Widespread white matter microstructural differences in schizophrenia across 4322 individuals: results from the ENIGMA Schizophrenia DTI Working Group.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Intergenerational transmission of post-traumatic stress disorder in Australian Vietnam veterans' families.

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.

Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume.

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)-1ß, 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-1ß 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-1ß 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.

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia.

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.

Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia.

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.

Cancer incidence in patients with schizophrenia and their first-degree relatives - a meta-analysis.

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 communication in schizophrenia: the role of poor pragmatics and poor mind-reading.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Schizotypy: phenotypic marker as risk factor.

OBJECTIVE: To evaluate measures of schizotypy as familial risk factors for schizophrenia with the aim of making recommendations for assessing schizotypy as part of screening procedures for identifying people at risk of schizophrenia. METHOD: Published studies using self-report and interview-based measures of schizotypy to assess relatives of patients with schizophrenia are reviewed. A parent study is reported evaluating the diagnostic accuracy of parental schizotypy as assessed by three questionnaire-based measures: the Chapman Perceptual Aberration and Physical Anhedonia Scales, and the Eysenck Psychoticism Scale. Group scores for these self-report ratings of 23 parent-pairs of patients with schizophrenia, 20 parent-pairs of patients with chronic nonpsychotic psychiatric disorder, and 19 parent-pairs of healthy comparison subjects are compared. RESULTS: Consistent with published evidence that self-report measures of psychosis-proneness and schizotypy do not consistently reflect familial risk factors that are specific for schizophrenia, scores on questionnaire measures of schizotypy did not distinguish the parents of patients with schizophrenia from the parents in the other two groups. CONCLUSIONS: Interview-based assessments of schizotypy better assess familial risk factors than self-report measures of schizotypy. Questionnaire measures of schizotypy should be supplemented by interview-based assessments when screening for individuals at risk of schizophrenia.

Increased levels of expression of an NMDARI splice variant in the superior temporal gyrus in schizophrenia.

Expression patterns of mRNAs for the NMDARI subunit (NRI) carboxy-terminus isoforms were investigated in postmortem brain tissue using isotopic in situ hybridization. Three brain regions (superior temporal, middle frontal and visual cortices) were examined in patients with schizophrenia (n = 6) and control subjects (n = 6). A 22% higher level of expression of the NRI isoform that contains neither spliced exon was observed in the superior temporal gyrus of patients with schizophrenia compared with controls (p = 0.01). No differences were observed in the expression of the other isoforms in the three regions studied. These data suggest that NRI alternative splicing might be abnormal in schizophrenia and reinforce previous findings implicating the superior temporal gyrus as a site of neural dysfunction in schizophrenia.

Apoptosis and schizophrenia: is the tumour suppressor gene, p53, a candidate susceptibility gene?

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.

Superior temporal gyral volumes and laterality correlates of auditory hallucinations in schizophrenia.

BACKGROUND: Previous studies have reported significant correlations, indicating an emerging relationship, between severity of auditory hallucinations and reduced size of temporal lobe cortical regions implicated in language processing. The present study used high-resolution magnetic resonance imaging (MRI) scanning, along with assessment of functional lateralization via a dichotic listening task (DLT), to extend these findings. METHODS: Thirty patients with schizophrenia and a history of auditory hallucinations participated in the study. All were completely right-handed. Eleven subjects were currently hallucinating at the time of the study. Volumetric T1-weighted MRI scans were obtained and regions of interest were manually traced using the BRAINS package (Andreasen et al 1993). Whole brain, bilateral temporal lobe, and anterior superior temporal gyrus volumes were calculated. Subjects completed a binaural consonant-vowel DLT. RESULTS: Increased severity of hallucinatory experience was significantly associated with smaller left anterior superior temporal gyrus volumes. Current hallucinators demonstrated a reduction in right ear advantage on the DLT. CONCLUSIONS: The results suggest that auditory hallucinations are subserved by a trait-like dysfunction in language-related neural networks, of which the superior temporal cortex forms one component. The findings are also consistent with theories proposing abnormal lateralization in the etiology of auditory hallucinations.

Effects of prepulses and d-amphetamine on performance and event-related potential measures on an auditory discrimination task.

RATIONALE: Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating, that is the processing of the startle stimulus (S2) is inhibited by the interfering processing of a closely preceding prepulse (S1). It has been demonstrated that PPI is disrupted in a variety of mental disorders and that several neurotransmitter systems, including dopamine, participate in the modulation of sensorimotor gating. Previous studies have also shown that a task-relevant S1 enhances PPI in healthy subjects but not in schizophrenic patients. These findings indicate an influence of attentional processes on sensorimotor gating and an impairment of this modulation in schizophrenia. OBJECTIVE: Assuming a dopamine-mediated suppression of S1 processing as a mechanism of resource management and selective attention, which might be impaired in certain mental disorders, the present study investigated the effects of the indirect dopaminergic agonist d-amphetamine on prepulse-altered S2 discrimination and event related potentials (ERPs). METHODS: Twelve healthy volunteers were tested in a double-blind, placebo-controlled experimental design. Here, S2 is the target in a difficult Go/NoGo auditory discrimination task. RESULTS: Confirming our previous results, S2 processing is "accentuated" by a weak acoustic prepulse in healthy subjects, thus leading to a lower rate of errors of omission but also to more false alarms (i.e. a liberal response bias). This performance change correlated with a prepulse-induced increase in the amplitude of the P3 ERP towards non-targets ("prepulse-induced non-target positivity"; PINTP). In addition, the results of the present study show that under prepulse conditions amphetamine disrupts "S2 accentuation" associated with a dose-related reduction of the P2 component of the S1 response and a plasma level related reduction of PINTP. CONCLUSIONS: These data suggest an involuntary attentional shift towards S1 processing with increasing dopamine-release similar to that observed in patients with schizophrenia or OCD. It is concluded that sensory gating alters selective attention via dopaminergic modulation.

