Clinical phenotypes of depressed patients with evidence of inflammation and somatic symptoms.

Funder: MQ: Transforming Mental Health; Grant(s): MQDS17\40, MQDS17/40Whether depressed patients with evidence of inflammation are more appropriate candidates for immunotherapies is being tested in several clinical trials, which are selecting patients based on elevated C-reactive protein (CRP) and inflammation-related symptoms. However, studies of the clinical and phenotypic profile of depressed patients with elevated CRP are relatively scarce. We have investigated detailed clinical characteristics of 84 depressed patients, grouped as those with (CRP≥3 mg/L) and without (CRP<3 mg/L) inflammation. All patients met the International Classification of Diseases 10th Revision criteria for current depressive episode and had somatic symptoms of depression. We report that depressed patients with inflammation are more likely to be older (P=0.04), have higher body mass index (P<0.01), and be on non-selective serotonin reuptake inhibitor anti-depressants (P=0.04). After adjusting for potential confounders, the inflammation group had higher depression severity (adjusted mean difference, 8.82; 95% CI, 3.91-13.72), somatic symptoms (adjusted mean difference, 3.25; 95% CI, 1.58-4.92), state anxiety (adjusted mean difference, 9.25; 95% CI, 3.82-14.67), perceived stress (adjusted mean difference, 4.58; 95% CI, 1.98-7.18), and fatigue (adjusted mean difference, 9.71; 95% CI, 3.09-6.33), but not anhedonia. The inflamed group also had poorer quality of life (adjusted mean difference, -0.18; 95% CI, -0.32-0.05). At individual depressive symptom level, the inflammation group had increased guilty feelings (adjusted odds ratio [OR], 7.28; 95% CI, 2.09-31.17), pessimism (adjusted OR, 5.38; 95% CI, 1.53-22.73), concentration difficulties (adjusted OR, 4.56; 95% CI, 1.32-19.02), and indecisiveness (adjusted OR, 4.21; 95% CI, 1.15-18.54). Our findings highlight the clinical features associated with inflammation in depressed patients with somatic symptoms, including poor quality of life, supporting the need for intervention targeting this group. These results could also aid patient and outcome selection in future clinical trials testing immunotherapies in depression. Replication of these findings in larger samples is required.This work was funded by a Wellcome Trust fellowship to GMK (grant code: 201486/Z/16/Z). GMK also acknowledges funding support from Cambridgeshire and Peterborough NHS Foundation Trust R&D Department (Grant code: G101481), the BMA Foundation (J Moulton grant 2019); the MQ: Transforming Mental Health (grant code: MQDS17/40); and the Medical Research Council UK (grant codes: MC_PC_17213 and MR/S037675/1). The BMA Foundation J Moulton grant supports ÉMF and the MRC grant MC_PC_17213 supports JTP. NK is supported by the International Max Planck Research School of Translational Psychiatry (IMPRS-TP). The funding sources had no role in study design; collection, analysis, and interpretation of data; writing of the report; and the decision to submit the paper for publication

Adapting the randomised controlled trial (RCT) for precision medicine: introducing the nested-precision RCT (npRCT)

Adaptations to the gold standard randomised controlled trial (RCT) have been introduced to decrease trial costs and avoid high sample sizes. To facilitate development of precision medicine algorithms that aim to optimise treatment allocation for individual patients, we propose a new RCT adaptation termed the nested-precision RCT (npRCT). The npRCT combines a traditional RCT (intervention A versus B) with a precision RCT (stratified versus randomised allocation to A or B). This combination allows online development of a precision algorithm, thus providing an integrated platform for algorithm development and its testing. Moreover, as both the traditional and the precision RCT include participants randomised to interventions of interest, data from these participants can be jointly analysed to determine the comparative effectiveness of intervention A versus B, thus increasing statistical power. We quantify savings of the npRCT compared to two independent RCTs by highlighting sample size requirements for different target effect sizes and by introducing an open-source power calculation app. We describe important practical considerations such as blinding issues and potential biases that need to be considered when designing an npRCT. We also highlight limitations and research contexts that are less suited for an npRCT. In conclusion, we introduce the npRCT as a novel precision medicine trial design strategy which may provide one opportunity to efficiently combine traditional and precision RCTs

Systemic Inflammation and Intelligence in Early Adulthood and Subsequent Risk of Schizophrenia and Other Non-Affective Psychoses: A Longitudinal Cohort and Co-Relative Study

