Publications by authors named "Robin M Murray"

489 Publications

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Biol Psychiatry 2021 Mar 23. Epub 2021 Mar 23.

Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois; Department of Psychiatry and Behavioral Sciences, North Shore University Health System, Evanston, Illinois.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Results: Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).

Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.972DOI Listing
March 2021

Psychological trauma and the genetic overlap between posttraumatic stress disorder and major depressive disorder.

Psychol Med 2021 Jun 4:1-10. Epub 2021 Jun 4.

Social, Genetic and Developmental Psychiatry Centre; Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Background: Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are commonly reported co-occurring mental health consequences of psychological trauma exposure. The disorders have high genetic overlap. Trauma is a complex phenotype but research suggests that trauma sensitivity has a heritable basis. We investigated whether sensitivity to trauma in those with MDD reflects a similar genetic component in those with PTSD.

Methods: Genetic correlations between PTSD and MDD in individuals reporting trauma and MDD in individuals not reporting trauma were estimated, as well as with recurrent MDD and single-episode MDD, using genome-wide association study (GWAS) summary statistics. Genetic correlations were replicated using PTSD data from the Psychiatric Genomics Consortium and the Million Veteran Program. Polygenic risk scores were generated in UK Biobank participants who met the criteria for lifetime MDD (N = 29 471). We investigated whether genetic loading for PTSD was associated with reporting trauma in these individuals.

Results: Genetic loading for PTSD was significantly associated with reporting trauma in individuals with MDD [OR 1.04 (95% CI 1.01-1.07), Empirical-p = 0.02]. PTSD was significantly more genetically correlated with recurrent MDD than with MDD in individuals not reporting trauma (rg differences = ~0.2, p < 0.008). Participants who had experienced recurrent MDD reported significantly higher rates of trauma than participants who had experienced single-episode MDD (χ2 > 166, p < 0.001).

Conclusions: Our findings point towards the existence of genetic variants associated with trauma sensitivity that might be shared between PTSD and MDD, although replication with better powered GWAS is needed. Our findings corroborate previous research highlighting trauma exposure as a key risk factor for recurrent MDD.
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http://dx.doi.org/10.1017/S0033291721000830DOI Listing
June 2021

The Independent Effects of Psychosocial Stressors on Subclinical Psychosis: Findings From the Multinational EU-GEI Study.

Schizophr Bull 2021 May 19. Epub 2021 May 19.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.

The influence of psychosocial stressors on psychosis risk has usually been studied in isolation and after the onset of the disorder, potentially ignoring important confounding relationships or the fact that some stressors that may be the consequence of the disorder rather than preexisting. The study of subclinical psychosis could help to address some of these issues. In this study, we investigated whether there was (i) an association between dimensions of subclinical psychosis and several psychosocial stressors including: childhood trauma, self-reported discrimination experiences, low social capital, and stressful life experiences, and (ii) any evidence of environment-environment (ExE) interactions between these factors. Data were drawn from the EUGEI study, in which healthy controls (N = 1497) and siblings of subjects with a psychotic disorder (N = 265) were included in six countries. The association between psychosocial stressors and subclinical psychosis dimensions (positive, negative and depressive dimension as measured by the Community Assessment of Psychic Experiences (CAPE) scale) and possible ExE interactions were assessed using linear regression models. After adjusting for sex, age, ethnicity, country, and control/sibling status, childhood trauma (β for positive dimension: 0.13, negative: 0.49, depressive: 0.26) and stressful life events (positive: 0.08, negative: 0.16, depressive: 0.17) were associated with the three dimensions. Lower social capital was associated with the negative and depression dimensions (negative: 0.26, depressive: 0.13), and self-reported discrimination experiences with the positive dimension (0.06). Our findings are in favor of independent, cumulative and non-specific influences of social adversities in subclinical psychosis in non-clinical populations, without arguments for E × E interactions.
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http://dx.doi.org/10.1093/schbul/sbab060DOI Listing
May 2021

Adult outcome of preterm birth: Implications for neurodevelopmental theories of psychosis.

Schizophr Res 2021 May 15. Epub 2021 May 15.

Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, UK; Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Preterm birth is associated with an elevated risk of developmental and adult psychiatric disorders, including psychosis. In this review, we evaluate the implications of neurodevelopmental, cognitive, motor, and social sequelae of preterm birth for developing psychosis, with an emphasis on outcomes observed in adulthood. Abnormal brain development precipitated by early exposure to the extra-uterine environment, and exacerbated by neuroinflammation, neonatal brain injury, and genetic vulnerability, can result in alterations of brain structure and function persisting into adulthood. These alterations, including abnormal regional brain volumes and white matter macro- and micro-structure, can critically impair functional (e.g. frontoparietal and thalamocortical) network connectivity in a manner characteristic of psychotic illness. The resulting executive, social, and motor dysfunctions may constitute the basis for behavioural vulnerability ultimately giving rise to psychotic symptomatology. There are many pathways to psychosis, but elucidating more precisely the mechanisms whereby preterm birth increases risk may shed light on that route consequent upon early neurodevelopmental insult.
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http://dx.doi.org/10.1016/j.schres.2021.04.007DOI Listing
May 2021

Public health psychiatry: an idea whose time has come.

