Introduction While research has extensively examined self-harm prevention and risk factors, fewer studies have explored recovery processes. Personally modifiable factors — lifestyle, skill-based, or behavioural aspects an individual can influence — may support self-harm recovery. This review aimed to identify these factors for young people and, secondarily, the barriers and facilitators affecting their implementation. Methods Recovery was defined symptomatically (reduction or cessation of self-harm) and personally, using the CHIME framework (Connectedness, Hope, Identity, Meaning, Empowerment). Five databases (Medline, CINAHL, PsycInfo, Embase, Web of Science) were searched in February 2025. Inductive coding identified personally modifiable factors, and the Consolidated Framework for Implementation Research (CFIR) guided analysis of barriers and facilitators. Results From 16,900 screened records, 35 studies were included. Common factors for symptom-based recovery (ceasing self-harm) included activities or hobbies (such as exercise, art, or music), social engagement with friends/family, harm minimisation techniques (e.g., holding ice cubes, elastic bands), and distraction methods. Online engagement and harm minimisation were double-edged, offering support but sometimes posing risks. Online forums fostered connectedness and empowerment, and recovery stories promoted hope (i.e. personal recovery). Barriers and facilitators varied; stigma often hindered offline discussion but encouraged anonymous online support. Conclusions Young people identify diverse, personally modifiable factors that guide self-harm recovery alone or with support. These factors are context- and person-dependent, underscoring the need for flexible, individualized approaches. Future research should also include low- and middle-income countries and include stratified analyses by sex and gender to capture a broader range of experiences and recovery pathways.

INTRODUCTION:Psychotic experiences (PEs) are associated with elevated blood markers of inflammation in both childhood and young adulthood. However, the relationship between persistent PEs, which are associated with the risk of mental disorders, and blood-based inflammatory markers, has not been previously investigated. To address this, we investigated two questions; the role of childhood inflammation and subsequent persistent PEs, and if persistence of PEs in youth is associated with adult inflammation. Secondary analysis of sex differences was conducted. METHODS:This study was conducted using the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 7,913). Two inflammatory markers (C-reactive protein(CRP) and Interleukin-6) were assessed in the blood in childhood(age 9). CRP and soluble urokinase Plasminogen Activator Receptor(suPAR) were measured in the blood in adulthood (age 24). PE states (transient, recurring, persistent) were measured using the Psychosis-like symptoms interview three time points (age 12, 18, 24). Multinomial logistic and linear regressions were used for analyses. Sex stratified analyses were conducted. Missing data were imputed with multiple imputation by chained equations. RESULTS:Persistence of PE in youth (age 11-24) was associated with elevated suPAR in adulthood, in a dose response (Transient:β = 0.11,95%CI[0.01,0.21]; Recurring:β = 0.20,95%CI[0.01,0.40]; Persistent: β = 0.53,95%CI[0.16,0.90]). When stratified by sex, the effect for suPAR occurred in women, but not men. Neither childhood inflammatory marker was associated with subsequent persistence of PEs. CONCLUSION:This study suggests that persistence of PEs are associated with elevated chronic inflammation into adulthood, particularly in women. This finding suggest persistent PE could be an indicator of long-term poor physical health outcomes.

Pregnancy has been posited as a period of unique vulnerability for Intimate Partner Violence (IPV) victimisation. This brief report examined the impact of COVID-19 lockdown on IPV victimisation during pregnancy by measuring post implementation changes in rates, with comparisons to the same period in non-lockdown years. Secondary data analysis of the Northern Ireland Maternity System (NIMATS) database containing pregnancy presentations to maternity services in Northern Ireland between January 2018 to June 2020 (n = 134,499 records) was conducted. Monthly rates of self-reported historical and current IPV disclosures were calculated, and rates of current IPV disclosures were compared across January to June for the years 2018–2020. Historical IPV rates decreased by 5.19