Changes in auditory selective attention and event-related potentials following oral administration of D-amphetamine in humans.

The effect of d-amphetamine on selective attention in humans was investigated by measuring event-related potentials (ERPs) during a complex auditory selective attention task (CSAT). The CSAT required subjects to make a button press response to infrequent target tones presented amongst tones that varied in pitch (high vs. low), location (left vs. right ear) and duration (51 ms vs. 102 ms). Healthy subjects completed the CSAT under three conditions: placebo, 10 mg and 20 mg d-amphetamine, at least one week apart. D-amphetamine produced a significant dose response increase in hit-rate and decrease in reaction time without changing false alarm rate. D-amphetamine reduced late PN to location irrelevant stimuli and pitch irrelevant stimuli in both the attended and unattended location. The effect of d-amphetamine was interpreted as a decrease in the maintenance of the attentional trace to irrelevant stimuli. However, these changes were accompanied by some evidence of processing of stimulus features in the unattended location. These results suggest that d-amphetamine improves selective attention, and decreases the maintenance of attention to irrelevant stimuli.

Risperidone versus haloperidol: I. Meta-analysis of efficacy and safety.

Haloperidol is widely considered a reference standard in antipsychotic therapy and is commonly used in comparative studies of the efficacy and safety of antipsychotic medication. Comparative clinical trials have shown that the novel antipsychotic agent risperidone tends to have greater efficacy (i.e., clinical response defined as a > or = 20% reduction in total scores on the Positive and Negative Syndrome Scale) than haloperidol in patients with chronic schizophrenia and poses less risk of extrapyramidal symptoms (EPS). We used DerSimonian and Laird's random-effects model to analyze pooled patient data from available randomized, double-masked, comparative trials of risperidone and haloperidol in patients with schizophrenia treated for at least 4 weeks at recommended doses. The purpose of the analysis was to determine whether there are significant overall differences in the rates of patient clinical response, prescription of anticholinergic agents, and treatment dropout. Six of the nine trials revealed in a literature search met all criteria for inclusion in the meta-analysis. The meta-analysis showed that in patients with chronic schizophrenia, risperidone therapy is associated with significantly higher response rates, significantly less prescribing of anticholinergic medication, and significantly lower treatment dropout rates than haloperidol. These results demonstrate the greater treatment efficacy associated with risperidone compared with haloperidol and suggest both a lower incidence of EPS and improved treatment compliance.

Risperidone versus haloperidol: II. Cost-effectiveness.

Australia and Canada are currently the only Western nations with government guidelines for analyzing the cost-effectiveness of drugs. We used guidelines issued by the Australian Pharmaceutical Benefits Advisory Committee to construct a model for comparing the cost-effectiveness of risperidone and haloperidol over a 2-year period in patients with chronic schizophrenia. Use of clozapine was also included in the analysis as an alternative treatment given to patients who proved unresponsive to therapy with haloperidol or risperidone. Results are expressed in Australian dollars. Cost-effectiveness was determined by using decision-analytic modeling to compare clinical outcomes and costs. The analytic model contained a decision tree for each of the compared agents that tracked the distribution of patients between treatment outcome pathways (i.e., scenarios). Distributions were based on probabilities derived from our meta-analysis results reported elsewhere and from other sources. Each scenario had an associated monetary cost that included all significant direct costs (i.e., hospital costs; outpatient costs; and the cost of drugs, the services of health care professionals, and government-subsidized hostel accommodation). The cost for a given outcome was the sum of costs for all scenarios leading to that outcome. Cost-effectiveness was expressed as the total cost per favorable outcome. The definition of a favorable outcome was one in which the patient was in a response phase at the end of the 2-year period. The probability of a patient experiencing a favorable outcome at the end of 2 years was 78.9% for risperidone versus 58.9% for haloperidol. The total cost of treatment for 2 years was $15,549.00 for risperidone versus $18,332.00 for haloperidol. The expected cost per favorable outcome was $19,709.00 for risperidone and $31,104.00 for haloperidol. Risperidone was more cost-effective than haloperidol and therefore was "dominant" in pharmacoeconomic terms because it produced a higher proportion of favorable outcomes at lower cost. Sensitivity analysis showed that the difference in clinical response rate was a key determinant of cost-effectiveness.

The effect of decreased catecholamine transmission on ERP indices of selective attention.

This study examines the effect of decreased catecholamine transmission on event-related potential (ERP) indices of selective attention. Intravenous clonidine (1.5 micrograms/kg Catapres), droperidol (15 micrograms/kg Droleptan), or placebo were administered to healthy adult males prior to performance of a multidimensional auditory selective attention task (SAT) in which dichotically presented sequences of tone pips varied on dimensions of location (left or right ear), pitch (high or low), and duration (short or long). Subjects were required to make a button press response to infrequent "target" stimuli that matched a prespecified stimulus on the three dimensions. ERPs were recorded during the task. Clonidine led to a significant increase of processing negativity (PN) over 200-400 ms at the irrelevant location. Droperidol led to a significant increase in reaction time (RT), a significant decrease in hit rate, and an attenuation of PN over the 200- to 400-ms and 400- to 700-ms epochs. Neither substance led to a significant change in P3 amplitude. The role of catecholamines in the selective attention subprocesses of "tuning" and "switching" is discussed.