Golam M. Khandaker

Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study.

IMPORTANCE Longitudinal studies have linked the systemic inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) with the risk of developing heart disease and diabetes mellitus, which are common comorbidities for depression and psychosis. Recent meta-analyses of cross-sectional studies have reported increased serum levels of these inflammatory markers in depression, first-episode psychosis, and acute psychotic relapse; however, the direction of the association has been unclear. OBJECTIVE To test the hypothesis that higher serum levels of IL-6 and CRP in childhood would increase future risks for depression and psychosis. DESIGN, SETTING, AND PARTICIPANTS The Avon Longitudinal Study of Parents and Children (ALSPAC)is a prospective general population birth cohort study based in Avon County, England. We have studied a subsample of approximately 4500 individuals from the cohort with data on childhood IL-6 and CRP levels and later psychiatric assessments. MEASUREMENT OF EXPOSURE Levels of IL-6 and CRP were measured in nonfasting blood samples obtained in participants at age 9 years. MAIN OUTCOMES AND MEASURES Participants were assessed at age 18 years. Depression was measured using the Clinical Interview Schedule-Revised (CIS-R) and Mood and Feelings Questionnaire (MFQ), thus allowing internal replication; psychotic experiences (PEs) and psychotic disorder were measured by a semistructured interview. RESULTS After adjusting for sex, age, body mass index, ethnicity, social class, past psychological and behavioral problems, and maternal postpartum depression, participants in the top third of IL-6 values compared with the bottom third at age 9 years were more likely to be depressed (CIS-R) at age 18 years (adjusted odds ratio [OR], 1.55; 95% CI, 1.13-2.14). Results using the MFQ were similar. Risks of PEs and of psychotic disorder at age 18 years were also increased with higher IL-6 levels at baseline (adjusted OR, 1.81; 95% CI, 1.01-3.28; and adjusted OR, 2.40; 95% CI, 0.88-6.22, respectively). Higher IL-6 levels in childhood were associated with subsequent risks of depression and PEs in a dose-dependent manner. CONCLUSIONS AND RELEVANCE Higher levels of the systemic inflammatory marker IL-6 in childhood are associated with an increased risk of developing depression and psychosis in young adulthood. Inflammatory pathways may provide important new intervention and prevention targets for these disorders. Inflammation might explain the high comorbidity between heart disease, diabetes mellitus, depression, and schizophrenia.

Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment

Complex interactions between the immune system and the brain might have important aetiological and therapeutic implications for neuropsychiatric brain disorders. A possible association between schizophrenia and the immune system was postulated over a century ago, and is supported by epidemiological and genetic studies pointing to links with infection and inflammation. Contrary to the traditional view that the brain is an immunologically privileged site shielded behind the blood-brain barrier, studies in the past 20 years have noted complex interactions between the immune system, systemic inflammation, and the brain, which can lead to changes in mood, cognition, and behaviour. In this Review, we describe some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, we think, will be of interest to psychiatric clinicians and researchers. We discuss potential mechanisms and therapeutic implications of these findings, including studies of anti-inflammatory drugs in schizophrenia, describe areas for development, and offer testable hypotheses for future investigations.

A quantitative meta-analysis of population-based studies of premorbid intelligence and schizophrenia

Objective A premorbid IQ deficit supports a developmental dimension to schizophrenia and its cognitive aspects that are crucial to functional outcome. Better characterisation of the association between premorbid IQ and the disorder may provide further insight into its origin and etiology. We aimed to quantify premorbid cognitive function in schizophrenia through systematic review and meta-analysis of longitudinal, population-based studies, and to characterize the risk of schizophrenia across the entire range of premorbid IQ. Method Electronic and manual searches identified general population-based cohort or nested case–control studies that measured intelligence before onset of schizophrenic psychosis using standard psychometric tests, and that defined cases using contemporaneous ICD or DSM. Meta-analyses explored dose–response relationships between premorbid cognitive deficit (using full-scale, verbal and performance IQ) and risk of schizophrenia. Meta-regression analyses explored relationships with age of illness onset, change in premorbid intelligence over time and gender differences. Results Meta-analysis of 4396 cases and over 745 000 controls from 12 independent studies confirmed significant decrements in premorbid IQ (effect size − 0.43) among future cases. Risk of schizophrenia operated as a consistent dose–response effect, increasing by 3.7% for every point decrease in IQ (p < 0.0001). Verbal and nonverbal measures were equally affected. Greater premorbid IQ decrement was associated with earlier illness onset (p < 0.0001). There was no evidence of a progressively increasing deficit during the premorbid period toward illness onset. Conclusions Strong associations between premorbid IQ and risk for schizophrenia, and age of illness onset argue for a widespread neurodevelopmental contribution to schizophrenia that operates across the entire range of intellectual ability. This also suggests higher IQ may be protective in schizophrenia, perhaps by increasing active cognitive reserve.

