There is renewed focus on the complement system in the pathogenesis of schizophrenia. In addition to providing aetiological insights, consistently dysregulated complement proteins in serum or plasma ...may have clinical utility as biomarkers.
We performed a systematic literature review searching PubMed, Embase and PsycINFO for studies measuring complement system activity or complement protein concentrations in serum or plasma from patients with schizophrenia compared to controls. Random-effects meta-analyses were performed to calculate pooled effect estimates (Hedges' g standardised mean difference SMD) for complement proteins whose concentrations were measured in three or more studies. The review was pre-registered on the PROSPERO database (CRD42018109012).
Database searching identified 1146 records. Fifty-eight full-text articles were assessed for eligibility and 24 studies included. Seven studies measured complement system activity. Activity of the classical pathway did not differ between cases and controls in four of six studies, and conflicting results were noted in two studies of alternative pathway activity. Twenty studies quantified complement protein concentrations of which complement components 3 (C3) and 4 (C4) were measured in more than three studies. Meta-analyses showed no evidence of significant differences between cases and controls for 11 studies of C3 (SMD 0.04, 95% confidence interval CI -0.29–0.36) and 10 studies of C4 (SMD 0.10, 95% CI -0.21–0.41).
Serological studies provide mixed evidence regarding dysregulation of the complement system in schizophrenia. Larger studies of a longitudinal nature, focusing on early phenotypes, could provide further insights regarding the potential role of the complement system in psychotic disorders.
The complement cascade is a major component of the immune defence against infection, and there is increasing evidence for a role of dysregulated complement in major psychiatric disorders. We ...undertook a directed proteomic analysis of the complement signalling pathway (n = 29 proteins) using data-independent acquisition. Participants were recruited from the UK avon longitudinal study of parents and children (ALSPAC) cohort who participated in psychiatric assessment interviews at ages 12 and 18. Protein expression levels at age 12 among individuals who reported psychotic experiences (PEs) at age 18 (n = 64) were compared with age-matched controls (n = 67). Six out of the 29 targeted complement proteins or protein subcomponents were significantly upregulated following correction for multiple comparisons (VTN↑, C1RL↑, C8B↑, C8A↑, CFH↑, and C5↑). We then undertook an unbiased plasma proteomic analysis of mice exposed to chronic social stress and observed dysregulation of 11 complement proteins, including three that were altered in the same direction in individuals with PE (C1R↑, CFH↑, and C5↑). Our findings indicate that dysregulation of the complement protein pathway in blood is associated with incidence of psychotic experiences and that these changes may reflect exposure to stress.
Previous systematic reviews and meta-analyses of cross-sectional data assessing the effect of cannabis on cognitive functioning and intelligence show inconsistent results. We hypothesized that ...frequent and dependent cannabis use in youth would be associated with Intelligence Quotient (IQ) decline. This study is a systematic review and meta-analysis. We searched Embase, PubMed and PsychInfo from inception to 24 January 2020. We included studies with non-treatment seeking samples and pre- and post-exposure measures of IQ. We requested data from authors if summary data was not available from published work. We preregistered our review with PROSPERO (ID no. CRD42019125624). We found seven cohort studies including 808 cases and 5308 controls. We found a significant effect for the association between frequent or dependent cannabis use in youth and IQ change, Cohen's d = −0.132 (95% CI −0.198 to −0.066) p < 0.001. Statistical heterogeneity between studies was also low at I2 = 0.2%. Study quality was moderate to high. This translates to an average decline of approximately 2 IQ points following exposure to cannabis in youth. Future studies should have longer periods of follow up to assess the magnitude of developmental impact.
Abstract
Background
Cannabis use in adolescence is a known risk factor for developing schizophrenia. Decline in intellectual functioning is a well-studied phenomenon of schizophrenia. Schizophrenia ...in its first classification was conceptualized as a dementia - ‘Dementia Praecox’ indicating a dominance of effect of cognitive symptoms on functioning at that time. First episode psychosis patients with histories of cannabis use compared to those without cannabis use have superior cognitive functioning suggesting different disease phenotypes. Our aim was to investigate whether cannabis had an effect on full scale IQ in general population samples to further inform understanding of this disease pathway.
