Blockade of N-methyl-D-aspartate receptors (NMDARs) produces behavior in healthy people that is similar to the psychotic symptoms and cognitive deficits of schizophrenia and can exacerbate symptoms ...in people with schizophrenia. However, an endogenous brain disruption of NMDARs has not been clearly established in schizophrenia. We measured mRNA transcripts for five NMDAR subunit mRNAs and protein for the NR1 subunit in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control (n=74) brains. Five NMDAR single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia were tested for association with NMDAR mRNAs in postmortem brain and for association with cognitive ability in an antemortem cohort of 101 healthy controls and 48 people with schizophrenia. The NR1 subunit (mRNA and protein) and NR2C mRNA were decreased in postmortem brain from people with schizophrenia (P=0.004, P=0.01 and P=0.01, respectively). In the antemortem cohort, the minor allele of NR2B rs1805502 (T5988C) was associated with significantly lower reasoning ability in schizophrenia. In the postmortem brain, the NR2B rs1805502 (T5988C) C allele was associated with reduced expression of NR1 mRNA and protein in schizophrenia. Reduction in NR1 and NR2C in the DLPFC of people with schizophrenia may lead to altered NMDAR stoichiometry and provides compelling evidence for an endogenous NMDAR deficit in schizophrenia. Genetic variation in the NR2B gene predicts reduced levels of the obligatory NR1 subunit, suggesting a novel mechanism by which the NR2B SNP may negatively influence other NMDAR subunit expression and reasoning ability in schizophrenia.
Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the ...extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca's and Wernicke's areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P<0.01). Using a two-step clustering procedure, we identified a subgroup of people displaying relatively elevated cytokine mRNA levels (17/43 people with schizophrenia and 9/42 controls). Individuals with schizophrenia in the elevated cytokine subgroup performed significantly worse than the low-cytokine subgroup on verbal fluency (F(1,40)=15.7, P<0.001). There was a 17% volume reduction of the left pars opercularis (POp) (Broca's area) in patients with elevated cytokines compared with patients with lower cytokines (F(1,29)=9.41, P=0.005). Negative linear relationships between IL-1β mRNA levels and both verbal fluency and left POp volume were found in schizophrenia. This study is among the first to link blood biomarkers of inflammation with both cognitive deficits and brain volume reductions in people with schizophrenia, supporting that those with elevated cytokines represent a neurobiologically meaningful subgroup. These findings raise the possibility that targeted anti-inflammatory treatments may ameliorate cognitive and brain morphological abnormalities in some people with schizophrenia.
Upregulation of the immune response may be involved in the pathogenesis of schizophrenia with changes occurring in both peripheral blood and brain tissue. To date, microarray technology has provided ...a limited view of specific inflammatory transcripts in brain perhaps due to sensitivity issues. Here we used SOLiD Next Generation Sequencing to quantify neuroimmune mRNA expression levels in the dorsolateral prefrontal cortex of 20 individuals with schizophrenia and their matched controls. We detected 798 differentially regulated transcripts present in people with schizophrenia compared with controls. Ingenuity pathway analysis identified the inflammatory response as a key change. Using quantitative real-time PCR we confirmed the changes in candidate cytokines and immune modulators, including interleukin (IL)-6, IL-8, IL-1β and SERPINA3. The density of major histocompatibility complex-II-positive cells morphologically resembling microglia was significantly increased in schizophrenia and correlated with IL-1β expression. A group of individuals, most of whom had schizophrenia, were found to have increased inflammatory mRNA expression. In summary, we have demonstrated changes in an inflammatory response pathway that are present in ∼40% of people diagnosed with schizophrenia. This suggests that therapies aimed at immune system attenuation in schizophrenia may be of direct benefit in the brain.
Objective: Controversy concerning cancer incidence in schizophrenia exists because of heterogeneous study findings.
Method: A meta‐analysis was performed on standardized incidence ratios (SIR) of ...cancer in patients with schizophrenia and first‐degree relatives and compared with general population samples.
Results: The pooled overall cancer incidence in patients was not significantly increased (SIR = 1.05, CI 0.95–1.15). Lung cancer incidence was slightly increased (SIR = 1.31, CI 1.01–1.71), but was reduced after adjusting for smoking prevalence. The incidence of several cancers unrelated to smoking was reduced in patients. Breast cancer rates were significantly increased in female patients. The pooled overall cancer incidence in siblings (SIR = 0.89, CI 0.84–0.94) and parents (SIR = 0.90, CI 0.88–0.93) was significantly reduced. A meta‐regression detected a significant relationship between cancer risk in the general population and relative risk in patients.
Conclusion: The meta‐analysis aided exploration of inconsistent study findings. There is a discrepancy between cancer risk exposure and cancer incidence in schizophrenia consistent with a protective effect.
Disturbed speech in schizophrenia may reflect pragmatic deficits of expressive language. Pragmatic comprehension deficits also occur in schizophrenia. This study investigated whether poor ...'mind-reading' (i.e. a general difficulty with inferring and monitoring other people's thoughts) causes pragmatic language impairments of both expression and comprehension in patients with schizophrenia.
Mind-reading (or theory of mind) was tested in patients with schizophrenia and in healthy controls using a false-belief picture-sequencing task. Pragmatic comprehension skills were assessed using a test of non-literal speech interpretation. Clinical ratings of formal thought disorder (FTD) indexed the expressive language deficits of patients. To control for possible contributory effects of executive dysfunction, inhibitory control was tested using capture picture-sequences and executive-planning was tested using the Tower of London task.