Background Schizophrenia is associated with impaired neurodevelopment as indexed by lower premorbid IQ. We examined associations between erythrocyte sedimentation rate (ESR), a marker of low-grade systemic inflammation, IQ, and subsequent schizophrenia and other non-affective psychoses (ONAP) to elucidate the role of neurodevelopment and inflammation in pathogenesis of psychosis. Methods Population-based data on ESR and IQ from 638213 Swedish men assessed during military conscription between 1969 and 1983 were linked to National Hospital Discharge Register for hospitalisation with schizophrenia and ONAP. The associations of ESR with IQ (cross-sectional) and psychoses (longitudinal) were investigated using linear and Cox-regression. Co-relative analysis was used to examine effects of shared familial confounding. We examined mediation and moderation of effect between ESR and IQ on psychosis risk. Results Baseline IQ was associated with subsequent risk of schizophrenia (adjusted HR per 1-point increase in IQ=0.961; 95% CI: 0.960-0.963) and ONAP (adjusted HR=0.973; 95% CI: 0.971-0.975). Higher ESR was associated with lower IQ in a dose-response fashion. High ESR was associated with increased risk for schizophrenia (adjusted HR=1.14; 95% CI: 1.01-1.28) and decreased risk for ONAP (adjusted HR=0.85; 95% CI: 0.74-0.96), although these effects were specific to one ESR band (7-10mm/hr). Familial confounding explained ESR-IQ but not ESR-psychoses associations. IQ partly mediated the ESR-psychosis relationships. Conclusions Lower IQ is associated with low-grade systemic inflammation and with increased risk of schizophrenia and ONAP in adulthood. Low-grade inflammation may influence schizophrenia risk by affecting neurodevelopment. Future studies should explore the differential effects of inflammation on different types of psychosis.The authors have no financial interests to disclose with regard to the content of this study. PBJ received an honorarium, that he donated to his department, from Roche (UK) for taking part in an advisory board to advise on education about schizophrenia for psychiatrists. GMK is supported by an Intermediate Clinical Fellowship from the Wellcome Trust (201486/Z/16/Z) and a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (grant no. 80354). PBJ acknowledges grant support from the Wellcome Trust (095844/Z/11/Z & 088869/Z/09/Z) and NIHR (RP-PG-0616-20003, Cambridge Biomedical Research Centre and CLAHRC East of England). HK acknowledges support from the Stanley Medical Research Institute. The funding bodies had no role in design, conduct, analysis or reporting of this study

Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms: A Genetic Correlation and 2-Sample Mendelian Randomization Study.

IMPORTANCE: Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin 6 (IL-6), a cytokine-stimulating CRP production, with individual depressive symptoms. However, it is unclear whether inflammatory activity is associated with individual depressive symptoms and to what extent metabolic dysregulation underlies the reported associations. OBJECTIVE: To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms. GWAS DATA SOURCES: Genome-wide association study (GWAS) summary data of European individuals, including the following: CRP levels (204 402 individuals); 9 individual depressive symptoms (3 of which did not differentiate between underlying diametrically opposite symptoms [eg, insomnia and hypersomnia]) as measured with the Patient Health Questionnaire 9 (up to 117 907 individuals); summary statistics for major depression, including and excluding UK Biobank participants, resulting in sample sizes of 500 199 and up to 230 214 individuals, respectively; insomnia (up to 386 533 individuals); body mass index (BMI) (up to 322 154 individuals); and height (up to 253 280 individuals). DESIGN: In this genetic correlation and 2-sample mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer single-nucleotide variant-based heritability and genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with CRP levels, IL-6 signaling, and BMI with depressive symptoms. The study dates were November 2019 to April 2020. RESULTS: Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)-controlled associations (genetic correlation range, 0.152-0.362; FDR P = .006 to P < .001) between CRP levels and depressive symptoms that were similar in size to genetic correlations of BMI with depressive symptoms. Two-sample MR analyses suggested that genetic upregulation of IL-6 signaling was associated with suicidality (estimate [SE], 0.035 [0.010]; FDR plus Bonferroni correction P = .01), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. Mendelian randomization analyses did not consistently show associations of higher CRP levels or IL-6 signaling with other depressive symptoms, but higher BMI was associated with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. CONCLUSIONS AND RELEVANCE: This study reports coheritability between CRP levels and individual depressive symptoms, which may result from the potentially causal association of metabolic dysregulation with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. The study also found that IL-6 signaling is associated with suicidality. These findings may have clinical implications, highlighting the potential of anti-inflammatory approaches, especially IL-6 blockade, as a putative strategy for suicide prevention.Wellcome Trust (grant code: 201486/Z/16/Z

Association of Childhood Infection With IQ and Adult Nonaffective Psychosis in Swedish Men: A Population-Based Longitudinal Cohort and Co-relative Study.