World Psychiatry 2021 Jun;20(2):222-223

Royal College of Surgeons of Ireland, Education & Research Centre, Beau-mont Hospital, Beaumont, Ireland.

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http://dx.doi.org/10.1002/wps.20868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129864PMC
June 2021

Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia.

Schizophr Bull 2021 May 14. Epub 2021 May 14.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy.
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http://dx.doi.org/10.1093/schbul/sbab052DOI Listing
May 2021

Duration of Untreated Psychosis in First-Episode Psychosis is not Associated With Common Genetic Variants for Major Psychiatric Conditions: Results From the Multi-Center EU-GEI Study.

Schizophr Bull 2021 May 8. Epub 2021 May 8.

Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy.

Duration of untreated psychosis (DUP) is associated with clinical outcomes in people with a diagnosis of first-episode psychosis (FEP), but factors associated with length of DUP are still poorly understood. Aiming to obtain insights into the possible biological impact on DUP, we report genetic analyses of a large multi-center phenotypically well-defined sample encompassing individuals with a diagnosis of FEP recruited from 6 countries spanning 17 research sites, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Genetic propensity was measured using polygenic scores for schizophrenia (SZ-PGS), bipolar disorder (BD-PGS), major depressive disorder (MDD-PGS), and intelligence (IQ-PGS), which were calculated based on the results from the most recent genome-wide association meta-analyses. Following imputation for missing data and log transformation of DUP to handle skewedness, the association between DUP and polygenic scores (PGS), adjusting for important confounders, was investigated with multivariable linear regression models. The sample comprised 619 individuals with a diagnosis of FEP disorders with a median age at first contact of 29.0 years (interquartile range [IQR] = 22.0-38.0). The median length of DUP in the sample was 10.1 weeks (IQR = 3.8-30.8). One SD increases in SZ-PGS, BD-PGS, MDD-PGS or IQ-PGS were not significantly associated with the length of DUP. Our results suggest that genetic variation does not contribute to the DUP in patients with a diagnosis of FEP disorders.
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http://dx.doi.org/10.1093/schbul/sbab055DOI Listing
May 2021

The relationship between cannabis and schizophrenia: a genetically informed perspective.

Addiction 2021 May 5. Epub 2021 May 5.

Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.

Background And Aims: While epidemiological studies support a role for heavy, high-potency cannabis use on first-episode psychosis, genetic models of causation suggest reverse causal effects of schizophrenia on cannabis use liability. We estimated the genetic relationship between cannabis use disorder (CUD) and schizophrenia (SCZ) and tested whether liability for CUD is causally associated with increased liability to SCZ while adjusting for tobacco smoking.

Design: This study used summary statistics from published genome-wide association studies (GWAS). We used genomic structural equation modeling, latent causal variable analysis, and multivariable Mendelian randomization to examine genetic relationships between CUD, cannabis ever-use, ever-smoked tobacco regularly, nicotine dependence and SCZ, and to test for a causal relationship between liability to CUD and liability to SCZ.

Setting: Genome-wide association studies were published previously as part of international consortia.

Participants: Sample sizes of the GWAS summary statistics used in this study ranged from 161 405 to 357 806 individuals of European ancestry.

Measurements: Genome-wide summary statistics for CUD and SCZ were the primary measurements, while summary statistics for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence were included as additional variables in the genomic structural equation models and the multivariable Mendelian randomization analyses.

Findings: Genetic liability to CUD was significantly associated with SCZ [β = 0.29, 95% confidence interval (CI) = 0.11, 0.46, P = 0.001], even when accounting for cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence as simultaneous predictors. We found mixed evidence of a causal relationship, with the latent causal variable analysis finding no evidence of causality (genetic causality proportion = -0.08, 95% CI = -0.40, 0.23, P = 0.87) but the multivariable Mendelian randomization analyses suggesting a significant, risk-increasing effect of CUD on liability to SCZ (β = 0.10, 95% CI = 0.02, 0.18, P = 0.02), accounting for the additional risk factors (cannabis ever-use, ever-smoked tobacco regularly and nicotine dependence).

Conclusions: Genetic liability for cannabis use disorder appears to be robustly associated with schizophrenia, above and beyond tobacco smoking and cannabis ever-use, with mixed evidence to support a causal relationship between cannabis use disorder and schizophrenia.
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http://dx.doi.org/10.1111/add.15534DOI Listing
May 2021

Structural Covariance of Cortical Gyrification at Illness Onset in Treatment Resistance: A Longitudinal Study of First-Episode Psychoses.