BACKGROUND:Positive childhood experiences (PCEs) have been associated with improved physical and mental health outcomes in later life, but how PCEs exert their impact is relatively unknown. We aimed to explore whether PCE exposure is associated with plasma inflammatory markers in early adulthood. METHODS:The study involved 2802 ALSPAC participants, who prospectively reported PCEs between the ages 0 and 17. PCEs were measured as a score from 0 to 10. The outcomes included age 24 soluble urokinase Plasminogen Activator Receptor (suPAR), tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP). Linear regressions explored the relationship between total PCE score and the inflammatory outcomes. Individual types of PCEs and modification by number of childhood trauma experiences were subsequently examined. RESULTS:No significant associations were identified between total PCE score and suPAR levels (β = -0.005, 95% CI [-0.016, 0.006]), TNF-α levels (β = -0.003, 95% CI [-0.027, 0.02)], IL-6 levels (β = -0.008, 95% CI [-0.035, 0.02]), and CRP levels (β = -0.006, 95% CI [-0.035, 0.022]) in early adulthood. 'High frequency contact with family and friends' was significantly associated with lower CRP levels even after adjustment for confounders (β = -0.13, CI [-0.24, -0.01], p = 0.03), but not multiple comparisons. No associations were found for the other types of PCEs. Trauma did not modify the PCE-inflammation relationship. CONCLUSION:Overall, there was limited evidence for associations between PCEs and early adult inflammation. Future research is warranted to explore alternative mechanisms by which PCEs may impact distal health outcomes.

BACKGROUND:Evidence from longitudinal studies demonstrates an association between pro-inflammatory markers and risk of psychiatric outcomes, however the role of immune regulators remain largely underexplored. HYPOTHESIS:We hypothesized that childhood immunomodulatory biomarkers are inversely associated with depression and psychosis-spectrum outcomes in adulthood. METHODS:We analysed data from 2,068 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC). Plasma samples collected at age 9 were assayed for immunomodulatory biomarkers (IL10, sCD5, sCD6, LAP TGF-β1, OPG, PD-L1, TRAIL, and LIFR) using Olink Inflammatory Panel. Psychiatric outcomes at age 24 included moderate-to-severe depression, psychotic experiences and negative symptoms. Logistic regression models tested associations between cytokine levels and binary outcomes, while linear regression models were used for negative symptoms score. These models were adjusted for sex, BMI at age 9, ethnicity, and paternal social class. Exploratory analyses additionally tested interactions between immunomodulatory biomarkers and early life trauma (ages 0-5). False discovery rate (FDR) correction was applied using Benjamini-Hochberg procedure. RESULTS:In our sample, 260 participants (12.6%) had moderate-to-severe depression (N = 148) and/or psychotic experiences (N = 141) at age 24. Childhood CD5 was associated with lower odds of depression (adjustedOR = 0.75, 95% CI: 0.63-0.90, FDR = 0.008) and negative symptoms (aβ = -0.31, 95% CI -0.55 to -0.07, FDR = 0.048). Childhood CD6 was similarly associated with lower odds of depression (aOR = 0.79, 95% CI: 0.67-0.94, FDR = 0.032), fewer negative symptoms (aβ = -0.38, 95% CI: -0.62 to -0.14, FDR = 0.016), and a lower odds of psychotic experiences (aOR = 0.78, 95% CI: 0.65-0.93, FDR = 0.040). None of the other biomarkers showed longitudinal associations following confounding adjustment. There was no evidence that childhood immunoregulatory biomarkers modified effect of early life trauma on psychiatric outcomes. CONCLUSIONS:Higher childhood CD5 and CD6 levels were associated with lower odds of depression and psychosis-spectrum outcomes in early adulthood, consistent with a role of early-life immune function, particularly immune regulation, in the aetiology of these conditions. However, effect-sizes were modest and further work is needed to clarify whether anti-inflammatory phenotypes are protective in developmental psychopathology.

Background Public and Patient Involvement (PPI) in mental health research is increasingly recognised as a moral and ethical imperative, necessary to increase the relevance and effectiveness of translation of research findings. Despite policy mandates and growing evidence of its benefits, PPI implementation in mental health research remains inconsistent. Little attention has been given to the state of scientific knowledge on PPI capacity strengthening in mental health research that can support more meaningful implementation. The aims of this scoping review are to: describe the content, implementation process, and theoretical underpinnings of PPI capacity-strengthening initiatives in mental health research; identify quantitative outcome measures and outcomes used to evaluate the initiatives’ impact on PPI contributors, research processes, and policy; and map barriers and enablers to the initiatives’ implementation. Methods This scoping review will follow JBI and PRISMA-ScR guidelines. Sources will include peer-reviewed articles, grey literature, and organisational materials describing training or skill-building initiatives for adult PPI contributors in mental health research. Searches will be conducted in MEDLINE, Embase, PsycINFO, and CINAHL, supplemented by hand-searching, targeted internet searches, and stakeholder consultation. Data extraction will capture descriptive details, initiative content, outcomes, and contextual factors, with barriers and enablers categorised according to the Consolidated Framework for Implementation Research (CFIR) domains. Conclusion This review will provide the first comprehensive synthesis of capacity-strengthening initiatives for PPI contributors in mental health research. Findings will inform the development of a co-designed blueprint for capacity-strengthening for PPI contributors, and progress broader efforts to embed lived experience expertise and general public perspectives equitably within mental health research systems.