Importance: Associations between childhood infection, IQ, and adult nonaffective psychosis (NAP) are well established. However, examination of sensitive periods for exposure, effect of familial confounding, and whether IQ provides a link between childhood infection and adult NAP may elucidate pathogenesis of psychosis further. Objectives: To test the association of childhood infection with IQ and adult NAP, to find whether shared familial confounding explains the infection-NAP and IQ-NAP associations, and to examine whether IQ mediates and/or moderates the childhood infection-NAP association. Design, Setting, and Participants: Population-based longitudinal cohort study using linkage of Swedish national registers. The risk set included all Swedish men born between 1973 and 1992 and conscripted into the military until the end of 2010 (n = 771 698). We included 647 515 participants in the analysis. Measurement of Exposures: Hospitalization with any infection from birth to age 13 years. Main Outcomes and Measures: Hospitalization with an International Classification of Diseases diagnosis of NAP until the end of 2011. At conscription around age 18 years, IQ was assessed for all participants. Results: At the end of follow-up, the mean (SD) age of participants was 30.73 (5.3) years. Exposure to infections, particularly in early childhood, was associated with lower IQ (adjusted mean difference for infection at birth to age 1 year: -1.61; 95% CI, -1.74 to -1.47) and with increased risk of adult NAP (adjusted hazard ratio for infection at birth to age 1 year: 1.19; 95% CI, 1.06 to 1.33). There was a linear association between lower premorbid IQ and adult NAP, which persisted after excluding prodromal cases (adjusted hazard ratio per 1-point increase in IQ: 0.976; 95% CI, 0.974 to 0.978). The infection-NAP and IQ-NAP associations were similar in the general population and in full-sibling pairs discordant for exposure. The association between infection and NAP was both moderated (multiplicative, β = .006; SE = 0.002; P = .02 and additive, β = .008; SE = 0.002; P = .001) and mediated (β = .028; SE = 0.002; P < .001) by IQ. Childhood infection had a greater association with NAP risk in the lower, compared with higher, IQ range. Conclusions and Relevance: Early childhood is a sensitive period for the effects of infection on IQ and NAP. The associations of adult NAP with early-childhood infection and adolescent IQ are not fully explained by shared familial factors and may be causal. Lower premorbid IQ in individuals with psychosis arises from unique environmental factors, such as early-childhood infection. Early-childhood infections may increase the risk of NAP by affecting neurodevelopment and by exaggerating the association of cognitive vulnerability with psychosis.Dr Khandaker is supported by an Intermediate Clinical Fellowship from the Wellcome Trust (201486/Z/16/Z) and a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (80354). Dr Jones reports having grant support from the Wellcome Trust (095844/Z/11/Z and 088869/Z/09/Z) and from the National Institute for Health Research: RP-PG-0616-20003, Cambridge Biomedical Research Centre and Collaboration for Leadership in Applied Health Research and Care East of England. Dr Dalman reports grant support from the Swedish Research Council. Dr Karlsson reports grant support from the Stanley Medical Research Institute

Novel neuronal surface autoantibodies in plasma of patients with depression and anxiety

Neuronal surface autoantibodies (NSAbs) against various antigens cause autoimmune encephalitis. Some of these antigens are also involved in the pathology of depression and anxiety. To study whether NSAbs are more common in plasma of individuals with depression and anxiety than in controls, and to investigate if NSAbs correlate with disease status, plasma samples of 819 individuals with a current diagnosis of depression and/or anxiety, 920 in remission and 492 individuals without these disorders were included in this study. Samples were tested by a combination of immunohistochemistry (IHC), staining on live rat hippocampus neurons and cell-based assay (CBA). By IHC, 50 (2.2%) samples showed immunoreactivity to rat brain tissue, with no significant differences between the aforementioned groups (22/819 vs 18/920 vs 11/492, P > 0.99). In addition, eight IHC positive samples were positive for NSAbs on live neurons (7/819 vs 0/920 vs 1/492, P = 0.006). The IHC-staining patterns of these eight samples were atypical for autoimmune encephalitis and accordingly, they tested negative for known NSAbs by CBA. No obvious difference in the clinical characteristics between individuals with or without NSAbs was observed. In conclusion, novel NSAbs were rare but predominately found in patients with current anxiety or depression indicating they might affect mental health in a small group of patients.info:eu-repo/semantics/publishedVersio

Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts.