Schizophr Bull 2021 Apr 14. Epub 2021 Apr 14.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject's contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges's g = 2.09, P < .001) and a reduced clustering coefficient (Hedges's g = 1.07, P < .001) with increased length (Hedges's g = -2.17, P < .001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r = .41, P = .001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes.
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http://dx.doi.org/10.1093/schbul/sbab035DOI Listing
April 2021

Employment and relationship outcomes in first-episode psychosis: A systematic review and meta-analysis of longitudinal studies.

Schizophr Res 2021 05 8;231:122-133. Epub 2021 Apr 8.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom; Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Psychiatry, St Vincent's Hospital Fairview, Dublin, Ireland.

As employment and relationship status are important long-term outcomes in individuals with a diagnosis of first episode psychosis (FEP) disorders, there is a need to elucidate more accurately the extent of these social deficits in people with FEP. This in turn can aid treatment planning and policy development ultimately ensuring more complete and sustainable recoveries. We carried out a systematic review and meta-analysis of longitudinal studies in FEP reporting on employment and relationship status during the illness course. Random effects meta-analyses and meta-regression analyses were employed. Seventy-four studies were included with a sample totalling 15,272 (range = 20-1724) FEP cases with an average follow-up duration of 8.3 years (SD = 7.2). 32.5% (95%CI = 28.5-36.9) of people with a diagnosis of FEP disorders were employed and 21.3% (95%CI = 16.5-27.1) were in a relationship at the end of follow-up. Studies from high-income countries and Europe had a higher proportion of people in employment at the end of follow-up compared to middle-income nations and non-European countries. The inverse was found for relationship status. The proportion of people with a diagnosis of FEP in employment decreased significantly with longer follow-up. Living with family, being in a relationship at first contact and Black and White ethnicities were identified as significant moderators of these outcomes. These findings highlight marked functional recovery deficits for people with FEP, although cultural factors need to be considered. They support the need for interventions to improve employment opportunities, and social functioning, both in early psychosis and during the longitudinal illness course.
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http://dx.doi.org/10.1016/j.schres.2021.03.013DOI Listing
May 2021

Association Between Specific Childhood Adversities and Symptom Dimensions in People With Psychosis: Systematic Review and Meta-Analysis.

Schizophr Bull 2021 Jul;47(4):975-985

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Despite the accepted link between childhood abuse and positive psychotic symptoms, findings between other adversities, such as neglect, and the remaining dimensions in people with psychosis have been inconsistent, with evidence not yet reviewed quantitatively. The aim of this study was to systematically examine quantitatively the association between broadly defined childhood adversity (CA), abuse (sexual/physical/emotional), and neglect (physical/emotional) subtypes, with positive, negative, depressive, manic, and disorganized dimensions in those with psychosis. A search was conducted across EMBASE, MEDLINE, PsychINFO, and Cochrane Libraries using search terms related to psychosis population, CA, and psychopathological dimensions. After reviewing for relevance, data were extracted, synthesized, and meta-analyzed. Forty-seven papers were identified, including 7379 cases across 40 studies examining positive, 37 negative, 20 depressive, 9 disorganized, and 13 manic dimensions. After adjustment for publication bias, general adversity was positively associated with all dimensions (ranging from r = 0.08 to r = 0.24). Most forms of abuse were associated with depressive (ranging from r = 0.16 to r = 0.32), positive (ranging from r = 0.14 to r = 0.16), manic (r = 0.13), and negative dimensions (ranging from r = 0.05 to r = 0.09), while neglect was only associated with negative (r = 0.13) and depressive dimensions (ranging from r = 0.16 to r = 0.20). When heterogeneity was found, it tended to be explained by one specific study. The depressive dimension was influenced by percentage of women (ranging from r = 0.83 to r = 1.36) and poor-quality scores (ranging from r = -0.21 and r = -0.059). Quality was judged as fair overall. Broadly defined adversity and forms of abuse increase transdimensional severity. Being exposed to neglect during childhood seems to be exclusively related to negative and depressive dimensions suggesting specific effects.
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http://dx.doi.org/10.1093/schbul/sbaa199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266673PMC
July 2021

A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse.

Schizophr Bull 2021 Jul;47(4):1116-1129

Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, Camberwell, London SE5 8AF, UK.