Most mental health difficulties (MHD) emerge during adolescence and early adulthood, placing young people at an increased risk for co-occurring physical and sexual health challenges. Shared models of care (SMOC) to connect specialist mental health care with physical and/or sexual health have been developed to address these health needs among young people with MHD. We aimed to identify and characterise SMOC that integrate physical and/or sexual healthcare for young people with MHD, and to synthesise SMOC implementation determinants using the Consolidated Framework for Implementation Research (CFIR) for policy makers, commissioners and practitioners seeking to strengthen youth-integrated service delivery. Five electronic databases and key grey literature sites were searched in October 2024. Studies were eligible for inclusion if they predominantly included young people (aged 10–25) with an MHD. SMOC had to address MHD as a primary concern or have parity with the physical and/or sexual health concern(s) being addressed. Key study details were extracted and were appraised using the mixed methods appraisal tool. Screening was conducted in duplicate, with extraction and appraisals conducted by one team member and verified by a second. Findings were thematically synthesised and mapped to CFIR domains to inform implementation planning in youth health systems. Search results identified 25 relevant SMOC to include in the review. Almost all models (n = 23/25) addressed shared care between mental and physical health, while nine addressed mental and sexual health and seven addressed mental, physical and sexual health needs. Reporting quality varied but most SMOC included referral pathways, assessment, treatment and external support components. Barriers frequently mapped to the inner and outer setting CFIR domains, with high staff turnover (n = 9) and societal stigma towards mental health (n = 7) common concerns. Enablers frequently mapped to the process and innovation constructs, including offering youth-specific care models (n = 7) and clear communication between services (n = 5). Despite evidence supporting the need for an integrated care approach, implementation remains limited by setting-specific barriers. Findings highlight the need for service planning and developing tailored, youth-specific models to ensure a holistic approach to care is available to young people experiencing MHD. Open Science Framework (osf.io/rj783).

Background Public and Patient Involvement (PPI) in mental health research is increasingly recognised as a moral and ethical imperative, necessary to increase the relevance and effectiveness of translation of research findings. Despite policy mandates and growing evidence of its benefits, PPI implementation in mental health research remains inconsistent. Little attention has been given to the state of scientific knowledge on PPI capacity strengthening in mental health research that can support more meaningful implementation. The aims of this scoping review are to: determine the state of knowledge concerning PPI in mental health research capacity-strengthening initiatives; identify the outcome measures used to evaluate the impact of capacity strengthening initiatives for PPI on contributors, research processes, and policy; and map the barriers and enablers to the implementation of capacity strengthening initiatives for PPI. Methods This scoping review will follow JBI and PRISMA-ScR guidelines. Sources will include peer-reviewed articles, grey literature, and organisational materials describing training or skill-building initiatives for adult PPI contributors in mental health research. Searches will be conducted in MEDLINE, Embase, PsycINFO, and CINAHL, supplemented by hand-searching, targeted internet searches, and stakeholder consultation. Data extraction will capture descriptive details, initiative content, outcomes, and contextual factors, with barriers and enablers categorised according to the Consolidated Framework for Implementation Research (CFIR) domains. Conclusion This review will provide the first comprehensive synthesis of capacity-strengthening initiatives for PPI contributors in mental health research. Findings will inform the development of a co-designed blueprint for capacity-strengthening for PPI contributors, and progress broader efforts to embed lived experience expertise and general public perspectives equitably within mental health research systems.