Funder: Partially supported by the Complex Trait Genetics programme of Amsterdam NeuroscienceFunder: Supported by the International Max Planck Research School of Translational Psychiatry (IMPRS-TP)Funder: MQ: Transforming Mental Health (MQ); doi: https://doi.org/10.13039/501100008162; Grant(s): MQDS17/40, MQDS17/40, MQDS17/40Funder: EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011264; Grant(s): PCIG12-GA-2012-334065Funder: BMA Foundation (J Moulton grant 2019)We examined whether inflammation is uniformly associated with all depressive and anxiety symptoms, and whether these associations are potentially causal. Data was from 147,478 individuals from the UK Biobank (UKB) and 2,905 from the Netherlands Study of Depression and Anxiety (NESDA). Circulating C-reactive protein (CRP) was measured in both cohorts and interleukin-6 (IL-6) in NESDA. Genetic instruments for these proteins were obtained from published GWAS and UKB. Depressive and anxiety symptoms were assessed with self-report questionnaires. In NESDA, neurovegetative (appetite, sleep, psychomotor) symptoms were disaggregated as increased vs. decreased. In joint analyses, higher CRP was associated with depressive symptoms of depressed mood (OR = 1.06, 95% CI = 1.05-1.08), altered appetite (OR = 1.25, 95%CI = 1.23-1.28), sleep problems (OR = 1.05, 95%CI = 1.04-1.06), and fatigue (OR = 1.12, 95% CI = 1.11-1.14), and with anxiety symptoms of irritability (OR = 1.06, 95% CI = 1.05-1.08) and worrying control (OR = 1.03, 95% CI = 1.02-1.04). In NESDA, higher IL-6 was additionally associated with anhedonia (OR = 1.30, 95% CI = 1.12-1.52). Higher levels of both CRP (OR = 1.27, 95% CI = 1.13-1.43) and IL-6 (OR = 1.26, 95% CI = 1.07-1.49) were associated with increased sleep. Higher CRP was associated with increased appetite (OR = 1.21, 95% CI = 1.08-1.35) while higher IL-6 with decreased appetite (OR = 1.45, 95% CI = 1.18-1.79). In Mendelian Randomisation analyses, genetically predicted higher IL-6 activity was associated with increased risk of fatigue (estimate = 0.25, SE = 0.08) and sleep problems (estimate = 0.19, SE = 0.07). Inflammation was associated with core depressive symptoms of low mood and anhedonia and somatic/neurovegetative symptoms of fatigue, altered sleep and appetite changes. Less consistent associations were found for anxiety. The IL-6/IL-6R pathway could be causally linked to depression. Experimental studies are required to further evaluate causality, mechanisms, and usefulness of immunotherapies for depressive symptoms

The Role of Schools in Early Adolescents’ Mental Health: Findings from the MYRIAD Study

This is the author accepted manuscript. The final version is available on open access from Elsevier via the DOI in this recordData Sharing: The corresponding study protocol can be found at https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-017-1917-4. R code is available from the Open Science Framework (https://osf.io/s63fm/?view_only=5ae58f6c053c4a16b5ddfccd0e6e1ece). The baseline data and codebook from the MYRIAD trial is available from Prof. Kuyken ([email protected]) upon request (release of data is subject to an approved proposal and a signed data access agreement).Objective: Recent studies suggest deteriorating youth mental health. The current UK policy emphasises the role of schools for mental health promotion and prevention, but little data exist on what aspects of schools explain pupils’ mental health. We explored school-level influences on the mental health of young people in a large school-based sample from the UK. Methods: We analysed baseline data from a large cluster randomized controlled trial (ISRCTN 86619085) collected between 2016‒2018 from mainstream UK secondary schools selected to be representative in relation to their quality rating, size, deprivation, mixed or single-sex pupil population and country. Participants were pupils in their first or second year of secondary school. We assessed whether school-level factors were associated with pupil mental health. Results: 26,885 pupils (response rate=90%), aged 11‒14 years, 55% female, attending 85 UK schools, were included. Schools accounted for 2.4% (95% CI=2.0‒2.8; p<0.0001) of the variation in psychopathology, 1.6% (95% CI=1.2‒2.1; p<0.0001) of depression and 1.4% (95% CI=1.0‒1.7; p<0.0001) of well-being. Schools in urban locations, with a higher percentage of free school meals and of White British, were associated with poorer pupil mental health. A more positive school climate was associated with better mental health. Conclusion: School-level variables, primarily related to contextual factors, characteristics of their pupil population, and school climate explain a small but significant amount of variability in young people’s mental health. This might be used to identify schools that are in need of more resources to support young people’s mental health.Wellcome TrustNational Institute for Health Research (NIHR)Medical Research Council (MRC