The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations to antipsychotic exposure can persist for months or years after stopping the medication-from animal studies, observation of tardive dyskinesia in patients, and the clustering of relapses in this time period after the cessation of antipsychotics. Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade. We, therefore, suggest that when antipsychotics are reduced, it should be done gradually (over months or years) and in a hyperbolic manner (to reduce D2 blockade "evenly"): ie, reducing by one quarter (or one half) of the most recent dose of antipsychotic, equivalent approximately to a reduction of 5 (or 10) percentage points of its D2 blockade, sequentially (so that reductions become smaller and smaller in size as total dose decreases), at intervals of 3-6 months, titrated to individual tolerance. Some patients may prefer to taper at 10% or less of their most recent dose each month. This process might allow underlying adaptations time to resolve, possibly reducing the risk of relapse on discontinuation. Final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a large decrease in D2 blockade when stopped. This proposal should be tested in randomized controlled trials.
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http://dx.doi.org/10.1093/schbul/sbab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266572PMC
July 2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Transl Psychiatry 2021 03 22;11(1):182. Epub 2021 Mar 22.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
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http://dx.doi.org/10.1038/s41398-021-01213-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985307PMC
March 2021

First-episode Psychosis and Migration in Italy: Results from a Study in the Italian Mental Health Services (Pep-Ita Study).

J Immigr Minor Health 2021 Jun 10;23(3):519-527. Epub 2021 Mar 10.

Department of Mental Health and Pathological Addiction, Local Health Authority, Bologna, Italy.

Background: Migrants present high rates of psychosis. A better understanding of this phenomenon is needed.

Methods: We conducted a multicentre First-Episode Psychosis (FEP) prospective study over two years (January 2012-December 2013) to evaluate first-generation migrants presenting with FEP at the participating Community Mental Health Centers (CMHCs).

Results: 109 FEP migrants were identified. Almost half of them were highly educated, employed and in a stable affective relationship. The average age was 32.8 (± 9.8) years, and the average length of stay in Italy was 8.6 (± 8.8) years. About 2/3 of patients were referred to CMHCs following Emergency Department access or psychiatric admission.

Conclusions: Our finding of a "high functioning portrait" of FEP migrants allow us to hypothesize that a high burden of negative psychosocial factors is likely to be needed for the FEP onset. Furtherly, mental health services should implement more appropriate resources and organizational methods to respond to migrants' health needs.
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http://dx.doi.org/10.1007/s10903-021-01168-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068695PMC
June 2021

Perceived major experiences of discrimination, ethnic group, and risk of psychosis in a six-country case-control study.

Psychol Med 2021 Mar 2:1-9. Epub 2021 Mar 2.

Department of Psychiatry, University of Cambridge, CambridgeCB2 0SZ, UK.

Background: Perceived discrimination is associated with worse mental health. Few studies have assessed whether perceived discrimination (i) is associated with the risk of psychotic disorders and (ii) contributes to an increased risk among minority ethnic groups relative to the ethnic majority.

Methods: We used data from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 2, a population-based case-control study of incident psychotic disorders in 17 catchment sites across six countries. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between perceived discrimination and psychosis using mixed-effects logistic regression models. We used stratified and mediation analyses to explore differences for minority ethnic groups.

Results: Reporting any perceived experience of major discrimination (e.g. unfair treatment by police, not getting hired) was higher in cases than controls (41.8% v. 34.2%). Pervasive experiences of discrimination (≥3 types) were also higher in cases than controls (11.3% v. 5.5%). In fully adjusted models, the odds of psychosis were 1.20 (95% CI 0.91-1.59) for any discrimination and 1.79 (95% CI 1.19-1.59) for pervasive discrimination compared with no discrimination. In stratified analyses, the magnitude of association for pervasive experiences of discrimination appeared stronger for minority ethnic groups (OR = 1.73, 95% CI 1.12-2.68) than the ethnic majority (OR = 1.42, 95% CI 0.65-3.10). In exploratory mediation analysis, pervasive discrimination minimally explained excess risk among minority ethnic groups (5.1%).

Conclusions: Pervasive experiences of discrimination are associated with slightly increased odds of psychotic disorders and may minimally help explain excess risk for minority ethnic groups.
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http://dx.doi.org/10.1017/S0033291721000453DOI Listing
March 2021

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

Elife 2021 Feb 26;10. Epub 2021 Feb 26.

Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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http://dx.doi.org/10.7554/eLife.58430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009672PMC
February 2021

Migration history and risk of psychosis: results from the multinational EU-GEI study.

Psychol Med 2021 Feb 10:1-13. Epub 2021 Feb 10.

Univ Paris Est Creteil (UPEC), AP-HP, Hôpitaux Universitaires « H. Mondor », DMU IMPACT, INSERM, IMRB, Fondation FondaMental, F-94010Creteil, France.

Background: Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration.

Methods: We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models.

Results: In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06-2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02-3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03-1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672-2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose-response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06-96.47, p = 0.007).

Conclusions: The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants.
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http://dx.doi.org/10.1017/S003329172000495XDOI Listing
February 2021

Rethinking the course of psychotic disorders: modelling long-term symptom trajectories.

