previous psychiatric hospitalization is associated with short-term mortality. METHODS AND RESULTS: This was a population-based retrospective cohort study of 159 888 patients discharged from hospital in Scotland (1991-2006) following a first NCCP hospitalization, using routinely collected morbidity and mortality data. All-cause and cardiovascular disease (CVD) mortality at 1 year following hospitalization was examined. A total of 3514 (4.4%) men and 3136 (3.9%) women with a first NCCP hospitalization had a psychiatric hospitalization in the 10 years preceding incident NCCP hospitalization. Those with a previous psychiatric hospitalization were younger and more socioeconomically deprived (SED). Overall, crude case fatality at 1 year was 4.4% in men and 3.7% in women. This was higher in patients with a previous psychiatric hospitalization compared with those without (overall: men 6.3 vs. 4.3%; women: 5.3 vs. 3.6%), in all age groups and all SED quintiles. Following adjustment (year of NCCP hospitalization, SED, co-morbid diabetes, and hypertension), the hazard of all-cause and CVD-specific death at 1 year was higher in men and women with a previous psychiatric hospitalization than without, with effect modification according to age group. CONCLUSION: Non-cardiac chest pain is not an entirely benign condition. Individuals with a hospital discharge diagnosis of NCCP who have a previous psychiatric hospitalization have a greater risk of death, all-cause, and CVD-specific, at 1 year, than those without. A NCCP hospitalization is an opportunity to engage, and where appropriate, intervene to modify cardiovascular risk in this difficult-to-reach and high-risk group.

Affectively salient meaning in random noise: a task sensitive to psychosis liability.

Stable differences in the tendency to attribute meaning and emotional value to experience may represent an indicator of liability to psychosis. A brief task was developed assessing variation in detecting affectively meaningful speech (speech illusion) in neutral random signals (white noise) and the degree to which this was associated with psychometric and familial vulnerability for psychosis. Thirty patients, 28 of their siblings, and 307 controls participated. The rate of speech illusion was compared between cases and controls. In controls, the association between speech illusion and interview-based positive schizotypy was assessed. The hypothesis of a dose-response increase in rate of speech illusion across increasing levels of familial vulnerability for psychosis (controls, siblings of patients, and patients) was examined. Patients were more likely to display speech illusions than controls (odds ratio [OR] = 4.0, 95% confidence interval [CI] = 1.4-11.7), also after controlling for neurocognitive variables (OR = 3.8, 95% CI = 1.04-14.1). The case-control difference was more accentuated for speech illusion perceived as affectively salient (positively or negatively appraised) than for neutrally appraised speech illusions. Speech illusion in the controls was strongly associated with positive schizotypy but not with negative schizotypy. In addition, the rate of speech illusion increased with increasing level of familial risk for psychotic disorder. The data suggest that the white noise task may be sensitive to psychometric and familial vulnerability for psychosis associated with alterations in top-down processing and/or salience attribution.

Early risk factors for suicide in an epidemiological first episode psychosis cohort.

BACKGROUND: Much remains unknown about whether there are early risk factors for suicide in psychosis. AIM: The aim of the study was to determine whether there are any identifiable early symptom clusters, aetiological factors or illness course markers for suicide in first episode psychosis. METHOD: A total of 2132 patients with first episode psychosis presenting to secondary care services in London (1965-2004; n=1474), Nottingham (1997-1999; n=195) and Dumfries and Galloway (1979-1998; n=463) were traced after up to 40 years (mean 13 years) following first presentation. Risk factors were identified from the Operational Checklist for Psychotic Disorders rated for the first year following presentation. RESULTS: Overall, there were 51 suicides and 373 deaths from other causes. Male gender (RR 2.84, 95% CI 1.20-6.69, p=0.02) and a cumulative threshold effect of symptoms early in the illness (RR 6.81, 95% CI 2.33-19.85, p<0.001) were associated with a higher propensity for later completed suicide. There was also a suggestion that early manic symptoms might increase the risk of later suicide irrespective of initial diagnosis. CONCLUSION: Suicide risk was associated with a cumulative threshold effect of symptoms and manic symptoms. As suicide is a relatively rare event in psychotic disorders, general population-based prevention strategies may have more impact in this vulnerable group as well as the wider population.

Reassessing the long-term risk of suicide after a first episode of psychosis.

