Effects of maltreatment and parental schizophrenia spectrum disorders on early childhood social-emotional functioning: a population record linkage study.

AIMS: Childhood maltreatment and a family history of a schizophrenia spectrum disorder (SSD) are each associated with social-emotional dysfunction in childhood. Both are also strong risk factors for adult SSDs, and social-emotional dysfunction in childhood may be an antecedent of these disorders. We used data from a large Australian population cohort to determine the independent and moderating effects of maltreatment and parental SSDs on early childhood social-emotional functioning. METHODS: The New South Wales Child Development Study combines intergenerational multi-agency data using record linkage methods. Multiple measures of social-emotional functioning (social competency, prosocial/helping behaviour, anxious/fearful behaviour; aggressive behaviour, and hyperactivity/inattention) on 69 116 kindergarten children (age ~5 years) were linked with government records of child maltreatment and parental presentations to health services for SSD. Multivariable analyses investigated the association between maltreatment and social-emotional functioning, adjusting for demographic variables and parental SSD history, in the population sample and in sub-cohorts exposed and not exposed to parental SSD history. We also examined the association of parental SSD history and social-emotional functioning, adjusting for demographic variables and maltreatment. RESULTS: Medium-sized associations were identified between maltreatment and poor social competency, aggressive behaviour and hyperactivity/inattention; small associations were revealed between maltreatment and poor prosocial/helping and anxious/fearful behaviours. These associations did not differ greatly when adjusted for parental SSD, and were greater in magnitude among children with no history of parental SSD. Small associations between parental SSD and poor social-emotional functioning remained after adjusting for demographic variables and maltreatment. CONCLUSIONS: Childhood maltreatment and history of parental SSD are associated independently with poor early childhood social-emotional functioning, with the impact of exposure to maltreatment on social-emotional functioning in early childhood of greater magnitude than that observed for parental SSDs. The impact of maltreatment was reduced in the context of parental SSDs. The influence of parental SSDs on later outcomes of maltreated children may become more apparent during adolescence and young adulthood when overt symptoms of SSD are likely to emerge. Early intervention to strengthen childhood social-emotional functioning might mitigate the impact of maltreatment, and potentially also avert future psychopathology.

How much do we know about schizophrenia and how well do we know it? Evidence from the Schizophrenia Library.

BACKGROUND: True findings about schizophrenia remain elusive; many findings are not replicated and conflicting results are common. Well-conducted systematic reviews have the ability to make robust, generalizable conclusions, with good meta-analyses potentially providing the closest estimate of the true effect size. In this paper, we undertake a systematic approach to synthesising the available evidence from well-conducted systematic reviews on schizophrenia. METHOD: Reviews were identified by searching Medline, EMBASE, CINAHL, Current Contents and PsycINFO. The decision to include or exclude reviews, data extraction and quality assessments were conducted in duplicate. Evidence was graded as high quality if reviews contained large samples and robust results; and as moderate quality if reviews contained imprecision, inconsistency, smaller samples or study designs that may be prone to bias. RESULTS: High- and moderate-quality evidence shows that numerous psychosocial and biomedical treatments are effective. Patients have relatively poor cognitive functioning, and subtle, but diverse, structural brain alterations, altered electrophysiological functioning and sleep patterns, minor physical anomalies, neurological soft signs, and sensory alterations. There are markers of infection, inflammation or altered immunological parameters; and there is increased mortality from a range of causes. Risk for schizophrenia is increased with cannabis use, pregnancy and birth complications, prenatal exposure to Toxoplasma gondii, childhood central nervous system viral infections, childhood adversities, urbanicity and immigration (first and second generation), particularly in certain ethnic groups. Developmental motor delays and lower intelligence quotient in childhood and adolescence are apparent. CONCLUSIONS: We conclude that while our knowledge of schizophrenia is very substantial, our understanding of it remains limited.

Childhood adversity in schizophrenia: a systematic meta-analysis.

BACKGROUND: Childhood adversity is a putative risk factor for schizophrenia, although evidence supporting this suggestion is inconsistent and controversial. The aim of this review was to pool and quality assess the current evidence pertaining to childhood adversity in people with schizophrenia compared to other psychiatric disorders and to non-psychiatric controls. METHOD: Included were case-control, cohort and cross-sectional studies. Medline, EMBASE and PsycINFO databases were searched. Study reporting was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and pooled evidence quality was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Twenty-five studies met inclusion criteria. Moderate to high quality evidence suggests increased rates of childhood adversity in schizophrenia compared to controls [odds ratio (OR) 3.60, p < 0.00001]. Increased childhood adversity was also reported in schizophrenia compared to anxiety disorders (OR 2.54, p = 0.007), although the effect was not significant in the subgroup analysis of five studies assessing only sexual abuse. No differences in rates of childhood adversity were found between schizophrenia and affective psychosis, depression and personality disorders whereas decreased rates of childhood adversity were found in schizophrenia relative to dissociative disorders and post-traumatic stress disorder (OR 0.03, p < 0.0001). CONCLUSIONS: This is the first meta-analysis to report a medium to large effect of childhood adversity in people with schizophrenia and to assess specificity for schizophrenia. Further research is required that incorporates longitudinal design and other potentially causal variables to assess additive and/or interactive effects.

Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis.