Background Self-harm is the most important predictor of suicide, one of the leading causes of death in young people globally. There is a dearth of studies examining the processes underpinning recovery for those who have self-harmed. In particular, there is a lack of studies identifying elements that people who have self-harmed can change or influence to improve their wellbeing i.e. personally modifiable factors. Identifying these factors is important for individuals and clinicians to reduce or cease self-harm behaviours and improve personal wellbeing. In addition, it is imperative to understand why implementing these personally modifiable factors may succeed or fail. This systematic review has two aims: firstly, to identify personally modifiable factors for self-harm recovery in young people; and secondly, to identify the implementation determinants (barriers and facilitators) of these factors. Methods The search strategy will employ terms relating to three concepts (i.e. ‘young people’, ‘self-harm’, and ‘personally modifiable factors’) and will use five databases for the search process: Medline, CINAHL, APA PsycInfo, Embase, and Web of Science. At least two independent reviewers will conduct the screening process using eligibility criteria, followed by data extraction and quality assessment of the included studies. The mixed methods appraisal tool (MMAT) will be used for quality assessment. Inductive coding will be used to identify the personally modifiable factors and the Consolidated Framework for Implementation Research (CFIR) will be used to analyse and summarise the implementation determinants for these factors. Conclusion Identifying personally modifiable factors for self-harm recovery, and the barriers and facilitators underpinning their implementation, could inform the design of effective public health interventions to reduce self-harm in young people. Registration PROSPERO registration number CRD420250650920

Individuals with mental health difficulties (MHD) have a substantial reduction in life expectancy compared to the general population. It is increasingly recognised that mental health services need to improve physical healthcare as a priority. Sexual health, including consideration of high-risk sexual behaviours, medication side effects, and challenges in romantic relationships, is a further important but under-recognised aspect of overall health. We discuss some of the current issues relating to physical and sexual health, with a particular focus on youth with MHD and how we might implement holistic care in Ireland. Prioritising the resourcing of these issues could facilitate the implementation of a Shared Model of Care as recommended in Ireland's National Mental Health Policy, Sharing the Vision.

Young people who self-harm are at an increased risk of suicide. Furthering our understanding of the risk factors for self-harm is essential for identifying high-risk groups, which can be used to inform the design of preventative interventions. This study used the Avon Longitudinal Study of Parents and Children (ALSPAC) and applied latent class analysis to the risk factors for self-harm at ages 13 and 17. Longitudinal associations between the latent classes and self-harm at ages 17 and 20 were examined. Cross-cohort comparisons were conducted between this study and a previous study using Irish data. At age 13 there was a low risk group, a peer problems group, and substance use group, similar for the two cohort studies, and a family conflict group, which was the least similar group to its matching group in the Irish study. All of these age 13 high-risk groups had approximately twice the relative risk (between 1.3 and 2.5) for self-harm at age 17 compared to the low risk group. The age 17 models were very similar across the two cohorts, each with a low risk group, a depression and high substance use group, a depression and low substance use group, and a substance use group. The relative risk of self-harm at age 20 for these high-risk groups compared the low risk group ranged from 3.6 to 8.0. These groups could help identify those at risk of self-harm and inform the design of prevention programmes to reduce self-harm behaviour in young people.

Advances in proteomic assay methodologies and genomics have significantly improved our understanding of the blood proteome. Schizophrenia and psychosis risk are linked to polygenic scores for schizophrenia and other mental disorders, as well as to altered blood and saliva levels of biomarkers involved in hormonal signaling, redox balance, and chronic systemic inflammation. The Accelerating Medicines Partnership® Schizophrenia (AMP®SCZ) aims to ascertain biomarkers that both predict clinical outcomes and provide insights into the biological processes driving clinical outcomes in persons meeting CHR criteria. AMP®SCZ will follow almost 2000 CHR and 640 community study participants for two years, assessing biomarkers at baseline and two-month follow-up including the collection of blood and saliva samples. The following provides the rationale and methods for plans to utilize polygenic risk scores for schizophrenia and other disorders, salivary cortisol levels, and a discovery-based proteomic platform for plasma analyses. We also provide details about the standardized methods used to collect and store these biological samples, as well as the study participant metadata and quality control measures related to preanalytical factors that could influence the values of the biomarkers. Finally, we discuss our plans for analyzing the results of blood- and saliva-based biomarkers. Watch Dr. Perkins discuss their work and this article: https://vimeo.com/1062879582?share=copy#t=0 .