Childhood infection and adult schizophrenia: A meta-analysis of population-based studies

Objective To determine whether exposures to infectious illness during childhood involving the CNS or elsewhere is associated with adult schizophrenia or other psychoses. Method Systematic review and meta-analysis of published literature identified by electronic and manual search meeting three inclusion criteria: population-base, objective assessment of childhood infection at the individual level, standard definition of adult psychotic outcomes. We calculated risk ratio for all CNS infection, and separately for viral and bacterial infection in relation to non-affective psychosis and schizophrenia, which was combined in meta-analysis. Results Seven studies were included. Meta-analysis involving 2424 cases and over 1.2 million controls showed CNS viral infection was associated with nearly two-fold increased risk of adult non-affective psychosis (risk ratio 1.70; 95% CI 1.13–2.55; p = 0.01). There was no significant heterogeneity between studies (p = 0.26; I2 = 20%). Separate meta-analysis involving 1035 cases and over 1.2 million controls suggested all childhood CNS infections, particularly viral infections, may be associated with nearly two-fold risk of adult schizophrenia. However, there was evidence of some heterogeneity between these studies (p = 0.07; I2 = 70%). CNS bacterial infections were not associated with risk of psychosis. Data on childhood infections with no obvious involvement of the CNS is insufficient. Conclusions These findings indicate childhood CNS viral infections increase the risk of adult psychotic illness. Possible mechanisms may include both direct effects of pathogens, and the effects of inflammatory response on the developing brain.

Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions

Inflammatory cytokines are commonly elevated in acute depression and are associated with resistance to monoaminergic treatment. To examine the potential role of cytokines in the pathogenesis and treatment of depression, we carried out a systematic review and meta-analysis of antidepressant activity of anti-cytokine treatment using clinical trials of chronic inflammatory conditions where depressive symptoms were measured as a secondary outcome. Systematic search of the PubMed, EMBASE, PsycINFO and Cochrane databases, search of reference lists and conference abstracts, followed by study selection process yielded 20 clinical trials. Random effect meta-analysis of seven randomised controlled trials (RCTs) involving 2370 participants showed a significant antidepressant effect of anti-cytokine treatment compared with placebo (standardised mean difference (SMD)=0.40, 95% confidence interval (CI), 0.22–0.59). Anti-tumour necrosis factor drugs were most commonly studied (five RCTs); SMD=0.33 (95% CI; 0.06–0.60). Separate meta-analyses of two RCTs of adjunctive treatment with anti-cytokine therapy and eight non-randomised and/or non-placebo studies yielded similar small-to-medium effect estimates favouring anti-cytokine therapy; SMD=0.19 (95% CI, 0.00–0.37) and 0.51 (95% CI, 0.34–0.67), respectively. Adalimumab, etanercept, infliximab and tocilizumab all showed statistically significant improvements in depressive symptoms. Meta-regression exploring predictors of response found that the antidepressant effect was associated with baseline symptom severity (P=0.018) but not with improvement in primary physical illness, sex, age or study duration. The findings indicate a potentially causal role for cytokines in depression and that cytokine modulators may be novel drugs for depression in chronically inflamed subjects. The field now requires RCTs of cytokine modulators using depression as the primary outcome in subjects with high inflammation who are free of other physical illnesses.

Is there a role for immune-to-brain communication in schizophrenia?

Schizophrenia is characterised by hallucinations, delusions, depression-like so-called negative symptoms, cognitive dysfunction, impaired neurodevelopment and neurodegeneration. Epidemiological and genetic studies strongly indicate a role of inflammation and immunity in the pathogenesis of symptoms of schizophrenia. Evidence accrued over the last two decades has demonstrated that there are a number of pathways through which systemic inflammation can exert profound influence on the brain leading to changes in mood, cognition and behaviour. The peripheral immune system-to-brain communication pathways have been studied extensively in the context of depression where inflammatory cytokines are thought to play a key role. In this review, we highlight novel evidence suggesting an important role of peripheral immune-to-brain communication pathways in schizophrenia. We discuss recent population-based longitudinal studies that report an association between elevated levels of circulating inflammatory cytokines and subsequent risk of psychosis. We discuss emerging evidence indicating potentially important role of blood–brain barrier endothelial cells in peripheral immune-to-brain communication, which may be also relevant for schizophrenia. Drawing on clinical and preclinical studies, we discuss whether immune-mediated mechanisms could help to explain some of the clinical and pathophysiological features of schizophrenia. We discuss implication of these findings for approaches to diagnosis, treatment and research in future. Finally, pointing towards links with early-life adversity, we consider whether persistent low-grade activation of the innate immune response, as a result of impaired foetal or childhood development, could be a common mechanism underlying the high comorbidity between certain neuropsychiatric and physical illnesses, such as schizophrenia, depression, heart disease and type-two diabetes.