Psychol Med 2021 Feb 4:1-10. Epub 2021 Feb 4.

ESRC Centre for Society and Mental Health, Institute of Psychiatry, Psychology, and Neuroscience, King's College, London, UK.

Background: The clinical course of psychotic disorders is highly variable. Typically, researchers have captured different course types using broad pre-defined categories. However, whether these adequately capture symptom trajectories of psychotic disorders has not been fully assessed. Using data from AESOP-10, we sought to identify classes of individuals with specific symptom trajectories over a 10-year follow-up using a data-driven approach.

Method: AESOP-10 is a follow-up, at 10 years, of 532 incident cases with a first episode of psychosis initially identified in south-east London and Nottingham, UK. Using extensive information on fluctuations in the presence of psychotic symptoms, we fitted growth mixture models to identify latent trajectory classes that accounted for heterogeneity in the patterns of change in psychotic symptoms over time.

Results: We had sufficient data on psychotic symptoms during the follow-up on 326 incident patients. A four-class quadratic growth mixture model identified four trajectories of psychotic symptoms: (1) remitting-improving (58.5%); (2) late decline (5.6%); (3) late improvement (5.4%); (4) persistent (30.6%). A persistent trajectory, compared with remitting-improving, was associated with gender (more men), black Caribbean ethnicity, low baseline education and high disadvantage, low premorbid IQ, a baseline diagnosis of non-affective psychosis and long DUP. Numbers were small, but there were indications that those with a late decline trajectory more closely resembled those with a persistent trajectory.

Conclusion: Our current approach to categorising the course of psychotic disorders may misclassify patients. This may confound efforts to elucidate the predictors of long-term course and related biomarkers.
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http://dx.doi.org/10.1017/S0033291720004705DOI Listing
February 2021

Investigating the effects of genetic risk of schizophrenia on behavioural traits.

NPJ Schizophr 2021 Jan 22;7(1). Epub 2021 Jan 22.

SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

To characterise the trait-effects of increased genetic risk for schizophrenia, and highlight potential risk mediators, we test the association between schizophrenia polygenic risk scores (PRSs) and 529 behavioural traits (personality, psychological, lifestyle, nutritional) in the UK Biobank. Our primary analysis is performed on individuals aged 38-71 with no history of schizophrenia or related disorders, allowing us to report the effects of schizophrenia genetic risk in the sub-clinical general population. Higher schizophrenia PRSs were associated with a range of traits, including lower verbal-numerical reasoning (P = 6 × 10), higher nervous feelings (P = 1 × 10) and higher self-reported risk-taking (P = 3 × 10). We follow-up the risk-taking association, hypothesising that the association may be due to a genetic propensity for risk-taking leading to greater migration, urbanicity or drug-taking - reported environmental risk factors for schizophrenia, and all positively associated with risk-taking in these data. Next, to identify potential disorder or medication effects, we compare the PRS-trait associations in the general population to the trait values in 599 medicated and non-medicated individuals diagnosed with schizophrenia in the biobank. This analysis highlights, for example, levels of BMI, physical activity and risk-taking in cases in the opposite directions than expected from the PRS-trait associations in the general population. Our analyses offer simple yet potentially revealing insights into the possible causes of observed trait-disorder associations, which can complement approaches such as Mendelian Randomisation. While we urge caution in causal interpretations in PRS cross-trait studies that are highly powered to detect weak horizontal pleiotropy or population structure, we propose that well-designed polygenic score analyses have the potential to highlight modifiable risk factors that lie on the path between genetic risk and disorder.
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http://dx.doi.org/10.1038/s41537-020-00131-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822841PMC
January 2021

Environmental Risk Factors in Bipolar Disorder and Psychotic Depression: A Systematic Review and Meta-Analysis of Prospective Studies.

Schizophr Bull 2021 Jul;47(4):959-974

Social, Genetics and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Objective: The aim of this systematic review and meta-analysis was to study the association between specific environmental risk factors (ERF) and later development of Bipolar disorder and Psychotic depression.

Methods: A systematic search of prospective studies was conducted in MEDLINE, EMBASE and PsycINFO databases, and supplemented by hand searching, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (registration number: CRD42018092253). Selected ERF included: pre-/peri-natal factors-paternal age at birth, maternal infection, obstetric complications, perinatal stress; early childhood factors-urbanicity at birth, childhood infection, childhood adversity; later life factors-substance misuse, ethnic minority and migration, urbanicity later in life, stressful life events, and traumatic head injury. Pooled effect sizes of the association between these ERF and affective psychoses were calculated from systematically selected studies. When studies examining each ERF were insufficient for meta-analysis, results were presented narratively.