Dysregulation of inflammatory mediators and complement cascade proteins has been implicated in psychosis. In the current study, we aimed to investigate the relationship between complement cascade proteins and inflammatory cytokines in blood from people at clinical high risk (CHR) for psychosis and at first episode of psychosis (FEP). Baseline blood samples from two cohorts of CHR participants [NEURAPRO (n = 153) and STEP (n = 146)], and one cohort of FEP patients [OPTiMiSE (n = 226)] were included. The blood levels of three Inflammatory markers including Interleukin (IL)-6, Tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) along with about 30 complement proteins were considered for the analyses. First, we evaluated the interrelationship between the inflammatory markers and then using regression models, we investigated their association with complement proteins. We detected positive associations among all three inflammatory markers IL-6, TNF-α, and CRP in CHR individuals, whereas in FEP positive association was observed only between IL-6 and TNF-α. Regression models showed strong positive associations for complement proteins C3, C4A, C4B, C5, CFB and CFI with all three inflammatory markers in both CHR cohorts. This indicates the presence of a complement related pro-inflammatory tone at risk of developing psychosis. In contrast, in the FEP cohort, complement proteins C1QA, C3, C5, FCN-2, and MASP2 showed an inverse association with TNF-α, and no association found with IL-6 or CRP. These results suggest a switch in the immune activity in the peripheral circulation of FEP compared to CHR. These novel findings propose that complement protein-targeted anti-inflammatory therapy could be effective at CHR state and hence could be used for early intervention in psychosis.

Background: Converging evidence supports the role of Matrix Metalloproteinases (MMPs) in psychiatric disorders. Originally identified as regulators of the extracellular matrix (ECM), MMPs' functions span multiple processes, including inflammation, synaptic plasticity, neuronal migration, and blood-brain barrier maintenance. Tissue Inhibitors of Metalloproteinases (TIMPs) are major regulators of MMPs. In the present study we examined the associations of plasma MMPs and TIMPs with mental disorders in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Methods: The present study was a nested case control study within the Avon Longitudinal Study of Parents and Children and comprised 374 participants who met criteria for psychiatric disorders (35 met the criteria for psychotic disorder, 201 for mild/moderate depressive disorder, and 266 for generalised anxiety disorder) and 401 controls. All cases and controls had were selected from the group of 4019 participants who had attended at age 24 years, completed psychiatric assessments and provided plasma samples. Plasma concentrations of MMP2, MMP3, MMP9 and TIMP-4 were quantified using proximity extension assays available on Olink (R) Cardiovascular Panel III. Logistic regression analysis compared standardised MMPs and TIMPs levels in cases and controls. Models were adjusted for sex, body mass index, and cigarette smoking. Results: There was evidence for an association between MMP3 and depressive disorder (Odds ratio [OR] 1.35, 95 % confidence interval [CI] 1.06-1.73). There was evidence for an association between TIMP4 and depressive disorder (OR 1.51, 95 % CI 1.22-1.88) and generalised anxiety disorder (OR 1.43, 95 % CI 1.19-1.72). There was no evidence for an association between MMPs and psychotic disorders. Conclusions: The study revealed that 24-year-olds with depressive and anxiety disorders exhibited elevated plasma concentrations of TIMP-4 compared to controls. There was evidence for an association between MMP3 and depressive disorder. These findings provide further support for the involvement of metalloproteinases as biomarkers in the pathophysiology of mental disorders during early adulthood.