A population-based study of atopic disorders and inflammatory markers in childhood before psychotic experiences in adolescence

Objective Schizophrenia is associated with atopy and increased inflammatory markers. We report a population-based longitudinal study of the associations between childhood atopic disorders, subsequent serum inflammatory markers, interleukin 6 (IL-6) and C-reactive protein (CRP), and the risk of psychotic experiences (PEs). Method PEs were assessed at age 13 years (n = 6785). Presence of clinician-diagnosed atopic disorders (asthma and eczema) was determined from parent-completed questionnaires at age 10 years (n = 7814). Serum IL-6 and CRP were measured at age 9 years (n = 5076). Logistic regression examined the association between (1) atopy and PEs, (2) inflammatory markers and PEs, and (3) mediating effects of inflammatory markers on the atopy–PEs association. Linear regression examined the association between atopy and inflammatory markers. Age, gender, social class, ethnicity and body mass index were included as potential confounders. Results At age 10 years, about 14% of the sample was reported to have asthma, 12% eczema, and 7% both asthma and eczema. Compared with children with no atopy, risk of PEs at age 13 years was increased for all of these groups; adjusted odds ratios (95% CI) were, respectively, 1.39 (1.10–1.77), 1.33 (1.04–1.69), and 1.44 (1.06–1.94). Atopy was associated with increased serum IL-6 and CRP; however, this did not mediate association between atopy and PEs. Inflammatory markers were not associated with later PEs. Conclusion Childhood atopic disorders increase the risk of psychotic experiences in adolescence. Follow-up of these individuals will be useful to determine the effect of atopy and inflammation on different trajectories of early-life PEs.

Childhood Epstein-Barr Virus infection and subsequent risk of psychotic experiences in adolescence: A population-based prospective serological study

BACKGROUND Several studies suggest a link between early-life infection and adult schizophrenia. Cross-sectional studies have reported: (1) increased prevalence of Epstein-Barr Virus (EBV), a member of the Herpesviridae family in schizophrenia; (2) a possible role of Herpes simplex virus in cognitive dysfunction in schizophrenia and healthy controls. We report a longitudinal serological study of early-life EBV infection, childhood IQ, and subsequent risk of psychotic experiences (PE) in adolescence. METHODS Serum antibodies to EBV (anti-VCA IgG) were measured in 530 participants from the ALSPAC cohort at age 4 years. Assessments for IQ at age 9 and PE at age 13 were attended by 401 and 366 of these individuals, respectively. Logistic regression calculated odds ratio (OR) for PE in EBV-exposed, compared with unexposed group. Mean IQ scores were compared between these groups; effect of IQ on the EBV-PE association was examined. Potential confounders included age, gender, ethnicity, social class, household crowding, and concurrent depression and anxiety. RESULTS About 25% of the sample was exposed to EBV at age 4. EBV exposure was associated with subsequent risk of definite PE in adolescence; OR 5.37 (95% CI 1.71-16.87), which remained significant after confounding adjustment. EBV-exposed individuals compared with unexposed performed worse on all IQ measures; mean difference in full-scale IQ 4.15 (95% CI 0.44-7.87); however, this was explained by socio-demographic differences. The EBV-PE association was not explained by IQ. CONCLUSIONS Early-life exposure to EBV is associated with PE in adolescence, consistent with a role of infection/immune dysfunction in the aetiology of psychosis.

Does maternal body mass index during pregnancy influence risk of schizophrenia in the adult offspring

Maternal obesity in pregnancy has been linked with several adverse outcomes in offspring including schizophrenia. The rising prevalence of obesity may contribute to an increase in the number of schizophrenia cases in the near future; therefore, it warrants further exploration. We reviewed current evidence regarding maternal body mass index (BMI) in pregnancy and risk of schizophrenia in adult offspring.

Serum C-reactive protein in adolescence and risk of schizophrenia in adulthood: A prospective birth cohort study

Highlights • This is one of the first longitudinal studies of serum CRP & subsequent schizophrenia.• Elevated serum CRP in adolescence is associated with risk of adult schizophrenia.• The CRP-schizophrenia association is consistent with a dose-response relationship.