Results: Forty-six studies were included for quantitative analyses among selected ERF for affective psychosis, with significant association found for paternal age >40 years (OR 1.17, 95%CI 1.12-1.23), early (OR 1.52, 95%CI 1.07-2.17) and late (OR 1.32, 95%CI 1.05-1.67) gestational age, childhood adversity (OR 1.33, 95%CI 1.18-1.50), substance misuse (OR 2.87, 95%CI 1.63-5.50), and being from an ethnic minority (OR 1.99, 95%CI 1.39-2.84).

Conclusions: These results suggest some shared environmental load between non-affective and affective psychosis, implying generalized risks for psychosis rather than for specific diagnostic categories. Nonetheless, published studies for some ERF in the affective psychoses are scarce, and further longitudinal studies are needed.
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http://dx.doi.org/10.1093/schbul/sbaa197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266635PMC
July 2021

The clinical characterization of the patient with primary psychosis aimed at personalization of management.

World Psychiatry 2021 Feb;20(1):4-33

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.

The current management of patients with primary psychosis worldwide is often remarkably stereotyped. In almost all cases an antipsychotic medica-tion is prescribed, with second-generation antipsychotics usually preferred to first-generation ones. Cognitive behavioral therapy is rarely used in the vast majority of countries, although there is evidence to support its efficacy. Psychosocial interventions are often provided, especially in chronic cases, but those applied are frequently not validated by research. Evidence-based family interventions and supported employment programs are seldom implemented in ordinary practice. Although the notion that patients with primary psychosis are at increased risk for cardiovascular diseases and diabetes mellitus is widely shared, it is not frequent that appropriate measures be implemented to address this problem. The view that the management of the patient with primary psychosis should be personalized is endorsed by the vast majority of clinicians, but this personalization is lacking or inadequate in most clinical contexts. Although many mental health services would declare themselves "recovery-oriented", it is not common that a focus on empowerment, identity, meaning and resilience is ensured in ordinary practice. The present paper aims to address this situation. It describes systematically the salient domains that should be considered in the characterization of the individual patient with primary psychosis aimed at personalization of management. These include positive and negative symptom dimensions, other psychopathological components, onset and course, neurocognition and social cognition, neurodevelopmental indicators; social functioning, quality of life and unmet needs; clinical staging, antecedent and concomitant psychiatric conditions, physical comorbidities, family history, history of obstetric complications, early and recent environmental exposures, protective factors and resilience, and internalized stigma. For each domain, simple assessment instruments are identified that could be considered for use in clinical practice and included in standardized decision tools. A management of primary psychosis is encouraged which takes into account all the available treatment modalities whose efficacy is supported by research evidence, selects and modulates them in the individual patient on the basis of the clinical characterization, addresses the patient's needs in terms of employment, housing, self-care, social relationships and education, and offers a focus on identity, meaning and resilience.
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http://dx.doi.org/10.1002/wps.20809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801854PMC
February 2021

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

Department of Psychiatry, Dokuz Eylül University, School of Medicine, Izmir, Turkey.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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http://dx.doi.org/10.1038/s41380-020-00969-zDOI Listing
January 2021

Development and validation of prediction model to estimate 10-year risk of all-cause mortality using modern statistical learning methods: a large population-based cohort study and external validation.

BMC Med Res Methodol 2021 01 6;21(1). Epub 2021 Jan 6.

Department of Behavioural Science and Health, Institute of Epidemiology and Health Care, University College London, London, UK.

Background: In increasingly ageing populations, there is an emergent need to develop a robust prediction model for estimating an individual absolute risk for all-cause mortality, so that relevant assessments and interventions can be targeted appropriately. The objective of the study was to derive, evaluate and validate (internally and externally) a risk prediction model allowing rapid estimations of an absolute risk of all-cause mortality in the following 10 years.

Methods: For the model development, data came from English Longitudinal Study of Ageing study, which comprised 9154 population-representative individuals aged 50-75 years, 1240 (13.5%) of whom died during the 10-year follow-up. Internal validation was carried out using Harrell's optimism-correction procedure; external validation was carried out using Health and Retirement Study (HRS), which is a nationally representative longitudinal survey of adults aged ≥50 years residing in the United States. Cox proportional hazards model with regularisation by the least absolute shrinkage and selection operator, where optimisation parameters were chosen based on repeated cross-validation, was employed for variable selection and model fitting. Measures of calibration, discrimination, sensitivity and specificity were determined in the development and validation cohorts.

Results: The model selected 13 prognostic factors of all-cause mortality encompassing information on demographic characteristics, health comorbidity, lifestyle and cognitive functioning. The internally validated model had good discriminatory ability (c-index=0.74), specificity (72.5%) and sensitivity (73.0%). Following external validation, the model's prediction accuracy remained within a clinically acceptable range (c-index=0.69, calibration slope β=0.80, specificity=71.5% and sensitivity=70.6%). The main limitation of our model is twofold: 1) it may not be applicable to nursing home and other institutional populations, and 2) it was developed and validated in the cohorts with predominately white ethnicity.