BACKGROUND:It is largely unknown whether the specific developmental stage at which childhood trauma occurs is related to inflammatory dysregulation in adulthood. We aimed to explore if trauma exposure at distinct developmental stages in childhood is differentially associated with the novel marker of chronic inflammation - soluble urokinase plasminogen activator receptor (suPAR), as well as with C-Reactive Protein (CRP) and Interleukin-6 (IL-6) levels in early adulthood. METHODS:Participants were drawn from the Avon Longitudinal Study of Parents and Children (n = 3272). The trauma variables represent any trauma exposure within early (0-4.9 years), middle (5-10.9 years), or late (11-17 years) childhood, and were derived from the responses to 121 questions collected via standardised questionnaires regarding traumatic experiences including physical abuse, sexual abuse, emotional abuse, emotional neglect, domestic violence, and bullying. Plasma suPAR, CRP and IL-6 samples were collected at age 24. Linear regression models assessed the relationship between trauma exposure at different developmental stages and the inflammatory markers, adjusting for sex, socio-economic status (SES) and child ethnicity. Latent profile analysis (LPA) identified age 24 inflammatory profiles and multinomial logistic regressions identified associations between childhood trauma and these latent groups. RESULTS:After adjustment for confounders, late childhood trauma was significantly associated with age 24 suPAR (β = 0.06, 95 % CI [.03, 0.1], p = 0.001), CRP (β = 0.09, 95 % CI [.01, 0.17], p = 0.04) and IL-6 (β = 0.1, 95 % CI [.02, 0.19], p = 0.02). The relationship between late trauma and suPAR survived additional adjustment for prior trauma (β = 0.06, 95 % CI [.01, 0.11], p = 0.03). Middle childhood trauma was significantly associated with IL-6 (β = 0.1, 95 % CI [.02, 0.18], p = 0.02). This attenuated after additionally adjusting for prior trauma (β = 0.11, 95 % CI [-0.09, 0.3], p = 0.29). There was little evidence of an association between early trauma and any inflammatory marker. Exposure to any trauma from 0-17 years was associated with elevated suPAR (β = 0.04, 95 % CI [.005, 0.07], p = 0.025) and IL-6 (β = 0.1, 95 % CI [.02, 0.18], p = 0.02) after adjustment for confounders. Additionally, LPA identified three distinct inflammatory profiles: 1. no inflammatory dysregulation; 2. elevated CRP and IL-6 levels; and 3. a high inflammatory group characterised by elevated levels of suPAR, CRP and IL-6. After adjustment for confounders, individuals with trauma either in early (RR = 2.31, 95 % CI [1.16, 4.6], p = 0.017), middle (RR = 2.72, 95 % CI [1.4, 5.29], p = 0.003) or late (RR = 3.37, 95 % CI [1.7, 6.64], p < 0.001) childhood had an increased risk of being in the high inflammatory group. The association between late childhood trauma and this high inflammatory group survived adjustment for prior trauma (RR = 3.69, 95 % CI [1.44, 9.47], p = 0.007). DISCUSSION:When the inflammatory markers were analysed independently, late childhood trauma showed a strong association with age 24 suPAR levels after adjusting for confounders and prior trauma. When the inflammatory markers were analysed in combination, those with late childhood trauma also were likely to have an elevated suPAR, CRP and IL-6 inflammatory profile. Collectively, the findings highlight the propensity of late childhood trauma (rather than early or mid-childhood trauma) for the dysregulation of suPAR in early adulthood and support the measurement of suPAR in combination with other markers to better characterise the effects of childhood trauma on adult inflammation. Future studies should use suPAR in combination with CRP and IL-6 to further explore the inflammatory contribution in the relationship between trauma and adverse health outcomes in adulthood.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

BACKGROUND:Markers of inflammation and cannabis exposure are associated with an increased risk of mental disorders. In the current study, we investigated associations between cannabis use and biomarkers of inflammation. METHODS:Utilizing a sample of 914 participants from the Avon Longitudinal Study of Parents and Children, we investigated whether interleukin-6 (IL-6), tumor necrosis factor α (TNFα), C-reactive protein (CRP), and soluble urokinase plasminogen activator receptor (suPAR) measured at age 24 were associated with past year daily cannabis use, less frequent cannabis use, and no past year cannabis use. We adjusted for a number of covariates including sociodemographic measures, body mass index, childhood trauma, and tobacco smoking. We found evidence of a strong association between daily or near daily cannabis use and suPAR. RESULTS:We did not find any associations between less frequent cannabis use and suPAR. We did not find evidence of an association between IL-6, TNFα or CRP, and cannabis use. CONCLUSIONS:Our finding that frequent cannabis use is strongly associated with suPAR, a biomarker of systemic chronic inflammation implicated in neurodevelopmental and neurodegenerative processes is novel. These findings may provide valuable insights into biological mechanisms by which cannabis affects the brain and impacts the risk of serious mental disorders.