False-belief picture-sequencing, understanding of irony and understanding of metaphors were all selectively impaired in the patients. Poor mind-reading (indexed by high error rate in sequencing false-belief stories) was associated with poor understanding of irony, but was unrelated to poor understanding of metaphors. Whereas poor appreciation of irony and poor mind-reading were associated with high ratings of positive formal thought disorder, high ratings of negative formal thought disorder were associated with poor understanding of metaphors and executive dysfunction.
Whereas poor mind-reading may contribute to positive aspects of formal thought disorder and impaired appreciation of irony in patients with schizophrenia; negative features of formal thought disorder and poor understanding of metaphors appear better explained by abnormal semantics. Overall, the findings of this study support the view that the functional basis of formal thought disorder in schizophrenia is not unitary.
There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, ...stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.
Cortical grey matter volume deficits and neuro-inflammation exist in patients with schizophrenia, although it is not clear whether elevated cytokines contribute to the cortical volume reduction. We ...quantified cortical and regional brain volumes in fixed postmortem brains from people with schizophrenia and matched controls using stereology. Interleukin (IL)-6, IL-1β, IL-8 and SERPINA3 messenger RNAs (mRNAs) were quantified in the contralateral fresh frozen orbitofrontal cortex. We found a small, but significant reduction in cortical grey matter (1.3%; F(1,85)=4.478, P=0.037) and superior frontal gyrus (6.5%; F(1,80)=5.700, P=0.019) volumes in individuals with schizophrenia compared with controls. Significantly reduced cortical grey matter (9.2%; F(1,24)=8.272, P=0.008) and superior frontal gyrus (13.9%; F(1,20)=5.374, P=0.031) volumes were found in cases with schizophrenia and 'high inflammation' status relative to schizophrenia cases with 'low inflammation' status in the prefrontal cortex. The expression of inflammatory mRNAs in the orbitofrontal cortex was significantly correlated with those in dorsolateral prefrontal cortex (all r>0.417, all P<0.022), except for IL-8. Moreover, average daily and lifetime antipsychotic intake negatively correlated with cortical grey matter and superior frontal gyrus volumes (all r<-0.362, all P<0.05). The results suggest that the reduction in cortical grey matter volume in people with schizophrenia is exaggerated in those who have high expression of inflammatory cytokines. Further, antipsychotic medication intake does not appear to ameliorate the reduction in brain volume.
This paper reviews the six published incidence studies of the relative risk of cancer in patients with schizophrenia compared with the general population. These studies used: incidence data, register ...case ascertainment, and controlled for age and sex. It is concluded that schizophrenia is associated with a lower risk of developing cancer. The role of apoptosis (programmed cell death) in cancer and brain development is briefly described. The possibility is explored that increased apoptosis may account for neurodevelopmental abnormalities as well as tumour resistance associated with schizophrenia. The authors propose that p53, a tumour suppressor gene central to regulation of apoptosis, should be investigated as a candidate susceptibility gene in schizophrenia.
Objective
To assess the association between parental post‐traumatic stress disorder (PTSD) and offspring PTSD and its specificity for other disorders in a non‐clinical epidemiological cohort of ...Australian Vietnam veterans, their partners and their sons and daughters.
Method
Veterans were interviewed twice, in 1992–1994 and 2005–2006; partners were interviewed in 2006–2007, and their offspring in 2012–2014. A total of 125 sons and 168 daughters were interviewed from 197 families, 137 of which also included partners who were the mothers of the children. Statistical analysis used multi‐level modelling to compute odds ratios and 95% confidence intervals while controlling for clustering effects within families. Parent PTSD diagnoses were examined for associations with offspring trauma exposure, PTSD and other psychiatric diagnoses.
Results
Veteran PTSD increased the risk of PTSD and no other disorder in both sons and daughters; partner PTSD did not. Veteran depression was also a risk factor for sons’ PTSD, and alcohol disorder was linked to alcohol dependence in sons and PTSD in daughters, but not when controlling for veteran PTSD.
Conclusion
We conclude that PTSD in a Vietnam veteran father increases the risk specifically for PTSD in his sons and daughters.
It is well documented that memory is heritable and that older adults tend to have poorer memory performance than younger adults. However, whether the magnitudes of genetic and environmental ...contributions to late-life verbal episodic memory ability differ from those at earlier ages remains unresolved. Twins from 12 studies participating in the Interplay of Genes and Environment in Multiple Studies (IGEMS) consortium constituted the analytic sample. Verbal episodic memory was assessed with immediate word list recall (N = 35,204 individuals; 21,792 twin pairs) and prose recall (N = 3805 individuals; 2028 twin pairs), with scores harmonized across studies. Average test performance was lower in successively older age groups for both measures. Twin models found significant age moderation for both measures, with total inter-individual variance increasing significantly with age, although it was not possible definitively to attribute the increase specifically to either genetic or environmental sources. Pooled results across all 12 studies were compared to results where we successively dropped each study (leave-one-out) to assure results were not due to an outlier. We conclude the models indicated an overall increase in variance for verbal episodic memory that was driven by a combination of increases in the genetic and nonshared environmental parameters that were not independently statistically significant. In contrast to reported results for other cognitive domains, differences in environmental exposures are comparatively important for verbal episodic memory, especially word list learning.
•Verbal episodic memory performance is poorer at older ages compared to midlife.•Individual variance in verbal episodic memory shows an increase across age.•Environmental variance unique to individuals is more important than genetic variance.•Genetic variance is greater for remembering a prose passage than a list of words.
PDF