Conclusions: A new prediction model that quantifies absolute risk of all-cause mortality in the following 10-years in the general population has been developed and externally validated. It has good prediction accuracy and is based on variables that are available in a variety of care and research settings. This model can facilitate identification of high risk for all-cause mortality older adults for further assessment or interventions.
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http://dx.doi.org/10.1186/s12874-020-01204-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789636PMC
January 2021

Schizophrenia polygenic risk predicts general cognitive deficit but not cognitive decline in healthy older adults.

Transl Psychiatry 2020 12 8;10(1):422. Epub 2020 Dec 8.

Department of Behavioural Science and Health, Institute of Epidemiology and Health Care, University College London, London, UK.

There has been a long argument over whether schizophrenia is a neurodegenerative disorder associated with progressive cognitive impairment. Given high heritability of schizophrenia, ascertaning if genetic susceptibility to schizophrenia is also associated with cognitive decline in healthy people would support the view that schizophrenia leads to an accelerated cognitive decline. Using the population representative sample of 6817 adults aged >50 years from the English Longitudinal Study of Ageing, we investigated associations between the biennial rate of decline in cognitive ability and the schizophrenia polygenic score (SZ-PGS) during the 10-year follow-up period. SZ-PGS was calculated based on summary statistics from the Schizophrenia Working Group of the Psychiatric Genomics Consortium. Cognition was measured sequentially across four time points using verbal memory and semantic fluency tests. The average baseline verbal memory was 10.4 (SD = 3.4) and semantic fluency was 20.7 (SD = 6.3). One standard deviation (1-SD) increase in SZ-PGS was associated with lower baseline semantic fluency (β = -0.25, 95%CI = -0.40 to -0.10, p = 0.002); this association was significant in men (β = -0.36, 95%CI = -0.59 to -0.12, p = 0.003) and in those who were aged 60-69 years old (β = -0.32, 95%CI = -0.58 to -0.05, p = 0.019). Similarly, 1-SD increase in SZ-PGS was associated with lower verbal memory score at baseline in men only (β = -0.12, 95%CI = -0.23 to -0.01, p = 0.040). However, SZ-PGS was not associated with a greater rate of decline in these cognitive domains during the 10-year follow-up. Our findings highlight that while genetic susceptibility to schizophrenia conveys developmental cognitive deficit, it is not associated with an ongoing cognitive decline, at least in later life. These results do not support the neo-Kraepelinian notion of schizophrenia as a genetically determined progressively deteriorating brain disease.
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http://dx.doi.org/10.1038/s41398-020-01114-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722936PMC
December 2020

Listening to our critics; the care of people with psychosis.

Authors:
Robin M Murray

Psychol Med 2020 12 7;50(16):2641-2642. Epub 2020 Dec 7.

Institute of Psychiatry, Denmark Hill, London, UK.

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http://dx.doi.org/10.1017/S0033291720004341DOI Listing
December 2020

Cannabis points to the synaptic pathology of mental disorders: how aberrant synaptic components disrupt the highest psychological functions
.

Dialogues Clin Neurosci 2020 09;22(3):251-258

The Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Cannabis can elicit an acute psychotic reaction, and its long-term use is a risk factor for schizophrenia. The main active psychoactive ingredient ∆-tetrahydrocannabinol (Δ-THC) activates cannabinoid 1 (CB1) receptors, which are localized to the terminals of glutamate and GABA neurons in the brain. The endogenous cannabinoids are involved in information processing and plasticity at synapses in the hippocampus, basal ganglia, and cerebral cortex. Exogenously applied CB receptor agonists disrupt neuronal dynamics and synaptic plasticity, resulting in cognitive deficits and impairment of the highest psychological functions. Various other pro-psychotic drugs, such as ketamine and methamphetamine, exert their effects in the same microdomain of synaptic spines as Δ-THC. Additionally, many of the most robust findings in psychiatric genetics include components that localize to dendritic spines and have important roles in information processing and plasticity.
.
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http://dx.doi.org/10.31887/DCNS.2020.22.3/pmorrisonDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605021PMC
September 2020

Predicting onset of early- and late-treatment resistance in first-episode schizophrenia patients using advanced shrinkage statistical methods in a small sample.

Psychiatry Res 2020 12 21;294:113527. Epub 2020 Oct 21.

Department of Biostatistics & Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.