Methods
We developed a search strategy through an iterative approach with a qualified information specialist. We searched three databases: Medline, Embase and PsychInfo. We included conference abstracts and full text publications in English. We contacted authors for additional information in cases where an effect size was not calculable. We included longitudinal studies of non-help-seeking young people in the community with a pre-drug exposure standardized measure of IQ prior to the age of 18 and a comparable measure at subsequent follow up. We defined the case group as individuals with a history of heavy cannabis use (more than 25 lifetime uses, at least weekly use for 6 months and/or meeting criteria for a cannabis use disorder) and the control group as similar young people who had no or very minimal experimental exposure to cannabis (<5 lifetime uses). Two reviewers independently extracted the data and assessed for bias using the Newcastle-Ottawa risk of bias tool. We performed random effects meta-analysis in Stata version 14 given expected heterogeneity in measurement of cannabis use across studies.
Results
We identified 7 cohort studies detailed in 6 reports including over 650 subjects and 5600 controls. Study designs included twin cohorts, representative cluster sampled community cohorts and birth cohort studies. Range of follow up was between 2 and 23 years. All studies showed relative decline in IQ of which two were statistically significant. Our findings show that cannabis use in youth is associated with modest IQ differences that equate to approximately to a 2-point decrease in young cannabis users. Studies examining twin pairs showed that twins discordant for cannabis use did not have divergent cognitive trajectories, however these analyses were relatively underpowered to find an effect.
Discussion
Our findings demonstrate the harmful effects of cannabis use on brain development in young people. These findings are of public health importance and provide further evidence for the detrimental effects of early cannabis use on mental health and cognition.
The identification of early biological changes associated with the psychotic disorder (PD) is important as it may provide clues to the underlying pathophysiological mechanisms. We undertook the first ...proteomic profiling of blood plasma samples of children who later develop a PD. Participants were recruited from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who also participated in psychiatric assessment interviews at age 18. Protein expression levels at age 11 were compared between individuals who developed PD at age 18 (n = 37) with population-based age-matched controls (n = 38). Sixty out of 181 plasma proteins profiled were found to be differentially expressed (P < .05) in children with an outcome of the PD. Thirty-four of these proteins were found to be differentially expressed following correction for multiple comparisons. Pathway analysis implicated the complement and coagulation cascade. A second, targeted proteomic approach was used to verify these findings in age 11 plasma from subjects who reported psychotic experiences at age 18 (n = 40) in comparison to age-matched controls (n = 66). Our findings indicate that the complement and coagulation system is dysregulated in the blood during childhood before the development of the PD.
Aim
Among different types of poly unsaturated fatty acids, omega‐3 fatty acids (FA) play a substantial role in brain development and functioning. This review was designed to evaluate and synthesize ...available evidence regarding omega‐3 FAs and functional outcome in the ultra‐high‐risk (UHR) population.
Methods
An electronic search in PubMed, EMBASE, PSYCINFO and COCHRANE search engines has been performed for all articles published until January 2019. The studies that have data regarding omega‐3 FAs and functional outcome in UHR population were included.
Results
Out of 397 nonduplicate citations, 19 articles met selection criteria. These articles were from four different primary studies, namely the Program of Rehabilitation and Therapy (PORT), the North American Prodromal Longitudinal Studies (NAPLS), Vienna High Risk study (VHR) and the NEURAPRO. The data from the NAPLS study found a positive correlation between functional improvement and frequency of dietary intake omega‐3 FA. Moreover, among the erythrocyte omega‐3 FA only eicosapentaenoic acid (EPA) showed a positive correlation with functional score. The VHR study found long‐term improvement in functional outcome in omega‐3 group compared to control, whereas such difference was noticed in the NEURAPRO. In the VHR study both omega‐3 and omega‐6 together predicted the functional improvement at 12 weeks.
Conclusions
The number of studies available remains insufficient and more studies with standardized outcome measures in a clinically comparable UHR population would be of more value to understand the clinical benefits of omega‐3 FA in the UHR population.
The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. ...The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort.
Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects.
Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p < .01) and associated with a higher concentration of smaller low-density lipoprotein cholesterol particles.
Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.
Recent evidence supports an association between systemic abnormalities and the pathology of psychotic disorders which has led to the search for peripheral blood-based biomarkers. Areas covered: Here, ...we summarize blood biomarker findings in schizophrenia from the literature identified by two methods currently driving biomarker discovery in the human proteome; mass spectrometry and multiplex immunoassay. From a total of 14 studies in the serum or plasma of drug-free schizophrenia patients; 47 proteins were found to be significantly altered twice or more, in the same direction. Pathway analysis was performed on these proteins, and the resulting pathways discussed in relation to schizophrenia pathology. Future directions are also discussed, with particular emphasis on the potential for high-throughput validation techniques such as data-independent analysis for confirmation of biomarker candidates. Expert commentary: We present promising findings that point to a convergence of pathophysiological mechanisms in schizophrenia that involve the acute-phase response, glucocorticoid receptor signalling, coagulation, and lipid and glucose metabolism.
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