CONTEXT: The long-term risk of suicide after a first episode of psychosis is unknown because previous studies often have been based on prevalence cohorts, been biased to more severely ill hospitalized patients, extrapolated from a short follow-up time, and have made a distinction between schizophrenia and other psychoses. OBJECTIVE: To determine the epidemiology of suicide in a clinically representative cohort of patients experiencing their first episode of psychosis. DESIGN: Retrospective inception cohort. SETTING: Geographic catchment areas in London, England (between January 1, 1965, and December 31, 2004; n = 2056); Nottingham, England (between September 1, 1997, and August 31, 1999; n = 203); and Dumfries and Galloway, Scotland (between January 1, 1979, and December 31, 1998; n = 464). PARTICIPANTS: All 2723 patients who presented for the first time to secondary care services with psychosis in the 3 defined catchment areas were traced after a mean follow-up period of 11.5 years. MAIN OUTCOME MEASURE: Deaths by suicide and open verdicts according to the International Classification of Diseases (seventh through tenth editions). RESULTS: The case fatality from suicide was considerably lower than expected from previous studies (1.9% [53/2723]); the proportionate mortality was 11.9% (53/444). Although the rate of suicide was highest in the first year after presentation, risk persisted late into follow-up, with a median time to suicide of 5.6 years. Suicide occurred approximately 12 times more than expected from the general population of England and Wales (standardized mortality ratio, 11.65; 95% confidence interval, 8.73-15.24), and 49 of the 53 suicides were excess deaths. Even a decade after first presentation-a time when there may be less intense clinical monitoring of risk-suicide risk remained almost 4 times higher than in the general population (standardized mortality ratio, 3.92; 95% confidence interval, 2.22-6.89). CONCLUSIONS: The highest risk of suicide after a psychotic episode occurs soon after presentation, yet physicians should still be vigilant in assessing risk a decade or longer after first contact. The widely held view that 10% to 15% die of suicide is misleading because it refers to proportionate mortality, not lifetime risk. Nevertheless, there is a substantial increase in risk of suicide compared with the general population.

Depressive symptoms and cognitive decline in community-dwelling older adults.

OBJECTIVES: To examine the temporal association between depressive symptoms and cognitive functioning and estimate the effect measure modification of the apolipoprotein E (APOE) epsilon4 allele on this relationship. DESIGN: Prospective cohort study. SETTING: General community. PARTICIPANTS: Population-based sample of 598 cognitively intact older adults aged 60 and older, with re-assessments after 3 (N=479) and 6 years (N=412). MEASUREMENTS: Depressive symptoms (Symptom Checklist) and neurocognitive functioning (memory, Visual Verbal Learning Test; attention, Stroop Color-Word Test; processing speed, Letter Digit Substitution Test; general cognition, Mini-Mental State Examination). Longitudinal associations were assessed using linear mixed models. The risk for cognitive impairment, no dementia (CIND) was examined using logistic regression. RESULTS: Adjusting for age, sex, education, and baseline cognition, the rate of change in memory z-scores was 0.00, -0.11, -0.20, and -0.37 for those in the lowest (reference group), second, third, and highest depressive symptom quartiles at baseline, respectively (P<.001 for highest vs lowest quartile). The odds ratios for developing CIND with amnestic features were 1.00, 0.87, 0.69, and 2.98 for the four severity groups (P=.05 for highest vs lowest quartile). Associations were strongest for those with persistent depressive symptoms, defined as high depressive symptoms at baseline and at least one follow-up visit. Results were similar for processing speed and global cognitive function but were not as strong for attention. No APOE interaction was observed. CONCLUSION: Depression and APOE act independently to increase the risk for cognitive decline and may provide targets for prevention and early treatment.

Seeking verisimilitude in a class: a systematic review of evidence that the criterial clinical symptoms of schizophrenia are taxonic.

This review examines whether there is evidence that the criterion symptoms of Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) schizophrenia are taxonic--that schizophrenia is not part of a single distribution of normality. Two taxometric methods, coherent cut kinetics (CCK) and latent variable modeling (LVM), are demonstrated to be sensitive to latent classes and, therefore, were regarded as providing relevant statistical evidence. A systematic literature search identified 24 articles describing analyses of 28 participant cohorts in which CCK or LVM methods were used with one or more criterion symptoms of schizophrenia. Virtually all analyses yielded results that, on first impression, favored taxonic over dimensional interpretations of the latent structure of schizophrenia. However, threats to the internal and external validity of these studies--including biased or inadequate analyses, violation of statistical assumptions, inadequate indicator screening, and the introduction of systematic error through recruitment and sampling--critically undermine this body of work. Uncertainties about the potential effects of perceptual biases, unimodal assessment, and item parceling are also identified, as are limitations in seeking to validate classes with single or double dissociations of outcomes. We conclude that there is no reason to seriously doubt a single-distribution model of schizophrenia because there is no evidence that provides a serious test of this null hypothesis. A second fundamental question remains outstanding: is schizophrenia truly a group of schizophrenias, with taxonic divisions separating its types? We make design and analysis suggestions for future research addressing these questions.

Evidence that better outcome of psychosis in women is reversed with increasing age of onset: a population-based 5-year follow-up study.

BACKGROUND: Female gender and later onset of psychosis are both associated with better outcome. However whether their effects are independent, is not known. METHOD: In 379 incident cases of psychoses, from an epidemiologically defined catchment area, admixture analysis was employed to generate age of onset classes. Five year course and outcome measured across clinical and social domains were used as dependent variables in regression analyses, to estimate associations of outcomes with gender, age of onset and gender by age of onset interaction. RESULTS: Three age of onset classes were identified: early (14-41 years), late (42-64 years) and very late onset psychosis (65-94 years). Overall, women had better outcomes, including milder delusions, fewer negative symptoms, less deterioration from baseline functioning, fewer hospital readmissions and shorter psychotic episodes. Later age of onset was also associated with better outcome, although in the very late onset class the results were mixed. There was a statistically significant gender by age of onset interaction (in the ratio scale) within this sample with men displaying poorer outcome in the early/late onset class, whereas women tended to have a worse outcome in the very late onset class. CONCLUSIONS: The favourable outcome in women becomes reversed in old age, suggesting gender-age-related differences in the distribution of aetiological factors for psychosis.