BACKGROUND:There is some evidence of an association between inflammation in the pathogenesis of mental disorders. Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic inflammation, which provides a more stable index of systemic inflammation than more widely used biomarkers. This review aims to synthesise studies that measured suPAR concentrations in individuals with a psychiatric disorder, to determine if these concentrations are altered in comparison to healthy participants. METHOD:Comprehensive literature searches from inception to October 2023 were conducted of five relevant databases (PubMed, Web of Science, Embase, Scopus, APA PsychInfo). Random-effects meta-analyses were performed to compare the standardised mean difference of blood suPAR levels (i.e. plasma or serum) for individuals with any psychiatric disorder relative to controls. Separate meta-analyses of suPAR levels were conducted for individuals with schizophrenia or other psychotic disorder and depressive disorder. Risk of bias was assessed using the Newcastle Ottawa Scale. Post-hoc sensitivity analyses included excluding studies at high risk of bias, and analyses of studies that measured suPAR concentrations either in serum or in plasma separately. RESULTS:The literature search identified 149 records. Ten full-text studies were screened for eligibility and 9 studies were included for review. Primary analyses revealed no significant difference in suPAR levels between individuals with any psychiatric disorder compared to controls (k = 7, SMD = 0.42, 95 % CI [-0.20, 1.04]). However, those with depressive disorder had elevated suPAR levels relative to controls (k = 3, SMD = 0.61, 95 % CI [0.34, 0.87]). Similarly, secondary analyses showed no evidence of a significant difference in suPAR levels in individuals with any psychiatric disorder when studies at high risk of bias were excluded (k = 6, SMD = 0.54, 95 % CI [-0.14, 1.22]), but elevated suPAR concentrations for those with schizophrenia or other psychotic disorder were found (k = 3, SMD = 0.98, 95 % CI [0.39, 1.58]). Furthermore, studies that analysed plasma suPAR concentrations found elevated plasma suPAR levels in individuals with any psychiatric disorder relative to controls (k = 5, SMD = 0.84, 95 % CI [0.38, 1.29]), while studies measuring serum suPAR levels in any psychiatric disorder did not find a difference (k = 2, SMD = -0.61, 95 % CI [-1.27, 0.04]). For plasma, elevated suPAR concentrations were also identified for those with schizophrenia or other psychotic disorder (k = 3, SMD = 0.98, 95 % CI [0.39, 1.58]). DISCUSSION:When studies measuring either only serum or only plasma suPAR were considered, no significant difference in suPAR levels were observed between psychiatric disorder groups, although significantly elevated suPAR levels were detected in those with moderate to severe depressive disorder. However, plasma suPAR levels were significantly elevated in those with any psychiatric disorder relative to controls, while no difference in serum samples was found. A similar finding was reported for schizophrenia or other psychotic disorder. The plasma findings suggest that chronic inflammatory dysregulation may contribute to the pathology of schizophrenia and depressive disorder. Future longitudinal studies are required to fully elucidate the role of this marker in the psychopathology of these disorders.

BACKGROUND:Immune dysregulation has been observed in patients with schizophrenia or first-episode psychosis, but few have examined dysregulation in those at clinical high-risk (CHR) for psychosis. The aim of this study was to examine whether the peripheral blood-based proteome was dysregulated in those with CHR. Secondly, we examined whether baseline dysregulation was related to current and future functioning and clinical symptoms. METHODS:We used data from participants of the North American Prodromal Longitudinal Studies (NAPLS) 2 and 3 (n = 715) who provided blood samples (Unaffected Comparison subjects (UC) n = 223 and CHR n = 483). Baseline proteomic data was quantified from plasma samples using mass spectrometry. Differential expression was examined between CHR and UC using logistic regression. Psychosocial functioning was measured using the Global Assessment of Functioning scale (GAF). Symptoms were measured using the subscale scores from the Scale of Psychosis-risk Symptoms; positive, negative, general, and disorganised. Three measures of each outcome were included: baseline, longest available follow-up (last follow-up) and most severe follow-up (MSF). Associations between the proteomic data, GAF and symptoms were assessed using ordinal regression. RESULTS:Of the 99 proteins quantified, six were differentially expressed between UC and CHR. However, only haptoglobin (HP) survived FDR-correction (OR:1.45, 95 %CI:1.23-1.69, padj = <0.001). HP was cross-sectionally and longitudinally associated with functioning and symptoms such that higher HP values were associated with poorer functioning and more severe symptoms. Results were evident after stringent adjustment and poorer functioning was observed in both NAPLS cohort separately. CONCLUSION:We demonstrate that elevated HP is robustly observed in those at CHR for psychosis, irrespective of transition to psychosis. HP is longitudinally associated with poorer functioning and greater symptom severity. These results agree with previous reports of increased HP gene expression in individuals at-risk for psychosis and with the dysfunction of the acute phase inflammatory response seen in psychotic disorders.