Evidence suggests there are two treatment-resistant schizophrenia subtypes (i.e. early treatment resistant (E-TR) and late-treatment resistant (L-TR)). We aimed to develop prediction models for estimating individual risk for these outcomes by employing advanced statistical shrinkage methods. 239 first-episode schizophrenia (FES) patients were followed-up for approximately 5 years after first presentation to psychiatric services; of these, n=56 (25.2%) were defined as E-TR and n=24 (12.6%) were defined as L-TR. Using known risk factors for poor schizophrenia outcomes, we developed prediction models for E-TR and L-TR using LASSO and RIDGE logistic regression models. Models' internal validation was performed employing Harrell's optimism-correction with repeated cross-validation; their predictive accuracy was assessed through discrimination and calibration. Both LASSO and RIDGE models had high discrimination, good calibration. While LASSO had moderate sensitivity for estimating an individual risk for E-TR and L-TR, sensitivity estimated for RIDGE model for these outcomes was extremely low, which was due to having a very large estimated optimism. Although it was possible to discriminate with sufficient accuracy who would meet criteria for E-TR and L-TR during the 5-year follow-up after first contact with mental health services for schizophrenia, further work is necessary to improve sensitivity for these models.
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http://dx.doi.org/10.1016/j.psychres.2020.113527DOI Listing
December 2020

Individualized prediction of 2-year risk of relapse as indexed by psychiatric hospitalization following psychosis onset: Model development in two first episode samples.

Schizophr Res 2021 02 14;228:483-492. Epub 2020 Oct 14.

Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; South London and Maudsley NHS Foundation Trust, Denmark Hill, Camberwell, London, UK.

Background: Although most patients with psychotic disorders experience relapse, it is not possible to predict whether or when an individual patient is going to relapse. We aimed to develop a multifactorial risk prediction algorithm for predicting risk of relapse in first episode psychosis (FEP).

Methods: Data from two prospectively collected cohorts of FEP patients (N = 1803) were used to develop three multiple logistic prediction models to predict risk of relapse (defined as hospitalization) within the first 2 years of onset of psychosis. Model 1 (M1) used data obtained from clinical notes (Sample 1) while model 2 (M2) applied the same set of predictors using data obtained from research interviews (Sample 2). The final model (Sample 2: M3) used the same predictors plus additional detailed information on predictors. Model performance was evaluated employing measures of overall accuracy, calibration, discrimination and internal validation.

Results: In both samples, the 2-year probability of psychiatric hospitalization was 37%. Of all the models, discrimination accuracy was lowest when limited information (such as socio-demographic and clinical parameters) was included in the prediction model. Model M3 using additional information (descriptors of pattern of cannabis, nicotine, alcohol and other illicit drug use) obtained from research interview had the best discrimination accuracy (Harrell's C index 0.749).

Conclusions: The measures that contributed most to predicting hospitalization are readily accessible in routine clinical practice, suggesting that a risk prediction tool based on these models would be clinically practicable following validation in independent samples and permit a personalized approach to relapse prevention in psychosis.
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http://dx.doi.org/10.1016/j.schres.2020.09.016DOI Listing
February 2021

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder.

Hum Brain Mapp 2020 Oct 7. Epub 2020 Oct 7.

Neuroscience Research Australia, Sydney, Australia.

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = -0.42, p = 3 × 10 ), with weak evidence of IQ reductions among BD-FDRs (d = -0.23, p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
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http://dx.doi.org/10.1002/hbm.25206DOI Listing
October 2020

Diagnostic stability and outcome after first episode psychosis.

J Ment Health 2021 Feb 22;30(1):104-112. Epub 2020 Sep 22.

King's College London, Health Services and Population Research Department, Institute of Psychiatry, Psychology & Neuroscience, London, UK.

Background: Individuals diagnosed with schizophrenia are often assigned other psychiatric diagnoses during their lives. The significance of changing diagnosis has not been widely studied.

Aims: Our aim was to examine the association between diagnostic change and later outcome.

Methods: Individuals' diagnostic history, clinical and social outcomes were extracted from the AESOP-10 study, a 10-year follow-up of first episode psychosis cases. The association between outcome and different patterns of diagnosis over time were assessed using linear or logistic regression.

Results: Individuals always diagnosed with schizophrenia ( = 136) had worse clinical and social outcomes at follow-up than those never diagnosed with schizophrenia ( = 163), being more likely to be symptomatic, unemployed, single, and socially isolated. There was no difference in outcome between individuals always diagnosed with schizophrenia and those changing to a diagnosis of schizophrenia ( = 60), and no difference in outcome between individuals never diagnosed with schizophrenia, and those changing from a diagnosis of schizophrenia ( = 44).

Conclusions: Individuals always and never diagnosed with schizophrenia had different outcomes. In cases of diagnostic instability participants had similar outcomes to those always assigned the diagnosis they changed to irrespective of initial diagnosis.
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http://dx.doi.org/10.1080/09638237.2020.1818191DOI Listing
February 2021