Brain-derived neurotrophic factor (BDNF) regulates the survival and growth of neurons, and influences synaptic efficiency and plasticity. Several studies report reduced peripheral (blood) levels of BDNF in schizophrenia, but findings are inconsistent. We undertook the first systematic review with meta-analysis of studies examining blood BDNF levels in schizophrenia compared with healthy controls, and examined potential effects of age, gender and medication. Included are individual studies of BDNF blood (serum or plasma) levels in schizophrenia (including schizoaffective disorder, or first episode psychosis), compared with age-matched healthy controls, obtained by electronic Medline and Embase searches, and hand searching. The decision to include or exclude studies, data extraction and quality assessment were completed by two independent reviewers. The initial search revealed 378 records, of which 342 were excluded on reading the Abstract, because they did not examine BDNF blood levels in schizophrenia compared with healthy controls. Of 36 papers screened in full, 17 were eligible for inclusion, but one was subsequently removed as an outlier. The remaining 16 studies provided moderate quality evidence of reduced blood BDNF levels in schizophrenia (Hedges g=-0.458, 95% confidence interval=-0.770 to -0.146, P<0.004, random effects model). Subgroup analyses reveal reduced BDNF in both drug-naïve and medicated patients, and in males and females with schizophrenia. Meta-regressions showed an association between reduced BDNF in schizophrenia and increasing age, but no effects of medication dosage. Overall, blood levels of BDNF are reduced in medicated and drug-naïve patients with schizophrenia; this evidence is of moderate quality, that is, precise but with considerable, unexplained heterogeneity across study results.

Quality assessment and comparison of evidence for electroconvulsive therapy and repetitive transcranial magnetic stimulation for schizophrenia: a systematic meta-review.

BACKGROUND: Randomized studies directly comparing the effects of electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) for depression generally favour ECT. ECT and rTMS have also been investigated for chronic symptoms of schizophrenia although there are no direct comparisons available. AIMS: We sought to determine the relative benefits and adverse outcomes of ECT and rTMS by comparing effect sizes reported in systematic reviews and to quality assess this evidence using GRADE and QUOROM guidelines. METHOD: Included are systematic reviews with meta-analysis published since 2000, reporting results for people with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder or first episode schizophrenia. Medline, Embase, CINAHL, Current Contents, PsycINFO and the Cochrane library were searched and hand searching was conducted. Data extraction and quality assessment were completed by two independent reviewers. RESULTS: Fifty-three of 58 reviews were excluded as they did not meet inclusion criteria. The remaining five have a low probability of reporting bias and show that high quality evidence suggests a short-term, medium to large treatment effect of rTMS for auditory hallucinations (d=0.88) but not other symptoms, for people treated with concurrent antipsychotics. For ECT, high quality evidence suggests a short-term small, significant effect for improvement in global symptoms, for people with or without concurrent antipsychotics (RR=0.76). There is no evidence for longer-term therapeutic or adverse effects of either treatment. CONCLUSIONS: It is worthwhile considering rTMS in cases where auditory hallucinations have not responded to antipsychotic medications and ECT where overall symptoms have not responded to antipsychotic medications.

Design of a chimeric 3-methyl-1,2,3-triazene with mixed receptor tyrosine kinase and DNA damaging properties: a novel tumor targeting strategy.

The mixed epidermal growth factor receptor (EGFR)-DNA targeting properties of SMA41, a 6-(3-methyl-1,2,3-triazen-1-yl)-4-anilinoquinazoline designed to release N(4)-m-tolyl-quinazoline-4,6-diamine henceforth referred to as SMA52 [an inhibitor of EGFR tyrosine kinase (TK)] and methyldiazonium (a DNA methylating species) were studied in the O(6)-methylguanine-DNA methyltransferase (MGMT)-proficient and high EGFR-expressing epidermoid carcinoma of the vulva cell line A431. The effects of SMA41 were compared with those of SMA52 alone, and temozolomide (TEM), a clinical prodrug of 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) that is inactive in MGMT-proficient cells. The results showed that 1) the chimeric SMA41 could degrade in serum-containing medium (t(1/2) of approximately 30 min) to generate, as predicted, the free inhibitor SMA52 as the most abundant metabolite (approximately 81% yield); 2) in contrast to SMA52 alone, the chimeric SMA41 and TEM induced significant DNA damage in A431 cells after 30-min or 2-h drug exposures, as confirmed by alkaline single-cell gel microelectrophoresis (comet) assay; 3) SMA41 showed 5-fold greater affinity for the ATP binding site of EGFR than independently synthesized SMA52 in an enzyme assay and blocked EGF-induced tyrosine phosphorylation and EGFR autophosphorylation in A431 cells in a dose-dependent manner; 4) these mixed targeting properties of SMA41, combined with its ability to be converted to another potent EGFR TK inhibitor (e.g., SMA52) by hydrolytic cleavage, translated into over 8-fold greater antiproliferative activity than TEM, which showed no EGFR targeting properties (IC(50) competitive binding >100 microM); 5) under continuous drug exposure (3-6-day sulforhodamine and clonogenic assays), SMA41 was almost equipotent with SMA52; however, in a short 2-h drug exposure followed by incubation in drug-free media, SMA52 showed an almost complete loss of antiproliferative activity over the whole dose range. In contrast, SMA41 retained almost 100% of its activity, indicating a more sustained growth inhibitory activity. The results in toto suggest that the superior antiproliferative activity of SMA41 may be due to a combination of events associated with its binary EGFR TK and DNA targeting properties.